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As filed with the Securities and Exchange Commission on May 3, 2021.

Registration No. 333-255319

 

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

 

Amendment No. 2

to

FORM F-1

REGISTRATION STATEMENT

UNDER

THE SECURITIES ACT OF 1933

 

 

Gyroscope Therapeutics Holdings plc

(Exact name of Registrant as specified in its charter)

 

 

 

England and Wales   2836   Not Applicable
(State or other jurisdiction of
incorporation or organization)
  (Primary Standard Industrial
Classification Code Number)
  (I.R.S. Employer
Identification Number)

Stevenage Bioscience Catalyst

Gunnels Wood Road

Stevenage, Hertfordshire, SG1 2FX

United Kingdom + 44 (0)1438 906770

(Address, including zip code, and telephone number, including area code, of Registrant’s principal executive offices)

 

 

Gyroscope USA, Inc.

2200 Renaissance Boulevard, Suite 410

King of Prussia, PA 19406

(267) 523-2100

(Name, address, including zip code, and telephone number, including area code, of agent for service)

 

 

Copies to:

 

Yasin Keshvargar

Richard D. Truesdell, Jr.

Marcel R. Fausten

Davis Polk & Wardwell LLP
450 Lexington Avenue
New York, NY 10017

(212) 450-4000

 

Dan Hirschovits

Davis Polk & Wardwell London LLP

5 Aldermanbury Square

London EC2V 7HR

United Kingdom

+44 20 7418 1300

 

Claire Keast-Butler

Cooley (UK) LLP

Dashwood

69 Old Broad Street

London EC2M 1QS

United Kingdom

+44 20 7583 4055

 

Eric Blanchard

Richard Segal

Divakar Gupta

Cooley LLP

55 Hudson Yards

New York, NY 10001

(212) 479-6000

 

 

Approximate date of commencement of proposed sale to the public: As soon as practicable after the effective date of this registration statement.

If any of the securities being registered on this Form are to be offered on a delayed or continuous basis pursuant to Rule 415 under the Securities Act of 1933, check the following box.  ☐

If this Form is filed to register additional securities for an offering pursuant to Rule 462(b) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.  ☐

If this Form is a post-effective amendment filed pursuant to Rule 462(c) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.  ☐

If this Form is a post-effective amendment filed pursuant to Rule 462(d) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.  ☐

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933.     

Emerging growth company  ☒

If an emerging growth company that prepares its financial statements in accordance with U.S. GAAP, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards† provided pursuant to Section 7(a)(2)(B) of the Securities Act.  ☐

 

The term “new or revised financial accounting standard” refers to any update issued by the Financial Accounting Standards Board to its Accounting Standards Codification after April 5, 2012.

 

 

CALCULATION OF REGISTRATION FEE

 

 

Title of each class of

securities to be registered

 

Amount to be

registered(1)(2)

 

Proposed

Maximum

Offering Price

Per Share

 

Proposed
maximum
aggregate

offering price(1)(2)

  Amount of
registration fee(3)

Ordinary shares, nominal value £0.005 per share(4)

  7,762,500   $22.00   $170,775,000   $18,631.56

 

 

(1)

Includes the additional ordinary shares represented by American Depositary Shares, or ADSs, that are issuable upon exercise of the underwriters’ option to purchase additional ADSs.

(2)

Calculated pursuant to Rule 457(a) under the Securities Act of 1933, as amended, based on an estimate of the proposed maximum aggregate offering price.

(3)

The registrant previously paid $10,910.00 in connection with the initial filing of the registration statement.

(4)

These ordinary shares are represented by ADSs, each of which represents one ordinary share of the registrant. ADSs issuable upon deposit of the ordinary shares registered hereby are being registered pursuant to a separate registration statement on Form F-6 (File No. 333-255647).

 

 

The Registrant hereby amends this registration statement on such date or dates as may be necessary to delay its effective date until the Registrant shall file a further amendment which specifically states that this registration statement shall thereafter become effective in accordance with Section 8(a) of the Securities Act of 1933, as amended, or until the registration statement shall become effective on such date as the Commission, acting pursuant to such Section 8(a), may determine.

 

 

 


Table of Contents

The information in this preliminary prospectus is not complete and may be changed. We may not sell these securities until the registration statement filed with the Securities and Exchange Commission is effective. This preliminary prospectus is not an offer to sell these securities and it is not soliciting an offer to buy these securities in any jurisdiction where the offer or sale is not permitted.

 

SUBJECT TO COMPLETION, DATED MAY 3, 2021

PRELIMINARY PROSPECTUS

 

American Depositary Shares

Gyroscope Therapeutics Holdings plc

(incorporated in England and Wales)

Representing 6,750,000 Ordinary Shares

 

 

We are offering 6,750,000 American Depositary Shares, or ADSs. Each ADS represents one ordinary share. The ADSs may be evidenced by American Depositary Receipts, or ADRs. This is our initial public offering, and no public market currently exists for our ADSs or ordinary shares. All of the ADSs are being sold by us.

We anticipate that the initial public offering price per ADS will be between $20.00 and $22.00. We have applied to list our ADSs on the Nasdaq Global Select Market under the symbol “VISN.”

Neither the U.S. Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or determined if this prospectus is truthful or complete. Any representation to the contrary is a criminal offense.

 

 

Investing in our ADSs involves a high degree of risk. Before buying any ADSs, you should carefully read the discussion of material risks of investing in our ADSs in “Risk Factors” beginning on page 16 of this prospectus.

We are an “emerging growth company” and a “foreign private issuer” as defined under the U.S. federal securities laws and, as such, will be subject to reduced public company reporting requirements. See “Prospectus Summary—Implications of Being an Emerging Growth Company and a Foreign Private Issuer” for additional information.

 

     Per ADS      Total  

Public offering price

   $                    $                

Underwriting discounts and commissions(1)

   $        $    

Proceeds, before expenses, to us

   $        $    

 

(1)

We have agreed to reimburse the underwriters for certain expenses. See “Underwriting” for additional information regarding underwriting compensation.

We have granted the underwriters an option to purchase up to 1,012,500 additional ADSs. If the underwriters exercise the option in full, the total underwriting discounts and commissions payable by us will be $            , and the total proceeds to us, before expenses, will be $            .

The underwriters expect to deliver the ADSs to purchasers on or about                     , 2021.

 

 

 

Morgan Stanley            Goldman Sachs & Co. LLC   Citigroup

The date of this prospectus is                    , 2021.


Table of Contents

TABLE OF CONTENTS

 

 

 

     Page  

Presentation of Financial and Other Information

     iii  

Summary

     1  

The Offering

     10  

Summary Financial and Other Information

     13  

Risk Factors

     16  

Special Note Regarding Forward-Looking Statements

     103  

Use of Proceeds

     105  

Corporate Reorganization

     107  

Capitalization

     111  

Dilution

     113  

Selected Financial and Other Information

     116  

Management’s Discussion and Analysis of Financial Condition and Results of Operations

     118  

Business

     135  

Management

     193  

Principal Shareholders

     210  

Related Party Transactions

     213  

Description of Share Capital and Articles of Association

     218  

Description of American Depositary Shares

     237  

Ordinary Shares and ADSs Eligible for Future Sale

     245  

Material Income Tax Considerations

     247  

Underwriting

     255  

Expenses of the Offering

     266  

Legal Matters

     267  

Experts

     268  

Change in Registrant’s Certifying Accountant

     269  

Enforcement of Judgments

     270  

Where You Can Find More Information

     272  

Index to Financial Statements

     F-1  

 

 

We and the underwriters have not authorized anyone to provide any information or to make any representations other than as contained in this prospectus or in any free writing prospectus prepared by or on behalf of us or to which we may have referred you. We and the underwriters take no responsibility for, and can provide no assurance as to the reliability of, any other information that others may give you. Neither we nor the underwriters are making an offer to sell the ADSs in any jurisdiction where the offer or sale is not permitted. This offering is being made in the United States and elsewhere solely on the basis of the information contained in this prospectus. You should assume that the information appearing in this prospectus is accurate only as of the date on the front cover of this prospectus, regardless of the time of delivery of this prospectus or any sale of the ADSs. Our business, financial condition, results of operations and prospects may have changed since the date on the front cover of this prospectus.

For investors outside the United States: Neither we nor the underwriters have done anything that would permit this offering or possession or distribution of this prospectus in any jurisdiction, other than the United States, where action for that purpose is required. Persons outside the United States who come into possession of this prospectus must inform themselves about, and observe any restrictions relating to, the offering of the ADSs and the distribution of this prospectus outside the United States.

 

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We are incorporated under the laws of England and Wales. Under the rules of the U.S. Securities and Exchange Commission, or the SEC, we are currently eligible for treatment as a “foreign private issuer.” As a foreign private issuer, we will not be required to file periodic reports and financial statements with the SEC as frequently or as promptly as domestic registrants whose securities are registered under the Securities Exchange Act of 1934, as amended, or the Exchange Act.

 

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PRESENTATION OF FINANCIAL AND OTHER INFORMATION

All references in this prospectus to “U.S. dollars,” “dollars” or “$” are to the U.S. dollar. All references to “pounds” or “£” are to pounds sterling.

Financial Statements

The accompanying consolidated financial statements have been prepared on the accrual basis of accounting and include the accounts of the Company and its subsidiaries. On December 17, 2020, Gyroscope Therapeutics Holdings Limited was incorporated under the laws of England and Wales to become the ultimate holding company for Gyroscope Therapeutics Limited pursuant to our corporate reorganization. See “Corporate Reorganization.” Prior to completion of this offering, Gyroscope Therapeutics Holdings Limited re-registered as a public limited company and changed its name to Gyroscope Therapeutics Holdings plc. The accompanying historical financial statements have not been retroactively adjusted to reflect our corporate reorganization. Prior to this offering, Gyroscope Therapeutics Holdings plc has only engaged in activities incidental to its formation, the corporate reorganization and this offering. Accordingly, a discussion and analysis of the results of operations and financial condition of Gyroscope Therapeutics Holdings plc for the period of its operations prior to the corporate reorganization would not be meaningful and are not presented. We have historically conducted our business through Gyroscope Therapeutics Limited and its subsidiaries, and therefore our historical consolidated financial statements present the consolidated results of operations of Gyroscope Therapeutics Limited. All intercompany balances and transactions have been eliminated in consolidation. Following the corporate reorganization, the historical consolidated financial statements of Gyroscope Therapeutics Holdings plc will be retrospectively adjusted to include the historical financial results of Gyroscope Therapeutics Limited for all periods presented.

We maintain the financial statements of each entity within our group in its functional currency. The majority of our expenses are incurred in pounds sterling, and the majority of our cash and cash equivalents are held in a combination of pounds sterling and U.S. dollars. We prepare our consolidated financial statements in accordance with generally accepted accounting principles in the United States, or U.S. GAAP, as issued by the Financial Accounting Standards Board, or FASB. Unless otherwise indicated, certain pounds sterling amounts contained in this prospectus have been translated into U.S. dollars at the rate was $1.3662 to £1.00, which was the noon buying rate of the Federal Reserve Bank of New York on December 31, 2020, the last business day of the fiscal year ended December 31, 2020.

Commencing with the fiscal year ended December 31, 2020, we modified our fiscal year end to end on December 31. Previously our fiscal year ended on January 31. As a result of this change, the fiscal year ended December 31, 2020 was an 11-month transition period which began on February 1, 2020 and ended on December 31, 2020. We refer to this as our fiscal year ended December 31, 2020. As a result, our fiscal year ended December 31, 2020 is not comparable to prior or subsequent fiscal years.

The financial information contained in this prospectus includes our consolidated financial statements at and for the fiscal year ended January 31, 2020 and the fiscal year ended December 31, 2020.

This financial information should be read in conjunction with “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and our consolidated financial statements, including the notes thereto, included elsewhere in this prospectus.

The financial information contained in this prospectus does not amount to statutory accounts within the meaning of section 434(3) of the Companies Act 2006.

Market, Industry and Other Data

Market data and certain industry forecast data used in this prospectus were obtained from internal reports and studies, where appropriate, as well as estimates, market research, publicly available information and industry publications. Industry publications generally state that the information they include has been obtained from sources believed to be reliable, but that the accuracy and completeness of such information is not guaranteed.

 

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Similarly, internal reports and studies, estimates and market research, which we believe to be reliable and accurately extracted by us for use in this prospectus, have not been independently verified. However, we believe such data is accurate and agree that we are responsible for the accurate extraction of such information from such sources and its correct reproduction in this prospectus.

This prospectus also contains estimates, projections and other information concerning our industry, our business and the markets for our investigational gene therapies. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties, and actual events or circumstances may differ materially from events and circumstances that are assumed in this information. Unless otherwise expressly stated, we obtained this industry, business, market and other data from our own internal estimates and research as well as from reports, research surveys, studies and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data and similar sources. See “Special Note Regarding Forward-Looking Statements” for more information.

In addition, assumptions and estimates of our and our industry’s future performance are necessarily subject to a high degree of uncertainty and risk due to a variety of factors, including those described in the section titled “Risk Factors.” These and other factors could cause our future performance to differ materially from our assumptions and estimates.

Rounding

We have made rounding adjustments to some of the figures included in this prospectus. Accordingly, numerical figures shown as totals in some tables may not be an arithmetic aggregation of the figures that preceded them.

Trademarks, Service Marks and Trade Names

We own various trademark registrations and applications, and unregistered trademarks, including “Gyroscope,” “Orbit” and our corporate logo. All other trade names, trademarks and service marks of other companies appearing in this prospectus are the property of their respective holders. Solely for convenience, the trademarks and trade names in this prospectus may be referred to without the ® and symbols, but such references should not be construed as any indicator that their respective owners will not assert, to the fullest extent under applicable law, their rights thereto. We do not intend to use or display other companies’ trademarks and trade names to imply a relationship with, or endorsement or sponsorship of us by, any other companies.

Corporate Reorganization

Unless otherwise indicated or the context otherwise requires, all references in this prospectus to the terms “Gyroscope,” “Gyroscope Therapeutics,” “the company,” “we,” “us” and “our” refer to (i) Gyroscope Therapeutics Limited and its subsidiaries, prior to the completion of the transfer of the shares of Gyroscope Therapeutics Limited to Gyroscope Therapeutics Holdings Limited pursuant to the share exchange agreement, (ii) Gyroscope Therapeutics Holdings Limited, Gyroscope Therapeutics Limited and their respective subsidiaries after the completion of the share exchange agreement and prior to the re-registration of Gyroscope Therapeutics Holdings Limited as a public limited company and (iii) Gyroscope Therapeutics Holdings plc, Gyroscope Therapeutics Limited and their respective subsidiaries after the re-registration of Gyroscope Therapeutics Holdings Limited as a public limited company. See “Corporate Reorganization” for more information.

 

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SUMMARY

This summary highlights information contained elsewhere in this prospectus. This summary does not contain all the information that may be important to you, and we urge you to read this entire prospectus carefully, including the “Risk Factors,” “Business” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections and our consolidated financial statements and notes to those statements included elsewhere in this prospectus, before deciding to invest in our ADSs.

Overview of Gyroscope Therapeutics

We are a global clinical-stage gene therapy company developing gene therapy beyond rare diseases. Our mission is to preserve sight and fight the devastating impact of blindness. Our science is grounded in the genetic understanding of patients with serious eye diseases to make medicines designed to have a meaningful impact. Our initial focus is age-related macular degeneration, or AMD, one of the leading causes of irreversible blindness, affecting more than 196 million people worldwide. We are developing a differentiated pipeline of recombinant adeno-associated virus, or rAAV, gene therapy candidates targeting genetic variants in the complement pathway that we believe to be key drivers of AMD. Our investigational gene therapies are designed as one-time treatments. Our lead investigational gene therapy, GT005, is advancing in an ongoing Phase I/II clinical trial and is being evaluated in Phase II clinical trials in two different genetically defined patient populations with geographic atrophy, or GA, an advanced form of dry AMD. We have received Fast Track designation from the U.S. Food and Drug Administration, or the FDA, for GT005 for the treatment of GA secondary to AMD.

Genetically-defined therapeutics have been successfully developed for rare inherited diseases of the eye. However, unlike other disease areas such as oncology, ophthalmology has yet to experience the proliferation of treatments specifically tailored towards a person’s genetics. We are aiming to change this with development of our gene therapies, as we believe one-time gene therapies could fundamentally change the way people suffering vision loss are treated and the outcomes they achieve. We have assembled a world-class team that has deep expertise in genetics, gene therapy, the complement system and ophthalmology, and have established the critical operations that we believe are required to deliver medicines to patients, including research, clinical development, scalable manufacturing and delivery technology. By bringing together the right people with the right expertise focusing on the right challenge, we aim to deliver on our promise to patients: Vision for Life.

Age-Related Macular Degeneration, a Leading Cause of Blindness

Our initial focus is AMD, which causes progressive and permanent vision impairment leaving many people not only with devastating vision loss, but also loss of their independence as they lose the ability to read, drive or even recognize the faces of loved ones. There are two forms of AMD known respectively as dry AMD and wet AMD, with dry AMD representing 85-90% of the 196 million global AMD cases.

As dry AMD advances and becomes more severe it can lead to GA, which is characterized by loss of central and color vision. GA currently affects an estimated population of more than three million patients in the United States, France, Germany, Italy, Spain and the United Kingdom. Despite the scale of dry AMD and GA, there are currently no FDA-approved treatments for these diseases.

Recent research, published in Seminars in Immunopathology in 2017, has shown that over activation of the complement system, a key part of the immune system, is an important driver of AMD because it can lead to unnecessary inflammation that damages healthy eye tissues. Variants in genes associated with the complement system are a key driver of this disease, according to a 2014 article in Molecular Immunology. Data published in several other recent papers has shown individuals with genetic variants in the Complement Factor I, or CFI,



 

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Complement Factor H, or CFH, and C3 genes have an increased risk of developing AMD (odds ratios = 5.1-32.0, 1.7-23, and 1.4-2.7, respectively). Based on data from SCOPE, our ongoing natural history study, we estimate that approximately 98% of all patients with dry AMD that has advanced to GA have at least one genetic variant in their complement genes. In particular, a 2016 publication in Nature Genetics by Fritsche et al. found genetic variations in the genes encoding the key complement regulatory proteins, CFI and CFH, have been strongly correlated (p < 1.0 × 10–8 and p < 1.2 × 10–6, respectively) with the development and progression of dry AMD. These proteins naturally regulate the complement system in order to maintain balance, according to a 2009 article in Advances in Immunology. We believe increasing expression of these proteins with gene therapy has the potential to reduce inflammation and slow the progression of dry AMD, with the goal of preserving patients’ eyesight. To support our aim of bringing gene therapies to one of the leading causes of blindness, we are generating large genotyping and natural history databases in GA.

Our Gene Therapy Development Pipeline

We are advancing a novel pipeline of differentiated investigational rAAV gene therapies for serious eye diseases that impact large numbers of patients. We are initially focused on variants in genes for natural complement pathway regulatory proteins associated with an increased risk of AMD. We have retained global development and commercialization rights to all our programs.

Our lead programs, GT005 and GT011, focus on two key targets—CFI and factor H like-1, or FHL1, a splice variant of CFH, respectively. We believe that CFI has potential for use in the broad population of patients with GA secondary to AMD, regardless of underlying genotype, with particular potential in the sub-population of GA patients with rare variants in their CFI gene. In addition, we believe FHL1 has potential for enhanced effect in patients with CFH-related genetic variants. We have designed our clinical strategy to evaluate GT005 in the broad population of patients with GA secondary to AMD, as well as GT005 and GT011 in the specific CFI and CFH-related genetic variant populations of patients with GA secondary to AMD where they have potential for enhanced effect.

Our pipeline is summarized below:

 

 

* FDA Fast Track designation granted

** We are currently contemplating the use of an AAV8 vector for this program. In addition, we are evaluating an alternative construct utilizing an AAV2 vector. We expect to progress only one of these programs into clinical development.

In addition to our lead programs, we expect to select a candidate for our preclinical bicistronic (dual target) investigational gene therapy program for wet AMD by the second half of 2021.

Our Lead Investigational Gene Therapy: GT005 for the Treatment of GA Secondary to AMD

Our lead investigational gene therapy, GT005, is designed to restore balance to an overactive complement system by increasing production of CFI, a natural complement regulatory protein. GT005 is designed as a



 

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one-time treatment for patients with GA secondary to AMD that we believe has the potential to slow the progression of disease. Our Phase II strategy for GT005 is based on research by two of our academic founders, Professor David Kavanagh and the late Professor Sir Peter Lachmann, whose scientific contributions helped lay a foundation for the development of our complement factor therapies and who have had continuing roles advising us and our board of directors as we have grown as a company. Professor David Kavanagh demonstrated in a genotyping study of people with and without AMD that rare genetic variants in the CFI gene were associated with a higher risk of developing advanced AMD. Professor Kavanagh currently serves as a special advisor to our board of directors, sits on our scientific advisory board and is one of our shareholders. The late Professor Sir Peter Lachmann showed that ex vivo CFI supplementation could dampen complement hyperactivity within serum of people with various AMD risk phenotypes, irrespective of their underlying genotype. Based on this research, we believe GT005 could address the broad population of GA patients irrespective of the underlying complement-related genotype, in addition to having a potentially enhanced treatment effect in GA patients who have rare variants in their CFI gene.

We are currently evaluating the safety and efficacy of GT005 administered as a single subretinal injection in our two Phase II, multicenter, randomized, controlled trials, EXPLORE and HORIZON. The primary endpoint for both trials is progression of GA over 48 weeks. EXPLORE is enrolling patients with GA secondary to AMD who have rare variants in their CFI gene associated with low CFI expression levels. We estimate this patient population represents more than 100,000 patients in the United States, France, Germany, Italy, Spain and the United Kingdom, or approximately 3% of the total GA patient population. HORIZON is enrolling a broad group of patients with GA secondary to AMD who have at least one genetic variant in a complement gene. The patient population being evaluated in HORIZON represents approximately 95% of the total GA population, which we have forecasted to grow to more than four million people in the United States, France, Germany, Italy, Spain and the United Kingdom by 2030. Patients in HORIZON will be stratified by genotype in order to identify additional genetic subgroups that may show an enhanced treatment effect. In addition, we have an ongoing Phase I/II open-label trial called FOCUS, which is evaluating the safety and dose response of GT005 in patients with GA secondary to AMD. The dose-escalation phase of FOCUS is complete, and patients are being enrolled into additional cohorts. To our knowledge, GT005 is the first investigational gene therapy in Phase II testing for the treatment of GA secondary to AMD.

Our goals with our initial GT005 clinical program are to characterize the safety profile of GT005, evaluate GT005’s ability to enhance CFI expression levels, evaluate its ability to modulate the complement system and, ultimately, evaluate its ability to provide clinical benefit. The open-label Phase I/II FOCUS trial is designed for initial evaluation of the first three goals, as well as for dose escalation. The randomized, controlled Phase II EXPLORE and HORIZON trials seek to further characterize the profile of GT005, provide initial data on clinical benefit in patients with GA and inform dose selection for future clinical development.

We are very encouraged by the initial data generated in the FOCUS trial. As of February 2021, 23 patients had been treated with GT005 across Cohorts 1-5. The three doses of GT005 being evaluated in FOCUS have been reported to be well tolerated with no signs of GT005-related inflammation and no treatment-related serious adverse events. There was one possible GT005-related adverse event of special interest, which was suspected choroidal neovascularization of moderate severity that was successfully treated with anti-VEGF therapy. As of February 2021, there were 26 ocular adverse events considered to be related to the surgical procedure; the majority were mild (23/26), while the remaining were moderate (3/26).

As of December 2020, interim CFI expression and complement modulation data were available from patients in Cohorts 1-3 and initial patients treated in Cohort 4, totaling 10 patients. The data showed that all three doses of GT005 induced a consistent, elevated and sustained expression of CFI compared to baseline in both the CFI rare variant and broad GA patients evaluated. Nine out of 10 patients treated with GT005 had increases in CFI levels, with an average increase of 146% compared to baseline (p=0.02). Of the nine patients with increased



 

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CFI levels, eight showed a sustained increase in CFI levels at week 24 and beyond, with our first patient showing a sustained increase in CFI levels at 84 weeks. The most recent measurement for the ninth patient with increased CFI levels was week 12. In addition, we observed significant and sustained decreases in the vitreous levels of key proteins associated with complement over-activation (Ba and C3 breakdown proteins: C3b, iC3b and C3c). These decreases in Ba and C3 breakdown proteins were observed in both the broad GA and CFI rare variant patients. There was a significant correlation between increased CFI levels and decreases in Ba levels (p=0.03). As we continue to enroll patients and collect data in the FOCUS trial, we expect to update our interim data periodically. We expect to report further data from FOCUS in 2021, final data from FOCUS in 2022 and topline results from EXPLORE and HORIZON in the first half of 2023.

We have invested significant resources and efforts in establishing the critical operations required to scale and deliver our medicines to large patient populations, if approved. Our global clinical infrastructure encompasses trial sites across eight countries; our proprietary, scalable and reproducible suspension manufacturing platform has been scaled to 200L and can generate yields of approximately 3,000 doses per batch; and our novel and proprietary Orbit Subretinal Delivery System, or Orbit SDS, has received FDA 510(k) clearance for microinjection into the subretinal space, based on delivery of balanced salt solution or BSS PLUS, a proprietary version of balanced salt solution. The use of the Orbit SDS for microinjection of cell or gene therapies is currently investigational. Our Orbit SDS technology complements our investigational gene therapies by providing a differentiated delivery device that aims to improve the precision and predictability of delivering therapies to the subretinal space within the eye. In addition, we have established in-house research capabilities to support analytical testing for our clinical trials and are generating large genotyping and natural history databases in GA. Bringing gene therapy solutions to large patient populations requires highly scalable infrastructure and we have and continue to invest in expanding both the scope and breadth of our capabilities.

Our Earlier Stage Investigational Gene Therapies

In addition to GT005, we are developing a broad pipeline of additional investigational gene therapy programs targeting both dry and wet AMD. Our second investigational gene therapy, GT011, is a preclinical rAAV gene therapy that is designed to induce expression of FHL1, a splice variant of CFH that we believe has advantageous characteristics for the treatment of GA secondary to AMD. CFH gene variants, and particularly variants within the FHL1 coding sequence, follow CFI gene variants as being among the highest risk factors for AMD. The CFH and FHL1 variant population represents approximately 40% of the total GA population. GT011 has advanced through the candidate selection stage and is proceeding to Investigational New Drug, or IND, enabling studies. We expect to file an IND application with the FDA for GT011 in the first half of 2022. In addition, we have multiple ongoing internal and collaboration research efforts to apply gene therapy to evaluate novel biologic targets for diseases of the eye, including a dual mechanism, or bicistronic, preclinical gene therapy program designed to target multiple biological pathways associated with wet AMD within one rAAV construct.

Our Culture and People

We have created a culture that defines how we operate: we care for our People, have passion for our Patients and deliver on our Promise. Based on these pillars, we have purposefully built an organization with deep scientific, development and commercial capabilities, along with expertise in genetics, gene therapy, the complement system and ophthalmology.

Members of our management team have world-class expertise in development and commercialization of ophthalmology drugs, complement, genetics and the manufacture and delivery of gene therapies. Members of our core management team have supported the development of over 40 therapies and have also led the commercial launch or lifecycle management of 25 approved products, including Lucentis. We also draw upon the collective expertise of 167 employees, of whom 38 have Ph.D.s or M.D.s, with significant experience across discovery, preclinical research, manufacturing and clinical development. Our team is located across three key biotechnology



 

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and gene therapy hubs in the world: London, Philadelphia and San Francisco. Our management team is supported by our board of directors, a group of renowned investors and industry veterans, including past and current C-suite executives of large global biopharmaceutical and innovative biotech companies.

We were founded by leading scholars who established the scientific basis for GT005, including the late Professor Sir Peter Lachmann, former emeritus Sheila Joan Smith Professor of Immunology at the University of Cambridge and David Kavanagh, Ph.D., Professor of Nephrology at the University of Newcastle. The pioneering work of Professor Kavanagh and the late Professor Sir Peter Lachmann provided the foundation of our clinical development program for GT005. We were founded by Syncona Limited, or Syncona, a leading healthcare investment company focused on founding, building and funding global leaders in life sciences. In addition, we have established scientific and clinical advisory boards comprised of experts in the fields of gene therapy, AMD, complement, human genetics and ocular drug discovery and development.

Our History and Achievements

Since our founding in 2016, we have rapidly executed on our strategic objectives. We filed a clinical trial application with the Medicines and Healthcare products Regulatory Agency in the United Kingdom in 2017 and an IND application with the FDA in the United States in 2018 for our lead investigational gene therapy, GT005, and have subsequently dosed patients in three ongoing clinical trials, with positive interim data reported from our ongoing Phase I/II FOCUS clinical trial in February 2021. In parallel with our preclinical and clinical development, we have developed a proprietary manufacturing platform capable of meeting our clinical and commercial needs across two rAAV serotypes. In 2019, we added delivery technology capabilities with the further development of the Orbit SDS device, for which we subsequently obtained FDA 510(k) clearance to further our goals of bringing gene therapies beyond rare diseases.

Our Strengths

Our ambition is to discover, develop and deliver novel gene therapies for large patient populations with serious eye diseases who currently have limited or no treatment options, starting with AMD. Our science is grounded in the genetic understanding of patients with serious eye diseases to make medicines designed to have a meaningful impact. We believe one-time gene therapies could fundamentally change the way people suffering from vision loss are treated and the outcomes they achieve.

We believe the following strengths will allow us to build our leadership position in AMD and other diseases of the eye, and achieve our longer-term goal of delivering gene therapies to people in need:

 

   

Global organization with leading expertise in genetics, gene therapy, the complement system and ophthalmology to advance a development pipeline of novel gene therapies for AMD;

 

   

Lead investigational gene therapy GT005, if approved, has potential to be the first gene therapy for the treatment of GA secondary to AMD;

 

   

Large genotyping and natural history databases in GA to support our goal of bringing gene therapies to one of the leading global causes of blindness;

 

   

Innovative in-house research capabilities that allow us to develop next-generation and novel investigational gene therapy programs;

 

   

Comprehensive in-house drug delivery capabilities, such as the Orbit Subretinal Delivery System;

 

   

Early investment into suspension manufacturing technology that is designed to be scalable for large patient populations; and



 

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World-class expertise in gene therapy drug development, manufacturing and product commercialization.

Our Strategy

Our goal is to unlock the full potential of ocular gene therapy to address large patient populations beyond rare diseases. The key elements of our strategy to achieve this are:

 

   

Complete the clinical development of, and obtain regulatory approval for, GT005, our lead investigational gene therapy;

 

   

Leverage the findings from our genotyping initiatives and ongoing natural history study, SCOPE, to identify patients and further inform our clinical development strategy;

 

   

Develop our earlier stage gene therapy programs, including GT011 and our bicistronic investigational gene therapy, and identify and develop further programs in AMD and other diseases of the eye;

 

   

Continue to advance our innovative proprietary delivery capabilities to broaden the number of patients our treatments can reach;

 

   

Expand our commercial manufacturing capabilities and infrastructure to streamline clinical development and enable commercial scale; and

 

   

Build upon our existing global presence and infrastructure.

Recent Developments

On March 26, 2021, we entered into a subscription agreement, pursuant to which we sold 53,478,259 series C1 preferred shares and 13,586,955 series C2 preferred shares to certain investors. The series C1 preferred shares and series C2 preferred shares, which we collectively refer to as series C preferred shares, have substantially the same rights and privileges, except with respect to liquidation preference, which is equivalent to their respective purchase prices. Pursuant to the subscription agreement, we sold the 67,065,214 series C preferred shares for a total of approximately $148.0 million (before deducting offering expenses of $1.4 million), consisting of (i) approximately $108.0 million of cash proceeds from the sale of the series C1 preferred shares, (ii) conversion of approximately $15.0 million aggregate principal amount of outstanding convertible loan notes for 6,521,738 series C1 preferred shares at a per share conversion price of $2.30, and (iii) conversion of approximately $25.0 million aggregate principal amount of outstanding convertible loan notes for 13,586,955 series C2 preferred shares at a per share conversion price of $1.84, which we collectively refer to as the Series C Financing, which closed on March 29, 2021. See “Related Party Transactions.” As of March 31, 2021, we had cash and cash equivalents of approximately $117.0 million.

On March 26, 2021, we amended and restated our exclusive patent license agreement with Syncona IP Holdco Limited. For a detailed description of certain terms of this agreement, see “Business—Collaborations and License Agreements.”

Risks Associated with Our Business

Our business is subject to a number of risks of which you should be aware before making an investment decision. You should carefully consider all of the information set forth in this prospectus and, in particular, should evaluate the specific factors set forth in the section titled “Risk Factors” before deciding whether to invest in our ADSs. Among these important risks are, but such risks are not limited to, the following:

 

   

We are a clinical-stage gene therapy company and have incurred significant net losses, and we expect to incur losses for the foreseeable future.



 

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We may never achieve or maintain profitability.

 

   

Even if we consummate this offering, we will need substantial additional funding to complete the development and commence commercialization of our investigational gene therapies, which may not be available on acceptable terms, if at all. If we are unable to obtain additional funding when required, we may be forced to delay, reduce or eliminate our investigational gene therapy programs or other operations.

 

   

We are heavily dependent on the success of our lead investigational gene therapy, GT005.

 

   

Our limited operating history may make it difficult for you to evaluate the success of our business to date and to assess our future viability.

 

   

In preparation of this offering, we identified material weaknesses in our internal control over financial reporting. If we are unable to successfully remediate the existing material weaknesses in our internal control over financial reporting, the accuracy and timing of our financial reporting may be adversely affected.

 

   

All of our investigational gene therapies are in preclinical or clinical development. Clinical trials are difficult to design and implement, and they involve a lengthy and expensive process with uncertain outcomes. We may encounter substantial delays in completing, or ultimately be unable to complete, the development of our current and future investigational gene therapies.

 

   

The COVID-19 pandemic has adversely impacted, and may continue to adversely impact, our business, including our planned clinical trials and ongoing and planned preclinical studies.

 

   

We may fail to demonstrate safety and efficacy of our investigational gene therapies to the satisfaction of applicable regulatory authorities.

 

   

We rely, and expect to continue to rely, on third parties to conduct our preclinical studies and clinical trials. If these third parties do not successfully carry out their contractual duties or meet expected deadlines, we may not be able to obtain regulatory approval for or commercialize our investigational gene therapies and our business could be substantially harmed.

 

   

We currently utilize, and expect to continue to utilize, third parties to conduct our product manufacturing, and these third parties may not perform satisfactorily.

 

   

We are dependent on a limited number of suppliers and, in some instances, a sole supplier, for some of our components and materials used in our investigational gene therapies and in our Orbit SDS device.

 

   

We face significant competition in an environment where multiple companies have ongoing clinical trials and are aiming to impact the patient unmet need. There is a possibility that our competitors may achieve regulatory approval before us or develop therapies that are more advanced or effective than ours, which may adversely affect our financial condition and our ability to successfully market or commercialize our investigational gene therapies.

 

   

We currently have no marketing or field force. If we are unable to establish effective sales and marketing capabilities or enter into agreements with third parties to market and sell GT005 or other investigational gene therapies that may be approved, we may not be successful in commercializing our investigational gene therapies or devices if and when approved, and we may be unable to generate any product revenue.

 

   

If we are unable to obtain, maintain and enforce patent protection for our current investigational gene therapies and devices, and any future investigational gene therapies or devices we may develop, or if the scope of the patent protection obtained is not sufficiently broad, our competitors or other third parties could develop and commercialize gene therapies and devices similar or identical to ours and our ability to successfully develop and commercialize our investigational gene therapies and devices may be adversely affected.



 

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We are, and may in the future be, subject to legal proceedings alleging that we are infringing, misappropriating or otherwise violating their intellectual property rights.

 

   

As an English public limited company, certain capital structure decisions will require shareholder approval, which may limit our flexibility to manage our capital structure.

Corporate Information

Gyroscope Therapeutics Holdings plc is a private limited company incorporated under the laws of England and Wales in December 2020 with nominal assets and liabilities and is to become the ultimate holding company of Gyroscope Therapeutics Limited and re-register as a public limited company. Gyroscope Therapeutics Limited was incorporated under the laws of England and Wales in April 2016. Our registered office is located at Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2FX, United Kingdom and our telephone number is +44 (0)1438 906770. Our website address is www.gyroscopetx.com. The information contained on or accessible through our website is not incorporated by reference into this prospectus, and you should not consider any information contained on, or that can be accessed through, our website as part of this prospectus or in deciding whether to purchase our ADSs. We have included our website address as an inactive textual reference only. Our agent for service of process in the United States is Gyroscope USA, Inc.

Corporate Reorganization

Prior to the completion of this offering, (i) Gyroscope Therapeutics Holdings Limited incorporated Gyroscope Holdings (UK) Limited, a new wholly owned subsidiary that will ultimately become the direct holding company of Gyroscope Therapeutics Limited and (ii) Gyroscope Therapeutics Holdings Limited re-registered as a public limited company and changed its name to Gyroscope Therapeutics Holdings plc. Pursuant to the terms of the corporate reorganization, the shareholders of Gyroscope Therapeutics Limited exchanged each of the shares held by them in Gyroscope Therapeutics Limited for the same number and class, and with the same rights attaching thereto, of newly issued shares of Gyroscope Therapeutics Holdings Limited and, as a result, Gyroscope Therapeutics Limited will become a wholly owned subsidiary of Gyroscope Therapeutics Holdings Limited.

In addition, each class of shares of Gyroscope Therapeutics Holdings plc (other than deferred shares) will be reorganized into one class of ordinary shares of Gyroscope Therapeutics Holdings plc at the ratios set forth under the section of this registration statement entitled “Corporate Reorganization” and will then be consolidated and subdivided to reflect an approximately 1-for-0.155 reverse split prior to the completion of this offering.

After this offering, it is expected that Gyroscope Holdings (UK) Limited (wholly owned by Gyroscope Therapeutics Holdings Limited) will acquire the entire issued share capital of Gyroscope Therapeutics Limited in exchange for an issue of shares in Gyroscope Holdings (UK) Limited and, as a result, Gyroscope Therapeutics Limited will become a wholly owned subsidiary of Gyroscope Holdings (UK) Limited. Please see “Corporate Reorganization” in this prospectus for more information.

Implications of Being an Emerging Growth Company and a Foreign Private Issuer

We qualify as an “emerging growth company” as defined in the Jumpstart Our Business Startups Act of 2012, as amended, or the JOBS Act. An emerging growth company may take advantage of specified reduced reporting and other burdens that are otherwise applicable generally to public companies in the United States. These provisions include:

 

   

a requirement to have only two years of audited financial statements in this prospectus and only two years of related “Management’s Discussion and Analysis of Financial Condition and Results of Operations” disclosure in this prospectus;



 

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reduced executive compensation disclosure; and

 

   

an exemption from the auditor attestation requirement in the assessment of our internal control over financial reporting pursuant to the Sarbanes-Oxley Act of 2002.

We may choose to take advantage of some but not all of these reduced disclosure requirements. We may take advantage of these provisions until we are no longer an emerging growth company. We will remain an emerging growth company until the earliest to occur of: (1) (a) the last day of the fiscal year following the fifth anniversary of the closing of this offering, (b) the last day of the fiscal year in which our annual gross revenue is $1.07 billion or more, or (c) the date on which we are deemed to be a “large accelerated filer,” under the rules of the SEC, which means the market value of our equity securities that is held by non-affiliates exceeds $700 million as of the end of our second quarter and (2) the date on which we have issued more than $1.0 billion in non-convertible debt during the prior three-year period.

In addition, under the JOBS Act, emerging growth companies can delay adopting new or revised accounting standards until such time as those standards apply to private companies. See “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Emerging Growth Company Status.” We have elected to use the extended transition period under the JOBS Act. Accordingly, our financial statements may not be comparable to the financial statements of public companies that comply with such new or revised accounting standards.

Upon the completion of this offering, we will report under the Exchange Act as a non-U.S. company with foreign private issuer status. Even after we no longer qualify as an emerging growth company, as long as we qualify as a foreign private issuer under the Exchange Act, we will be exempt from certain provisions of the Exchange Act that are applicable to U.S. domestic public companies, including:

 

   

the sections of the Exchange Act regulating the solicitation of proxies, consents or authorizations with respect to a security registered under the Exchange Act;

 

   

the requirement to comply with Regulation Fair Disclosure, or Regulation FD, which regulates selective disclosure of material information;

 

   

the sections of the Exchange Act requiring insiders to file public reports of their share ownership and trading activities and liability for insiders who profit from trades made in a short period of time; and

 

   

the rules under the Exchange Act requiring the filing with the SEC of quarterly reports on Form 10-Q containing unaudited financial and other specified information, or current reports on Form 8-K upon the occurrence of specified significant events.

Both foreign private issuers and emerging growth companies are also exempt from certain more stringent executive compensation disclosure rules. Thus, even if we no longer qualify as an emerging growth company, but remain a foreign private issuer, we will continue to be exempt from the more stringent compensation disclosures required of companies that are neither an emerging growth company nor a foreign private issuer. As a result, we do not know if some investors will find our ADSs less attractive, which may result in a less active trading market for our ADSs or more volatility in the price of our ADSs.

As a result of the above, the information contained in this prospectus may be different from the information you receive from other public companies in which you hold shares.



 

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THE OFFERING

This summary highlights information presented in greater detail elsewhere in this prospectus. This summary is not complete and does not contain all the information you should consider before investing in our ADSs. You should carefully read this entire prospectus before investing in our ADSs including “Risk Factors” and our consolidated financial statements.

 

Issuer

Gyroscope Therapeutics Holdings plc

 

Offering

We are offering 6,750,000 ADSs, each ADS representing one ordinary share.

 

Option to purchase additional ADSs

We have granted the underwriters the right to purchase up to an additional 1,012,500 ADSs from us within 30 days of the date of this prospectus.

 

Ordinary shares (including in the form of ADSs) to be outstanding immediately after this offering

29,229,659 ordinary shares

 

ADSs to be outstanding immediately after this offering

6,750,000 ADSs

 

American Depositary Shares

Each ADS represents one ordinary share, nominal value £0.005 per share. The ADSs may be evidenced by American Depositary Receipts, or ADRs. The depositary will hold the ordinary shares underlying the ADSs in a custody account with the custodian, and you will have the rights of an ADS holder or beneficial owner (as applicable) as provided in the deposit agreement among us, the depositary and holders and beneficial owners of ADSs from time to time. To better understand the terms of our ADSs, see “Description of American Depositary Shares.” We also encourage you to read the deposit agreement, the form of which is filed as an exhibit to the registration statement of which this prospectus forms a part.

 

Depositary

The Bank of New York Mellon

 

Custodian

The Bank of New York Mellon

Listing

We have applied to list our ADSs on the Nasdaq Global Select Market under the symbol “VISN.”

 

Use of proceeds

We estimate that the net proceeds to us from this offering, after deducting the underwriting discounts and commissions and estimated offering expenses payable by us, to be approximately $127.8 million, or $147.6 million if the underwriters exercise their option to purchase additional ADSs in full, based on an assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus.

 

  We currently intend to use the net proceeds from this offering, together with our existing cash, as follows:

 

   

approximately $90.0 million to $130.0 million to advance our lead product candidate, GT005, including to fund our



 

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ongoing Phase I/II FOCUS clinical trial, ongoing Phase II EXPLORE clinical trial and our ongoing Phase II HORIZON clinical trial;

 

   

approximately $10.0 million to $20.0 million to advance our product candidate, GT011; and

 

   

the balance for the development of our other preclinical programs and general corporate purposes, including general and administrative expenses and working capital.

 

  See “Use of Proceeds” for a more complete description of the intended use of proceeds from this offering.

 

Directed Share Program

At our request, the underwriters have reserved up to 337,500 ADSs, or 5% of the ADSs offered pursuant to this prospectus, for sale at the initial public offering price per ADS through a directed share program, to directors, officers, employees and certain other individuals associated with us. The number of ADSs available for sale to the general public will be reduced by the number of reserved ADSs sold to these individuals. Any reserved ADSs not purchased by these individuals will be offered by the underwriters to the general public on the same basis as the other ADSs offered pursuant to this prospectus. See “Underwriting—Directed Share Program.”

 

Risk factors

See “Risk Factors” and the other information included in this prospectus for a discussion of factors you should consider before deciding to invest in our ADSs.

Unless otherwise stated in this prospectus, the number of our ordinary shares to be outstanding after this offering is based on 22,479,659 ordinary shares issued and outstanding as of December 31, 2020 (based on an initial public offering price of $21.00 per share, which is the midpoint of the price range set forth on the cover of this prospectus, and after giving effect to the issuance of our series C preferred shares in March 2021 (which will be redesignated into 10,426,692 ordinary shares prior to the closing of this offering) and the corporate reorganization) and after giving further effect to the issuance of a number of ordinary shares in the form of ADSs as set forth on the cover of this prospectus to be issued and sold by us in this offering, and excludes:

 

   

336,533 ordinary shares issuable upon the exercise of options outstanding as of December 31, 2020 with a weighted-average exercise price of $6.33 per share;

 

   

2,294,243 ordinary shares issuable upon the exercise of options outstanding after December 31, 2020 with a weighted-average exercise price of $14.79 per share;

 

   

1,040,946 deferred shares outstanding as of December 31, 2020 and any other deferred shares issued and outstanding as of the date of this prospectus;

 

   

3,361,411 ordinary shares authorized for future issuance under our 2021 Equity Incentive Plan (including 2,288,108 ordinary shares reserved for future issuance under our Series C Share Option Plan that will be transferred to our 2021 Equity Incentive Plan upon its effectiveness and including the grants of options to be made in connection with this offering described below) to be adopted in connection with this offering;

 

   

292,297 ordinary shares authorized for future issuance under our Gyroscope Therapeutics Holdings plc Sharesave Plan (UK), or the Sharesave Plan, to be adopted in connection with this offering;



 

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292,297 ordinary shares authorized for future issuance under our 2021 Employee Share Purchase Plan, or the 2021 ESPP, to be adopted in connection with this offering; and

 

   

the expected grant of options to purchase approximately 1,315,335 ordinary shares (based on an amount equal to 4.5% of the ordinary shares outstanding after this offering) to our directors, officers and other employees in connection with this offering, with an exercise price equal to the initial public offering price.

Unless otherwise indicated, all information contained in this prospectus also reflects and assumes:

 

   

the consummation of the Series C Financing, including the issuance of 67,065,214 of our series C preferred shares in March 2021 (which will be redesignated into 10,426,692 ordinary shares as a part of the transactions described under “Corporate Reorganization” prior to the closing of this offering) and the receipt of the net proceeds therefrom;

 

   

the consummation of the transactions described under “Corporate Reorganization” prior to the closing of this offering (including the approximately 1-for-0.155 reverse split of all our ordinary shares prior to completion of this offering);

 

   

an initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus;

 

   

no exercise of the option granted to the underwriters to purchase up to an additional 1,012,500 ADSs in connection with this offering; and

 

   

no purchase of ADSs by directors, officers, employees or certain other individuals through our directed share program.

Following the reorganization into a single class of ordinary shares as described above, such ordinary shares will be consolidated and subdivided to reflect an approximately 1-for- 0.155 reverse split of such ordinary shares and the balance of any ordinary shares will be redesignated as deferred shares prior to completion of this offering.

Such reorganization will involve (without limitation) the redesignation of classes of shares, the consolidation and/or the subdivision of shares pursuant to the terms of the articles of association of the Company in effect at such time as described above. The number of ordinary shares that each current shareholder of Gyroscope Therapeutics Holdings plc receives will be rounded up or down to the nearest whole share. Therefore, upon consummation of the corporate reorganization and prior to the completion of this offering, assuming an initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover of this prospectus, the current shareholders of Gyroscope Therapeutics Holdings plc will hold an aggregate of approximately 22,479,659 ordinary shares of Gyroscope Therapeutics Holdings plc. In the event of a $1.00 increase in the assumed initial public offering price per ADS to $22.00 per ADS, the current shareholders of Gyroscope Therapeutics Holdings plc will hold an aggregate of approximately 22,504,077 ordinary shares of Gyroscope Therapeutics Holdings plc. In the event of a $1.00 decrease in the assumed initial public offering price per ADS to $20.00 per ADS, the current shareholders of Gyroscope Therapeutics Holdings plc will hold an aggregate of approximately 22,451,130 ordinary shares of Gyroscope Therapeutics Holdings plc.



 

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SUMMARY FINANCIAL AND OTHER INFORMATION

The following tables present our summary consolidated financial data. We derived the summary consolidated statements of operations and comprehensive loss data for the fiscal year ended January 31, 2020 and the fiscal year ended December 31, 2020 and the summary consolidated balance sheet data as of December 31, 2020 from our audited financial statements included elsewhere in this prospectus. Our historical results for the fiscal year ended January 31, 2020 are not directly comparable to the fiscal year ended December 31, 2020, for which we had an 11-month fiscal year. We prepare our financial statements in accordance with accounting principles generally accepted in the United States, or U.S. GAAP, as issued by the Financial Accounting Standards Board, or FASB.

We maintain the financial statements of each entity within the group in its local currency, which is also the entity’s functional currency. Monetary assets and liabilities denominated in currencies other than the functional currency are translated into the functional currency at rates of exchange prevailing at the balance sheet dates. Non-monetary assets and liabilities denominated in foreign currencies are translated into the functional currency at the exchange rates prevailing at the date of the transaction. Exchange gains or losses arising from foreign currency transactions are included in other expense, net in the consolidated statement of comprehensive loss.

For financial reporting purposes our financial statements have been presented in U.S. dollars, the reporting currency. The financial statements of entities are translated from their functional currency into the reporting currency as follows: assets and liabilities are translated at the exchange rates at the balance sheet dates, revenue and expenses are translated at the average exchange rates and shareholders’ equity is translated based on historical exchange rates. Translation adjustments are not included in determining net loss but are included as a foreign exchange adjustment to other comprehensive loss, a component of shareholders’ equity.

As of December 31, 2020, the last business day of the fiscal year ended December 31, 2020, the representative exchange rate was $1.3662 to £1.00, which was the noon buying rate of the Federal Reserve Bank of New York on such date.

Except as noted below, the following tables and notes thereto have not been retroactively adjusted to reflect our corporate reorganization (including the approximately 1-for-0.155 reverse split of all our ordinary shares prior to completion of this offering) as described under “Corporate Reorganization.”



 

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This financial information should be read in conjunction with “Presentation of Financial and Other Information,” “Corporate Reorganization,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and our consolidated financial statements, including the notes thereto, included elsewhere in this prospectus. Our historical results are not necessarily indicative of the results that may be expected in the future.

 

     Fiscal Year Ended
January 31,

2020
    Fiscal Year Ended
December 31,

2020
 
     (in thousands, except for share and per share data)  

Consolidated Statements of Operations and Comprehensive Loss Data:

    

Revenue

   $ 2,966     $ 864  

Cost of revenue

     1,053       112  
  

 

 

   

 

 

 

Gross profit

     1,913       752  

Operating expenses:

    

Research and development

     24,844       41,307  

General and administrative

     16,998       24,389  
  

 

 

   

 

 

 

Total operating expenses

     41,842       65,696  
  

 

 

   

 

 

 

Loss from operations

     (39,929     (64,944
  

 

 

   

 

 

 

Other income (expense), net:

    

Other income (expense), net

     (144     825  

Interest expense, net

     (9     (174

Benefit from R&D tax credit

     6,264       10,857  
  

 

 

   

 

 

 

Total other income, net

     6,111       11,508  
  

 

 

   

 

 

 

Loss before income taxes

     (33,818     (53,436

Income tax benefit

     283       264  
  

 

 

   

 

 

 

Net loss

   $ (33,535   $ (53,172
  

 

 

   

 

 

 

Other comprehensive income

    

Foreign exchange translation adjustment

     1,956       (1,965

Total comprehensive loss attributable to ordinary shareholders—basic and diluted

   $ (31,579   $ (55,137
  

 

 

   

 

 

 

Net loss per share attributable to ordinary shareholders—basic and diluted

   $ (12.89   $ (11.15
  

 

 

   

 

 

 

Weighted average ordinary shares outstanding—basic and diluted

     2,602,516       4,767,392  
  

 

 

   

 

 

 

Pro forma net loss attributable to ordinary shareholders(1)

     $ (53,172
    

 

 

 

Pro forma net loss per share attributable to ordinary shareholders—basic and diluted(1)

     $ (4.89
    

 

 

 

Pro forma weighted average shares of ordinary shares used in computing net loss per share attributable to ordinary shareholders—basic and diluted(1)

       10,865,526  
    

 

 

 

 

(1)

Pro forma net loss attributable to ordinary shareholders, pro forma net loss per share attributable to ordinary shareholders—basic and diluted (unaudited) and pro forma weighted average ordinary shares outstanding—basic and diluted (unaudited) gives effect to our corporate reorganization (including the approximately 1-for-0.155 reverse split of all our ordinary shares prior to completion of this offering) as described under “Corporate Reorganization” as if such transactions had occurred on February 1, 2020.



 

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    As of December 31, 2020  
                    Actual                                  Pro Forma(1)                  Pro Forma As Adjusted(2)  
    (in thousands, except share data)  

Consolidated Balance Sheets Data:

     

Cash and cash equivalents

  $ 20,915     $ 142,510     $ 270,545  

Working capital(3)

    (6,644     140,379       269,792  

Total assets

    48,387       169,982       296,389  

Total debt

    45,383       19,955       18,577  

Preferred shares

    1       —         —    

Ordinary shares

    —         1       29  

Additional paid-in capital

    112,682       265,527       393,284  

Accumulated other comprehensive loss

    (874     (874     (874

Accumulated deficit

    (108,805     (114,627     (114,627

Total shareholders’ equity

    3,004       150,027       277,812  

 

(1)

The unaudited pro forma balance sheet data gives effect to (i) the consummation of the Series C Financing and our receipt of net proceeds therefrom and (ii) our proposed corporate reorganization (including the approximately 1-for-0.155 reverse split of all our ordinary shares prior to completion of this offering) as described under “Corporate Reorganization” as if such transactions had occurred on December 31, 2020.

(2)

The unaudited pro forma as adjusted balance sheet data gives effect to (i) the consummation of the Series C Financing and our receipt of net proceeds therefrom, (ii) our proposed corporate reorganization (including the approximately 1-for-0.155 reverse split of all our ordinary shares prior to completion of this offering) as described under “Corporate Reorganization” as if such transactions had occurred on December 31, 2020 and (iii) the issuance and sale of 6,750,000 ADSs in this offering by us at an assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, and the application of the net proceeds of the offering, after deducting underwriting discounts and commissions and estimated offering expenses payable by us, as set forth under “Use of Proceeds.” Each $1.00 increase or decrease in the assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, would increase or decrease the pro forma as adjusted amount of each of cash, working capital, total assets and total shareholders’ equity by $6.3 million, assuming that the number of ADSs offered by us, as set forth on the cover page of this prospectus, remains the same, and after deducting underwriting discounts and commissions. An increase or decrease of 1,000,000 in the number of ADSs offered by us, as set forth on the cover page of this prospectus, would increase or decrease the pro forma as adjusted amount of each of cash, working capital, total assets and total shareholders’ equity by $19.5 million, assuming the assumed initial public offering price per ADS remains the same, and after deducting underwriting discounts and commissions. This pro forma as adjusted information is illustrative only and will depend on the actual initial public offering price and other terms of this offering determined at pricing.

(3)

We define working capital as current assets less current liabilities.



 

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RISK FACTORS

Investing in our ADSs involves a high degree of risk. Before deciding whether to invest in the ADSs, you should carefully consider the risks described below and all other information contained in this prospectus, including our consolidated financial statements and the related notes included elsewhere in this prospectus. We believe the risks described below are the risks that are material to us as of the date of this prospectus. The occurrence of any of the events or developments described below could harm our business, financial condition, results of operations and growth prospects. In these circumstances, the market price of our ADSs could decline and you may lose all or part of your investment. You should also carefully review the cautionary statements referred to under “Special Note Regarding Forward-Looking Statements.” Our actual results could differ materially and adversely from those anticipated in this prospectus.

Risks Related to Our Financial Position and Need for Additional Capital

We are a clinical-stage gene therapy company and have incurred significant net losses, and we expect to incur losses for the foreseeable future.

We are a clinical-stage gene therapy company with a limited operating history. Since our inception in 2016, we have incurred significant net losses. Our net losses were $33.5 million and $53.2 million for the fiscal years ended January 31, 2020 and December 31, 2020, respectively. As of December 31, 2020, we had an accumulated deficit of $108.8 million. We have financed our operations primarily through private placements of preferred shares and convertible loan notes, a substantial portion of which have been issued to Syncona. To date, we have devoted substantially all of our efforts to research, development and manufacturing of our investigational gene therapies, including clinical development of our lead investigational gene therapy, GT005, as well as building out our management team. We expect to continue to incur significant expenses and increasing operating losses for the foreseeable future as we continue our research and development efforts and seek to obtain regulatory approval and commercialization of our investigational gene therapies, particularly if we advance our investigational gene therapies into later-stage clinical development, which is generally more expensive than early-stage development. These net losses will adversely impact our shareholders’ equity and net assets and may fluctuate significantly from quarter to quarter and year to year. We anticipate that our expenses will increase substantially if, and as, we:

 

   

continue research and development of our investigational gene therapies, including our ongoing clinical trials including our ongoing SCOPE natural history study, our ongoing FOCUS Phase I/II open label study of GT005, our two ongoing EXPLORE and HORIZON Phase II clinical trials of GT005, and our planned ORACLE long-term follow up study;

 

   

initiate clinical trials and preclinical studies for GT011, our bicistronic gene therapy program or any additional investigational gene therapies that we may pursue in the future and further develop our pipeline of investigational gene therapies;

 

   

prepare our biologics license application, or BLA, and marketing authorization application, or MAA, for each of our investigational gene therapies and otherwise seek regulatory approval for any investigational gene therapies that successfully complete clinical trials;

 

   

prepare 510(k) clearance submission or premarket approval, or PMA, applications for future generations of Orbit SDS or other medical devices we may develop;

 

   

manufacture our investigational gene therapies in accordance with current good manufacturing practices, or cGMP, for clinical trials or potential commercial sales;

 

   

establish and validate in-house or contracted commercial-scale cGMP manufacturing capabilities;

 

   

develop, manufacture and validate medical devices, including Orbit SDS, to deliver our investigational gene therapies;

 

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establish a sales, marketing and distribution infrastructure to commercialize any investigational gene therapies or device for which we may obtain marketing approval;

 

   

develop, maintain, expand, protect and enforce our intellectual property portfolio;

 

   

acquire or in-license other product candidates and technologies;

 

   

add clinical, scientific, operational, financial and management information systems and personnel, including personnel to support our investigational gene therapies and delivery system development, and potential future commercialization efforts;

 

   

confirm, maintain or obtain freedom to operate for any of our owned or licensed technologies and investigational gene therapies;

 

   

expand our operations in the United States, the United Kingdom and Europe and potentially other countries;

 

   

incur additional legal, accounting and other expenses associated with operating as a public company; and

 

   

incur additional setbacks or delays to the initiation or completion of preclinical studies, product development or clinical trials, or any disruption or delays to the supply of our investigational gene therapies or medical devices, due to COVID-19.

We may never succeed in any or all of these activities and, even if we obtain regulatory approval of and are successful in commercializing one or more of our investigational gene therapies, we may incur substantial research and development and other expenditures to develop and market additional product candidates. We may encounter unforeseen expenses, difficulties, complications, delays and unknown factors that may adversely affect our business. The size of our future net losses will depend, in part, on the rate of future growth of our expenses and our ability to generate revenue.

We may never achieve or maintain profitability.

We do not know if or when we will become profitable. To date, we have not commercialized any products or generated any revenue from sales of our investigational gene therapies. We do not expect to generate any revenue from sales of our investigational gene therapies in the foreseeable future and, even if we do, we may never generate revenues that are significant or large enough to achieve profitability. Even if one or more of the investigational gene therapies that we develop is approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved investigational gene therapies and any medical devices we may develop. Our expenses could increase beyond our current expectations if we are required by the U.S. Food and Drug Administration, or the FDA, the UK Medicines and Healthcare products Regulatory Agency, or the MHRA, the European Medicines Agency, or the EMA, or other regulatory agencies to perform clinical trials or studies in addition to those that we currently anticipate.

If we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Our failure to become and remain profitable would decrease the value of our ADSs and could impair our ability to raise capital, maintain our research and development efforts, expand our business or continue our operations. A decline in the value of our ADSs also could cause you to lose all or part of your investment.

Even if we consummate this offering, we will need substantial additional funding to complete the development and commence commercialization of our investigational gene therapies, which may not be available on acceptable terms, if at all. If we are unable to obtain additional funding when required, we may be forced to delay, reduce or eliminate our investigational gene therapy programs or other operations.

The development of investigational gene therapies is capital intensive. Since our inception, we have used substantial amounts of cash to fund our operations and expect our expenses to increase substantially in

 

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connection with our ongoing and planned activities. In order to fund further operations, we will need to raise capital in addition to the net proceeds of this offering. We may seek these funds through a combination of private and public equity offerings, debt financings, government grants, strategic collaborations and licensing arrangements. Additional financing may not be available when we need it or may not be available on terms that are favorable to us.

To date, we have financed our operations primarily through private placements of preferred shares and convertible loan notes, a substantial portion of which have been issued to Syncona. Since May 2016, we have received an aggregate of $259.3 million cash proceeds from the private placement of preferred shares and convertible loan notes. As of March 31, 2021, we had approximately $117.0 million in cash and cash equivalents. We estimate that our net proceeds from this offering will be $127.8 million, based on an assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, after deducting underwriting discounts and commissions and estimated offering expenses payable by us. We believe that, based on our current operating plan, the net proceeds from this offering, together with our existing capital resources, including the net proceeds from the Series C Financing, will be sufficient to fund our anticipated operations through mid-2023. We expect our expenses to increase in connection with our ongoing activities, particularly as we continue the research, development and manufacturing of, initiate further clinical trials of and seek marketing approval for our most advanced investigational gene therapy, GT005. In addition, if we obtain marketing approval for our investigational gene therapies, we expect to incur significant expenses related to product sales, medical affairs, marketing, manufacturing and distribution. Furthermore, upon the completion of this offering, we expect to incur additional costs associated with operating as a public company. Any COVID-19-related program setbacks or delays due to changes in federal or state laws or clinical site policies could further impact our programs and increase our expenditures. Our future capital requirements, both near and long term, will depend on many factors, including:

 

   

the scope, progress, results and costs of laboratory testing, manufacturing and clinical development for our most advanced investigational gene therapy, GT005;

 

   

the scope, progress, results and costs of laboratory testing, manufacturing, preclinical and clinical development of our current preclinical assets, GT011 and our bicistronic gene therapy program, and any future investigational gene therapies;

 

   

the extent to which we acquire or in-license other product candidates and technologies;

 

   

the number of potential new investigational gene therapies we may identify and decide to develop;

 

   

successful development of companion diagnostics, if required or desired, for use with our investigational gene therapies;

 

   

the costs of ongoing development, manufacture, regulatory approval and commercialization of Orbit SDS or other medical device products we may develop;

 

   

our ability to establish and maintain collaborations and license agreements on favorable terms, if at all;

 

   

the costs, timing and outcome of potential future commercialization activities, including manufacturing, marketing, sales and distribution for our investigational gene therapies, for which we receive marketing approval;

 

   

the impact of COVID-19 on the initiation or completion of preclinical studies or clinical trials and the supply of our investigational gene therapies;

 

   

the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims;

 

   

the sales price and availability of adequate third-party coverage and reimbursement for our investigational gene therapies, if and when approved; and

 

   

the costs of operating as a public company.

 

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Developing investigational gene therapies and conducting preclinical studies and clinical trials is a time-consuming, expensive and uncertain process that takes years to complete, and we may never generate the necessary data or results required to obtain marketing approval and achieve product sales. In addition, our investigational gene therapies, if approved, may not achieve commercial success. Our product revenues, if any, will primarily be derived from or based on sales of investigational gene therapies that may not be commercially available for many years, if at all. Accordingly, we will need to continue to rely on additional financing to achieve our business objectives. Adequate additional financing may not be available to us on acceptable terms, if at all. Furthermore, any additional capital-raising efforts may divert our management from their day-to-day activities, which may adversely affect our ability to develop and commercialize our current and future investigational gene therapies, if approved.

If we are unable to obtain adequate funding on a timely basis, we may be required to significantly curtail, delay or discontinue our research and development programs of our investigational gene therapies or any commercialization efforts, be unable to expand our operations or be unable to otherwise capitalize on our business opportunities, any of which could harm our business and potentially cause us to discontinue operations.

We are heavily dependent on the success of our lead investigational gene therapy, GT005.

We currently have no gene therapies that are approved for commercial use and may never be able to develop marketable gene therapies or other products. We expect that a substantial portion of our efforts and expenditures for the foreseeable future will be devoted to GT005. Accordingly, our business currently depends heavily on the successful clinical development, regulatory approval and commercialization of GT005. We cannot be certain that GT005 will receive regulatory approval or be successfully commercialized even if we receive regulatory approval. If we were required to discontinue development of GT005, or if GT005 does not receive regulatory approval, fails to achieve significant market acceptance, or fails to receive reimbursement at all or at sufficient levels, we would be delayed by many years in our ability to achieve profitability, if ever, and may not be able to generate sufficient revenue to continue our business.

Our limited operating history may make it difficult for you to evaluate the success of our business to date and to assess our future viability.

Since our inception in 2016, we have devoted substantially all of our resources to developing GT005, identifying and developing other investigational gene therapies, developing and obtaining regulatory clearances for the Orbit SDS, developing our manufacturing platform, building our intellectual property portfolio and providing general and administrative support for these operations. Our most advanced investigational gene therapy, GT005, is being evaluated in our two ongoing Phase II clinical trials and an ongoing Phase I/II clinical trial. We have not yet demonstrated our ability to successfully complete Phase II or Phase III clinical trials or other pivotal clinical trials, obtain regulatory approvals, manufacture a product at scale sufficient to meet potential target populations or arrange for a third party to do so on our behalf or conduct sales and marketing activities necessary for successful product commercialization. We will need to eventually transition from a company with a research and development focus to a company capable of undertaking commercial activities. In addition, given our limited operating history, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors in achieving our business objectives.

Additionally, we expect our financial condition and operating results to continue to fluctuate significantly from quarter to quarter and year to year due to a variety of factors, many of which are beyond our control, such as delays and disruptions at clinical sites due to COVID-19. Consequently, any predictions you make about our future success or viability may not be as accurate as they could be if we had a longer operating history or more experience developing investigational gene therapies.

 

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In preparation of this offering, we identified material weaknesses in our internal control over financial reporting. If we are unable to successfully remediate the existing material weaknesses in our internal control over financial reporting, the accuracy and timing of our financial reporting may be adversely affected.

Although we are not yet subject to the certification or attestation requirements of Section 404, in the course of reviewing our financial statements in preparation for this offering, management identified deficiencies that we concluded represented material weaknesses in our internal control over financial reporting attributable to our lack of formal processes and procedures and our lack of maintaining a sufficient complement of accounting and finance personnel commensurate with our accounting and reporting requirements. SEC guidance regarding management’s report on internal control over financial reporting defines a material weakness as a deficiency or combination of deficiencies in internal control over financial reporting, such that there is a reasonable possibility that a material misstatement of our annual or interim financial statements will not be prevented or detected and corrected on a timely basis.

During the fiscal year ended December 31, 2020, we commenced measures to remediate the material weaknesses by expanding the capacity and expertise of our internal accounting and finance staff and implementing a formalized control framework, which remediation measures are ongoing. There can be no assurance that we will be successful in pursuing these measures or that these measures will significantly improve or remediate the material weaknesses described above. There is also no assurance that we have identified all of our material weaknesses or that we will not in the future have additional material weaknesses. If we fail to remediate the material weaknesses or to meet the demands that will be placed upon us as a public company, including the requirements of the Sarbanes-Oxley Act, we may be unable to accurately report our financial results, or report them within the time frames required by law. Failure to comply with Section 404 could also potentially subject us to sanctions or investigations by the SEC or other regulatory authorities. There is no assurance that we will be able to remediate the material weaknesses in a timely manner, or at all, or that in the future, additional material weaknesses will not exist or otherwise be discovered. If our efforts to remediate the material weaknesses identified are not successful, or if other material weaknesses or other deficiencies occur, our ability to accurately and timely report our financial position could be impaired, which could result in late filings of our required reports under the Exchange Act, restatements of our consolidated financial statements, a decline in the price of our ADSs, suspension or delisting of our ADSs from the Nasdaq Stock Market LLC, or Nasdaq, and could adversely affect our reputation, results of operations and financial condition. Accordingly, material weaknesses may still exist when we report on the effectiveness of our internal control over financial reporting for purposes of our attestation when required by reporting requirements under the Exchange Act or Section 404 after this offering.

Risks Related to the Discovery, Development and Regulatory Approval of our Investigational Gene Therapies

There are no approved therapies that act by increasing production of CFI and few approved therapies that act by targeting the complement system. As a result of our novel approach, we may face increased difficulty in successfully developing and commercializing GT005 or other product candidates.

GT005, our lead investigational gene therapy, is designed to restore balance to an overactive complement system by increasing production of CFI, a regulatory protein of the complement system. There are no approved therapies that act by increasing production of CFI and only a few approved therapies that act by inhibiting the complement system, none of which are treatments for AMD. We have not yet demonstrated efficacy and safety for GT005 or any other investigational gene therapy in a pivotal trial or obtained marketing approval of any investigational gene therapy. We have evaluated GT005 in preclinical studies and in our ongoing clinical trials, including an ongoing Phase I/II clinical trial and two additional ongoing Phase II clinical trials, but we have not yet advanced GT005 into Phase III clinical development or obtained regulatory approval to market any gene therapy based on our therapeutic approaches. As a result, GT005 may not demonstrate in patients any or all of the clinical benefits we believe it may possess, and the regulatory approval process for novel investigational gene therapies such as ours can be more expensive, less predictable and longer than for other, better known or extensively studied therapeutic approaches or biopharmaceutical or other product candidates.

 

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In addition, there are currently no approved treatments for dry AMD or GA. As a result, the design and conduct of clinical trials for these diseases and other indications we may pursue will be subject to increased risk and uncertainty. If we are unsuccessful in our development and commercialization efforts of GT005, we may not be able to advance any of our investigational gene therapies, raise additional capital, expand our business or continue our operations.

Our investigational gene therapies are based on a novel technology, which makes it difficult to predict the timing and costs of development and of subsequently obtaining regulatory approval. Very few recombinant adeno-associated virus-based, or rAAV, in vivo gene therapy products have been approved by the FDA, EMA or MHRA to date.

We have concentrated our research and development efforts on GT005, our most advanced investigational gene therapy, for the treatment of AMD.

Because we are developing this investigational gene therapy for which there is little clinical trial experience, there is an increased risk that the FDA, EMA, MHRA or other regulatory authorities may not consider the endpoints of our clinical trials to be sufficient for marketing approval. The product specifications and the clinical trial requirements of the FDA, EMA, MHRA or other regulatory authorities and the criteria these regulators use to determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of such product candidate. The regulatory approval process for novel product candidates such as ours is unclear and may be lengthier and more expensive than the process for other, better-known or more extensively studied product candidates. For example, the FDA generally requires multiple well-controlled clinical trials to provide the evidence of effectiveness necessary to support a BLA, although FDA guidance provides that reliance on a single pivotal trial may be appropriate if the trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potential serious outcome, and where confirmation of the result in a second trial would be practically or ethically impossible.

Regulatory requirements governing gene and cell therapy products have changed frequently and may continue to change in the future. Moreover, there is substantial, and sometimes uncoordinated, overlap in those responsible for regulation of existing gene therapy products and cell therapy products. The FDA has established the Office of Tissues and Advanced Therapies, or OTAT, within its Center for Biologics Evaluation and Research, or CBER, to consolidate the review of gene therapy and related products, and has established the Cellular, Tissue and Gene Therapies Advisory Committee, or CTGTAC, a panel of medical and scientific experts and consumer representatives, to advise CBER in its review. Gene therapy clinical trials conducted at institutions that receive funding for recombinant DNA research from the National Institutes of Health, or the NIH, are also subject to review by the Novel and Exceptional Technology and Research Advisory Committee, or NExTRAC, formerly known as the NIH Office of Biotechnology Activities’ Recombinant DNA Advisory Committee, or the RAC. Clinical gene therapy clinical trials involving recombinant DNA are also subject to review and oversight by an institutional biosafety committee, or IBC, a local institutional committee that reviews and oversees basic and clinical research conducted at the institution participating in the clinical trial. In addition, the FDA, EMA and the NIH have each expressed interest in further regulating biotechnology, including gene therapy and genetic testing. For example, the EMA advocates a risk-based approach to the development of a gene therapy product. Agencies at both the federal and state level in the United States, as well as U.S. congressional committees and other governments and governing agencies, have also expressed interest in further regulating the biotechnology industry. Although the FDA decides whether individual gene therapy protocols may proceed, the review processes and determinations of other reviewing bodies can impede or delay the initiation of a clinical study, even if the FDA has reviewed the study and approved its initiation. Conversely, the FDA can place an IND application on clinical hold even if such other entities have provided a favorable review. Such action may delay or prevent further development and commercialization of some or all of our investigational gene therapies.

Complex regulatory environments exist in other jurisdictions in which we might consider seeking regulatory approvals for our investigational gene therapies, further complicating the regulatory landscape. For example, in

 

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the European Union, a special committee called the Committee for Advanced Therapies was established within the EMA in accordance with Regulation (EC) No 1394/2007 on advanced-therapy medicinal products to assess the quality, safety and efficacy of advanced-therapy medicinal products, and to follow scientific developments in the field. Advanced-therapy medicinal products include gene therapy products as well as somatic cell therapy products and tissue engineered products.

These regulatory review committees and advisory groups, and the new guidelines they promulgate, may lengthen the regulatory review process, require us to perform additional preclinical studies or clinical trials, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our current or future investigational gene therapies or lead to significant post-approval limitations or restrictions. As we advance our investigational gene therapies, we will be required to consult with these regulatory and advisory groups and comply with applicable guidelines. If we fail to do so, we may be required to delay or discontinue development of our investigational gene therapies. These additional processes may result in a review and approval process that is longer than we otherwise would have expected. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product to market could decrease our ability to generate sufficient product revenue, and our business, financial condition, results of operations and prospects would be harmed. Even if our investigational gene therapies are approved, we expect that the FDA, EMA and MHRA will require us to submit follow-up data regarding our clinical trial participants for a number of years after approval. If this follow-up data show negative long-term safety or efficacy outcomes for these patients, the regulatory authority may revoke its approval or change the label of our products in a manner that could have an adverse impact on our business.

In addition, adverse developments in clinical trials of gene therapy products conducted by others may cause the FDA, EMA, MHRA or other regulatory authorities to change the requirements for approval of our investigational gene therapies. Similarly, the FDA, EMA, MHRA or other regulatory authorities may issue new guidelines concerning the development and marketing authorization for gene therapy products and require that we comply with these new guidelines. Although numerous companies are currently advancing gene therapy products through clinical trials, to our knowledge, only a few rAAV gene therapy products have received marketing authorization from the FDA, EMA, MHRA or other regulatory authorities to date.

As a result of these factors, it is difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for GT005 in either the United States, the European Union or the United Kingdom or how long it will take to commercialize our other investigational gene therapies. Additionally, approvals by the EMA or MHRA may not be indicative of what the FDA may require for approval, and vice versa.

All of our investigational gene therapies are in preclinical or clinical development. Clinical trials are difficult to design and implement, and they involve a lengthy and expensive process with uncertain outcomes. We may encounter substantial delays in completing, or ultimately be unable to complete, the development of our current and future investigational gene therapies.

Before obtaining marketing approval from regulatory authorities for the sale of our investigational gene therapies, we must conduct extensive clinical trials to demonstrate the safety and efficacy of the investigational gene therapies. Clinical testing is expensive, time-consuming and uncertain as to outcome. To date, we have not completed any clinical trials required for the approval of any of our investigational gene therapies. We expect to report further data from our Phase I/II FOCUS clinical trial of GT005 for AMD in 2021, final data from FOCUS in 2022 and topline results from our ongoing Phase II clinical trials of GT005 for AMD in the first half of 2023. We expect to commence a pivotal program following completion of these trials, subject to agreement with regulatory authorities. We cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, if at all. For example, in November 2019, the FDA placed a clinical hold on our EXPLORE trial of GT005 pending submission of additional Chemistry, Manufacturing and Controls information, or CMC, data pertaining to testing and product administration. The clinical hold was subsequently removed in February 2020 following review of this information. A failure of one or more clinical trials can occur at any stage of testing and

 

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failure may result from a multitude of factors, including, among other things, flaws in study design, dose selection issues, placebo effects, patient enrollment criteria and failure to demonstrate favorable safety or efficacy traits. In addition, our drug development programs may contemplate the development of companion diagnostics, which are assays or tests to identify an appropriate patient population. Companion diagnostics are subject to regulation as medical devices and must themselves be cleared or approved for marketing by the FDA or certain other foreign regulatory agencies before we may commercialize our investigational gene therapies. Events that may prevent successful or timely completion of clinical development include:

 

   

delays in reaching a consensus with the FDA, MHRA, EMA or other regulatory authorities on trial design and application approval;

 

   

delays in reaching agreement on acceptable terms with prospective contract research organizations, or CROs, and clinical trial sites;

 

   

delays in opening clinical trial sites or obtaining required institutional review board or independent ethics committee approval at each clinical trial site;

 

   

delays related to approval of the use of genetically modified organisms, or GMO, applications with regulatory authorities;

 

   

delays in finding and recruiting suitable patients to participate in our ongoing and future clinical trials;

 

   

additional delays to clinical trials or to the supply of our or our collaborators’ candidates due to COVID-19;

 

   

successful development of companion diagnostics, if necessary or desired, for use with our investigational gene therapies;

 

   

imposition of a clinical hold by regulatory authorities as a result of a serious adverse event or after an inspection of our clinical trial operations or clinical trial sites;

 

   

failure by us, any CROs we engage or any other third parties to adhere to clinical trial requirements;

 

   

failure to perform in accordance with good clinical practice, or GCP, or applicable regulatory guidelines in Europe and other international markets;

 

   

delays in the manufacture, testing, release and delivery of our investigational gene therapies to the clinical trial sites, including delays by third parties who have been contracted by us to perform some or all of these functions;

 

   

delays in having patients complete participation in a clinical trial or return for post-treatment follow-up;

 

   

clinical trial sites discontinuing participation in or patients dropping out of a clinical trial;

 

   

selection of clinical endpoints that require prolonged periods of clinical observation or analysis of the resulting data;

 

   

retention of control group patients in our ongoing and planned clinical trials;

 

   

occurrence of serious adverse events associated with the product candidate that are viewed to outweigh its potential benefits;

 

   

occurrence of serious adverse events in clinical trials of the same class of agents or different classes of agents with the same target conducted by other sponsors;

 

   

changes in regulatory requirements and guidance that require amending or submitting new clinical protocols; and

 

   

business interruptions resulting from geopolitical actions, including war and terrorism, global pandemics or natural disasters, including earthquakes, typhoons, floods and fires.

 

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We anticipate expanding our ongoing and future clinical trials to new trial sites as we continue to enroll patients in our ongoing trials and commence future trials. However, there can be no assurance that we will successfully open new clinical trial sites and obtain any required approvals for such trial sites on a timely basis, or at all. Any failure to successfully open new clinical trial sites on a timely basis could delay or prevent the successful completion of our clinical trials. Any inability to successfully complete preclinical and clinical development could result in additional costs to us or impair our ability to generate revenues from product sales, regulatory and commercialization milestones and royalties. In addition, if we make manufacturing or formulation changes to our investigational gene therapies, we may need to conduct additional studies to confirm comparability between our modified investigational gene therapies to previous versions. Clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our investigational gene therapies or allow our competitors to bring products to market before we do, which could impair our ability to successfully commercialize our investigational gene therapies and may harm our business, financial condition, results of operations and prospects.

The COVID-19 pandemic has adversely impacted, and may continue to adversely impact, our business, including our planned clinical trials and ongoing and planned preclinical studies.

In December 2019, COVID-19 was reported to have surfaced in Wuhan, China. Since then, the virus has spread to most countries across the world, including Europe, the United Kingdom and all 50 states within the United States, resulting in the World Health Organization characterizing COVID-19 as a pandemic. As a result of measures imposed by the governments in affected regions, many commercial activities, businesses, schools and elective medical procedures have been suspended as part of quarantines and other measures intended to contain this pandemic. As the COVID-19 pandemic continues to spread around the globe, we have experienced or may experience disruptions that could severely impact our business and clinical trials, including:

 

   

delays or difficulties in clinical site initiation, including difficulties in recruiting clinical site investigators and clinical site staff;

 

   

delays or difficulties in enrolling and retaining patients in any clinical trials, particularly for the aging patient population in our clinical trials for our investigational gene therapies to treat GA, who are at a higher risk of severe illness or death from COVID-19;

 

   

delays in enrolling patients in clinical trials if and when alternative treatment options become available

 

   

difficulties interpreting data from our clinical trials due to the possible effects of COVID-19 on patients or the differences in the timing of patient sampling due to COVID-19 related delays;

 

   

reduced capacity at clinical sites for patients due to requirements for social distancing and the use of personal protective equipment;

 

   

diversion of healthcare resources away from the conduct of clinical trials, including the diversion of hospitals serving as our clinical trial sites and hospital staff supporting the conduct of clinical trials;

 

   

interruption of key clinical trial activities, such as clinical trial site monitoring, due to limitations on travel imposed or recommended by federal or state governments, employers and others;

 

   

interruption or delays in the operations of the FDA, EMA, MHRA or other regulatory authorities, which may impact review and approval timelines;

 

   

limitations in resources that would otherwise be focused on the conduct of our business, our preclinical studies or our clinical trials, including because of sickness or the desire to avoid contact with large groups of people or as a result of government-imposed “shelter in place” or similar working restrictions;

 

   

interruptions, difficulties or delays arising in our existing operations and company culture as a result of all of our employees working remotely, including those hired during the COVID-19 pandemic;

 

   

delays in receiving approval from regulatory authorities to initiate our clinical trials;

 

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delays in clinical sites receiving the supplies and materials needed to conduct our clinical trials from third parties, including due to any interruptions, difficulties or delays arising as a result of their employees working remotely;

 

   

interruptions in preclinical and clinical studies due to restricted or limited operations at the CROs conducting such studies;

 

   

interruption in global freight and shipping that may affect the transport of clinical trial materials, such as investigational drug product or medical devices to be used in our clinical trials;

 

   

changes in regulations as part of a response to the COVID-19 pandemic which may require us to change the ways in which our clinical trials are to be conducted, to discontinue the clinical trials altogether or which may result in unexpected costs;

 

   

delays in testing, development and manufacturing of our investigational gene therapies due to the potential increased restricted capacity of our third-party service providers after the widespread distribution of a efficacious vaccine or other treatment for COVID-19;

 

   

delays in necessary interactions with regulators, ethics committees and other important agencies and contractors due to limitations in employee resources or forced furlough of government or contractor personnel; and

 

   

refusal of the FDA, EMA, MHRA or other regulatory authorities to accept data from clinical trials in affected geographies outside of their respective jurisdictions.

We are still assessing the impact that the COVID-19 pandemic has had and may continue to have on our ability to effectively conduct our business operations as planned, and there can be no assurance that we will be able to avoid a material impact on our business from the spread of COVID-19 or its consequences, including disruption to our business and downturns in business sentiment generally or in our industry or due to shutdowns that may be requested or mandated by federal, state and local governmental authorities. As a result of the COVID-19 pandemic, many of our employees are currently telecommuting, which may impact certain of our operations over the near term and long term.

Additionally, certain third parties with whom we engage or may engage, including collaborators, contract organizations, third-party manufacturers, suppliers, clinical trial sites and regulators, are similarly adjusting their operations and assessing their capacity in light of the COVID-19 pandemic. If these third parties experience shutdowns or continued business disruptions, our ability to conduct our business in the manner and on the timelines presently planned could be materially and negatively impacted. For example, as a result of the COVID-19 pandemic, there could be delays in the procurement of materials or manufacturing supply chain for one or more of our investigational gene therapies, which could delay or otherwise impact our preclinical studies and our planned clinical trials. We may also experience delays in the testing, development and manufacturing of our investigational gene therapies as a result of the recent U.S. government-mandated prioritization of COVID-19 vaccine development and production orders related to Operation Warp Speed, which may restrict the capacity of our third-party service providers. Additionally, all of our preclinical studies are conducted by CROs, which could be discontinued or delayed as a result of the pandemic. It is also likely that the disproportionate impact of COVID-19 on hospitals and clinical sites will have an impact on recruitment and retention for our planned clinical trials. In addition, certain clinical trial sites for product candidates similar to ours have experienced, and others may experience in the future, delays in collecting, receiving and analyzing data from patients enrolled in clinical trials due to limited staff at such sites, limitation or suspension of on-site visits by patients, including for follow-up visits, or patients’ reluctance to visit the clinical trial sites during the pandemic, and we may experience similar delays for our current and future clinical trials. CROs have also made certain adjustments to the operation of such trials in an effort to ensure the monitoring and safety of patients and minimize risks to trial integrity during the pandemic in accordance with the guidance issued by the FDA, EMA, MHRA and other regulatory authorities and may need to make further adjustments in the future that could impact the timing or enrollment of our clinical trials. Many of these adjustments are new and untested, may not be

 

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effective, may increase costs, and may have unforeseen effects on the enrollment, progress and completion of these trials and the findings from these trials. While we are currently continuing our preclinical activities and progressing in our plans for clinical trials, we have experienced delays in our clinical trial enrollment and may further experience delays in the completion of our preclinical studies, the initiation of our planned clinical trials, patient selection or enrollment or in the progression of our activities related to our planned clinical trials, may need to suspend our clinical trials if and when commenced, and may encounter other negative impacts to such trials due to the effects of the COVID-19 pandemic.

We may be required to develop and implement additional clinical trial policies and procedures designed to help protect participants from COVID-19. For example, in March 2020, the FDA issued a guidance, which the FDA subsequently updated, on conducting clinical trials during the pandemic, which describes a number of considerations for sponsors of clinical trials impacted by the pandemic, including the requirement to include in the clinical trial report contingency measures implemented to manage the clinical trial and any disruption of the clinical trial as a result of the COVID-19 pandemic; a list of all participants affected by the COVID-19-pandemic related study disruption by unique subject identifier and by investigational site and a description of how the individual’s participation was altered; and analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., participant discontinuation from investigational product or study, alternative procedures used to collect critical safety or efficacy data) on the safety and efficacy results reported for the clinical trial. In June 2020, the FDA also issued a guidance on good manufacturing practice considerations for responding to COVID-19 infection in employees in drug products manufacturing, including recommendations for manufacturing controls to prevent contamination of drugs. The EMA, MHRA and other regulatory authorities have also issued similar types of COVID-19 related guidance.

The global outbreak of COVID-19 continues to rapidly evolve. During the fourth quarter of 2020, another wave of COVID-19 infections emerged. As a result, countries imposed strict lockdowns, in particular in the United States, the United Kingdom and Europe. Vaccines for COVID-19 were also approved in the United States, the United Kingdom and certain other countries in the fourth quarter of 2020. While the COVID-19 pandemic has adversely affected our business in the past, the extent of the impact of the pandemic or timing, availability and effectiveness of a vaccine for COVID-19 on our business and financial results remains uncertain. A continued and prolonged pandemic or public health crisis, such as the COVID-19 pandemic, may continue to adversely affect our business, and any future health pandemics, epidemics or outbreaks could have a material negative impact on our business, financial condition and operating results.

To the extent the COVID-19 pandemic continues to adversely affect our business, financial condition and operating results, it may also have the effect of heightening many of the risks described in this “Risk Factors” section.

We may fail to demonstrate safety and efficacy of our investigational gene therapies to the satisfaction of applicable regulatory authorities.

Before obtaining marketing approval from regulatory authorities for the sale of any investigational gene therapies, including GT005, we may identify and develop, we must complete preclinical development and then conduct extensive clinical trials to demonstrate the safety and efficacy in humans of any such investigational gene therapies. Clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome. A failure of one or more clinical trials can occur at any stage of testing. The outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial, such as the interim results for our ongoing open-label Phase I/II FOCUS clinical trial for GT005, do not necessarily predict final results. Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses. Many companies that have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their product candidates. The clinical trial process may fail to ultimately demonstrate that GT005 is safe for humans and effective for indicated uses. This failure would cause us to abandon further clinical development of GT005, which is our lead investigational gene therapy.

 

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If the results of our ongoing or future clinical trials for GT005 or other investigational gene therapies do not demonstrate the efficacy of our investigational gene therapies, or if there are safety concerns or serious adverse events associated with our investigational gene therapies, we may:

 

   

be delayed in obtaining marketing approval for our investigational gene therapies and clearance or approval for any companion diagnostics from applicable regulatory authorities, if at all;

 

   

obtain approval for indications or patient populations that are not as originally intended or desired;

 

   

obtain approval with labeling that includes significant use or distribution restrictions, safety warnings or contraindications;

 

   

be subject to additional post-marketing requirements;

 

   

be subject to changes in the way the product is handled or administered;

 

   

be required to perform additional clinical trials to support approval, which may be time-consuming or costly, or be subject to additional post-marketing testing requirements;

 

   

have regulatory authorities suspend or revoke their approval of the product or impose restrictions on its distribution in the form of a risk evaluation and mitigation strategy, or REMS, or a risk management plan, or RMP;

 

   

be sued; or

 

   

experience damage to our reputation.

Our development costs will increase if we experience delays in testing or marketing approvals. We do not know whether any of our preclinical studies or clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all. Significant preclinical study or clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our investigational gene therapies or allow our competitors to bring products to market before we do and impair our ability to successfully commercialize our investigational gene therapies.

Gene therapies are novel, complex and difficult to manufacture. We have a limited manufacturing history and could experience production problems that result in delays in our development or commercialization programs or otherwise adversely affect our business.

Our investigational gene therapies require processing steps that are more complex than those required for most chemical pharmaceuticals. Moreover, unlike chemical pharmaceuticals, the physical and chemical properties of a biologic such as our modified virus generally cannot be fully characterized. As a result, assays of the finished product may not be sufficient to ensure that the product will perform in the intended manner. Accordingly, we employ multiple assurance steps to control our manufacturing process to produce our investigational gene therapies strictly and consistently in compliance with cGMP and other regulatory requirements. Problems with the manufacturing process, including even minor deviations from the normal process, could result in product defects or manufacturing failures that result in lot failures, product recalls, product liability claims or insufficient inventory. We may encounter problems achieving adequate quantities and quality of clinical-grade materials that meet FDA, MHRA, EMA or other applicable standards or specifications with consistent and acceptable production yields and costs.

In addition, the FDA, EMA, MHRA and other regulatory authorities may require us to submit samples of any lot of any approved product together with the protocols showing the results of applicable tests at any time. Under some circumstances, the FDA, EMA, MHRA and other regulatory authorities may require that we not distribute a lot until the agency authorizes its release. Slight deviations in the manufacturing process, including those affecting quality attributes and stability, may result in unacceptable changes in the product that could result in lot failures or product recalls. Lot failures or product recalls could cause us to delay product launches or clinical trials, which could be costly to us and otherwise harm our business, financial condition, results of operations and prospects.

 

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We have a limited history of manufacturing our investigational gene therapies, including GT005. To date, we have manufactured GT005 for our clinical program through an adherent platform, and we currently plan to utilize a suspension platform to meet the potential demand of a Phase III pivotal program and commercialization. As we transition to suspension manufacturing, we will be required to demonstrate the comparability between our adherent and suspension manufacturing processes to regulatory authorities, and we may not be successful in doing so. The manufacturing processes we use to produce GT005 are complex, and there are no assurances that we will be able to produce sufficient quantities of GT005, or any other investigational gene therapies we may seek to develop, due to several factors, including equipment malfunctions, facility contamination, raw material shortages or contamination, natural disasters, disruption in utility services, human error, COVID-19 or disruptions in the operations of our suppliers. In addition, if we experience a batch failure of our current supplies of our investigational gene therapies, including GT005, we may have insufficient inventory for our ongoing and planned preclinical and clinical studies, which may potentially delay progression of our preclinical or clinical development of any investigational gene therapies we may develop.

In addition, the large-scale manufacture of gene therapies is largely untested. We are currently evaluating GT005 in our ongoing HORIZON Phase II clinical trial for a broad GA population, and if approved for this indication and other indications in the future, may require large-scale manufacturing to produce adequate quantities for the intended patient population. While we designed GT005 to be a therapy targeted specifically to the eye, instead of a systemic therapy, if we are unable to scale our manufacturing and maintain the manufacturing process at acceptable levels of quality and efficacy, we may not be able to supply the required number of doses for clinical trials or commercial supply, and our business could be harmed.

Although we plan to build and operate our own manufacturing facility in the medium-to-long term, we plan to continue to use one or more qualified contract manufacturing organizations, or CMOs, for the supply of product for our clinical trials and commercial supply, and one or more qualified CROs for product release assays. As a result, the supply of product for our clinical trials and commercial supply is reliant upon the performance of these outsourced organizations. See “—Risks Related to Our Reliance on Third Parties—We currently utilize, and expect to continue to utilize, third parties to conduct our product manufacturing, and these third parties may not perform satisfactorily.” Any failure to produce commercial materials or meet demand to support a commercial launch of our investigational gene therapies could delay or prevent the development of our investigational gene therapies and would have a negative impact on our business, financial condition and results of operations.

Success in preclinical studies or clinical trials may not be indicative of results in future clinical trials.

Success in preclinical testing and early clinical trials does not ensure that later clinical trials will generate the same results or otherwise provide adequate data to demonstrate the efficacy and safety of a product candidate. Frequently, product candidates that have shown promising results in early clinical trials have subsequently suffered significant setbacks in later clinical trials. To date, our clinical trials have involved small patient populations and because of the small sample size, the interim results of these clinical trials may be subject to substantial variability and may not be indicative of either future interim or final results. In addition, the design of a clinical trial can determine whether its results will support approval of a product and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced. There is a high failure rate for drugs and biological products proceeding through clinical trials. Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials even after achieving promising results in preclinical testing and earlier-stage clinical trials. Data obtained from preclinical and clinical activities are subject to varying interpretations, which may delay, limit or prevent regulatory approval. In addition, we may experience regulatory delays or rejections as a result of many factors, including due to changes in regulatory policy during the period of our investigational gene therapy development. Any such delays could negatively impact our business, financial condition, results of operations and prospects.

Additionally, one of our trials is an open-label study, where both the patient and investigator know whether the patient is receiving the investigational product candidate or either an existing approved drug or placebo, and

 

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none of our ongoing clinical trials are patient-masked. Most typically, open-label clinical trials test only the investigational product candidate and sometimes do so at different dose levels. Open-label clinical trials are subject to various limitations that may exaggerate any therapeutic effect as patients in open-label clinical trials are aware when they are receiving treatment. Similarly, because our clinical trials involve surgical delivery, there is no sham procedure given to control arm patients and, accordingly, patients are not masked as to their control status. In addition, open-label clinical trials may be subject to an “investigator bias” where those assessing and reviewing the physiological outcomes of the clinical trials are aware of which patients have received treatment and may interpret the information of the treated group more favorably given this knowledge. Therefore, it is possible that positive results observed in open-label trials, such as those we have conducted, will not be replicated in later assessor-masked trials, and it will be possible in all of our clinical trials that the results are impacted by the patients’ awareness of their randomization to the control or treatment arms.

Interim, “topline,” and preliminary data from our clinical trials that we announce or publish from time to time may change as more patient data become available and are subject to confirmation, audit and verification procedures that could result in material changes in the final data.

From time to time, we may publicly disclose interim or topline data from our preclinical studies and clinical trials, which is based on a preliminary analyses of then-available data, and the results and related findings and conclusions are subject to change following a more comprehensive review of the data related to the particular study or trial. We also make assumptions, estimations, calculations and conclusions as part of our analyses of data, and we may not have received or had the opportunity to fully and carefully evaluate all data. As a result, the topline or preliminary results that we report may differ from future results of the same studies, or different conclusions or considerations may qualify such results, once additional data have been received and fully evaluated. Topline data also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data we previously published. As a result, topline data should be viewed with caution until the final data are available. From time to time, we may also disclose interim data from our clinical trials. Interim or preliminary data from clinical trials are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment and treatment continues and more patient data become available or as patients from our clinical trials continue other treatments for their disease. Adverse differences between preliminary or interim data and final data could significantly harm our business prospects. Further, disclosure of interim data by us or by our competitors could result in volatility in the price of our ordinary shares after this offering.

Further, others, including regulatory agencies, may not accept or agree with our assumptions, estimates, calculations, conclusions or analyses or may interpret or weigh the importance of data differently, which could impact the potential of the particular program, the likelihood of marketing approval or commercialization of the particular product candidate, any approved product, and our company in general. In addition, the information we choose to publicly disclose regarding a particular study or clinical trial is derived from information that is typically extensive, and you or others may not agree with what we determine is material or otherwise appropriate information to include in our disclosure.

If the interim, topline, or preliminary data that we report differ from actual results, or if others, including regulatory authorities, disagree with the conclusions reached, our ability to obtain approval for, and commercialize, our product candidates may be harmed, which could harm our business, operating results, prospects or financial condition.

We may find it difficult to enroll patients in our clinical trials, which could delay or prevent us from proceeding with clinical trials of our investigational gene therapies.

Identifying and qualifying patients to participate in clinical trials of our investigational gene therapies is critical to our success. The timing of our clinical trials depends on our ability to recruit patients to participate, as well as completion of required follow-up periods. If patients are unwilling to enroll in our gene therapy clinical

 

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trials because of the COVID-19 pandemic and related restrictions on travel or healthcare institution policies, negative publicity from adverse events related to the biotechnology or gene therapy fields, competitive clinical trials for similar patient populations or for other reasons, the timeline for recruiting patients, conducting studies and obtaining regulatory approval of our investigational gene therapies may be delayed. These delays could result in increased costs, delays in advancing our investigational gene therapies, delays in testing the effectiveness of our investigational gene therapies or termination of clinical trials altogether.

Patient enrollment can be affected by many factors, including:

 

   

size of the patient population and process for identifying patients;

 

   

eligibility and exclusion criteria for our clinical trials;

 

   

competing studies or trials with similar eligibility criteria;

 

   

the use of surgical delivery in our clinical trials rather than IVT procedures;

 

   

perceived risks and benefits of our investigational gene therapies or gene therapy treatment in general;

 

   

severity of the disease under investigation;

 

   

the standard of care in the diseases under investigation, and potential new developments in the treatment landscape during our clinical trials;

 

   

perceived frequency and severity of the potential or demonstrated adverse events in our clinical trials;

 

   

the impacts of the COVID-19 pandemic;

 

   

proximity and availability of clinical trial sites for prospective patients;

 

   

ability to obtain and maintain patient consent;

 

   

efforts to facilitate timely enrollment;

 

   

patient dropouts prior to completion of clinical trials;

 

   

the age characteristics of our target study populations;

 

   

patient referral practices of physicians; and

 

   

ability to monitor patients adequately during and after treatment.

Importantly, we are exploring GT005 in both a broad population of patients with GA secondary to AMD and a population of GA patients with a rare variant genotype. We may experience difficultly enrolling patients in our clinical trials, as there are currently no approved treatments for dry AMD or GA, and patients may not seek treatment for these conditions. In particular, because the incidence of patient subpopulations with a particular genotype may be small, such as the CFI rare variant genotype, it can be challenging to identify and recruit these patients into our clinical trials, including EXPLORE. While we are conducting our genotyping initiatives and SCOPE natural history study, in part, to assist us in identifying and enrolling these patients, we may nevertheless experience challenges with identification and enrollment of patients.

We are conducting certain of our clinical trials in foreign countries and our ability to successfully initiate, enroll and complete clinical trials in any foreign country is subject to numerous risks unique to conducting business in foreign countries, including:

 

   

difficulty in establishing or managing relationships with CROs and physicians;

 

   

different standards for the conduct of clinical trials;

 

   

absence in some countries of established groups with sufficient regulatory expertise for review of gene therapy protocols;

 

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inability to locate qualified local consultants, physicians and partners; and

 

   

the potential burden of complying with a variety of foreign laws, medical standards and regulatory requirements, including the regulation of pharmaceutical and biotechnology products and treatment.

If we have difficulty enrolling a sufficient number of patients or finding additional clinical trial sites to conduct our clinical trials as planned, we may need to delay, limit or terminate ongoing or planned clinical trials, any of which could have an adverse effect on our business, financial condition, results of operations and prospects. In addition, it is possible that the COVID-19 pandemic may have an impact on the workforce of the third parties and CROs on which we rely, which could adversely impact our ability to conduct preclinical studies and clinical trials of our investigational gene therapies on expected timeframes or to complete such studies and trials.

Our ability to receive regulatory approval from the FDA in the United States may be impacted by the fact that some of the clinical trials for our investigational gene therapies conducted to date are being conducted in part in the United Kingdom and other foreign jurisdictions, and the FDA may not accept data from trials conducted in such locations.

To date, some of the clinical trials conducted on our investigational gene therapies are being conducted in part in the United Kingdom and other jurisdictions outside of the United States. Although the FDA may accept data from clinical trials conducted outside the United States and not under an IND in place with the FDA, acceptance of such data is subject to conditions imposed by the FDA. For example, the clinical trial must be well-designed and conducted and performed by qualified investigators in accordance with ethical principles. The trial population must also adequately represent the U.S. population, and the data must be applicable to the U.S. population and U.S. medical practice in ways that the FDA deems clinically meaningful. In addition, while these clinical trials are subject to the applicable local laws, FDA acceptance of the data will depend on its determination that the trials also complied with all applicable U.S. laws and regulations. If the FDA does not accept the data from any trial that we conduct outside the United States, it would likely result in the need for additional trials, which would be costly and time-consuming and would delay or permanently halt our development of the applicable investigational gene therapies.

In addition, in order to commence a clinical trial in the United States, we are required to seek FDA acceptance of an investigational new drug, or IND, for each of our investigational gene therapies. While we have two active INDs for our lead product, GT005 for the treatment of GA secondary to AMD, we cannot provide assurance that any future IND we submit to the FDA, or any similar clinical trial approvals we submit in other countries, will be accepted. Additionally, delays in submitting an IND may occur as a result of the COVID-19 pandemic, including as a result of the impact of the COVID-19 pandemic on preclinical testing and clinical trial sites. We may also be required to conduct additional preclinical testing prior to submitting an IND for any of our investigational gene therapies, and the results of any such testing may not be positive. Consequently, we may be unable to successfully and efficiently execute and complete necessary clinical trials in a way that leads to a BLA submission and approval of our investigational gene therapies. We may require more time and incur greater costs than our competitors and may not succeed in obtaining regulatory approvals of investigational gene therapies that we develop. Failure to commence or complete, or delays in, our planned clinical trials, could prevent us from or delay us in commercializing our investigational gene therapies.

Our investigational gene therapies and the process for administering our investigational gene therapies may cause serious adverse, undesirable or unacceptable side effects or have other properties that could delay or prevent their regulatory approval, limit their commercial potential or result in significant negative consequences following any potential marketing approval.

Undesirable side effects that may be caused by our investigational gene therapies could cause us or regulatory authorities to interrupt, delay or halt clinical trials and could result in a more restrictive label or the

 

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delay or denial of regulatory approval by the FDA, EMA, MHRA or other comparable foreign regulatory authorities. During the conduct of clinical trials, patients may report changes in their health, including illnesses, injuries and discomforts, to their study doctor. Often, it is not possible to determine whether the product candidate being studied caused these conditions. Various illnesses, injuries and discomforts have been reported from time to time during clinical trials of our investigational gene therapies. Regulatory authorities may draw different conclusions or require additional testing to confirm these determinations.

In addition, it is possible that as we test our investigational gene therapies in larger, longer and more extensive clinical programs, or as use of these investigational gene therapies becomes more widespread if they receive regulatory approval, illnesses, injuries, discomforts and other adverse events that were observed in earlier trials, as well as conditions that did not occur or went undetected in previous trials, will be reported by patients. Many times, side effects are only detectable after investigational products are tested in large-scale, Phase III clinical trials or, in some cases, after they are made available to patients on a commercial scale after approval. If additional clinical experience indicates that our investigational gene therapies cause serious or life-threatening side effects, the development of our investigational gene therapies may fail or be delayed, or, if the product candidate has received regulatory approval, such approval may be suspended or revoked, which would harm our business, prospects, operating results and financial condition.

There have been several significant adverse side effects in gene therapy treatments in the past. While our investigational gene therapies are designed to be effective only in the eye in order to reduce these side effects, gene therapy is still a relatively new approach to disease treatment and adverse side effects have occurred. There also is the potential risk of delayed and longer-term adverse events following exposure to gene therapy products due to persistent biologic activity of the genetic material or other components of products used to carry the genetic material.

In the FOCUS study, as of February 3, 2021, the date of our last analysis of safety data, there were 26 ocular adverse events considered to be related to the surgical procedure; the majority were mild (mild n=23; moderate n=3). Mild adverse events occurring in more than one patient included retinal hemorrhage (5/23), conjunctival hemorrhage (3/23), cataract (2/23), keratitis (2/23) and vitreous floaters (2/23). The moderate adverse events included cataract (2/3) and sub-retinal pigment epithelium injection (1/3). Two adverse events of special interest were reported in separate patients. One was a suspected choroidal neovascularization of moderate severity, which was successfully treated with anti-VEGF therapy. The other was a sustained (i.e., over more than one study visit) reduced visual acuity over 30 letters, which was considered to be of mild severity and attributed to corneal abrasion during surgery, that has recovered to within seven letters of baseline. These adverse events may deleteriously impact safety or effectiveness. Other potential adverse events may occur in our ongoing or planned clinical trials for GT005. Any such adverse events could also occur in any clinical trials we may conduct in the future for any of future investigational gene therapies. If we are unable to mitigate or avoid one or more of the adverse effects described above or any other adverse effects, we may decide or be required to halt or delay further clinical development of our investigational gene therapies. In addition to any potential side effects caused by our investigational gene therapies themselves, the process of administering them through the related surgical procedure could also result in adverse side effects. If any such adverse events occur, our clinical trials could be suspended or terminated.

We may observe other adverse events or serious adverse events in our GT005 clinical trials, or in any other clinical trials that we may conduct in the future. If we are unable to demonstrate that such adverse events and serious adverse events have been adequately addressed or that they were caused by the administration process or related procedures, the FDA, MHRA, EMA or other regulatory authorities could order us to cease further development of, or deny approval of GT005, or any of our other future investigational gene therapies.

Even if we are able to demonstrate that any serious adverse events are not product-related or have otherwise been adequately addressed, such occurrences could affect patient recruitment or the ability of enrolled patients to complete the clinical trial. Moreover, if we elect or are required to delay, suspend or terminate any clinical trial of any of our investigational gene therapies, the commercial prospects of such product candidate may be harmed

 

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and our ability to generate product revenues from such product candidate may be delayed or eliminated. Any of these occurrences may harm our ability to develop other investigational gene therapies, and may harm our business, financial condition and prospects.

Additionally, if we or others later identify undesirable side effects caused by any of our investigational gene therapies, several potentially significant negative consequences could result, including:

 

   

our clinical trials may be put on hold;

 

   

regulatory authorities may suspend or revoke approvals of such product candidate;

 

   

regulatory authorities may require additional warnings on the label;

 

   

we may be required to change the way a product candidate is handled or administered, or conduct additional clinical trials;

 

   

we could be sued and held liable for harm caused to patients; and

 

   

our reputation may suffer.

Any of these events could prevent us from achieving or maintaining market acceptance of our investigational gene therapies.

Even if we complete the necessary preclinical studies and clinical trials, we cannot predict when or if we will obtain regulatory approval to commercialize a product candidate, or if such approval will cover the indications we seek.

We cannot commercialize a product until the appropriate regulatory authorities have reviewed and approved the product candidate. In the United States, for our investigational gene therapy products, this will require preparation and submission of a biologics license application, or BLA. Comparable applications for marketing authorization are required in other jurisdictions. Even if our investigational gene therapies demonstrate safety and efficacy in clinical studies, the regulatory agencies may not complete their review processes in a timely manner, or we may not be able to obtain regulatory approval. Additional delays may result if an FDA Advisory Committee, the MHRA Commission on Human Medicines, the EMA Committee for Medicinal Products for Human Use or some other expert advisory group for a regulatory authority recommends non-approval or restrictions on approval. In addition, we may experience delays or rejections based upon additional government regulation from future legislation or administrative action, or changes in regulatory agency policy during the period of product development, clinical studies and the review process.

We are currently evaluating our lead investigational gene therapy, GT005, in three ongoing clinical trials in patients with GA secondary to AMD: in the FOCUS Phase I/II trial, in the HORIZON Phase II trial in a broad population of patients with GA secondary to AMD and in the EXPLORE Phase II trial in patients with GA secondary to AMD who have CFI rare variants. Regulatory agencies also may approve an investigational gene therapy for fewer or more limited indications than requested or may grant approval subject to the performance of post-marketing studies. For example, we are currently evaluating GT005 through our ongoing HORIZON trial for the treatment of a broad population of patients with GA secondary to AMD; however, the resulting approval may be for a narrower indication than we seek. We may also choose to pursue approval for an indication for a different population than we are currently evaluating in our ongoing clinical trials, and we cannot assure you that we will pursue approval for all indications currently being evaluated. In addition, regulatory agencies may not approve the labeling claims that are necessary or desirable for the successful commercialization of our investigational gene therapies. If we are unable to obtain necessary regulatory approvals, our business, prospects, financial condition and results of operations may suffer.

 

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Any contamination in our manufacturing process, shortages of raw materials or failure of any of our key suppliers to deliver necessary components could result in delays in our clinical development or marketing schedules.

Given the nature of biologics manufacturing, there is a risk of contamination. Any contamination could adversely affect our ability to produce investigational gene therapies on schedule and could, therefore, harm our results of operations and cause reputational damage. Some of the raw materials required in our manufacturing process are derived from biologic sources. Such raw materials are difficult to procure and may be subject to contamination or recall. A material shortage, contamination, recall or restriction on the use of biologically derived substances in the manufacture of our investigational gene therapies, could adversely impact or disrupt the manufacture or production of clinical material and, if any of our investigational gene therapies are approved, commercial manufacturing of these approved products. Any of these factors could adversely affect our development timelines and our business, financial condition, results of operations and prospects.

We may not be successful in our efforts to identify or discover additional investigational gene therapies and may fail to capitalize on programs or investigational gene therapies that may be a greater commercial opportunity or for which there is a greater likelihood of success.

The success of our business depends upon our ability to identify, develop and commercialize a pipeline of gene therapy treatments for diseases of the eye, including AMD. Research programs to identify new investigational gene therapies require substantial technical, financial and human resources. Although certain of our investigational gene therapies are currently in clinical or preclinical development, we may fail to identify other potential investigational gene therapies for clinical development for several reasons. For example, our research may be unsuccessful in identifying additional potential investigational gene therapies, or our potential investigational gene therapies may be shown to have harmful side effects, may be commercially impracticable to manufacture or may have other characteristics that may make the products unmarketable or unlikely to receive marketing approval.

Additionally, because we have limited resources, we may forego or delay pursuit of opportunities with certain programs or investigational gene therapies or for indications that later prove to have greater commercial potential. Our spending on current and future research and development programs may not yield any commercially viable products. If we do not accurately evaluate the commercial potential for a particular product candidate, we may relinquish valuable rights to that product candidate through strategic collaboration, licensing or other arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate. Alternatively, we may allocate internal resources to a product candidate in a therapeutic area in which it would have been more advantageous to enter into a partnering arrangement.

If any of these events occur, we may be forced to abandon our development efforts with respect to a particular investigational gene therapy or fail to develop a potentially successful investigational gene therapy, which could have a negative impact on our business, financial condition, results of operations and prospects.

If we are unable to successfully identify patients who are likely to benefit from therapy with any investigational gene therapies we develop, or experience significant delays in doing so, we may not realize the full commercial potential of any medicines we may develop.

Our success may depend, in part, on our ability to identify patients who are likely to benefit from therapy with any medicines we may develop, which requires those potential patients to be tested to determine potential CFI rare variant genotypes. We have instituted genotyping initiatives, including our ongoing SCOPE natural history study, which assist in identifying potential patients for our investigational gene therapies. However, because the incidence of certain patient subpopulations with a particular genotype may be small, such as the CFI rare variant population, it can be challenging to identify and recruit these patients into our clinical trials. If we, or

 

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any third parties that we engage to assist us, are unable to successfully identify such patients, or experience delays in doing so, then:

 

   

our ability to develop any investigational gene therapies may be adversely affected if we are unable to appropriately select patients for enrollment in our clinical trials; and

 

   

we may not realize the full commercial potential of any investigational gene therapies we develop that receive marketing approval if, among other reasons, we are unable to appropriately select patients who are likely to benefit from therapy with our medicines.

Any investigational gene therapies we develop may require use of a companion diagnostic to identify patients who are likely to benefit from therapy. If safe and effective use of any of our investigational gene therapies we may develop depends on a companion diagnostic, we may not receive marketing approval, or marketing approval may be delayed, if we are unable to or are delayed in developing, identifying, or obtaining regulatory approval or clearance for the companion diagnostic product for use with our investigational gene therapy. Identifying a manufacturer of the companion diagnostic and entering into an agreement with the manufacturer could also delay the development of our investigational gene therapies. As a result of these factors, we may be unable to successfully develop and realize the commercial potential of any investigational gene therapies we may identify and develop, which would negatively impact our business, financial condition and results of operations.

Regulatory compliance for medical devices is expensive, complex and uncertain, and a failure to comply could lead to enforcement actions against us and other negative consequences for our business.

Orbit SDS and other medical devices we may develop for use with our investigational gene therapies are subject to extensive regulation by the FDA in the United States, our Notified Body in the European Union and certain other non-U.S. regulatory agencies. Complying with these regulations is costly, time-consuming, complex and uncertain. Government regulations specific to medical devices are wide-ranging and include, among other things, oversight of:

 

   

product design, development, manufacture (including suppliers) and testing;

 

   

laboratory, preclinical and clinical trials;

 

   

product safety and effectiveness;

 

   

product labeling;

 

   

product storage and shipping;

 

   

record keeping;

 

   

premarket clearance or approval;

 

   

marketing, advertising and promotion;

 

   

product sales and distribution;

 

   

product changes;

 

   

product recalls; and

 

   

post-market surveillance and reporting of deaths or serious injuries and certain malfunctions.

Before a new medical device, or a new intended use for an existing medical device, can be marketed in the United States, a company must first submit and receive either 510(k) clearance, de novo classification, or PMA approval from the FDA, unless an exemption applies. In the 510(k) clearance process, before a device may be marketed, the FDA must determine that a proposed device is substantially equivalent to a legally-marketed predicate device, which includes a device that has been previously cleared through the 510(k) process, a device

 

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that was legally marketed prior to May 28, 1976 (pre-amendments device), a device that was originally on the U.S. market pursuant to an approved PMA and later down-classified, or a 510(k)-exempt device. To be substantially equivalent, the proposed device must have the same intended use as the predicate device, and either (a) have the same technological characteristics as the predicate device or (b) have different technological characteristics, not raise different questions of safety or effectiveness than the predicate device and be demonstrated as safe and effective as the predicate device. Clinical data are sometimes required to support substantial equivalence.

In the process of obtaining PMA approval, the FDA must determine that the application provides reasonable assurance that the proposed device is safe and effective for its intended use based, in part, on extensive data, including, but not limited to, technical, preclinical, clinical trial, manufacturing and labeling data. The PMA process is typically required for devices that are deemed to pose the greatest risk, such as life-sustaining, life-supporting or implantable devices.

Both the 510(k) and PMA processes can be expensive, lengthy and unpredictable. We may not be able to obtain any necessary clearances or approval or may be unduly delayed in doing so, which will negatively affect our business, financial condition and results of operations. Furthermore, even if we are granted regulatory clearances or approvals, they may include significant limitations on the indicated uses for the product, which may limit the market for the product. Although we have obtained 510(k) clearance to market Orbit SDS for microinjection into the subretinal space, we may be required to recall the device if safety or efficacy problems develop, and we have not yet received 510(k) clearance for use of Orbit SDS for delivery of gene or cell therapies.

In order to market our products in member countries of the European Economic Area, or EEA, our products must comply with the essential requirements of the European Union Medical Devices Directive (Council Directive 93/42/EEC), or MDD. Compliance with these requirements is a prerequisite to be able to affix the Conformité Européene mark, or CE Mark, to our products, without which they cannot be sold or marketed in the EEA. To demonstrate compliance with the essential requirements, we must undergo a conformity assessment procedure, which varies according to the type of medical device and its classification. Except for low-risk medical devices (Class I non-sterile, non-measuring devices), where the manufacturer can issue an European Commission Declaration of Conformity based on a self-assessment of the conformity of its products with the essential requirements of the MDD, a conformity assessment procedure requires the intervention by of an organization accredited by a member state of the EEA to conduct conformity assessments, or a Notified Body. Depending on the relevant conformity assessment procedure, the Notified Body would typically audit and examine the technical file and the quality system for the manufacture, design and final inspection of our devices. The Notified Body issues a certificate of conformity following successful completion of a conformity assessment procedure conducted in relation to the medical device and its manufacturer and their conformity with the essential requirements. This certificate entitles the manufacturer to affix the CE Mark to its medical devices after having prepared and signed a related EC Declaration of Conformity.

As a general rule, demonstration of conformity of medical devices and their manufacturers with the essential requirements must be based, among other things, on the evaluation of clinical data supporting the safety and performance of the products during normal conditions of use. Specifically, a manufacturer must demonstrate that the device achieves its intended performance during normal conditions of use, that the known and foreseeable risks, and any adverse events, are minimized and acceptable when weighed against the benefits of its intended performance, and that any claims made about the performance and safety of the device are supported by suitable evidence. If we fail to remain in compliance with applicable European laws and directives, we would be unable to continue to affix the CE Mark to Orbit SDS, which would prevent us from marketing Orbit SDS within the EEA.

In May 2017, the EU adopted a new Medical Devices Regulation (EU) 2017/745, or MDR, which will repeal and replace the MDD with effect from 26 May 2021. The MDR does not set out a radically new system,

 

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but envisages, among other things, stricter controls of medical devices, including strengthening of the conformity assessment procedures, increased expectations as regards clinical data for devices and pre-market regulatory review of high-risk devices. Under transitional provisions, medical devices with Notified Body certificates issued under the MDD prior to 26 May 2021 may continue to be placed on the market for the remaining validity of the certificate, until 27 May 2024 at the latest. After the expiry of any applicable transitional period, only devices that have been CE marked under the MDR may be placed on the market in the EEA.

Further, all of our potential products and improvements of our current devices will be subject to extensive regulation and will likely require permission from regulatory agencies and ethics boards to conduct clinical trials and clearance or approval from the FDA and non-U.S. regulatory agencies prior to commercial sale and distribution.

Any enforcement action by the FDA and other comparable non-U.S. regulatory agencies could have a material adverse effect on our business, financial condition and results of operations. Our failure to comply with applicable regulatory requirements could result in enforcement action by the FDA or state or international agencies, which may include any of the following actions:

 

   

untitled letters, warning letters, fines, injunctions, consent decrees and civil penalties;

 

   

unanticipated expenditures to address or defend such actions;

 

   

customer notifications for repair, replacement or refunds;

 

   

recall, detention or seizure of our products;

 

   

operating restrictions or partial suspension or total shutdown of production;

 

   

refusing or delaying our requests for 510(k) clearance or PMA approval of new devices or modified devices;

 

   

operating restrictions;

 

   

withdrawing 510(k) clearances or PMA approvals that have already been granted;

 

   

refusal to grant export approval for our products; or

 

   

criminal prosecution.

If any of these events were to occur, it would have a material and adverse effect on our business, financial condition and results of operations.

The FDA and the Federal Trade Commission, or FTC, also regulate the advertising and promotion of our devices to ensure that the claims we make are consistent with our regulatory clearances and approvals, that there are adequate data to substantiate the claims and that our promotional labeling and advertising is neither false nor misleading in any respect. If the FDA or FTC determines that any of our advertising or promotional claims are misleading, not substantiated or not permissible, we may be subject to enforcement actions, including warning letters, and we may be required to revise our promotional claims and make other corrections or restitutions.

Modifications to our marketed devices may require new 510(k) clearances or approval of PMA supplements, or may require us to cease marketing or recall the modified products until clearances or approvals are obtained.

Modifications to Orbit SDS or other medical devices we may develop for the administration of our investigational gene therapies may require new regulatory approvals or clearances, including 510(k) clearances or approval of PMA supplements in the United States or the approval of our Notified Body in the European Union, or require us to recall or cease marketing the modified systems until these clearances or approvals are obtained. The FDA requires device manufacturers to initially make and document a determination of whether or

 

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not a modification requires a new approval, supplement or clearance. For a 510(k)-cleared device, a manufacturer may determine that a modification could not significantly affect safety or efficacy and does not represent a major change in its intended use, so that no new 510(k) clearance is necessary. However, the FDA can review a manufacturer’s decision and may disagree. The FDA may also on its own initiative determine that a new clearance or approval is required. We have made modifications to Orbit SDS in the past and may make additional modifications in the future that we believe do not or will not require additional clearances or approvals. If the FDA disagrees and requires new clearances or approvals for the modifications, we may be required to recall and to stop marketing Orbit SDS as modified, which could require us to redesign Orbit SDS or seek new marketing authorizations and harm our operating results. In these circumstances, we may be subject to significant enforcement actions.

If a manufacturer determines that a modification to a FDA-cleared device could significantly affect its safety or effectiveness, or would constitute a major change in its intended use, then the manufacturer must file for a new 510(k) clearance or possibly a new PMA or approval of a PMA supplement. Similarly, in the European Union, if a manufacturer wishes to make a change to a device that could affect conformity with the essential requirements of the MDD or with the conditions prescribed for use of the device, it must obtain the approval of its Notified Body. Where we determine that modifications to Orbit SDS require a new 510(k) clearance or PMA approval in the United States or Notified Body approval in the European Union, we may not be able to obtain those additional clearances or approvals for the modifications or additional indications in a timely manner, or at all. Obtaining clearances and approvals can be a time-consuming process, and delays in obtaining required future clearances or approvals would adversely affect our ability to introduce new or enhanced products in a timely manner, which in turn would harm our future growth.

If we or our suppliers for Orbit SDS fail to comply with ongoing FDA or other foreign regulatory authority requirements, or if we experience unanticipated problems with our product, it could be subject to restrictions or future withdrawal from the market.

Even though we have obtained 510(k) clearance for Orbit SDS, it and any other device for which we obtain clearance or approval, and the manufacturing processes, post-market surveillance, post-approval clinical data and promotional activities for such device, will be subject to continued regulatory review, oversight, requirements and periodic inspections by the FDA and other domestic and foreign regulatory bodies. In particular, we and our suppliers are required to comply with FDA’s Quality System Regulation, or QSR, and other regulations enforced outside the United States which cover the manufacture of our products and the methods and documentation of the design, testing, production, control, quality assurance, labeling, packaging, storage and shipping of medical devices. Regulatory bodies, such as the FDA, enforce the QSR and other regulations through periodic inspections. The failure by us or one of our suppliers (to the extent they are contract manufacturers) to comply with applicable statutes and regulations administered by the FDA and other regulatory bodies, or the failure to timely and adequately respond to any adverse inspectional observations or product safety issues, could result in, among other things, any of the following enforcement actions:

 

   

untitled letters, warning letters, fines, injunctions, consent decrees and civil penalties;

 

   

unanticipated expenditures to address or defend such actions;

 

   

customer notifications for repair, replacement, refunds;

 

   

recall, detention or seizure of our products;

 

   

operating restrictions or partial suspension or total shutdown of production;

 

   

refusing or delaying our requests for 510(k) clearance or PMA approval of new devices or modified devices;

 

   

operating restrictions;

 

   

withdrawal of 510(k) clearances on PMA approvals that have already been granted;

 

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refusal to grant export approval for our devices; or

 

   

criminal prosecution.

If any of these actions were to occur it would harm our reputation and cause our product sales and profitability to suffer and may prevent us from generating revenue. Furthermore, our key component suppliers may not currently be or may not continue to be in compliance with all applicable regulatory requirements which could result in our failure to produce our devices on a timely basis and in the required quantities, if at all.

In addition, we are required to conduct costly post-market testing and surveillance to monitor the safety or effectiveness of our devices, and we must comply with medical device reporting requirements, including the reporting of certain adverse events and malfunctions related to our products. Later discovery of previously unknown problems with our products, including unanticipated adverse events or adverse events of unanticipated severity or frequency, manufacturing problems, or failure to comply with regulatory requirements such as QSR, may result in changes to labeling, restrictions on such products or manufacturing processes, withdrawal of the products from the market, voluntary or mandatory recalls, a requirement to repair, replace or refund the cost of any medical device we manufacture or distribute, fines, suspension of regulatory approvals, product seizures, injunctions or the imposition of civil or criminal penalties which would adversely affect our business, operating results and prospects.

Delays in obtaining regulatory approval of our manufacturing process and facility or disruptions in our manufacturing process may delay or disrupt our product development and commercialization efforts.

Before we can begin to commercially manufacture our investigational gene therapies, whether in a third-party facility or in our own facility, once established, we must obtain regulatory approval from the FDA for our manufacturing process and facility. A manufacturing authorization must also be obtained from the MHRA and the appropriate regulatory authorities in the European Union. In addition, we or a third-party manufacturer must pass a pre-approval inspection of the manufacturing facility by the FDA before our investigational gene therapies can obtain marketing approval. In order to obtain approval, we will need to ensure that all of our processes, methods and equipment are compliant with cGMP, and perform extensive audits of vendors, contract laboratories and suppliers. If any of our vendors, contract laboratories or suppliers are found to be noncompliant with cGMP, we may experience delays or disruptions in manufacturing while we work with these third parties to remedy the violation or while we work to identify suitable replacement vendors. The cGMP requirements govern quality control of the manufacturing process and documentation policies and procedures. In complying with cGMP, we will be obligated to expend time, money and effort in production, quality control and quality assurance to assure that the product meets applicable specifications and other requirements. Further, there are no Mutual Recognition Agreements in place between the United States and the European Union or United Kingdom with respect to advanced therapy medicinal products, and we will require local importation, quality control/quality assurance review and quality planning release for these jurisdictions. If we fail to comply with these requirements, we would be subject to possible regulatory action and may not be permitted to market any product candidate that we may develop.

If we or our third-party manufacturers fail to comply with applicable cGMP regulations, the FDA, MHRA, EMA and other regulatory authorities can impose regulatory sanctions including, among other things, refusal to approve a pending application for a new product candidate or suspension or revocation of a preexisting approval. Such an occurrence may cause our business, financial condition, results of operations and prospects to be harmed.

Additionally, if the supply from our third-party manufacturers is interrupted, there could be a significant disruption in commercial supply of our investigational gene therapies. We do not currently have a backup manufacturer of our investigational gene therapy supply for clinical trials or, if approved, commercial supply. An alternative manufacturer would need to be qualified through a supplement to its regulatory filing, which could

 

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result in further delays. The regulatory authorities also may require additional clinical trials if a new manufacturer is relied upon for commercial production. Switching manufacturers may involve substantial costs and could result in a delay in our desired clinical and commercial timelines.

We may seek priority review designation for one or more of our investigational gene therapies, but we might not receive such designation, and even if we do, such designation may not lead to a faster regulatory review or approval process.

If the FDA determines that a product candidate offers a treatment for a serious condition and, if approved, the product would provide a significant improvement in safety or effectiveness, the FDA may designate the product candidate for priority review. A priority review designation means that the goal for the FDA to review an application is six months, rather than the standard review period of ten months. In either case where the product candidate is a new molecular entity then the review period runs from the 60-day application filing date. We may request priority review for our investigational gene therapies. The FDA has broad discretion with respect to whether or not to grant priority review status to a product candidate, so even if we believe a particular product candidate is eligible for such designation or status, in particular if such product candidate has received a Fast Track designation (as we have for GT005 in the broad population of patients with GA secondary to AMD and in patients with GA secondary to AMD who have CFI rare variants), Breakthrough Therapy designation or regenerative medicine advanced therapy, or RMAT, designation, the FDA may decide not to grant it. Moreover, a priority review designation does not result in expedited development and does not necessarily result in expedited regulatory review or approval process or necessarily confer any advantage with respect to approval compared to conventional FDA procedures. Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or at all.

We may seek a conditional marketing authorization in Europe for some or all of our current investigational gene therapies, but we may not be able to obtain or maintain such designation.

As part of its marketing authorization process, the EMA may recommend the grant of marketing authorizations for certain categories of medicinal products on the basis of less complete data than are normally required, when doing so may meet unmet medical needs of patients and serve the interest of public health. In such cases, it is possible for the Committee for Medicinal Products for Human Use, or CHMP, to recommend the granting of a marketing authorization, subject to certain specific obligations to be reviewed annually, which is referred to as a conditional marketing authorization. This may apply to certain medicinal products for human use that fall under the jurisdiction of the EMA, including those that aim at the treatment, the prevention, or the medical diagnosis of seriously debilitating or life-threatening diseases and those designated as orphan medicinal products.

A conditional marketing authorization may be granted when the CHMP finds that, although comprehensive clinical data referring to the safety and efficacy of the medicinal product have not been supplied, all the following requirements are met:

 

   

the risk-benefit balance of the medicinal product is positive;

 

   

it is likely that the applicant will be in a position to provide the comprehensive clinical data;

 

   

unmet medical needs will be fulfilled; and

 

   

the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.

The granting of a conditional marketing authorization is restricted to situations in which only the clinical part of the application is not yet fully complete. Incomplete preclinical or quality data may only be accepted if duly justified and only in the case of a product intended to be used in emergency situations in response to public health threats. Conditional marketing authorizations are valid for one year, on a renewable basis. The holder will

 

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be required to complete ongoing trials or to conduct new trials with a view to confirming that the benefit-risk balance is positive. In addition, specific obligations may be imposed in relation to the collection of pharmacovigilance data.

Granting a conditional marketing authorization allows medicines to reach patients with unmet medical needs earlier than might otherwise be the case and will ensure that additional data on a product are generated, submitted, assessed and acted upon. Although we may apply to the EMA for a conditional marketing authorization for one or more of our investigational gene therapies, the CHMP may ultimately not agree that the requirements for such conditional marketing authorization have been satisfied and hence delay the commercialization of our investigational gene therapies.

Even if we obtain regulatory approval for a product candidate, our investigational gene therapies will remain subject to regulatory oversight.

Even if we obtain regulatory approval for our investigational gene therapies, they will be subject to ongoing regulatory requirements for manufacturing, labeling, packaging, storage, distribution, advertising, promotion, sampling, recordkeeping, reporting and submission of clinical safety and other post-market information. Any regulatory approvals that we receive for our investigational gene therapies may also be subject to limitations on the approved indicated uses for which the product may be marketed or to the conditions of approval, or contain requirements for potentially costly post-marketing testing, including Phase IV clinical trials, and surveillance to monitor the quality, safety and efficacy of the product. For example, the holder of an approved BLA is obligated to monitor and report adverse events and any failure of a product to meet the specifications in the BLA. FDA guidance advises that patients treated with some types of gene therapy undergo follow-up observations for potential adverse events for as long as 15 years. The holder of an approved BLA also must submit new or supplemental applications and obtain FDA approval for certain changes to the approved product, product labeling or manufacturing facilities or processes. In addition, the holder of a BLA must comply with the FDA’s advertising and promotion requirements, such as those related to the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling, known as “off-label use.” Advertising and promotional materials must comply with FDA rules and are subject to FDA review, in addition to other potentially applicable federal and state laws.

In addition, product manufacturers and their facilities are subject to payment of user fees and continual review and periodic inspections by the FDA and other regulatory authorities for compliance with cGMP requirements and adherence to commitments made in the BLA or foreign marketing application. If we, or a regulatory authority, discover previously unknown problems with a product, such as adverse events of unanticipated severity or frequency, or problems with the facility where the product is manufactured or if a regulatory authority disagrees with the promotion, marketing or labeling of that product, a regulatory authority may impose restrictions relative to that product, the manufacturing facility or us, including requiring recall or withdrawal of the product from the market or suspension of manufacturing.

If we fail to comply with applicable regulatory requirements following approval of our investigational gene therapies, a regulatory or enforcement authority may:

 

   

issue a warning letter asserting that we are in violation of the law;

 

   

seek an injunction or impose administrative, civil or criminal penalties or monetary fines;

 

   

suspend or revoke regulatory approval;

 

   

suspend any ongoing clinical trials;

 

   

refuse to approve a pending BLA or comparable foreign marketing application (or any supplements thereto) submitted by us or our strategic partners;

 

   

restrict the marketing or manufacturing of the product;

 

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seize or detain the product or otherwise require the withdrawal of the product from the market;

 

   

refuse to permit the import or export of the product; or

 

   

refuse to allow us to enter into supply contracts, including government contracts.

Any government investigation of alleged violations of law could require us to expend significant time and resources in response and could generate negative publicity. The occurrence of any event or penalty described above may inhibit our ability to commercialize our investigational gene therapies and adversely affect our business, financial condition, results of operations and prospects.

In addition, the FDA’s policies, and those of the EMA and other regulatory authorities, may change and additional government regulations may be enacted that could prevent, limit or delay regulatory approval of our investigational gene therapies. We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative action, either in the United States or abroad. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we may have obtained and we may not achieve or sustain profitability, which would negatively impact our business, financial condition, results of operations and prospects.

Even if we obtain and maintain approval for our investigational gene therapies in a major pharmaceutical market such as the United States, we may never obtain approval for our investigational gene therapies in other major markets.

In order to market any products in a country or territory, we must establish and comply with numerous and varying regulatory requirements of such countries or territories regarding safety and efficacy. Clinical trials conducted in one country may not be accepted by regulatory authorities in other countries, and regulatory approval in one country does not mean that regulatory approval will be obtained in any other country. Approval procedures vary among countries and can involve additional product testing and validation and additional administrative review periods. Seeking regulatory approvals in all major markets could result in significant delays, difficulties and costs for us and may require additional preclinical studies or clinical trials, which would be costly and time-consuming. Regulatory requirements can vary widely from country to country and could delay or prevent the introduction of our investigational gene therapies in those countries. Satisfying these and other regulatory requirements is costly, time-consuming, uncertain and subject to unanticipated delays. In addition, our failure to obtain regulatory approval in any country may delay or have negative effects on the process for regulatory approval in other countries. We currently do not have any investigational gene therapies approved for sale in any jurisdiction, whether in the United States, Europe or any other international markets, and we do not have experience in obtaining regulatory approval in international markets. If we fail to comply with regulatory requirements in international markets or to obtain and maintain required approvals, our target market will be reduced and our ability to realize the full market potential of our investigational gene therapies will be compromised.

Risks Related to Our Reliance on Third Parties

We rely, and expect to continue to rely, on third parties to conduct our preclinical studies and clinical trials. If these third parties do not successfully carry out their contractual duties or meet expected deadlines, we may not be able to obtain regulatory approval for or commercialize our investigational gene therapies and our business could be substantially harmed.

We have relied upon and plan to continue to rely upon third parties, including independent clinical investigators and third-party CROs, to conduct some of our preclinical studies and our clinical trials in accordance with applicable regulatory requirements and to monitor and manage data for our ongoing preclinical and clinical programs. We rely on these parties for execution of our preclinical studies and clinical trials, and

 

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control only certain aspects of their activities. Nevertheless, we are responsible for ensuring that each of our preclinical studies and clinical trials is conducted in accordance with the applicable protocol and legal, regulatory and scientific standards, and our reliance on these third parties does not relieve us of our regulatory responsibilities. We and our third-party contractors and CROs are required to comply with GCP requirements, which are regulations and guidelines enforced by the FDA, the Competent Authorities of the Member States of the EEA and comparable foreign regulatory authorities for all of our investigational gene therapies in clinical development. Regulatory authorities enforce these GCP requirements through periodic inspections of trial sponsors, principal investigators and clinical trial sites. If we fail to exercise adequate oversight over any of our CROs or if we or any of our CROs fail to comply with applicable GCP requirements, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, MHRA, EMA or other regulatory authorities may require us to perform additional clinical trials before approving our marketing applications. We cannot assure you that upon a regulatory inspection of us or our CROs or other third parties performing services in connection with our clinical trials, such regulatory authority will determine that any of our clinical trials complies with GCP regulations. In addition, our clinical trials must be conducted with product produced under applicable cGMP regulations. Our failure to comply with these regulations may require us to repeat clinical trials, which would delay the regulatory approval process.

Further, these investigators and CROs are not our employees and we will not be able to control, other than by contract, the amount of resources, including time, which they devote to our investigational gene therapies and clinical trials. If independent investigators or CROs fail to devote sufficient resources to the development of our investigational gene therapies, or if their performance is substandard, it may delay or compromise the prospects for approval and commercialization of our investigational gene therapies. In addition, the use of third-party service providers requires us to disclose our proprietary information to these parties, which could increase the risk that this information will be misappropriated.

Our existing and future CROs have or may have the right to terminate their agreements with us in the event of an uncured material breach. In addition, some of our CROs have an ability to terminate their respective agreements with us if it can be reasonably demonstrated that the safety of the patients participating in our clinical trials warrants such termination, if we make a general assignment for the benefit of our creditors or if we are liquidated.

If any of our relationships with these third-party CROs terminate, we may not be able to enter into arrangements with alternative CROs or to do so on commercially reasonable terms. If CROs do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they cannot perform their contractual duties or obligations due to the impacts of COVID-19 on their operations or at the sites they are overseeing, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols, regulatory requirements or for other reasons, our clinical trials may be extended, delayed or terminated and we may not be able to obtain regulatory approval for or successfully commercialize our investigational gene therapies. As a result, our results of operations and commercial prospects would be harmed, our costs could increase and our ability to generate revenues could be delayed.

Switching or engaging additional CROs involves additional cost and requires our management’s time and focus. In addition, there is a natural transition period when a new CRO commences work. As a result, delays could occur, which could materially impact our ability to meet our desired clinical development timelines. Though we carefully manage our relationships with our contracted laboratories and CROs, there can be no assurance that we will not encounter challenges or delays in the future or that these delays or challenges will not have a material adverse impact on our business, financial condition and results of operations.

In addition, investigators for our clinical trials may serve as scientific advisors or consultants to us from time to time and receive compensation in connection with such services, including equity awards and option grants, and may have other financial interests in our company. We are required to collect and provide financial

 

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disclosure notifications or certifications for our clinical investigators to the FDA, MHRA, EMA and other regulatory authorities. If the FDA, MHRA, EMA or other regulatory authority concludes that a financial relationship between us and a clinical investigator has created a conflict of interest or otherwise affected interpretation of the trial, the FDA, MHRA, EMA or other regulatory authority may question the integrity of the data generated at the applicable clinical trial site and the utility of the clinical trial itself may be jeopardized. This could result in a delay in approval, or rejection, of our marketing applications by the FDA, MHRA, EMA or other regulatory authority and may ultimately lead to the denial of marketing approval of our current and future investigational gene therapies.

Our reliance on third parties requires us to share our trade secrets, which increases the possibility that a competitor or other third party will discover our trade secrets or that our trade secrets will be misappropriated or disclosed.

We have engaged CMOs to manufacture and quality test our lead investigational gene therapy, GT005, and collaborate with various organizations and academic institutions for the advancement of our gene therapy programs, and we must, at times, share our proprietary technology and confidential information, including trade secrets as a part of these third-party relationships. We seek to protect our proprietary technology, in part, by entering into confidentiality agreements and, if applicable, material transfer agreements, collaborative research agreements, consulting agreements and other similar agreements with our collaborators, advisors, employees, consultants and contractors (including CMOs) prior to beginning research or disclosing any proprietary information. These agreements typically limit the rights of the third parties to use or disclose our confidential information, including our trade secrets. Despite the contractual provisions employed when working with third parties, the need to share trade secrets and other confidential information increases the risk that such trade secrets become known by our competitors or other third parties, are inadvertently incorporated into the technology of others or are disclosed or used in violation of these agreements. Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor’s or other third party’s discovery of our proprietary technology and confidential information or other unauthorized use or disclosure of such technology or information would impair our competitive position and may have an adverse effect on our business, financial condition, results of operations and prospects. For more information on risks relating to our reliance on trade secrets see “—Risks Related to Our Intellectual Property.”

We currently utilize, and expect to continue to utilize, third parties to conduct our product manufacturing, and these third parties may not perform satisfactorily.

We currently rely on CMOs for the manufacturing of clinical batches and intend to continue to rely on third parties to manufacture our preclinical study and clinical trial product supplies until we sufficiently develop our in-house manufacturing capabilities. For example, we are party to a manufacturing services agreement, pursuant to which we plan to manufacture GT005 for our ongoing and planned clinical studies. Our supplier is a full service CMO that provides services to a number of other companies in addition to us, and as a result, may experience competing customer demands. We also rely on CMOs for the manufacture of our other gene therapies and our Orbit SDS device. Such reliance on third-party manufacturers may expose us to different risks than if we were to manufacture our gene therapies and Orbit SDS device ourselves.

If our third-party manufacturers do not successfully carry out their contractual obligations, meet expected deadlines, or manufacture GT005 in accordance with regulatory requirements, if they experience capacity issues with respect to producing GT005 as a result of competing demands on their manufacturing capacity or as a result of impacts of COVID-19 or if there are disagreements between us and these third-party manufacturers, we will not be able to supply the material needed in order to complete clinical studies, or may be delayed in completing these studies. In addition, the preclinical studies required to support future IND submissions and the future clinical trials required for regulatory approval of GT005 or any other investigational gene therapies we may develop, to the extent that we rely on CMOs for manufacturing capabilities for these programs, may similarly be impacted by the same factors. In such instances, we may need to enter into an appropriate replacement third-

 

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party relationship, which may not be readily available or available on acceptable terms, which would cause additional delay or increased expense prior to the approval of GT005 or any of our other investigational gene therapies we may develop, and would thereby have a negative impact on our business, financial condition, results of operations and prospects. We also plan to develop an in-house commercial manufacturing facility and infrastructure, which will require significant expenses, diversion of management resources and time. There can be no assurance that we will successfully develop this in-house manufacturing facility or that, in doing so, we will not encounter challenges or delays in the future or that these delays or challenges will not have a material adverse impact on our business, financial condition and results of operations.

Under certain circumstances, our current CMOs are entitled to terminate their engagements with us. If we need to enter into alternative arrangements, it could delay our development activities. Our reliance on our CMOs for certain manufacturing activities will reduce our control over these activities but will not relieve us of our responsibility to ensure compliance with all required regulations. If our current CMOs, or any future third-party manufacturers, do not successfully carry out their contractual duties, meet expected deadlines or manufacture our investigational gene therapies in accordance with regulatory requirements, or if there are disagreements between us and our CMOs or any future third-party manufacturers, we will not be able to complete, or may be delayed in completing, the preclinical studies required to support future IND submissions and the clinical trials required for approval of our investigational gene therapies.

In addition to our current CMOs, we may rely on additional third parties to manufacture components of our investigational gene therapies in the future and to perform quality testing, and reliance on these third parties entails risks to which we would not be subject if we manufactured the investigational gene therapies ourselves, including:

 

   

reduced control for certain aspects of manufacturing activities;

 

   

termination or nonrenewal of manufacturing and service agreements with third parties in a manner or at a time that is costly or damaging to us; and

 

   

disruptions to the operations of our third-party manufacturers and service providers caused by conditions unrelated to our business or operations, including the bankruptcy of the manufacturer or service provider.

Any of these events could lead to clinical trial delays or failure to obtain regulatory approval or impact our ability to successfully commercialize any of our investigational gene therapies. Some of these events could be the basis for FDA, MHRA, EMA or other regulatory authority action, including injunction, recall, seizure or total or partial suspension of product manufacture.

To the extent we rely on a third-party manufacturing facility for clinical trial or commercial supply, that third party will be subject to significant regulatory oversight with respect to manufacturing our investigational gene therapies.

The preparation of therapeutics for clinical trials or commercial sale is subject to extensive regulation. Components of a finished therapeutic product approved for commercial sale or used in later stage clinical trials must be manufactured in accordance with cGMP requirements. These regulations govern manufacturing processes and procedures, including record keeping, and the implementation and operation of quality systems to control and assure the quality of investigational products and products approved for sale. Poor control of production processes can lead to the introduction of outside agents or other contaminants, or to inadvertent changes in the properties or stability of a product candidate that may not be detectable in final product testing. We must supply all necessary documentation in support of a BLA or MAA on a timely basis and must adhere to the FDA’s and EMA’s cGMP requirements which are enforced, in the case of the FDA, through its facilities inspection program. To the extent that we utilize third-party facilities for commercial supply, the third party’s facilities and quality systems must pass an inspection for compliance with the applicable regulations as a

 

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condition of regulatory approval. In addition, the regulatory authorities may, at any time, audit or inspect the third-party manufacturing facility or the associated quality systems for compliance with the regulations applicable to the activities being conducted. If these facilities do not pass a plant inspection, the FDA will not approve the BLA.

If our CMOs cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements of the FDA, MHRA, EMA or other regulatory authorities, they will not be able to secure or maintain regulatory approval for their manufacturing facilities. In addition, we have no direct control over the ability of our CMOs to maintain adequate quality control, quality assurance and qualified personnel. Furthermore, all of our CMOs are engaged with other companies to supply or manufacture materials or products for such companies, which exposes our CMOs to regulatory risks for the production of such materials and products. As a result, failure to meet the regulatory requirements for the production of those materials and products may generally affect the regulatory clearance of our CMOs’ facilities. Our failure, or the failure of third parties, to comply with applicable regulations could result in sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension or revocation of approvals, seizures or recalls of investigational gene therapies or products, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect supplies of our products and investigational gene therapies.

Our potential future dependence upon others for the manufacture of our investigational gene therapies may adversely affect our future profit margins and our ability to commercialize any products that receive regulatory approval on a timely and competitive basis.

We are dependent on a limited number of suppliers and, in some instances, a sole supplier, for some of our components and materials used in our investigational gene therapies and in our Orbit SDS device.

We currently depend on a limited number of suppliers and, in some instances, a sole supplier, for some of the components and equipment necessary for the production of our viral vectors, drug product and in our Orbit SDS device. We may not be able to enter into longer-term supply agreements to assure supply of these components and equipment. Moreover, we cannot be sure that these suppliers will remain in business, or that they will not be purchased by one of our competitors or another company that is not interested in continuing to produce these materials for our intended purpose. Our use of a sole or a limited number of suppliers of raw materials, components and finished goods exposes us to several risks, including disruptions in supply, price increases, late deliveries and an inability to meet customer demand. There are, in general, relatively few alternative sources of supply for these components. These vendors may be unable or unwilling to meet our future demands for our clinical trials or commercial sale. Establishing additional or replacement suppliers for these components could take a substantial amount of time and it may be difficult to establish replacement suppliers who meet regulatory requirements. Any disruption in supply from any supplier or manufacturing location could lead to supply delays or interruptions which would damage our business, financial condition, results of operations and prospects.

If we are required to switch to a replacement supplier, the manufacture and delivery of our investigational gene therapy could be interrupted for an extended period, adversely affecting our business. Establishing additional or replacement suppliers may not be accomplished quickly. If we are able to find a replacement supplier, the replacement supplier would need to be qualified and may require additional regulatory authority approval, which could result in further delay. For example, the FDA , MHRA, EMA or other regulatory authorities could require additional supplemental data, manufacturing data and comparability data up to and including clinical trial data if we rely upon a new supplier. While we seek to maintain adequate inventory of the components and materials used in our investigational gene therapies, any interruption or delay in the supply of components or materials, or our inability to obtain components or materials from alternate sources at acceptable prices in a timely manner, could impair our ability to conduct our clinical trials and, if our investigational gene therapies are approved, to meet the demand of our customers and cause them to cancel orders.

 

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In addition, as part of the FDA’s approval of our investigational gene therapies, the FDA must review and approve the individual components of our production process, which includes raw materials, the manufacturing processes and facilities of our suppliers. Some of our current suppliers have not undergone this process nor have they had any components included in any product approved by the FDA.

Our reliance on these suppliers subjects us to a number of risks that could harm our reputation, business and financial condition, including, among other things:

 

   

the interruption of supply resulting from modifications to or discontinuation of a supplier’s operations;

 

   

delays in product shipments resulting from uncorrected defects, reliability issues, or a supplier’s variation in a component;

 

   

delays in performance due to COVID-19;

 

   

a lack of long-term supply arrangements for key components with our suppliers;

 

   

the inability to obtain adequate supply in a timely manner, or to obtain adequate supply on commercially reasonable terms;

 

   

difficulty and cost associated with locating and qualifying alternative suppliers for our components in a timely manner;

 

   

production delays related to the evaluation and testing of products from alternative suppliers and corresponding regulatory qualifications;

 

   

a delay in delivery due to our suppliers prioritizing other customer orders over ours;

 

   

damage to our reputation caused by defective components produced by our suppliers;

 

   

increased cost of our warranty program due to product repair or replacement based upon defects in components produced by our suppliers;

 

   

fluctuation in delivery by our suppliers due to changes in demand from us or their other customers; and

 

   

an inability to obtain or delay in obtaining supply due to general economic disruptions, including as a result of geopolitical events, global pandemics or natural disasters.

If any of these risks materialize, costs could significantly increase and our ability to conduct our clinical trials and, if our investigational gene therapies are approved, to meet demand for our products could be impacted.

We may seek to establish collaborations and, if we are not able to establish them on commercially reasonable terms, we may have to alter our development and commercialization plans.

We may pursue collaborations for the development and commercialization of one or more of our investigational gene therapies. We face significant competition in seeking appropriate collaborators. Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of factors. Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or applicable foreign regulatory authorities, the potential market for the subject product candidate, the costs and complexities of manufacturing and delivering such product candidate to patients, the potential of competing products and the existence of uncertainty with respect to its ownership of technology, which can exist if there is a challenge to such ownership without regard to the merits of the challenge and industry and market conditions generally. The collaborators may also consider alternative investigational gene therapies or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us for its investigational gene therapies.

 

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Collaborations are complex and time-consuming to negotiate and document. In addition, there have been a significant number of business combinations among large pharmaceutical companies that have resulted in a reduced number of potential future collaborators.

We may not be able to negotiate collaborations on a timely basis, on acceptable terms, or at all. If we are unable to do so, we may have to curtail the development of the product candidate for which we are seeking to collaborate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or reduce the scope of any sales or marketing activities or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which may not be available to us on acceptable terms, or at all. If we do not have sufficient funds, we may not be able to further develop our investigational gene therapies or bring them to market and generate product revenue.

If we enter into collaborations with third parties for the development and commercialization of our investigational gene therapies, our prospects with respect to those investigational gene therapies will depend in significant part on the success of those collaborations.

We may seek to enter into collaborations for the development and commercialization of certain of our investigational gene therapies. If we enter into such collaborations, we will have limited control over the amount and timing of resources that our collaborators will dedicate to the development or commercialization of our investigational gene therapies. Our ability to generate revenues from these arrangements will depend on any future collaborators’ abilities to successfully perform the functions assigned to them in these arrangements. In addition, any future collaborators may have the right to abandon research or development projects and terminate applicable agreements, including funding obligations, prior to or upon the expiration of the agreed upon terms.

Collaborations involving our investigational gene therapies pose a number of risks, including the following:

 

   

collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations;

 

   

collaborators may not perform their obligations as expected;

 

   

collaborators may not pursue development and commercialization of our investigational gene therapies or may elect not to continue or renew development or commercialization programs, based on clinical trial results, changes in the collaborators’ strategic focus or available funding or external factors, such as an acquisition, that divert resources or create competing priorities;

 

   

collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon an investigational gene therapy, repeat or conduct new clinical trials or require a new formulation of an investigational gene therapy for clinical testing;

 

   

collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our investigational gene therapies;

 

   

a collaborator with marketing and distribution rights to one or more products may not commit sufficient resources to the marketing and distribution of such product or products;

 

   

disagreements with collaborators, including disagreements over proprietary rights, contract interpretation or the preferred course of development, might cause delays or termination of the research, development or commercialization of investigational gene therapies, might lead to additional responsibilities for us with respect to investigational gene therapies, or might result in litigation or arbitration, any of which would be time-consuming and expensive;

 

   

collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation;

 

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collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability;

 

   

we may be required to invest resources and attention into such collaboration, which could distract from other business objectives;

 

   

disputes may arise between the collaborators and us regarding ownership of or other rights in the intellectual property generated in the course of the collaborations; and

 

   

collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development or commercialization of the applicable investigational gene therapies.

Collaboration agreements may not lead to development or commercialization of investigational gene therapies in the most efficient manner or at all. If any future collaborator of ours is involved in a business combination, it could decide to delay, diminish or terminate the development or commercialization of any product candidate licensed to it by us.

Risks Related to Commercialization of Our Investigational Gene Therapies and Orbit SDS

We face significant competition in an environment where multiple companies have ongoing clinical trials and are aiming to impact the patient unmet need. There is a possibility that our competitors may achieve regulatory approval before us or develop therapies that are more advanced or effective than ours, which may adversely affect our financial condition and our ability to successfully market or commercialize our investigational gene therapies.

The biotechnology and pharmaceutical industries, including the gene therapy field, are characterized by rapidly changing technologies, significant competition and a strong emphasis on intellectual property. We face substantial competition from many different sources, including large and specialty pharmaceutical and biotechnology companies, academic research institutions, government agencies and public and private research institutions.

New developments, including the development of other pharmaceutical technologies and methods of treating disease, occur in the pharmaceutical and life sciences industries at a rapid pace. Developments by competitors may render our investigational gene therapies less competitive or noncompetitive. We anticipate that we will face intense and increasing competition as new treatments enter the market and as advances for patients become available.

We are aware of a number of companies focused on developing ophthalmic gene therapies, including 4-D Molecular Therapeutics, Adverum and REGENXBIO, among others. Furthermore, we are aware of multiple companies developing treatments for GA secondary to AMD, including Apellis, Gemini, Hemera, IVERIC bio, NGM Biopharmaceuticals and Roche, among others. We are also aware that several other companies, including Alkeus Pharmaceuticals Inc., Allegro Ophthalmics, LLC, Allergan Inc., Astellas Pharma Inc., Boehringer Ingelheim, EyePoint Pharmaceuticals, Inc., Genentech, Lineage Cell Therapeutics, Inc., Regenerative Patch Technologies, LLC and Stealth BioTherapeutics Corp. (working in collaboration with Alexion Pharmaceuticals, Inc.), are pursuing development programs for the treatment of GA or dry AMD using different mechanisms of action outside of the complement system. See “Business—Competition.”

Many of our potential competitors, alone or with their strategic partners, have substantially greater financial, technical and other resources, such as larger research and development, clinical, marketing and manufacturing organizations. Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among a smaller number of competitors. Our commercial opportunity could be reduced or eliminated if competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any investigational gene therapy that we may develop. Competitors also may obtain FDA, MHRA, EMA or other regulatory approval for their

 

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products more rapidly or earlier than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. Additionally, technologies developed by our competitors may render our investigational gene therapies less competitive or noncompetitive, and we may not be successful in marketing our investigational gene therapies against competitors.

In addition, as a result of the expiration or successful challenge of our patent rights, we could face more litigation with respect to the validity or scope of patents relating to our competitors’ products. The availability of our competitors’ products could limit the demand, and the price we are able to charge, for any investigational gene therapy that we may develop and commercialize.

We currently have no marketing or field force. If we are unable to establish effective sales and marketing capabilities or enter into agreements with third parties to market and sell GT005 or other investigational gene therapies that may be approved, we may not be successful in commercializing our investigational gene therapies or devices if and when approved, and we may be unable to generate any product revenue.

If our ongoing Phase I/II and Phase II clinical trials for GT005 and a subsequent Phase III pivotal program for GT005 are successful and GT005 is approved for commercialization, we currently intend to seek to commercialize GT005 in the United States, United Kingdom, Europe and potentially other countries which would require a specialized field force. However, we currently do not have an established marketing or sales team for the marketing, sales and distribution of any of our gene therapies. In order to commercialize GT005, if approved, or any of our other investigational gene therapies that may be approved, we must build marketing, sales, distribution, managerial and potential other capabilities or make arrangements with third parties to perform these services, and we may not be successful in doing so.

There are risks involved with both establishing our own sales and marketing capabilities and entering into arrangements with third parties to perform these services. For example, recruiting and training a field force is expensive and time-consuming and, if not planned and executed effectively, could delay any product launch. If the commercial launch of an investigational gene therapy for which we recruit a field force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses. This may be costly and our investment would be lost if we cannot retain or reallocate our sales and marketing personnel.

Factors that may inhibit our efforts to commercialize our investigational gene therapies or devices on our own include:

 

   

our inability to recruit, train and retain adequate numbers of effective field and marketing personnel;

 

   

the inability of field personnel to obtain sufficient access to physicians or educate adequate numbers of physicians on the benefits and risks of prescribing any future product that we may develop;

 

   

delays in commercialization due to COVID-19; and

 

   

unforeseen costs and expenses associated with creating an independent sales and marketing organization.

If we enter into arrangements with third parties to perform sales, marketing and distribution services, our product revenue or the profitability to us from these revenue streams is likely to be lower than if we were to market and sell any investigational gene therapies or devices that we develop ourselves. In addition, we may not be successful in entering into arrangements with third parties to market and sell our investigational gene therapies or devices or may be unable to do so on terms that are favorable to us. We likely will have little control over such third parties and any of them may fail to devote the necessary resources and attention to market and sell our investigational gene therapies or devices effectively. Even if our investigational gene therapies are approved, if we are unable to successfully market our products, we will not be able to generate significant revenues from such

 

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products. If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties, we may not be successful in commercializing our investigational gene therapies or devices.

The market opportunities for our investigational gene therapies may be smaller than we anticipate.

We are focusing our primary research and development efforts on expanding gene therapy beyond rare diseases, especially conditions related to AMD. Our understanding of both the number of people who have AMD and the subset of populations that we are currently evaluating in our clinical trials who have the potential to benefit from our GT005 investigational gene therapy treatment, including the a broad population of patients with GA secondary to AMD and the population of patients with GA secondary to AMD with CFI rare variants, are based on estimates and expectations. These estimates have been derived from a variety of sources, including our research, our ongoing SCOPE natural history study, scientific literature, patient foundations and publicly available databases, and may prove to be incorrect. Further, new or updated sources may reveal a change in the estimated number of patients, and the number of patients may turn out to be lower than expected. Even if original estimates of prevalence and incidence prove correct, our ongoing and planned clinical trials may fail to show the efficacy of GT005 in either, or both, patient populations. The number of patients in the United States, the United Kingdom, the European Union and elsewhere may turn out to be lower than expected, may not be otherwise amenable to treatment with our investigational gene therapies or patients may become increasingly difficult to identify and access, all of which would adversely affect our business, financial condition, results of operations and prospects.

Additionally, the potential addressable patient population for our current programs or future investigational gene therapies may be limited. The ultimate market opportunity for our investigational gene therapies will depend on, among other things, the final labeling for such investigational gene therapies as agreed with the FDA or comparable foreign regulatory authorities, acceptance by the medical community and patients, potential competition and drug pricing and reimbursement, and overall patient access. Even if we obtain significant market share for any investigational gene therapies, if approved, if the potential target populations are small, we may never achieve profitability without obtaining marketing approval for additional indications.

Further, there are several factors that could contribute to making the actual number of patients who receive our potential products, if and when approved, less than the potentially addressable market. These include the lack of widespread availability of, and limited reimbursement for, new therapies in many underdeveloped markets. Further, the severity of the progression of a disease up to the time of treatment will likely diminish the total potential therapeutic benefit conferred by a gene therapy due to irreversible organ or tissue damage (for example, complete blindness in the context of AMD). Lastly, certain patients’ immune systems might prohibit the successful delivery of certain gene therapy products to the target tissue, thereby limiting the treatment outcomes.

The commercial success of our investigational gene therapies will depend upon their degree of market acceptance by physicians, patients, third-party payors and others in the medical community.

Ethical, social and legal concerns about gene therapy could result in additional regulations restricting or prohibiting our investigational gene therapies, if and when approved. Even with the requisite approvals from the FDA, MHRA, EMA and other regulatory authorities internationally, the commercial success of our investigational gene therapies will depend, in part, on the acceptance of physicians, patients and third-party payors of gene therapy products in general, and our investigational gene therapies in particular, as medically necessary, cost-effective and safe. Any product that we commercialize may not gain acceptance by physicians, patients, third-party payors and others in the medical community. If these products do not achieve an adequate level of acceptance, we may not generate significant product revenue and may not become profitable. The degree of market acceptance of gene therapy products and, in particular, our investigational gene therapy, if approved for commercial sale, will depend on several factors, including:

 

   

the efficacy and safety of our investigational gene therapy as demonstrated in clinical trials;

 

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the potential and perceived advantages of our investigational gene therapy over alternative treatments;

 

   

the availability and cost of treatment relative to alternative treatments;

 

   

patient awareness of, and willingness to seek, genotyping as appropriate and indicated;

 

   

the willingness of physicians to prescribe, and the target patient population to try, new therapies;

 

   

the prevalence and severity of any side effects;

 

   

product labeling or product insert requirements of the FDA, MHRA, EMA or other regulatory authorities, including any limitations or warnings contained in a product’s approved labeling;

 

   

the timing of market introduction of the candidate as well as competitive products;

 

   

patient willingness to undergo surgical medical procedures;

 

   

publicity concerning our investigational gene therapies or competing products and treatments;

 

   

any restrictions on the use of our products together with other medications;

 

   

the effectiveness of sales and marketing efforts; and

 

   

favorable market access, including third-party payer coverage and adequate reimbursement.

Even if a potential product displays a favorable efficacy and safety profile in preclinical studies and clinical trials, market acceptance of the product will not be fully known until after it is launched.

Surgery-related adverse events involving the use of Orbit SDS, or any other medical device we may develop, could negatively impact us.

All surgical procedures carry some risk. The use of Orbit SDS in surgical procedures is required to be performed by ophthalmologists who have received special training. While we take efforts to train surgeons on the use of the Orbit SDS device in the procedure, we cannot be certain that such training is adequate or effective for all surgeons. Further, these training efforts may require significant effort or expense, even if effective. A surgery-related adverse event involving the use of Orbit SDS may lessen or cease the demand for the use of the device for other gene or cell therapies or increase regulatory scrutiny. In addition, a surgery-related adverse event may result in a clinical hold, delays in the completion of any ongoing or planned clinical trials and decrease our ability to complete development of our investigational gene therapies, including our lead investigational gene therapy, GT005, which we are currently delivering to patients using Orbit SDS in cohorts of our ongoing Phase I/II FOCUS clinical trial. In addition, Patients could experience adverse events or outcomes following a surgical procedure due to a variety of different factors, including deficits in the skill, experience and preparedness of the surgeon, the existence of underlying conditions or overall poor health of the patient, and defects, age and misuse of medical products used in the procedure. Should any surgery-related adverse event occur during the use of Orbit SDS, or any other medical device product we may develop, there could be adverse publicity, increased scrutiny from regulatory agencies and a loss of goodwill, even if it is ultimately shown to be caused by factors other than our device, which could negatively affect our business, financial condition and results of operations and impair our ability to grow our business.

We may be unable to successfully demonstrate to surgeons or key opinion leaders the merits of Orbit SDS, compared to those of our competitors, which may make it difficult to establish our product as a standard of care and achieve market acceptance.

Surgeons play a primary role in determining the course of treatment and, ultimately, the type of products that will be used to treat a patient. Our success will depend in part on our ability to effectively market and demonstrate to surgeons the merits of Orbit SDS and subretinal gene therapy delivery compared to competing delivery methods. Acceptance of our products and technologies depends on educating surgeons as to the

 

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distinctive characteristics, clinical benefits, safety and cost-effectiveness of our products and technologies as compared to those of our competitors, and on training surgeons in the proper use of our product and surgical procedure. The safety and efficacy of Orbit SDS is not yet supported by long-term clinical data in large numbers of patients. If we are not successful in convincing surgeons of the merits of Orbit SDS as used to deliver our products or educating them on the use of our products, they may not use our products or may not use them effectively and we may be unable to increase our sales, sustain our growth or achieve and sustain profitability.

Furthermore, it is possible many surgeons, hospitals and healthcare facilities may be unwilling to adopt Orbit SDS unless they determine, based on experience, clinical data and published peer-reviewed journal articles, that our products and technologies provide benefits or are attractive and cost-effective as the current delivery standard. Additionally, surgeons may be reluctant to change their surgical treatment practices for the following reasons, among others:

 

   

existing relationships with competitors and distributors that sell competitive products;

 

   

lack or perceived lack of evidence supporting additional patient benefits;

 

   

perceived liability risks generally associated with the use of new products, technologies and procedures;

 

   

less attractive availability of coverage and reimbursement by third-party payors compared to competitive products and procedures and other techniques;

 

   

costs associated with the purchase of new products and equipment; and

 

   

inexperience with our products and the time commitment that may be required for training.

In addition, we believe recommendations and support of our products and technologies by influential surgeons and key opinion leaders in our industry are essential for market acceptance and establishment of Orbit SDS as a standard of care for subretinal delivery of gene therapy. If we do not receive support from such surgeons and key opinion leaders, if long-term data do not show the benefits of using our products and technologies or if the benefits offered by our products and technologies are not sufficient to justify their cost, surgeons, hospitals and other healthcare providers may not use our products and we might be unable to establish our products and technologies as a standard of care and achieve market acceptance.

The training required for physicians to use our Orbit SDS could reduce the market acceptance of the product or any of our investigational gene therapies or future gene therapies.

As with any new method or technique, physicians must undergo a thorough training program before they are qualified to perform a surgery using Orbit SDS. Physicians could experience difficulty with the technique necessary to successfully utilize the device, and may not achieve the technical competency necessary to complete the training program. Even after successfully completing the training program, physicians could still experience difficulty using Orbit SDS, and, as a result, limit its use significantly in their practices or cease utilizing it altogether. In addition, if physicians are uncomfortable using Orbit SDS and restrict their use of the device, they may be reluctant to administer any of our investigational gene therapies or future gene therapies that utilize Orbit SDS as a delivery platform.

In addition, we may experience difficulty growing the number of physicians who complete our training program if patient demand is low, if the length of time necessary to train each physician is longer than expected, if the capacity of our staff to train physicians is less than expected, or if we are unable to sufficiently grow our sales organization. All of these events would lead to fewer trained physicians qualified on our Orbit SDS procedure, which may decrease the demand for our investigational gene therapies and negatively affect our business, financial condition and results of operations, and impair our ability to grow our business.

 

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The insurance coverage and reimbursement status of newly approved products is uncertain. Failure to obtain or maintain adequate coverage and reimbursement for our investigational gene therapies, if approved, could limit our ability to market those products and decrease our ability to generate product revenue.

In the United States and certain markets in other countries, patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party payors, such as Medicare, Medicaid, TRICARE, the Veterans Administration, managed care organizations, private health insurers and other organizations, to reimburse all or part of the associated healthcare costs. We expect the cost of a single administration of gene therapy products, such as those we are developing, to be substantial, when and if they achieve regulatory approval. We expect that coverage and adequate reimbursement by government and private payors will be essential for most patients to be able to afford these treatments. Accordingly, sales of our investigational gene therapy will depend substantially, both domestically and abroad, on the extent to which the costs of our investigational gene therapy will be reimbursed by third-party payors.

Coverage and reimbursement by a third-party payor may depend upon several factors, including the third-party payor’s determination that use of a product is:

 

   

a covered benefit under its health plan;

 

   

safe, effective and medically necessary;

 

   

appropriate for the specific patient;

 

   

cost-effective; and

 

   

neither experimental nor investigational.

There is significant uncertainty related to third-party coverage and reimbursement of newly approved products. Government authorities and other third-party payors decide which drugs and treatments they will cover and the amount of reimbursement. There is no uniform policy for coverage and reimbursement in the United States. In the United States, the principal decisions about reimbursement for new medicines are typically made by the U.S. Centers for Medicare & Medicaid Services, or CMS, an agency within the Department of Health and Human Services, or HHS. CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare and private payors tend to follow CMS to a substantial degree. However, no uniform policy of coverage and reimbursement exists among third-party payors. Therefore, coverage and reimbursement for products can differ significantly from payor to payor. One payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage and adequate reimbursement.

Obtaining coverage and reimbursement for a product from third-party payors is a time-consuming and costly process that could require us to provide to the payor supporting scientific, clinical and cost-effectiveness data. In addition to the costs required to obtain FDA or other comparable regulatory approvals, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity. Companies may also need to provide discounts to purchasers, private health plans or government healthcare programs. Nonetheless, product candidates may not be considered medically necessary or cost effective. We also may not be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement. If coverage and reimbursement are not available, or are available only at limited levels, we may not be able to successfully commercialize our investigational gene therapies. Even if coverage is provided, the approved reimbursement amount may not be adequate to realize a sufficient return on our investment.

Currently, at least one gene therapy product has been approved for coverage and reimbursement by CMS, the agency responsible for administering the Medicare program, but it is still difficult to predict what CMS will decide with respect to coverage and reimbursement for fundamentally novel products such as ours, as there is no body of established practices and precedents for these types of products. Moreover, reimbursement agencies in the European Union may be more conservative than CMS. For example, several cancer drugs have been

 

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approved for reimbursement in the United States and have not been approved for reimbursement in certain EU Member States. It is difficult to predict what third-party payors will decide with respect to the coverage and reimbursement for our investigational gene therapies.

Moreover, increasing efforts by government and third-party payors in the United States and other jurisdictions to cap or reduce healthcare costs may cause such organizations to limit both coverage and the level of reimbursement for new products approved and, as a result, they may not cover or provide adequate payment for our investigational gene therapies. Payors increasingly are considering new metrics as the basis for reimbursement rates, such as average sales price, average manufacturer price and actual acquisition cost. The existing data for reimbursement based on some of these metrics are relatively limited, although certain states have begun to survey acquisition cost data for the purpose of setting Medicaid reimbursement rates, and CMS has begun making pharmacy National Average Drug Acquisition Cost publicly available on at least a monthly basis. Therefore, it may be difficult to project the impact of these evolving reimbursement metrics on the willingness of payors to cover investigational gene therapies that we or our partners are able to commercialize. We expect to experience pricing pressures in connection with the sale of any of our investigational gene therapies once they obtain marketing authorization, due to the trend toward managed healthcare, the increasing influence of health maintenance organizations and additional legislative changes. The downward pressure on healthcare costs in general, particularly prescription drugs and surgical procedures and other treatments, has become intense. As a result, increasingly high barriers are being erected to the entry of new products such as ours.

The containment of healthcare costs has become a priority of federal, state and foreign governments, and the prices of drugs have been a focus in this effort. The U.S. government, state legislatures and foreign governments have shown significant interest in implementing cost-containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs. For example, in the United States, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or the PPACA, contains provisions that may reduce the profitability of products, including, for example, increased rebates for products sold to Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies’ share of sales to federal healthcare programs. Further, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several recent congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to product pricing, align U.S. drug prices with international prices, contain the cost of drugs, review the relationship between pricing and manufacturer patient support programs and reform government program reimbursement methodologies for products.

Outside the United States, international operations generally are subject to extensive government price controls and other market regulations, and increasing emphasis on cost-containment initiatives in the European Union, Canada and other countries may put pricing pressure on us. For example, a limited number of gene therapy products were approved in the European Union but are yet to be widely commercially available. In many countries, the prices of medical products are subject to varying price control mechanisms as part of national health systems or are subject to negotiation with a single government payor. We may not be able to agree to a price with the relevant government payor and if we do, in general, the prices of medicines under such systems are substantially lower than in the United States. Other countries allow companies to fix their own prices for medical products, but monitor and control company profits. Additional foreign price controls or other changes in pricing regulation could restrict the amount that we are able to charge for our investigational gene therapies. Accordingly, in markets outside the United States, the reimbursement for our investigational gene therapies may be reduced compared with the United States and may be insufficient to generate commercially reasonable product revenues.

Additionally, in countries where the pricing of gene therapy products is subject to governmental control, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product. In addition, there can be considerable pressure by governments and other stakeholders on prices and reimbursement levels, including as part of cost containment measures. Political, economic and

 

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regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Reference pricing used by various EU Member States and parallel distribution, or arbitrage between low-priced and high-priced member states, can further reduce prices. To obtain reimbursement or pricing approval in some countries, we may be required to conduct a clinical trial that compares the cost-effectiveness of our investigational gene therapies to other available therapies. If reimbursement of our products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business could be harmed.

Due to the potential for our investigational gene therapy to offer therapeutic benefit in a single administration, we face uncertainty related to pricing and reimbursement for this investigational gene therapy.

The potential for long-term therapeutic benefit from a single administration presents particular challenges to pricing review and negotiation for our investigational gene therapies for which we may obtain marketing authorization. If we are unable to obtain adequate levels of reimbursement, our ability to support our development and commercial infrastructure and to successfully market and sell our investigational gene therapy for which we may obtain marketing approval will be adversely affected.

We anticipate that our investigational gene therapy may provide long-term, durable benefit with a single administration. This is a different paradigm than that of other pharmaceutical therapies, which often require an extended course of treatment or frequent administration. As a result, governments and other payors may be reluctant to provide the significant level of reimbursement that we seek at the time of administration of our gene therapies or may seek to tie reimbursement to clinical evidence of continuing therapeutic benefit over time. Although we anticipate that our investigational gene therapy will need to be administered only once, there may be situations in which we may need to re-administer, which may further complicate the pricing and reimbursement for our investigational gene therapy. In addition, in light of the anticipated cost of these therapies, governments and other payors may be particularly restrictive in making coverage decisions. We may be required to generate sufficient clinical and econometric evidence for the value of our gene therapies in order to convince these decision makers, and may not be able to do so on a cost-effective basis or at all. These factors could limit our commercial success and harm our business.

Our gene therapy approach utilizes vectors derived from viruses, which may be perceived as unsafe or may result in unforeseen adverse events. Negative public opinion and increased regulatory scrutiny of gene therapy may damage public perception of the safety of our investigational gene therapies and adversely affect our ability to conduct our business or obtain regulatory approvals for our investigational gene therapies.

Gene therapy remains a novel technology, with only a limited number of gene therapy products approved to date. Public perception may be influenced by claims that gene therapy is unsafe, and gene therapy may not gain the acceptance of the public or the medical community. In particular, our success will depend upon physicians who specialize in the treatment of genetic diseases targeted by our investigational gene therapies, prescribing treatments that involve the use of our investigational gene therapies in lieu of, or in addition to, existing treatments with which they are familiar and for which greater clinical data may be available. More restrictive government regulations or negative public opinion would have an adverse effect on our business, financial condition, results of operations and prospects and may delay or impair the development and commercialization of our investigational gene therapies or demand for any products we may develop. Serious adverse events in our clinical trials, or other clinical trials involving gene therapy products or our competitors’ products, even if not ultimately attributable to the relevant investigational gene therapies, and the resulting publicity, could result in increased government regulation, unfavorable public perception, potential regulatory delays in the testing or approval of our investigational gene therapies, stricter labeling requirements for those investigational gene therapies that are approved and a decrease in demand for any such investigational gene therapies.

 

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Risks Related to Our Intellectual Property

If we are unable to obtain, maintain and enforce patent protection for our current investigational gene therapies and devices, and any future investigational gene therapies or devices we may develop, or if the scope of the patent protection obtained is not sufficiently broad, our competitors or other third parties could develop and commercialize gene therapies and devices similar or identical to ours and our ability to successfully develop and commercialize our investigational gene therapies and devices may be adversely affected.

Our success depends, in large part, on our ability to seek, obtain and maintain patent protection in the United States and other countries with respect to our technologies, such as Orbit SDS, and our investigational gene therapies, including GT005. We seek to protect our proprietary position by filing patent applications in the United States, the United Kingdom and elsewhere, related to certain technologies and our investigational gene therapies that are important to our business. The risks associated with patent rights generally apply to patent rights that we in-license now or in the future, as well as patent rights that we may own now or in the future. With respect to GT005, we rely on our license from Syncona IP Holdco Limited, or Syncona IP; however, the U.S. patent application we license from Syncona has not been granted as an issued patent. In addition, we do not own any issued U.S. or foreign patents or patent applications with claims directed to GT005.

The patent prosecution process is expensive, time-consuming and complex, and we may not be able to file, prosecute, maintain, enforce or license all necessary or desirable patent applications at a reasonable cost or in a timely manner. We may not be able to obtain or maintain patent applications and patents due to the subject matter claimed in such patent applications and patents being in disclosures in the public domain. In some cases, the work of certain academic researchers in the gene therapy field has entered the public domain, which may preclude our ability to obtain patent protection for certain inventions relating to such work. For example, the use of complement factors in therapy, including AAV vectors comprising transgenes for complement factors, other than Complement Factor I, is in the public domain and may preclude our ability to obtain patent protection for GT005, including composition of matter claims. While we believe that the claims in our patent applications directed to GT005 are patentable, there can be no guarantee that any such claims, including our composition of matter claims, will issue at all or in a form that provides meaningful protection for GT005. In addition, it is possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection. Although we enter into nondisclosure and confidentiality agreements with parties who have access to confidential or patentable aspects of our research and development output, such as our employees, corporate collaborators, outside scientific collaborators, contract manufacturers, consultants, advisors and other third parties, any of these parties may breach these agreements and disclose such output before a patent application is filed, thereby jeopardizing our ability to seek patent protection. Consequently, we may not be able to prevent any third party from using any of our technology that is in the public domain to compete with our investigational gene therapies and technologies.

Other parties have developed technologies that may be related or competitive to our own technologies and such parties may have filed or may file patent applications, or may have obtained or may obtain patents, claiming inventions that may overlap or conflict with those claimed in our own or licensed patent applications or issued patents. We may not be aware of all third-party intellectual property rights potentially relating to Orbit SDS and our current and future investigational gene therapies, including GT005, or devices. Publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and in other jurisdictions are typically not published until 18 months after filing, or, in some cases, not at all. Therefore, we cannot know with certainty whether the inventors of our owned or licensed patents and applications were the first to make the inventions claimed in those patents or pending patent applications, or that they were the first to file for patent protection of such inventions. If a third party can establish that we or our licensors were not the first to make or the first to file for patent protection of such inventions, our owned or licensed patent applications may not issue as patents and even if issued, may be challenged and invalidated or rendered unenforceable.

The patent position of biotechnology and pharmaceutical companies involves complex legal and factual questions and has, in recent years, been the subject of much litigation. As a result, the issuance, scope, validity,

 

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enforceability and commercial value of any patent rights are highly uncertain. Our pending and future owned and licensed patent applications may not result in patents being issued which protect our technology or investigational gene therapies, effectively prevent others from commercializing competitive technologies and gene therapies or otherwise provide any competitive advantage. In fact, patent applications may not issue as patents at all. In addition, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance.

Furthermore, patents have a limited lifespan. In the United States, the natural expiration of a patent is generally 20 years after it is filed. Various extensions may be available; however, the life of a patent, and the protection it affords, is limited. Given the amount of time required for the development, testing and regulatory review of new gene therapies, patents protecting such gene therapies might expire before or shortly after such gene therapies are commercialized. As a result, our owned and licensed patent portfolio may not provide us with adequate and continuing patent protection sufficient to exclude others from commercializing products similar to Orbit SDS or our investigational gene therapies, including biosimilar versions of such products.

The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability and our owned and licensed patents may be challenged in courts or patent offices in the United States and abroad. For example, we may be subject to a third-party submission of prior art to the U.S. Patent and Trademark Office, or USPTO, challenging the validity of one or more claims of our owned or licensed patents. Such submissions may also be made prior to a patent’s issuance, precluding the granting of a patent based on one of our owned or licensed pending patent applications. A third party may also claim that our owned or licensed patent rights are invalid or unenforceable in a litigation. The outcome following legal assertions of invalidity and unenforceability is unpredictable. An adverse result in any legal proceeding could put one or more of our owned or in-licensed patents at risk of being invalidated or interpreted narrowly and could allow third parties to commercialize our products and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize products without infringing third-party patent rights. In addition, we may become involved in derivation, reexamination, inter partes review, post-grant review or interference proceedings and other similar proceedings in foreign jurisdictions (e.g., opposition proceedings) challenging the validity, priority or other features of patentability of our owned or licensed patent rights. For example, one European patent that we exclusively license from Syncona IP relates to rAAV vectors for use in the treatment or prevention of age-related macular degeneration, which relate to GT005, was subject to an opposition proceeding. While the European Patent Office Opposition Division maintained the patent in amended form, such decision may be appealed to the Boards of Appeal and it is uncertain when or in what manner the Boards of Appeal will act on any such appeal. Such challenges may result in loss of patent rights, exclusivity, or in patent claims being narrowed, invalidated, or held unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the scope and duration of the patent protection of Orbit SDS or our technology and investigational gene therapies. Such challenges also may result in substantial cost and require significant time from our scientists and management, even if the eventual outcome is favorable to us. Any of the foregoing, could have a material adverse effect on our business, financial condition, results of operations and prospects.

Even if they are unchallenged, our owned and licensed patents and pending patent applications, if issued, may not provide us with any meaningful protection or prevent competitors from designing around our patent claims to circumvent our owned or licensed patents by developing similar or alternative technologies or therapeutics in a non-infringing manner. For example, a third party may develop a competitive product that provides benefits similar to one or more of our investigational gene therapies but that uses a vector or an expression construct that falls outside the scope of our patent protection. If the patent protection provided by the patents and patent applications we own or license is not sufficiently broad to impede such competition, our ability to successfully commercialize our investigational gene therapies could be negatively affected, which could have a material adverse effect on our business, financial condition, results of operations and prospects.

 

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We are, and may in the future be, subject to legal proceedings alleging that we are infringing, misappropriating or otherwise violating their intellectual property rights.

Our commercial success depends upon our ability and the ability of our future collaborators to develop, manufacture, market and sell our investigational gene therapies, including GT005, and Orbit SDS and use our proprietary technologies without infringing, misappropriating or otherwise violating the intellectual property of third parties. The biotechnology and pharmaceutical industries are characterized by extensive and complex litigation regarding patents and other intellectual property rights. We currently are, and may in the future become, party to, or be threatened with, adversarial proceedings or litigation where our competitors or other third parties may assert claims against us, alleging that our therapeutics, manufacturing methods, formulations, administration methods or delivery devices infringe, misappropriate or otherwise violate their intellectual property rights, including patents and trade secrets.

Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future, regardless of their merit. For example, we are aware of a third-party issued patent relating to a method of delivering products subretinally that could be construed to cover use of Orbit SDS in the United States. If such patent were to be asserted against us, we believe we would have defenses against any such assertion; however, there can be no assurance that any such defenses will be successful. If our defenses to such assertion were unsuccessful, we could be liable for damages, which could be significant and include treble damages and attorneys’ fees if we are found to willfully infringe such patent, and, unless we obtain a license to such patent, we could be precluded from commercializing Orbit SDS or any investigational gene therapy that is ultimately held to infringe such patent, any of which could have a material adverse effect on our business, financial condition, results of operations and prospects.

Patent and other types of intellectual property litigation can involve complex factual and legal questions, and their outcome is uncertain. Even if we believe such claims are without merit, a court of competent jurisdiction could hold that these third-party patents are valid, enforceable and infringed, which could adversely affect our ability to commercialize Orbit SDS or our investigational gene therapies and technology. In order to successfully challenge the validity of any such U.S. patent in federal court, we would need to overcome a presumption of validity. As this burden is a high one requiring us to present clear and convincing evidence as to the invalidity of any such U.S. patent claim, there is no assurance that a court of competent jurisdiction would invalidate the claims of any such U.S. patent or find that Orbit SDS or our investigational gene therapies or technology did not infringe any such claims. Further, even if we were successful in defending against any such claims, such claims could require us to divert substantial financial and management resources that we would otherwise be able to devote to our business.

If we are found, or believe there is a risk that we may be found, to infringe, misappropriate or otherwise violate a third party’s valid and enforceable intellectual property rights, we could be forced, including by court order, to cease developing, manufacturing and commercializing the infringing technology, investigational gene therapy or device and we could be found liable for monetary damages, including treble damages and attorneys’ fees if we are found to have willfully infringed a patent or other intellectual property right. Further, we may be required to redesign the technology, investigational gene therapy or device in a non-infringing manner which may not be commercially feasible. We could also be required or may choose to obtain a license from such third party to continue developing, manufacturing and marketing our technology, investigational gene therapies or devices. However, we may not be able to obtain any required license on commercially reasonable terms or at all. Even if we were able to obtain a license, it could be nonexclusive, thereby giving our competitors and other third parties access to the same technologies licensed to us, and it could require us to make substantial licensing and royalty payments.

Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on us. For example, on June 11, 2020, ISCI Holdings, Inc., or ISCI, filed a complaint against us and our indirect subsidiary, Orbit Biomedical Inc., or Orbit, in the United States District Court for the

 

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Eastern District of Pennsylvania, alleging that, among other things, we and Orbit misappropriated trade secrets relating to ISCI’s iTrack 275 device through the development and commercialization of the Orbit SDS. For more information regarding our litigation with ISCI, please see “Business—Legal Proceedings.” If we or Orbit are found to have misappropriated ISCI’s trade secrets, rights relating to Orbit SDS may be placed in a constructive trust for the benefit of ISCI or we may be required to cease manufacturing and commercializing Orbit SDS, be found liable for monetary damages, which may be significant, and may be required to obtain a license from ISCI for such trade secrets, which may not be available on commercially reasonable terms, on an exclusive basis or at all. Even if we were ultimately to prevail, our litigation with ISCI could require us to divert substantial financial and management resources that we would otherwise be able to devote to our business. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

Given the vast number of patents in our field of technology, we cannot be certain or guarantee that we do not infringe existing patents or that we will not infringe patents that may be granted in the future. Many companies and institutions have filed, and continue to file, patent applications related to gene therapy and related manufacturing methods. Some of these patent applications have already been allowed or issued and others may issue in the future. Since this area is competitive and of strong interest to pharmaceutical and biotechnology companies, there will likely be additional patent applications filed and additional patents granted in the future, as well as additional research and development programs expected in the future. If a patent holder believes the manufacture, use, sale or importation of Orbit SDS or one of our investigational gene therapies infringes its patent, the patent holder may sue us even if we have licensed other patent protection for our technology. Moreover, we may face patent infringement claims from nonpracticing entities that have no relevant product revenue and against whom our owned or licensed patent portfolio may therefore have no deterrent effect.

It is also possible that we have failed to identify relevant third-party patents or applications. Because patent applications can take many years to issue, may be confidential for 18 months or more after filing and can be revised before issuance, there may be applications now pending which may later result in issued patents that may be infringed by the manufacture, use, sale or importation of Orbit SDS and any investigational gene therapies and we may not be aware of such patents. Furthermore, applications filed before November 29, 2000 and certain applications filed after that date that will not be filed outside the United States may remain confidential until a patent issues. It is difficult for industry participants, including us, to identify all third-party patent rights that may be relevant to Orbit SDS or our investigational gene therapies and technologies because patent searching is imperfect due to differences in terminology among patents, incomplete databases and the difficulty in assessing the meaning of patent claims. We may fail to identify relevant patents or patent applications or may identify pending patent applications of potential interest but incorrectly predict the likelihood that such patent applications may issue with claims of relevance to our technology. In addition, we may be unaware of one or more issued patents that would be infringed by the manufacture, sale or use of Orbit SDS or a current or future investigational gene therapy, or we may incorrectly conclude that a third-party patent is invalid, unenforceable or not infringed by our activities. Additionally, pending patent applications that have been published can, subject to certain limitations, be later amended in a manner that could cover Orbit SDS or our technologies, our investigational gene therapies or the use of our investigational gene therapies. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

Our rights to develop and commercialize our investigational gene therapies are subject, in part, to the terms and conditions of licenses granted to us by others. If we fail to comply with our obligations in the agreements under which we license intellectual property rights from third parties or otherwise experience disruptions to our business relationships with our licensors, we could lose license rights that are important to our business.

We are heavily reliant upon licenses from third parties to certain patent rights and proprietary technology that are important or necessary to the development of our technology and investigational gene therapies, including GT005. For example, we rely on a license from Syncona IP for certain intellectual property relating to GT005. Further development and commercialization of our current investigational gene therapies, and

 

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development of any future investigational gene therapies or devices may, require us to enter into additional license or collaboration agreements. Our future licenses may not provide us with exclusive rights to use the licensed intellectual property and technology, or may not provide us with exclusive rights to use such intellectual property and technology in all relevant fields of use and in all territories in which we may wish to develop or commercialize our technology and investigational gene therapies in the future. Thus, patents licensed to us could be put at risk of being invalidated or interpreted narrowly in litigation filed by or against our licensors or another licensee or in administrative proceedings brought by or against our licensors or another licensee in response to such litigation or for other reasons. As a result, we may not be able to prevent competitors or other third parties from developing and commercializing competitive products, including in territories covered by our licenses.

Additionally, our current license agreements impose, and future agreements may impose, various development, diligence, commercialization and other obligations on us and require us to meet development timelines, or to exercise commercially reasonable efforts to develop and commercialize licensed products, in order to maintain the licenses. For example, our license agreement with Syncona IP imposes various development obligations on us, including, an obligation to use commercially reasonable efforts to develop a therapeutic product to deliver complement factors via subretinal injection of rAAV and our license agreement with Cambridge Enterprise Limited, or CE, also imposes various development obligations on us, including an obligation to use commercially reasonable efforts to develop a Complement Factor I therapy. For more information on the terms of the license agreements with Syncona IP and CE see “Business—Collaborations and License Agreements.”

In spite of our efforts, our current and future licensors might conclude that we have materially breached our obligations under our license agreements and might therefore terminate such license agreements, thereby removing or limiting our ability to develop and commercialize products and technology covered by these license agreements. Disputes may arise with respect to our current or future licensing agreement include disputes relating to:

 

   

the scope of rights granted under the license agreement and other interpretation-related issues;

 

   

our financial or other obligations under the license agreement;

 

   

the extent to which our technology and investigational gene therapies infringe on intellectual property of the licensor that is not subject to the licensing agreement;

 

   

the sublicensing of patent and other rights;

 

   

our diligence obligations under the license agreements and what activities satisfy those diligence obligations;

 

   

the inventorship or ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our licensors and us and our partners; and

 

   

the priority of invention of patented technology.

If disputes over intellectual property that we have licensed prevent or impair our ability to maintain our current licensing arrangements on acceptable terms, we may be unable to successfully develop and commercialize our investigational gene therapies. If our licenses are terminated, we may lose our rights to develop and market our technology and investigational gene therapies, including GT005, lose patent protection for our investigational gene therapies and technology, experience significant delays in the development and commercialization of our investigational gene therapies, or incur liability for damages. In addition, we may seek to obtain additional licenses from our licensors and, in connection with obtaining such licenses, we may agree to amend our existing licenses in a manner that may be more favorable to the licensors, including by agreeing to terms that could enable third parties, including our competitors, to receive licenses to a portion of the intellectual property that is subject to our existing licenses and to compete with our investigational gene therapies.

Furthermore, if our licenses are terminated, or if the underlying patents fail to provide the intended exclusivity, competitors or other third parties would have the freedom to seek regulatory approval of, and to

 

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market, products identical or competitive to ours and we may be required to cease our development and commercialization of certain of our investigational gene therapies. Moreover, if disputes over intellectual property that we license prevent or impair our ability to maintain other licensing arrangements on commercially acceptable terms, we may be unable to successfully develop and commercialize the affected investigational gene therapies. In addition, certain of these license agreements, may not be assignable by us without the consent of the respective licensor, which may have an adverse effect on our ability to engage in certain transactions. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

Our license agreements are, and future license agreements are likely to be, complex, and certain provisions in such agreements may be susceptible to multiple interpretations. The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business, financial condition, results of operations and prospects.

Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by government patent agencies, and our patent protection could be reduced or eliminated as a result of noncompliance with these requirements.

Periodic maintenance fees, renewal fees, annuity fees and various other government fees on patents and/or applications will be due to be paid to the USPTO and various government patent agencies outside of the United States over the lifetime of our owned or licensed patents and patent applications. We rely on our outside counsel or our licensing partners to pay these fees due to U.S. and non-U.S. patent agencies. The USPTO and various non-U.S. government patent agencies require compliance with several procedural, documentary, fee payment and other similar provisions during the patent application process. We are also dependent on our licensors to take the necessary action to comply with these requirements with respect to our licensed intellectual property. In many cases, an inadvertent lapse can be cured by payment of a late fee or by other means in accordance with the applicable rules. There are situations, however, in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. In such an event, potential competitors might be able to enter the market and this circumstance could have a material adverse effect on our business, financial condition, results of operations and prospects.

We may not be able to obtain and protect our intellectual property rights throughout the world.

Filing, prosecuting and defending patents on Orbit SDS and our investigational gene therapies in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the United States are less extensive than those in the United States. In some cases, we or our licensors may not be able to obtain patent protection for certain technology and investigational gene therapies outside the United States. In addition, the laws of some foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the United States, even in jurisdictions where we do pursue patent protection. Consequently, we may not be able to prevent third parties from practicing our or our licensors’ inventions in all countries outside the United States, even in jurisdictions where we or our licensors do pursue patent protection or from selling or importing products made using our or our licensors’ inventions in and into the United States or other jurisdictions. Competitors may use our technologies in jurisdictions where we and our licensors have not pursued and obtained patent protection to develop their own products and, further, may export otherwise infringing products to territories where we have patent protection, but enforcement is not as strong as that in the United States. These products may compete with our investigational gene therapies and our or our licensors’ patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries, particularly certain developing countries, do

 

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not favor the enforcement of patents, trade secrets and other intellectual property protection, particularly those relating to biotechnology products, which could make it difficult for us to stop the infringement of our patents, if pursued and obtained, or marketing of competing products in violation of our proprietary rights generally. Proceedings to enforce our or our licensors’ patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us. We or our licensors may not prevail in any lawsuits that we or our licensors initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.

Many countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties. In addition, many countries limit the enforceability of patents against government agencies or government contractors. In these countries, the patent owner may have limited remedies, which could materially diminish the value of such patent. If we or any of our licensors is forced to grant a license to third parties with respect to any patents relevant to our business, our business, financial condition, results of operations and prospects could be materially and adversely affected.

Issued patents covering Orbit SDS or our investigational gene therapies could be found invalid or unenforceable if challenged in court or before administrative bodies in the United States or abroad.

Our owned and licensed patents and patent applications may be subject to priority, validity, inventorship and enforceability disputes. If we or our licensors are unsuccessful in any of these proceedings, such patents and patent applications may be narrowed, invalidated or held unenforceable, we may be required to obtain licenses from third parties, which may not be available on commercially reasonable terms or at all, or we may be required to cease the development, manufacture and commercialization of Orbit SDS or one or more of the investigational gene therapies we may develop, including GT005. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

If one of our licensing partners or we initiate legal proceedings against a third party to enforce a patent covering Orbit SDS or our investigational gene therapies, assuming such a patent has issued or does issue, the defendant could counterclaim that such patent covering Orbit SDS or our investigational gene therapies is invalid or unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity or unenforceability are commonplace. Grounds for a validity challenge could include an alleged failure to meet any of several statutory requirements, including lack of novelty, obviousness, written description, non-enablement or failure to claim patent-eligible subject matter. Grounds for an unenforceability assertion could include an allegation that someone connected with prosecution of the patent withheld information material to patentability from the USPTO, or made a misleading statement, during prosecution. Third parties also may raise similar claims before administrative bodies in the United States or abroad, even outside the context of litigation. Such mechanisms include reexamination, post-grant review, inter partes review, interference proceedings, derivation proceedings and equivalent proceedings in foreign jurisdictions. For example, European patent no. EP3262066, a European patent that we exclusively license from Syncona IP relating to rAAV vectors for use in the treatment or prevention of age-related macular degeneration, which relates to GT005, is currently subject to an opposition proceeding and oral proceedings are scheduled for February 24, 2021. Although we exclusively license other patents and patent applications, which we believe cover GT005, an adverse decision in this proceeding could result in the revocation or cancellation of, or amendment to, such patent that would narrow the scope of our overall patent protection for GT005. Any future patent-related proceedings could result in the revocation or cancellation of or amendment to our patents in such a way that they no longer cover Orbit SDS or our investigational gene therapies or prevent third parties from competing with Orbit SDS or our investigational gene therapies. The outcome following legal assertions of invalidity and unenforceability is unpredictable. With respect to the validity question, for example, we cannot be certain that there is no invalidating prior art, of which the patent examiner and we or our licensing partners were unaware during prosecution. If a third party were to

 

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prevail on a legal assertion of invalidity or unenforceability, we could lose at least part, and perhaps all, of the patent protection on Orbit SDS or our investigational gene therapies. Such a loss of patent protection could have a material adverse effect on our business, financial condition, results of operations and prospects.

If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.

In addition to the protection afforded by patents, we rely on trade secret protection and confidentiality agreements to protect proprietary know-how that is not patentable or that we elect not to patent, processes for which patents are difficult to enforce and any other elements of our investigational gene therapy discovery and development processes that involve proprietary know-how, information or technology that is not covered by patents. However, trade secrets can be difficult to protect and some courts inside and outside the United States are less willing or unwilling to protect trade secrets. We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our employees, consultants, scientific advisors and contractors and other parties who have access to them. However, we may not be able to prevent the unauthorized disclosure or use of our technical know-how or other trade secrets by the parties to these agreements. Monitoring unauthorized uses and disclosures is difficult and we do not know whether the steps we have taken to protect our proprietary technologies will be effective. If any of the collaborators, scientific advisors, employees and consultants who are parties to these agreements breach or violate the terms of any of these agreements, we may not have adequate remedies for any such breach or violation. As a result, we could lose our trade secrets and third parties could use our trade secrets to compete with Orbit SDS or our investigational gene therapies and technology.

We cannot guarantee that we have entered into such agreements with each party that may have or has had access to our trade secrets or proprietary technology and processes. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems; however, such systems and security measures may be breached, and we may not have adequate remedies for any breach.

In addition, our trade secrets may otherwise become known or be independently discovered by competitors or other third parties. Competitors or third parties could purchase Orbit SDS or our investigational gene therapies and attempt to replicate some or all of the competitive advantages we derive from our development efforts, willfully infringe our intellectual property rights, design around our protected technology or develop their own competitive technologies that fall outside the scope of our intellectual property rights. If any of our trade secrets were to be lawfully obtained or independently developed by a competitor or other third party, we would have no right to prevent them, or those to whom they communicate such trade secrets, from using that technology or information to compete with us. If our trade secrets are not adequately protected so as to protect our market against competitors’ products, our business, financial condition, results of operations and prospects could be materially and adversely affected.

Intellectual property litigation and proceedings could cause us to spend substantial resources and distract our personnel from their normal responsibilities.

Litigation or other legal proceedings relating to intellectual property claims, with or without merit, are unpredictable and generally expensive and time-consuming. Competitors may infringe our patents or the patents of our licensing partners, should such patents issue, or we may be required to defend against claims of infringement, misappropriation or other violation. In addition, our patents or the patents of our licensing partners also may in the future become, involved in inventorship, priority, or validity disputes. To counter infringement or unauthorized use claims, to defend against claims of infringement, misappropriation or other violations of intellectual property and to defend against claims that our or our licensor’s intellectual property are invalid or unenforceable can be expensive and time-consuming. Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses and could distract

 

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our scientific and management personnel from their normal responsibilities. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our shares. Such litigation or proceedings could substantially increase our operating losses and reduce the resources available for development activities or any future sales, marketing or distribution activities.

We may not have sufficient financial or other resources to adequately conduct such litigation or proceedings. Some of our competitors or other third parties may be able to sustain the costs of such litigation or proceedings more effectively than we can because of their greater financial resources and more mature and developed intellectual property portfolios. Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could have a material adverse effect on our business, financial condition, results of operations and prospects.

We may be subject to claims asserting that our employees, consultants or advisors have wrongfully used or disclosed alleged trade secrets of their current or former employers or claims asserting ownership of what we regard as our own intellectual property.

Certain of our employees, consultants or advisors are currently, or were previously, employed at universities or other biotechnology or pharmaceutical companies, including our competitors or potential competitors, as well as our academic partners. Although we try to ensure that our employees, consultants and advisors do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that these individuals or we have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such individual’s current or former employer. Litigation may be necessary to defend against these claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights. An inability to incorporate such technologies or features would harm our business and may prevent us from successfully commercializing Orbit SDS or our investigational gene therapies or at all. In addition, we may lose personnel as a result of such claims and any such litigation or the threat thereof may adversely affect our ability to hire employees or contract with independent contractors. A loss of key personnel or their work product could hamper or prevent our ability to commercialize Orbit SDS or our investigational gene therapies, which would have a material adverse effect on our business, results of operations, financial condition and prospects. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management.

In addition, while it is our policy to require our employees and contractors who may be involved in the conception or development of intellectual property to execute agreements assigning such intellectual property to us, we may be unsuccessful in executing such an agreement with each party who, in fact, conceives or develops intellectual property that we regard as our own. Moreover, even when we obtain agreements assigning intellectual property to us, the assignment of intellectual property rights may not be self-executing or the assignment agreements may be breached, and we may be forced to bring claims against third parties, or defend claims that they may bring against us, to determine the ownership of what we regard as our intellectual property. Furthermore, individuals executing agreements with us may have preexisting or competing obligations to a third party, such as an academic institution, and thus an agreement with us may be ineffective in perfecting ownership of inventions developed by that individual. Disputes about the ownership of intellectual property that we may own may have a material adverse effect on our business, financial condition, results of operations and prospects.

In addition, we or our licensors may in the future be subject to claims by former employees, consultants or other third parties asserting an ownership right in our owned or licensed patents or patent applications. An adverse determination in any such submission or proceeding may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could

 

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limit our ability to stop others from using or commercializing similar technology and therapeutics, without payment to us, or could limit the duration of the patent protection covering Orbit SDS and our technology and investigational gene therapies. Such challenges may also result in our inability to develop, manufacture or commercialize Orbit SDS and our investigational gene therapies without infringing third-party patent rights. In addition, if the breadth or strength of protection provided by our owned or licensed patents and patent applications is threatened, it could dissuade companies from collaborating with us to license, develop or commercialize current or future investigational gene therapies or devices. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

We may not be successful in obtaining necessary rights to Orbit SDS or our investigational gene therapies through acquisitions and in-licenses.

We currently have certain rights to the intellectual property, through licenses from third parties, to develop and commercialize our investigational gene therapies, including GT005. Because our programs may require the use of additional intellectual property or proprietary rights held by these or other third parties, the growth of our business likely will depend, in part, on our ability to acquire, in-license or use these intellectual property or proprietary rights. We may be unable to acquire or in-license any compositions, methods of use, processes or other intellectual property from third parties that we identify as necessary for Orbit SDS or our investigational gene therapies on commercially reasonable terms, or at all. Even if we are able to in-license any such necessary intellectual property, it could be on nonexclusive terms, thereby giving our competitors and other third parties access to the same intellectual property licensed to us, and it could require us to make substantial licensing and royalty payments. The licensing or acquisition of third-party intellectual property rights is a competitive area, and several more established companies may pursue strategies to license or acquire third-party intellectual property rights that we may consider attractive or necessary. These established companies may have a competitive advantage over us due to their size, capital resources and greater clinical development and commercialization capabilities. In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us. We also may be unable to license or acquire third-party intellectual property rights on terms that would allow us to make an appropriate return on our investment.

If we are unable to successfully obtain rights to required third-party intellectual property or maintain the existing intellectual property rights we have licensed, we may be required to expend significant time and resources to redesign Orbit SDS or our investigational gene therapies, or to develop or license replacement technology, all of which may not be feasible on a technical or commercial basis, and we may have to abandon development of Orbit SDS or our investigational gene therapies which could have a material adverse effect on our business, financial condition, results of operations and prospects.

Changes in U.S. patent law could diminish the value of patents in general, thereby impairing our ability to protect Orbit SDS or our investigational gene therapies.

Changes in either the patent laws or interpretation of the patent laws in the United States could increase the uncertainties and costs surrounding the prosecution of patent applications and the enforcement or defense of issued patents. Assuming that other requirements for patentability are met, prior to March 2013, in the United States, the first to invent the claimed invention was entitled to the patent, while outside the United States, the first to file a patent application was entitled to the patent. After March 2013, under the Leahy-Smith America Invents Act, or the America Invents Act, enacted in September 2011, the United States transitioned to a first inventor to file system in which, assuming that other requirements for patentability are met, the first inventor to file a patent application will be entitled to the patent on an invention regardless of whether a third party was the first to invent the claimed invention. The America Invents Act also includes a number of significant changes that affect the way patent applications are prosecuted and also may affect patent litigation. These include allowing third-party submission of prior art to the USPTO during patent prosecution and additional procedures to challenge the validity of a patent by USPTO administered post-grant proceedings, including post-grant review, inter partes review and derivation proceedings. The America Invents Act and its implementation could increase the

 

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uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business, financial condition, results of operations and prospects.

The patent positions of companies engaged in the development and commercialization of biologics and pharmaceuticals are particularly uncertain. Court rulings may narrow the scope of patent protection available in certain circumstances and weaken the rights of patent owners in certain situations, including for patents relating to genetic molecules. We cannot predict how decisions by the courts, the U.S. Congress or the USPTO may impact the value of our patents. Any similar adverse changes in the patent laws of other jurisdictions could also have a material adverse effect on our business, financial condition, results of operations and prospects. Depending on future actions by the U.S. Congress, the federal courts and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could have a material adverse effect on our existing patent portfolio and our ability to protect and enforce our intellectual property in the future. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

We may need to obtain patent term extension and equivalent extensions outside of the United States for Orbit SDS or our investigational gene therapies, including GT005.

Depending upon the timing, duration and specifics of any FDA marketing approval of Orbit SDS or our investigational gene therapies, including GT005, one or more U.S. patents that we license or may own in the future may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, or the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent extension term of up to five years as compensation for patent term lost during the FDA regulatory review process based on the first regulatory approval for a particular drug or biologic. A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent may be extended and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended. In Europe, supplementary protection certificates are available to extend a patent term up to five years to compensate for patent term lost during regulatory review, and can be extended for an additional six months if data from clinical trials is obtained in accordance with an agreed-upon pediatric investigation plan. Although all countries in Europe must provide supplementary protection certificates, there is no unified legislation among European countries and so supplementary protection certificates must be applied for and granted on a country-by-country basis. This can lead to a substantial cost to apply for and receive these certificates, which may vary among countries or not be provided at all.

We may not be granted any extensions for which we apply in the United States or any other jurisdiction because of, for example, failing to exercise due diligence during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents or otherwise failing to satisfy applicable requirements. Moreover, the applicable time period or the scope of patent protection afforded could be less than we request. In addition, to the extent we wish to pursue patent term extension based on a patent that we in-license from a third party, we would need the cooperation of that third party. If we are unable to obtain patent term extension, or the foreign equivalent, or if the term of any such extension is less than we request, our competitors may be able to enter the market sooner, and our revenue could be reduced. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

If our trademarks and trade names are not adequately protected, then we may not be able to build name recognition in our markets of interest.

Our current and future trademark applications in the United States and in foreign jurisdictions may not be allowed or may subsequently be opposed. Once filed and registered, our trademarks or trade names may be challenged, infringed, circumvented or declared generic or determined to be infringing on other marks. As a means to enforce our trademark rights and prevent infringement, we may be required to file trademark claims

 

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against third parties or initiate trademark opposition proceedings. This can be expensive and time-consuming, particularly for a company of our size. We may not be able to protect our rights to these trademarks and trade names, which we need to build name recognition among potential partners or customers in our markets of interest. At times, competitors may adopt trade names or trademarks similar to ours, thereby impeding our ability to build brand identity and possibly leading to market confusion. In addition, there could be potential trade name or trademark infringement claims brought by owners of other registered trademarks or trademarks that incorporate variations of our registered or unregistered trademarks or trade names. Over the long term, if we are unable to establish name recognition based on our trademarks and trade names, then we may not be able to compete effectively and our business may be adversely affected. Our efforts to enforce or protect our proprietary rights related to trademarks, trade secrets, domain names, copyrights or other intellectual property may be ineffective and could result in substantial costs and diversion of resources. Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

Intellectual property rights do not necessarily address all potential threats.

The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights have limitations, and may not adequately protect our business or permit us to maintain our competitive advantage. For example:

 

   

others may be able to make gene therapy products and delivery systems that are similar to ours, but that are not covered by the claims of the patents that we license or may own in the future;

 

   

we, or our license partners or future collaborators, might not have been the first to make the inventions covered by the issued patent or pending patent applications that we license or may own in the future;

 

   

we, or our license partners or future collaborators, might not have been the first to file patent applications covering certain of our or their inventions;

 

   

others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our owned or licensed intellectual property rights;

 

   

others may circumvent our regulatory exclusivities, such as by pursuing approval of a competitive gene therapy via the traditional approval pathway based on their own clinical data, rather than relying on the abbreviated pathway provided for biosimilar applicants;

 

   

it is possible that our pending licensed patent applications or those that we may own in the future will not lead to issued patents;

 

   

issued patents that we hold rights to now or in the future may be held invalid or unenforceable, including as a result of legal challenges by our competitors;

 

   

others may have access to the same intellectual property rights licensed to us in the future on a nonexclusive basis;

 

   

our competitors might conduct research and development activities in countries where we do not have patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets;

 

   

we may not develop additional proprietary technologies that are patentable;

 

   

the patents or other intellectual property rights of others may have an adverse effect on our business; or

 

   

we may choose not to file a patent for certain trade secrets or know-how, and a third party may subsequently file a patent covering such intellectual property.

Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

 

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Risks Related to other Government Regulation

The withdrawal of the United Kingdom from the European Union, commonly referred to as “Brexit,” may adversely impact our ability to obtain regulatory approvals of our investigational gene therapies in the European Union or the United Kingdom, result in restrictions or imposition of taxes and duties for importing our investigational gene therapies into the European Union or the United Kingdom, and require us to incur additional expenses in order to develop, manufacture and commercialize our investigational gene therapies in the European Union or the United Kingdom.

The United Kingdom is a major market for pharmaceutical products. Following the result of a referendum in 2016, the United Kingdom formally left the European Union on January 31, 2020, commonly referred to as “Brexit.” Pursuant to the formal withdrawal arrangements agreed to by the United Kingdom and the European Union, the United Kingdom entered into a transition period until December 31, 2020, or the Transition Period, during which the United Kingdom remained within the European Union single market and customs union and European Union rules continued to apply in the United Kingdom. On December 30, 2020, the United Kingdom and European Union signed a trade and cooperation agreement, or the Trade and Cooperation Agreement, which includes an agreement on free trade between the two parties.

There is now considerable uncertainty resulting from a lack of precedent and the complexity of the United Kingdom and EU’s intertwined legal regimes as to how Brexit will impact the life sciences industry in Europe, including our company, including with respect to ongoing or future clinical trials. Since a significant proportion of the regulatory framework in the United Kingdom applicable to our business and our investigational gene therapies is derived from EU directives and regulations, the withdrawal could materially impact the regulatory regime with respect to the development, manufacture, importation, approval and commercialization of our investigational gene therapies in the United Kingdom or the European Union. The impact will largely depend on the model and means by which the United Kingdom’s relationship with the European Union is governed post-Brexit and the extent to which the United Kingdom chooses to diverge from the EU regulatory framework. For example, following the Transition Period, Great Britain is no longer covered by the centralized procedures for obtaining EU-wide marketing authorizations and our products therefore require a separate marketing authorization from the MHRA to allow us to market such products in Great Britain. It is unclear as to whether the relevant authorities in the EU and the United Kingdom are adequately prepared for the additional administrative burden caused by Brexit. Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, would prevent us from or delay us commercializing our product candidates in the United Kingdom and/or the EEA and restrict our ability to generate revenue and achieve and sustain profitability. In the short term, following the expiry of the Transition Period there is a risk of disrupted import and export processes due to a lack of administrative processing capacity by the respective United Kingdom and EU customs agencies that may delay time-sensitive shipments and may negatively impact our product supply chain. Further, under current plans, orphan designation in the United Kingdom (or Great Britain, depending on whether there is a prior centralized marketing authorization in the EEA) following Brexit is to be based on the prevalence of the condition in Great Britain as opposed to the previous position where prevalence in the EU was the determinant. It is therefore possible that conditions that were, during the Transition Period, designated as orphan conditions in the United Kingdom will no longer be and that conditions not previously designated as orphan conditions in the European Union will be designated as such in the United Kingdom.

If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the United Kingdom and/or EEA for our product candidates, which could significantly and materially harm our business. There is a degree of uncertainty regarding the overall impact that Brexit will have on (i) the marketing of pharmaceutical products; (ii) the process to obtain regulatory approval in the United Kingdom for product candidates; or (iii) the award of exclusivities that are normally part of the EU legal framework (for instance Supplementary Protection Certificates, Pediatric Extensions or Orphan exclusivity).

Brexit may also result in a reduction of funding to the EMA once the United Kingdom no longer makes financial contributions to European institutions, such as the EMA. If funding for the EMA is so reduced, it could

 

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create delays in the EMA issuing regulatory approvals for our investigational gene therapies and, accordingly, have a material adverse effect on our business, financial condition, results of operations or prospects.

In addition, we may be required to pay taxes or duties or be subjected to other hurdles in connection with the importation of our investigational gene therapies into the European Union or the United Kingdom, or we may incur expenses in establishing a manufacturing facility in the European Union in order to circumvent such hurdles. If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the United Kingdom or the European Union for our investigational gene therapies, or incur significant additional expenses to operate our business, which could significantly and materially harm or delay our ability to generate revenues or achieve profitability of our business.

As a result of Brexit, other European countries may seek to conduct referenda with respect to their continuing membership with the European Union. Given these possibilities and others we may not anticipate, as well as the absence of comparable precedent, it is unclear what financial, regulatory and legal implications the withdrawal of the United Kingdom from the European Union will have, how such withdrawal will affect us, and the full extent to which our business could be adversely affected.

We may be liable for stamp duty in connection with the Corporate Reorganization.

In connection with the Corporate Reorganization, there has been a transfer of the entire issued share capital of Gyroscope Therapeutics Limited to Gyroscope Therapeutics Holdings Limited pursuant to the share exchange agreement prior to the completion of this offering. We have made an application to Her Majesty’s Revenue & Customs, or HMRC, for such transfer to be adjudicated as not chargeable to stamp duty by virtue of section 77 of the Finance Act 1986. While it is expected that all of the conditions of section 77 of the Finance Act 1986 can be satisfied and relief should be available, if such relief is not forthcoming we will be required to pay 0.5% stamp duty of the value of the consideration given for that transfer, which is expected to be, broadly, 0.5% of the value of the Gyroscope Therapeutics Limited share capital transferred.

Healthcare legislative reform measures may have a negative impact on our business and results of operations.

In the United States and some foreign jurisdictions, there have been, and continue to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our investigational gene therapies, restrict or regulate post-approval activities and affect our ability to profitably sell any investigational gene therapies for which we obtain marketing approval.

In March 2010, the PPACA was passed, which substantially changed the way healthcare is financed by both the government and private insurers, and significantly impacts the U.S. pharmaceutical industry. The PPACA, among other things: (i) addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected; (ii) increased the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extends the rebate program to individuals enrolled in Medicaid managed care organizations; (iii) established annual fees and taxes on manufacturers of certain branded prescription drugs; (iv) expanded the availability of lower pricing under the 340B drug pricing program by adding new entities to the program; and (v) established a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (increased to 70% pursuant to the Bipartisan Budget Act of 2018, effective as of January 1, 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D. Additionally, in the United States, the Biologics Price Competition and Innovation Act of 2009, or BPCIA, created an abbreviated approval pathway for biological products that are demonstrated to be “highly similar” (biosimilar) or “interchangeable” with a FDA-approved biological product. This pathway allows competitors to reference data

 

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from biological products already approved after twelve years from the time of approval. This could expose us to potential competition by lower-cost biosimilars even if we commercialize an investigational gene therapy faster than our competitors. Moreover, the creation of this abbreviated approval pathway does not preclude or delay a third party from pursuing approval of a competitive product candidate via the traditional approval pathway based on their own clinical trial data.

Additional changes that may affect our business include those governing enrollment in federal healthcare programs, reimbursement changes, rules regarding prescription drug benefits under the health insurance exchanges and fraud and abuse and enforcement. Continued implementation of the PPACA and the passage of additional laws and regulations may result in the expansion of new programs such as Medicare payment for performance initiatives, and may impact existing government healthcare programs, such as by improving the physician quality reporting system and feedback program. For each state that does not choose to expand its Medicaid program, there likely will be fewer insured patients overall, which could impact the sales, business and financial condition of manufacturers of branded prescription drugs. Where patients receive insurance coverage under any of the new Medicaid options made available through the PPACA, manufacturers may be required to pay Medicaid rebates on that resulting drug utilization.

There have been executive, judicial and congressional challenges. Former President Trump signed several Executive Orders designed to delay the implementation of certain provisions of the PPACA or otherwise circumvent some of the requirements for health insurance mandated by the PPACA. While Congress has not passed comprehensive repeal legislation to date, it has enacted laws that modify certain provisions of the PPACA such as the Tax Cuts and Jobs Act of 2017, or TCJA, which decreased, effective January 1, 2019, the tax-based shared responsibility payment imposed by the PPACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year, commonly referred to as the “individual mandate,” to $0. On December 14, 2018, a federal district court in Texas ruled the individual mandate is a critical and inseverable feature of the PPACA, and therefore, because it was repealed as part of the TCJA, the remaining provisions of the PPACA are invalid as well. On December 18, 2019, the Fifth Circuit U.S. Court of Appeals held that the individual mandate is unconstitutional, and remanded the case to the lower court to reconsider its earlier invalidation of the full PPACA. The U.S. Supreme Court is currently reviewing this case, although it is unclear when a decision will be made. On February 10, 2021, the Biden administration withdrew the federal government’s support for overturning the PPACA. Further, although the U.S. Supreme Court has not yet ruled on the constitutionality of the PPACA, President Biden issued an executive order to initiate a special enrollment period for purposes of obtaining health insurance coverage through the PPACA marketplace, which began on February 15, 2021 and will remain open through August 15, 2021. The executive order also instructs certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the PPACA. It is unclear how the Supreme Court ruling, other such litigation, and the healthcare reform measures of the Biden administration will impact the PPACA and our business.

Other legislative changes have been proposed and adopted in the United States since the PPACA was enacted. On January 22, 2018, former President Trump signed a continuing resolution on appropriations for fiscal year 2018 that delayed the implementation of certain PPACA-mandated fees, including the so called “Cadillac” tax on certain high cost employer-sponsored insurance plans, the annual fee imposed on certain health insurance providers based on market share and the medical device excise tax on nonexempt medical devices. However on December 20, 2019, former President Trump signed into law the Further Consolidated Appropriations Act (H.R. 1865), which permanently repealed the Cadillac tax, and the medical device excise tax and, effective January 1, 2021, also eliminated the health insurer tax. On January 2, 2013, the American Taxpayer Relief Act of 2012, or ATRA, was signed into law, which, among other things, reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress. A Joint Select

 

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Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs. This includes aggregate reductions of Medicare payments to providers up to 2% per fiscal year, and, due to subsequent legislative amendments, such reductions will remain in effect through 2030 unless additional Congressional action is taken. However, the Medicare sequester reductions under the Budget Control Act are suspended from May 1, 2020 through December 31, 2021, due to the COVID-19 pandemic.

There has been increasing legislative and enforcement interest in the United States with respect to specialty drug pricing practices. Specifically, there have been several recent U.S. Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement methodologies for drugs. At the federal level, the Trump administration used several means to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives. For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing. As a result, the FDA also released a final rule on September 24, 2020 providing guidance for states to build and submit importation plans for drugs from Canada. Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law. The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation. The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed until January 1, 2023. On November 20, 2020, CMS issued an interim final rule implementing former President Trump’s Most Favored Nation executive order, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effective January 1, 2021. On December 28, 2020, the United States District Court in Northern California issued a nationwide preliminary injunction against implementation of the interim final rule. It is unclear whether the Biden administration will work to reverse these measures or pursue similar policy initiatives.

At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. These measures could reduce the ultimate demand for our investigational gene therapies, once approved, or put pressure on our product pricing.

Our ability to generate revenue from investigational gene therapies could be adversely affected by changes in healthcare spending and policy in the United States and abroad. In the United States, the European Union and other potentially significant markets for our investigational gene therapies, government authorities and third-party payors are increasingly attempting to limit or regulate the price of medical products and services, particularly for new and innovative products and therapies, which has resulted in lower average selling prices. Furthermore, the increased emphasis on managed healthcare in the United States and on country and regional pricing and reimbursement controls in the European Union and United Kingdom will put additional pressure on product pricing, reimbursement and usage, which may adversely affect our future product sales and results of operations. These pressures can arise from rules and practices of managed care groups, judicial decisions and governmental laws and regulations related to Medicare, Medicaid and healthcare reform, pharmaceutical reimbursement policies and pricing in general.

 

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There have been, and likely will continue to be, legislative and regulatory proposals at the foreign, federal and state levels directed at broadening the availability of healthcare and containing or lowering the cost of healthcare. We cannot predict the initiatives that may be adopted in the future, particularly in light of the recent U.S. presidential election. The continuing efforts of the government, insurance companies, managed care organizations and other payors of healthcare services to contain or reduce costs of healthcare or impose price controls may adversely affect:

 

   

the demand for our investigational gene therapies, if we obtain regulatory approval;

 

   

our ability to set a price that we believe is fair for our investigational gene therapies;

 

   

our ability to generate revenue and achieve or maintain profitability;

 

   

the level of taxes that we are required to pay; and

 

   

the availability of capital.

We expect that the PPACA, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we receive for any approved product. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our investigational gene therapies.

We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our investigational gene therapies or additional pricing pressures. Further, it is possible that additional government action is taken in response to the COVID-19 pandemic.

We are subject to the UK Bribery Act 2010, the U.S. Foreign Corrupt Practices Act of 1977 and other anti-corruption laws, as well as export control laws, import and customs laws, trade and economic sanctions laws and other laws governing our operations.

Our operations are subject to anti-corruption laws, including the UK Bribery Act 2010, or the Bribery Act, the U.S. Foreign Corrupt Practices Act of 1977, as amended, or the FCPA, the U.S. domestic bribery statute contained in 18 U.S.C. §201, the U.S. Travel Act, and other anti-corruption laws that apply in countries where we do business. The Bribery Act, the FCPA and these other laws generally prohibit us and our employees and intermediaries from authorizing, promising, offering, or providing, directly or indirectly, improper or prohibited payments, or anything else of value, to government officials or other persons to obtain or retain business or gain some other business advantage. Under the Bribery Act, we may also be liable for failing to prevent a person associated with us from committing a bribery offense. We and our suppliers operate in a number of jurisdictions that pose a high risk of potential Bribery Act or FCPA violations, and we participate in collaborations and relationships with third parties whose corrupt or illegal activities could potentially subject us to liability under the Bribery Act, FCPA or local anti-corruption laws, even if we do not explicitly authorize or have actual knowledge of such activities. In addition, we cannot predict the nature, scope or effect of future regulatory requirements to which our international operations might be subject or the manner in which existing laws might be administered or interpreted.

We are also subject to other laws and regulations governing our international operations, including regulations administered by the governments of the United Kingdom and the United States, and authorities in the European Union, including applicable export control regulations, economic sanctions and embargoes on certain countries and persons, anti-money laundering laws, import and customs requirements and currency exchange regulations, collectively referred to as the Trade Control laws.

 

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There is no assurance that we will be completely effective in ensuring our compliance with all applicable anti-corruption laws, including the Bribery Act, the FCPA or other legal requirements, including Trade Control laws. If we are not in compliance with the Bribery Act, the FCPA and other anti-corruption laws or Trade Control laws, we may be subject to criminal and civil penalties, disgorgement and other sanctions and remedial measures, and legal expenses, which could have an adverse impact on our business, financial condition, results of operations and liquidity. Likewise, any investigation of any potential violations of the Bribery Act, the FCPA, other anti-corruption laws or Trade Control laws by the United Kingdom, United States or other authorities could also have an adverse impact on our reputation, our business, results of operations and financial condition.

Our relationships with healthcare providers and physicians and third-party payors will be subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.

Healthcare providers, including physicians, and third-party payors in the United States and elsewhere play a primary role in the recommendation and prescription of pharmaceutical products. Arrangements with third-party payors and customers can expose pharmaceutical manufacturers to broadly applicable fraud and abuse and other healthcare laws and regulations, including, without limitation, the federal Anti-Kickback Statute, the federal False Claims Act, or FCA, and the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which may constrain the business or financial arrangements and relationships through which such companies sell, market and distribute biopharmaceutical products. In particular, the research of our investigational gene therapies, as well as the promotion, sales and marketing of healthcare items and services, as well as certain business arrangements in the healthcare industry, are subject to extensive laws designed to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of discounting, marketing and promotion, structuring and commissions, certain customer incentive programs and other business arrangements generally. Activities subject to these laws also involve the improper use of information obtained in the course of patient recruitment for clinical trials. The applicable federal, state and foreign healthcare laws and regulations laws that may affect our ability to operate include, but are not limited to:

 

   

the federal Anti-Kickback Statute, which prohibits, among other things, persons or entities from knowingly and willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe or rebate), directly or indirectly, overtly or covertly, in cash or in kind, in return for either the referral of an individual to a person for the furnishing of items or services reimbursable under a federal health care program, such as the Medicare and Medicaid programs, or the purchase, lease, order, or recommendation or arrangement for the purchase, lease, order, or recommendation of a good, facility, item or service reimbursable under a federal healthcare program. This statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand, and prescribers, purchasers and formulary managers on the other. The PPACA amended the intent requirement of the federal Anti-Kickback Statute, such that a person or entity no longer needs to have actual knowledge of this statute or specific intent to violate it. In addition, a claim submitted for payment to any federal health care program that includes items or services that were made as a result of a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA. There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution;

 

   

federal civil and criminal false claims laws, including the FCA, and civil monetary penalty laws, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment or approval from Medicare, Medicaid or other third-party payors that are false or fraudulent. A claim that includes items or services resulting from a violation of the federal Anti-Kickback Statute or certain marketing practices, including off-label promotion, may implicate the FCA. Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims. The

 

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FCA also permits a private individual acting as a “whistleblower” to bring qui tam actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery;

 

   

HIPAA, which imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters. Similar to the federal Anti-Kickback Statute, a person or entity can be found guilty of violating HIPAA without actual knowledge of the statute or specific intent to violate it;

 

   

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their implementing regulations, which impose certain requirements relating to the privacy and security of individually identifiable health information maintained by covered entities subject to the rule, such as health plans, healthcare clearinghouses and healthcare providers, and by their respective business associates (entities that perform certain functions or activities that involve the creation, use, receipt, maintenance or disclosure of individually identifiable health information on behalf of covered entities) and their covered subcontractors. HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions;

 

   

federal transparency laws, including the federal Physician Payment Sunshine Act and its implementing regulations, that require manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to the CMS information related to: (i) payments or other “transfers of value” made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals and (ii) ownership and investment interests held by physicians and their immediate family members. Effective January 1, 2022, these reporting obligations will extend to include transfers of value made in the previous year to certain non-physician providers, including physician assistants, nurse practitioners, clinical nurse specialists, certified registered nurse anesthetists, anesthesiologist assistants and certified nurse midwives;

 

   

federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers; and

 

   

analogous state and foreign laws and regulations, such as anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by third-party payors, including private insurers, and may be broader in scope than their federal equivalents; laws that require biopharmaceutical companies to comply with the biopharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers and other potential referral sources; laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers, marketing expenditures or drug pricing; laws that require the registration of biopharmaceutical sales representatives; and laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant

 

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criminal, civil and administrative sanctions including monetary penalties, damages, fines, disgorgement, reputational harm, imprisonment and exclusion from participation in government funded healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of noncompliance with these laws, reputational harm and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations. Further, if any of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to significant criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs. Any action for violation of these laws, even if successfully defended, could cause a biopharmaceutical manufacturer to incur significant legal expenses and divert management’s attention from the operation of the business. Prohibitions or restrictions on sales or withdrawal of future marketed products could materially affect business in an adverse way.

The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the European Union and United Kingdom. The provision of benefits or advantages to physicians is governed by the national anti-bribery laws of EU Member States and the United Kingdom. Infringement of these laws could result in substantial fines and imprisonment. Payments made to physicians in certain EU Member States must be publicly disclosed. Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization or the regulatory authorities of the individual EU Member States. These requirements are provided in the national laws, industry codes or professional codes of conduct, applicable in the EU Member States and the United Kingdom. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

The risk of our being found in violation of these laws is increased by the fact that many of them have not been fully interpreted by the regulatory authorities or the courts, and their provisions are open to a variety of interpretations. Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business. The shifting compliance environment and the need to build and maintain robust and expandable systems to comply with multiple jurisdictions with different compliance or reporting requirements increases the possibility that a healthcare company may run afoul of one or more of the requirements.

Our internal information technology systems, or those of our third-party vendors, contractors, or consultants, may fail or suffer security breaches, loss or leakage of data and other disruptions, which could result in disruption of our services, compromise sensitive information related to our business, or prevent us from accessing critical information, potentially exposing us to liability or otherwise adversely affecting our business.

We are increasingly dependent upon information technology systems, infrastructure and data to operate our business. In the ordinary course of business, we collect, store and transmit confidential information (including but not limited to intellectual property, proprietary business information and personal information). It is critical that we do so in a secure manner to maintain the confidentiality and integrity of such confidential information. We also have outsourced elements of our operations to third parties, and as a result we manage a number of third-party vendors and other contractors and consultants who have access to our confidential information.

Despite the implementation of security measures, given the size and complexity of our internal information technology systems and those of our third-party vendors and other contractors and consultants, and the increasing amounts of confidential information that they maintain, such information technology systems are potentially vulnerable to breakdown or other damage or interruption from service interruptions, system malfunction, natural disasters, terrorism, war, and telecommunication and electrical failures. Such information technology systems are additionally vulnerable to security incidents from inadvertent or intentional actions by our employees, third-party

 

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vendors, contractors, consultants, business partners, or other third parties, or from cyberattacks by malicious third parties (including the deployment of harmful malware, ransomware, denial-of-service attacks, social engineering, and other means to affect service reliability and threaten the confidentiality, integrity, and availability of information). Any of the foregoing may compromise or disable our system infrastructure, or that of our third-party vendors and other contractors and consultants or lead to data leakage. The risk of a security breach or disruption, particularly through cyberattacks including supply chain attacks such as SolarWinds or cyber intrusion, including by computer hackers, foreign governments, and cyber terrorists, has generally increased as the number, intensity, and sophistication of attempted attacks and intrusions from around the world have increased. We may not be able to anticipate all types of security threats, and we may not be able to implement preventive measures effective against all such security threats. The techniques used by cyber criminals change frequently, may not be recognized until launched, and can originate from a wide variety of sources, including outside groups such as third-party service providers, organized crime affiliates, terrorist organizations, or hostile foreign governments or agencies. To the extent that any disruption or security breach were to result in a loss or interruption of, or damage to, our data or applications, or those of our third-party vendors and other contractors and consultants, or inappropriate disclosure of confidential information, we could incur liability and reputational damage and the further development and commercialization of our investigational gene therapies, Orbit SDS or other devices we may develop could be compromised or delayed. We do not currently hold cybersecurity insurance and the costs related to significant security breaches or disruptions could be material and cause us to incur significant expenses. If the information technology systems of our third-party vendors and other contractors and consultants become subject to disruptions or security breaches, we may have insufficient recourse against such third parties and we may have to expend significant resources to mitigate the impact of such an event, and to develop and implement protections to prevent future events of this nature from occurring.

We cannot assure you that our data protection efforts and our investment in information technology will prevent breakdowns, data leakages, breaches in our systems, or those of our third-party vendors and other contractors and consultants, or other cyber incidents that could have a material adverse effect upon our reputation, business, operations, or financial condition. For example, if such an event were to occur and cause interruptions in our operations, or those of our third-party vendors and other contractors and consultants, it could result in a material disruption or delay of the development of our investigational gene therapies. Furthermore, significant disruptions of our internal information technology systems or those of our third-party vendors and other contractors and consultants, or security breaches could result in the loss, misappropriation, or unauthorized access, use, or disclosure of, or the prevention of access to, confidential information, which could result in financial, legal, business and reputational harm to us. For example, any such event that leads to unauthorized access, use, or disclosure of personal information, including personal information regarding our customers or employees, could harm our reputation directly, compel us to comply with federal or state breach notification laws and foreign law equivalents, subject us to mandatory corrective action, and otherwise subject us to liability under laws and regulations that protect the privacy and security of personal information, which could result in significant legal and financial exposure and reputational damages that could potentially have a material adverse effect on our business, financial condition, results of operations and prospects.

We are subject to stringent privacy laws, information security laws, regulations, policies and contractual obligations related to data privacy and security and changes in such laws, regulations, policies and contractual obligations could adversely affect our business.

We are subject to data privacy and protection laws and regulations that apply to the collection, transmission, storage and use of personally identifying information, which among other things, impose certain requirements relating to the privacy, security and transmission of personal information. The legislative and regulatory landscape for privacy and data protection continues to evolve in jurisdictions worldwide, and there has been an increasing focus on privacy and data protection issues with the potential to affect our business. Failure to comply with any of these laws and regulations could result in enforcement action against us, including fines, imprisonment of company officials and public censure, claims for damages by affected individuals, damage to

 

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our reputation and loss of goodwill, any of which could have a material adverse effect on our business, financial condition, results of operations or prospects.

There are numerous U.S. federal and state laws and regulations relating to privacy and security of personal information. In particular, regulations promulgated pursuant to HIPAA establish privacy and security standards that limit the use and disclosure of individually identifiable health information, or protected health information, and require the implementation of administrative, physical and technological safeguards to protect the privacy of protected health information and ensure the confidentiality, integrity and availability of electronic protected health information. Determining whether protected health information has been handled in compliance with applicable privacy standards and our contractual obligations can be complex and may be subject to changing interpretation.

If we are unable to properly protect the privacy and security of protected health information, we could be found to have breached our contracts. Further, if we fail to comply with applicable privacy laws, including applicable HIPAA privacy and security standards, we could face civil and criminal penalties. The U.S. Department of Health and Human Services, or HHS, has the discretion to impose penalties without attempting to first resolve violations. HHS enforcement activity can result in financial liability and reputational harm, and responses to such enforcement activity can consume significant internal resources. In addition, state attorneys general are authorized to bring civil actions seeking either injunctions or damages in response to violations that threaten the privacy or security of the personal information of state residents. We cannot be sure how these regulations will be interpreted, enforced or applied to our operations. In addition to the risks associated with enforcement activities and potential contractual liabilities, our ongoing efforts to comply with evolving laws and regulations at the federal and state level may be costly and require ongoing modifications to our policies, procedures and systems.

Data privacy remains an evolving landscape at both the domestic and international level, with new regulations coming into effect. For example, the State of California enacted the California Consumer Privacy Act of 2018, or CCPA, which went into effect on January 1, 2020 and requires companies that process information on California residents to make new disclosures to consumers about their data collection, use and sharing practices, allow consumers to opt out of certain data sharing with third parties and provide a new cause of action for data breaches. Additionally, California voters approved a new privacy law, the California Privacy Rights Act, or CPRA, in the November 3, 2020 election. Effective starting on January 1, 2023, the CPRA will significantly modify the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information. The CPRA also creates a new state agency that will be vested with authority to implement and enforce the CCPA and the CPRA. New legislation proposed or enacted in various other states will continue to shape the data privacy environment nationally. Certain state laws may be more stringent or broader in scope, or offer greater individual rights, with respect to confidential, sensitive and personal information than federal, international or other state laws, and such laws may differ from each other, which may complicate compliance efforts.

In addition, all 50 U.S. states and the District of Columbia have enacted breach notification laws that may require us to notify patients, employees or regulators in the event of unauthorized access to or disclosure of personal or confidential information experienced by us or our service providers. These laws are not consistent, and compliance in the event of a widespread data breach is difficult and may be costly. Moreover, states have been frequently amending existing laws, requiring attention to changing regulatory requirements. We also may be contractually required to notify patients or other counterparties of a security breach. Although we may have contractual protections with our service providers, any actual or perceived security breach could harm our reputation and brand, expose us to potential liability or require us to expend significant resources on data security and in responding to any such actual or perceived breach. Any contractual protections we may have from our service providers may not be sufficient to adequately protect us from any such liabilities and losses, and we may be unable to enforce any such contractual protections. In addition to government regulation, privacy advocates and industry groups have and may in the future propose self-regulatory standards from time to time. These and other industry standards may legally or contractually apply to us, or we may elect to comply with such standards.

 

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In addition, the European Union’s General Data Protection Regulation (EU) 2016/679, or GDPR, became applicable on May 25, 2018. The GDPR imposes onerous accountability obligations requiring data controllers and processors to maintain a record of their data processing and policies. The GDPR imposes certain other onerous obligations, including: obligations for controllers and processors to appoint data protection officers in certain circumstances; increased transparency obligations to data subjects for controllers (including presentation of certain information in a concise, intelligible and easily accessible form about how their personal data is used and their rights vis-à-vis that data and its use); the obligation to carry out so-called data protection impact assessments in certain circumstances; limitations on collection and retention of personal data through ‘purpose,’ ‘data minimization’ and ‘storage limitation’ principles; obligations to implement ‘privacy by design’; obligations to honor increased rights for data subjects (such as rights for individuals to be ‘forgotten,’ rights to data portability, rights to object, etc. in certain circumstances); a heightened and codified standard of data subject consent; obligations to implement certain technical and organizational safeguards to protect the security and confidentiality of personal data; obligations to agree to certain specific contractual terms and to take certain measures when engaging third-party processors and joint controllers; and the obligation to provide notice of certain significant personal data breaches to the relevant supervisory authority(ies) and affected individuals. In addition, the GDPR materially expanded the definition of what constitutes personal data (including, for example, by expressly clarifying that the GDPR applies to ‘pseudonymized’ and key-coded data).

The GDPR imposes strict rules on the transfer of personal data to countries outside the EEA, including the United States. In response, the European Union and United States agreed in 2016 to a transfer framework for data transferred from the European Union to the United States, called the EU-US Privacy Shield, but the EU-US Privacy Shield was invalidated in July 2020 by the Court of Justice of the European Union, or CJEU, in a case known colloquially as “Schrems II.” The standard contractual clauses issued by the European Commission, or the EC, for the transfer of personal data, or any successor version(s) of those clauses, may be similarly invalidated by the CJEU and/or courts in the United Kingdom in all or certain circumstances. While the CJEU upheld the adequacy of the standard contractual clauses in principle in Schrems II, it made clear that reliance on those clauses alone may not necessarily be sufficient in all circumstances. Use of the standard contractual clauses must now be assessed on a case-by-case basis taking into account the legal regime applicable in the destination country, in particular regarding applicable surveillance laws and relevant rights of individuals with respect to the transferred data. In the context of any given transfer, where the legal regime applicable in the destination country may or does conflict with the intended operation of the standard contractual clauses, the decision in Schrems II and subsequent draft guidance from the European Data Protection Board, or EDPB, would require the parties to that transfer to implement certain supplementary technical, organizational and/or contractual measures to rely on the standard contractual clauses as a GDPR-compliant ‘transfer mechanism.’ However, the aforementioned draft guidance from the EDPB on such supplementary technical, organizational and/or contractual measures appears to conclude that no combination of such measures could be sufficient to allow effective reliance on the standard contractual clauses in the context of transfers of personal data ‘in the clear’ to recipients in countries where the power granted to public authorities to access the transferred data goes beyond that which is ‘necessary and proportionate in a democratic society’—which may, following the CJEU’s conclusions in Schrems II on relevant powers of U.S. public authorities and commentary in that draft EDPB guidance, include the U.S. in certain circumstances (e.g., where Section 702 of the US Foreign Intelligence Surveillance Act applies). As supervisory authorities issue further guidance on personal data export mechanisms, including circumstances where the standard contractual clauses can and cannot be used, and/or start taking enforcement action, we could suffer additional costs, complaints, and/or regulatory scrutiny, investigations or fines, and/or if we are otherwise unable to transfer personal data between and among countries and regions in which we operate, it could affect the manner in which we perform our operations or provide our services, the geographical location or segregation of our relevant systems and operations, and/or could adversely affect our financial results and generally increase compliance risk.

Fines for non-compliance with the GDPR are significant—the greater of €20 million or 4% of global turnover. In addition to administrative fines, a wide variety of other potential enforcement powers are available to competent supervisory authorities in respect of potential and suspected violations of the GDPR, including

 

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extensive audit and inspection rights, and powers to order temporary or permanent bans on all or some processing of personal data carried out by non-compliant actors. The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

Notwithstanding the notes above pertaining to the broadly uniform manner in which the GDPR has direct effect in the laws of EEA members states, the GDPR also provides that EEA member states make their own further laws and regulations to introduce specific requirements related to the processing of ‘special categories of personal data,’ including personal data related to health, biometric data used for unique identification purposes and genetic information, as well as personal data related to criminal offences or convictions—for example, the United Kingdom adopted the Data Protection Act 2018, which ‘implements’ and complements the GDPR in this regard. This fact may lead to greater divergence on the law that applies to the processing of such data types across the EEA and United Kingdom, compliance with which, as and where applicable, may increase our costs and could increase our overall compliance risk. Such member state specific regulations could also limit our ability to collect, use and share data in the context of our EEA and/or United Kingdom establishments (regardless of where any processing in question occurs), and/or could cause our compliance costs to increase, ultimately having an adverse impact on our business, and harming our business and financial condition.

Further, the United Kingdom’s vote in favor of exiting the EU, often referred to as Brexit, and ongoing developments in the United Kingdom have created uncertainty with regard to data protection regulation in the United Kingdom. As of January 1, 2021, and the expiry of transitional arrangements agreed to between the United Kingdom and EU, data processing in the United Kingdom is governed by a United Kingdom version of the GDPR (combining the GDPR and the Data Protection Act 2018), exposing us to two parallel regimes, each of which potentially authorizes similar fines and other potentially divergent enforcement actions for certain violations. Pursuant to the Trade and Cooperation Agreement, which went into effect on January 1, 2021, the United Kingdom and EU agreed to a specified period during which the United Kingdom will be treated like an EU member state in relation to transfers of personal data to the United Kingdom for four months from January 1, 2021. This period may be extended by two further months. Unless the European Commission makes an ‘adequacy finding’ in respect of the United Kingdom before the expiration of such specified period, the United Kingdom will become an ‘inadequate third country’ under the GDPR and transfers of data from the EEA to the United Kingdom will require an ‘transfer mechanism,’ such as the standard contractual clauses. Furthermore, following the expiration of the specified period, there will be increasing scope for divergence in application, interpretation and enforcement of the data protection law as between the United Kingdom and EEA. In addition, as of January 1, 2021, the United Kingdom Information Commissioner’s Office is not able to be our ‘lead supervisory authority’ in respect of any ‘cross border processing’ for the purposes of the GDPR. In the event that we are unable to, or do not, designate a lead supervisory authority in an EEA member state, we would not be able to benefit from the GDPR’s ‘one stop shop’ mechanism. Amongst other things, this would mean that, in the event of a violation of the GDPR affecting data subjects across the United Kingdom and the EEA, we could be investigated by, and ultimately fined by the United Kingdom Information Commissioner’s Office and the supervisory authority in each and every EEA member state where data subjects have been affected by such violation. Other countries have also passed or are considering passing laws requiring local data residency or restricting the international transfer of data.

In addition to the foregoing, a breach of privacy laws or data security laws, particularly those resulting in a significant security incident or breach involving the misappropriation, loss or other unauthorized use or disclosure of sensitive or confidential patient or consumer information, could have a material adverse effect on our business, reputation and financial condition. As a data controller, we are accountable for any third-party service providers we engage to process personal data on our behalf, including our CROs. We attempt to mitigate the associated risks by performing security assessments and due diligence of our vendors and taking appropriate steps to require all such third-party providers with data access to sign agreements that accord with the requirements of the GDPR, and obligating such providers to only process data according to our instructions and to take sufficient security measures to protect such data. There is no assurance that these contractual measures

 

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and our own privacy and security-related safeguards will protect us from all risks associated with the third-party processing, storage and transmission of such information.

Compliance with the GDPR, including as implemented in the United Kingdom, has been and will continue to a rigorous and time-intensive process that may increase our cost of doing business or require us to change our business practices, and despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational harm in connection with our activities carried out in the context of our United Kingdom and EEA operations.

It is possible that these laws may be interpreted and applied in a manner that is inconsistent with our practices and our efforts to comply with the evolving data protection rules may be unsuccessful. If so, this could result in government-imposed fines or orders requiring that we change our practices, which could adversely affect our business. We must devote significant resources to understanding and complying with this changing landscape. Failure to comply with federal, state and international laws regarding privacy and security of personal information could expose us to penalties under such laws. Any such failure by us or our third party processors to comply with data protection and privacy laws could result insignificant government-imposed fines or orders requiring that we change our practices, claims for damages or other liabilities, regulatory investigations and enforcement action, litigation and significant costs for remediation, any of which could adversely affect our business. Even if we are not determined to have violated these laws, government investigations into these issues typically require the expenditure of significant resources and generate negative publicity, which could harm our business, financial condition, results of operations or prospects.

If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur substantial costs that could have a material adverse effect on the success of our business.

We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the generation, handling, use, storage, treatment, manufacture, transportation and disposal of, and exposure to, hazardous materials and wastes, as well as laws and regulations relating to occupational health and safety. Our operations involve the use of hazardous and flammable materials, including chemicals and biologic materials. Our operations also produce hazardous waste products. We generally contract with third parties for the disposal of these materials and wastes or make use of waste disposal infrastructure at our leased facilities. We cannot completely eliminate the risk of contamination or injury from these materials. In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties. We do not carry specific biological or hazardous waste insurance coverage, and our property, casualty and general liability insurance policies specifically exclude coverage for damages and fines arising from biological or hazardous waste exposure or contamination. Accordingly, in the event of contamination or injury, we could be held liable for damages or be penalized with fines in an amount exceeding our resources, and our clinical trials or regulatory approvals could be suspended.

Although we maintain workers’ compensation insurance for certain costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials or other work related injuries, this insurance may not provide adequate coverage against potential liabilities. We do not maintain insurance for toxic tort claims that may be asserted against us in connection with our storage or disposal of biologic, chemical or hazardous materials.

In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations, which have tended to become more stringent over time and as we grow as a company. These current or future laws and regulations may impair our research, development or production efforts. Failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions or liabilities, which could adversely affect our business, financial condition, results of operations and prospects.

 

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Risks Related to Our Employee Matters, Managing our Growth and Other Risks Relating to Our Business Operations

Our future success depends on our ability to retain key employees, consultants and advisors and to attract, retain and motivate qualified personnel.

We are highly dependent on members of our executive team, including our Chief Executive Officer Khurem Farooq, the loss of whose services may adversely impact the achievement of our objectives. While we have entered, or expect to enter, into employment agreements with each of our executive officers, any of them could leave our employment at any time. We face a variety of risks and uncertainties in case of management transition, including diversion of management attention from business concerns, failure to retain other key personnel or loss of institutional knowledge. In addition, the loss of the services of any of our executive officers, other key employees and other scientific and medical advisors, and an inability to find suitable replacements could result in delays in product development and harm our business.

The unexpected loss of service of one or more of our key employees and the failure to transfer knowledge and effect a smooth transition might impede the achievement of our research, development and commercialization objectives, and may have an adverse impact on our business, resulting from the loss of such person’s knowledge of our business and years of experience in gene therapy research. The inability to effectively manage key employee transitions and management changes in the future may have an adverse effect on our future business and reputation.

Recruiting and retaining other qualified employees, consultants and advisors for our business, including scientific and technical personnel, also will be critical to our success. There currently is a shortage of skilled individuals with substantial gene therapy experience, which is likely to continue. As a result, competition for skilled personnel, including in gene therapy research and vector manufacturing, is intense and the turnover rate can be high. We may not be able to attract and retain personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies and academic institutions for individuals with similar skill sets. In addition, failure to succeed in preclinical studies or clinical trials or applications for marketing approval may make it more challenging to recruit and retain qualified personnel. The inability to recruit, or loss of services of certain executives, key employees, consultants or advisors, may impede the progress of our research, development and commercialization objectives and have an adverse effect on our business, financial condition, results of operations and prospects.

We conduct our operations at our facilities in Hertfordshire and London (United Kingdom), Philadelphia and San Francisco (United States). The United Kingdom and United States are headquarters to many other biopharmaceutical companies and many academic and research institutions. Competition for skilled personnel in our market is intense and may limit our ability to hire and retain highly qualified personnel on acceptable terms or at all. Changes to UK, EU or U.S. immigration and work authorization laws and regulations, including those that restrain the flow of scientific and professional talent, can be significantly affected by political forces and levels of economic activity. Our business may be materially adversely affected if legislative or administrative changes to immigration or visa laws and regulations impair our hiring processes and goals or projects involving personnel who are not UK or U.S. citizens.

In addition, COVID-19 could affect our employees or the employees of companies with which we do business, including our suppliers and CMOs, thereby disrupting our business operations. Quarantines and travel restrictions imposed by governments in the jurisdictions in which we and the companies with which we do business operate could materially impact the ability of employees to access preclinical and clinical sites, laboratories, manufacturing sites and offices. We have implemented work-at-home policies and may experience limitations in employee resources. Our increased reliance on personnel working from home may negatively impact productivity, or disrupt, delay, or otherwise adversely impact our business. In addition, this could increase our cybersecurity risk, create data accessibility concerns, and make us more susceptible to communication disruptions, any of which could adversely impact our business operations or delay necessary interactions with regulators, research or clinical trial sites, manufacturing sites and our third-party contractors.

 

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If we are unable to manage expected growth in the scale and complexity of our operations, our performance may suffer.

If we are successful in executing our business strategy, we will need to expand our managerial, operational, financial and other systems and resources to manage our operations, continue our research and development activities and, in the longer term, build a commercial infrastructure to support commercialization of any of our investigational gene therapies that are approved for sale. It is likely that our management, finance, development personnel, systems and facilities currently in place may not be adequate to support this future growth. Our need to effectively manage our operations, growth and any future investigational gene therapies requires that we continue to develop more robust business processes and improve our systems and procedures in each of these areas and to attract and retain sufficient numbers of talented employees. Future growth would impose significant added responsibilities on members of management, including:

 

   

identifying, recruiting, integrating, maintaining and motivating additional employees;

 

   

managing our internal development efforts effectively, including the clinical and FDA review process for our investigational gene therapies, while complying with our contractual obligations to contractors and other third parties; and

 

   

improving our operational, financial and management controls, reporting systems and procedures.

Our future financial performance and our ability to commercialize our investigational gene therapies will depend, in part, on our ability to effectively manage any future growth, and our management may also have to divert a disproportionate amount of its attention away from day-to-day activities in order to devote a substantial amount of time to managing these growth activities. We may be unable to successfully implement these tasks on a larger scale and, accordingly, may not achieve our research, development and growth goals.

Our employees, principal investigators, consultants and commercial partners may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements and insider trading.

We are exposed to the risk of fraud or other misconduct by our employees, principal investigators, consultants and commercial partners. Misconduct by these parties could include intentional failures to comply with FDA or EMA regulations or the regulations applicable in other jurisdictions, provide accurate information to the FDA, MHRA, EMA and other regulatory authorities, comply with healthcare fraud and abuse laws and regulations in the United States and abroad, report financial information or data accurately or disclose unauthorized activities to us. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices. These laws and regulations restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements. Such misconduct also could involve the improper use of information obtained in the course of clinical trials or interactions with the FDA, MHRA, EMA or other regulatory authorities, which could result in regulatory sanctions and cause serious harm to our reputation.

We have adopted a code of conduct applicable to all of our employees, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent these activities may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from government investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, financial condition, results of operations and prospects, including the imposition of significant criminal, civil and administrative sanctions, such as monetary penalties, damages, fines, disgorgement, imprisonment, and exclusion from participation in government funded healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of noncompliance with these laws, reputational harm, and we may be required to curtail or restructure our operations.

 

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Product liability lawsuits against us could cause us to incur substantial liabilities and could limit commercialization of any investigational gene therapy that we may develop.

We face an inherent risk of product liability as a result of the planned clinical testing of our investigational gene therapies and will face an even greater risk if we commercialize any products. For example, we may be sued if our investigational gene therapies cause or are perceived to cause injury or are found to be otherwise unsuitable during clinical testing, manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability or a breach of warranties. Claims could also be asserted under state consumer protection acts. If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit commercialization of our investigational gene therapies that receive marketing approvals, if any. Even successful defenses would require significant financial and management resources. Regardless of the merits or eventual outcome, liability claims may result in:

 

   

decreased demand for any investigational gene therapy that we may develop;

 

   

loss of revenue;

 

   

substantial monetary awards to trial participants or patients;

 

   

initiation of investigations by regulators;

 

   

significant time and costs to defend the related litigation;

 

   

a diversion of management’s time and our resources;

 

   

withdrawal of clinical trial participants;

 

   

recalls, withdrawals or labeling, marketing or promotional restrictions of our investigational gene therapies that receive marketing approvals, if any;

 

   

the inability to commercialize any investigational gene therapies that we may develop;

 

   

exhaustion of any available insurance and our capital resources;

 

   

injury to our reputation and significant negative media attention; or

 

   

a decline in our ADS price.

Although we maintain product liability insurance coverage, such insurance may not be adequate to cover all liabilities that we may incur. We anticipate that we may need to increase our insurance coverage each time we commence a clinical trial and if we successfully commercialize any investigational gene therapy. Insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise.

As a company based outside of the United States, our business is subject to economic, political, regulatory and other risks associated with international operations.

As a company headquartered and incorporated in the United Kingdom, our business is subject to risks associated with conducting business outside of the United States. Many of our suppliers and clinical trial relationships are located outside the United States. Accordingly, our future results could be harmed by a variety of factors, including:

 

   

economic weakness, including inflation, or political instability in particular non-U.S. economies and markets;

 

   

differing and changing regulatory requirements for product approvals;

 

   

differing jurisdictions could present different issues for securing, maintaining or obtaining freedom to operate in such jurisdictions;

 

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potentially reduced protection for intellectual property rights;

 

   

difficulties in compliance with different, complex and changing laws, regulations and court systems of multiple jurisdictions and compliance with a wide variety of foreign laws, treaties and regulations;

 

   

changes in non-U.S. regulations and customs, tariffs and trade barriers;

 

   

changes in non-U.S. currency exchange rates of the pound sterling, U.S. dollar, euro and currency controls;

 

   

changes in a specific country’s or region’s political or economic environment, including the implications of the recent withdrawal of the United Kingdom from the European Union;

 

   

trade protection measures, import or export licensing requirements or other restrictive actions by governments;

 

   

differing reimbursement regimes and price controls in certain non-U.S. markets;

 

   

negative consequences from changes in tax laws;

 

   

compliance with tax, employment, immigration and labor laws for employees living or traveling abroad, including, for example, the variable tax treatment in different jurisdictions of options granted under our share option schemes or equity incentive plans;

 

   

workforce uncertainty in countries where labor unrest is more common than in the United States;

 

   

litigation or administrative actions resulting from claims against us by current or former employees or consultants individually or as part of class actions, including claims of wrongful terminations, discrimination, misclassification or other violations of labor law or other alleged conduct;

 

   

difficulties associated with staffing and managing international operations, including differing labor relations;

 

   

production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; and

 

   

business interruptions resulting from geopolitical actions, including war and terrorism, or natural disasters including earthquakes, typhoons, floods, fires and pandemics, including COVID-19.

Exchange rate fluctuations may materially affect our results of operations and financial condition.

Owing to the international scope of our operations, fluctuations in exchange rates, particularly between the pound sterling and the U.S. dollar, may adversely affect us. Although we are headquartered in the United Kingdom, we source research and development, manufacturing, consulting and other services from the United States and the European Union. Further, potential future revenue may be derived from abroad, particularly from the United States. As a result, our business and the price of our ADSs may be affected by fluctuations in foreign exchange rates not only between the pound sterling and the U.S. dollar, but also the euro, which may have a significant impact on our results of operations and cash flows from period to period. Currently, we do not have any exchange rate hedging arrangements in place.

We or the third parties upon whom we depend may be adversely affected by earthquakes or other natural disasters and our business continuity and disaster recovery plans may not adequately protect us from a serious disaster.

Natural disasters could severely disrupt our operations, and those of our CROs, CMOs and other contractors and consultants, and have a material adverse effect on our business, results of operations, financial condition and prospects. For example, we have facilities located in California, which in the past has experienced both severe earthquakes and wildfires. If a natural disaster, power outage or other event occurred that prevented us from

 

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using all or a significant portion of our headquarters, that damaged critical infrastructure, such as the manufacturing facilities of our third-party contract manufacturers, or that otherwise disrupted operations, it may be difficult or, in certain cases, impossible for us to continue our business for a substantial period of time. We rely on third-party manufacturers to produce our investigational gene therapies. Our ability to obtain clinical supplies of our investigational gene therapies could be disrupted if the operations of these suppliers are affected by a man-made or natural disaster or other business interruption. The disaster recovery and business continuity plans we have in place currently are limited and are unlikely to prove adequate in the event of a serious disaster or similar event. We may incur substantial expenses as a result of the limited nature of our disaster recovery and business continuity plans, which, particularly when taken together with our lack of earthquake insurance, could have a material adverse effect on our business, financial condition, results of operations and prospects.

General Risk Factors

There has been no prior market for our ordinary shares or the ADSs and an active, liquid and orderly trading market may not develop for our ADSs or be sustained following this offering, which could harm the market price of our ADSs and make it difficult for you to sell your ADSs.

This offering constitutes the initial public offering of our ADSs, and no public market has previously existed for our ADSs or ordinary shares. We have applied to list the ADSs on the Nasdaq Global Select Market and we expect our ADSs to be quoted on the Nasdaq Global Select Market, subject to completion of customary procedures in the United States. Any delay in the commencement of trading of the ADSs on the Nasdaq Global Select Market would impair the liquidity of the market for the ADSs and make it more difficult for holders to sell the ADSs.

Prior to this offering, there was no public trading market for our ordinary shares or ADSs. Although we have applied to list our ADS on the Nasdaq Global Select Market, an active trading market for our ADSs may never develop or be sustained following this offering. You may not be able to sell your ADSs quickly or at the market price if trading in our ADSs is not active. The initial offering price will be determined by negotiations among the lead underwriters and us. Among the factors to be considered in determining the initial public offering price are our future prospects and the prospects of our industry in general, our revenue, net income and certain other financial and operating information in recent periods, and the market prices of securities and certain financial and operating information of companies engaged in activities similar to ours. However, there can be no assurance that, following the completion of this offering, the ADSs will trade at a price equal to or greater than the public offering price.

The significant share ownership position of our executive officers, directors and principal shareholders may limit your ability to influence corporate matters.

Upon the closing of this offering, our executive officers, directors and shareholders who owned more than 5% of our outstanding ordinary shares before this offering, including entities affiliated with Syncona, will, in the aggregate, beneficially own ordinary shares representing approximately 64.2% of our outstanding share capital (or 62.0% if the underwriters exercise their option to purchase additional ADSs in full) in each case based on 29,229,659 ordinary shares outstanding as of December 31, 2020 after giving effect to conversion of our outstanding preferred shares, the corporate reorganization and assuming the sale of 6,750,000 ADSs (or 7,762,500 ADSs if the underwriters exercise their option to purchase additional ADSs in full) in this offering.

As a result, if these shareholders, and particularly shareholders affiliated with Syncona, were to choose to act together, they would be able to control all matters submitted to our shareholders for approval, as well as our management and affairs. For example, these persons, if they choose to act together, would control the election, re-election and removal of directors and approval of any merger, scheme of arrangement, consolidation or sale of all or substantially all of our assets. This concentration of ownership control may:

 

   

delay, defer or prevent a change in control;

 

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entrench our management and the board of directors; or

 

   

impede a merger, scheme of arrangement, consolidation, takeover or other business combination involving us that other shareholders may desire.

The interests of this group of shareholders may not always coincide with your interests or the interests of other shareholders and they may act in a manner that advances their best interests and not necessarily those of other shareholders, including seeking a premium value for their ADSs. Any of these consequences could adversely affect the market price of our ADSs.

You will experience substantial dilution as a result of this offering.

You will suffer immediate and substantial dilution in the net tangible book value of the ADSs if you purchase ADSs in this offering. Based on an assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, after giving effect to this offering, purchasers of ADSs in this offering will experience immediate dilution in net tangible book value of $(2.36) per ADS. In addition, after giving effect to this offering, investors purchasing ADSs in this offering will contribute 35.3% of the total amount invested by shareholders since inception but will only own 23.1% of the ordinary shares outstanding. See “Dilution” for a more detailed description of the dilution to new investors in the offering.

Raising additional capital may cause dilution to our existing shareholders, restrict our operations or cause us to relinquish valuable rights.

We may seek additional capital through a combination of public and private equity offerings, debt financings, strategic partnerships and alliances and licensing arrangements. To the extent that we raise additional capital through the sale of equity, convertible debt securities or other equity-based derivative securities, your ownership interest will be diluted, and the terms may include liquidation or other preferences that adversely affect your rights as holder of ADSs. Any indebtedness we incur would result in increased fixed payment obligations and could involve restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business. Any debt or additional equity financing that we raise may contain terms that are not favorable to us or our shareholders. Furthermore, the issuance of additional securities, whether equity or debt, by us, or the possibility of such issuance, may cause the market price of our ADSs to decline and existing shareholders may not agree with our financing plans or the terms of such financings. If we raise additional funds through strategic partnerships, collaborations, and alliances and licensing arrangements with third parties, we may have to relinquish valuable rights to our intellectual property, technologies or our investigational gene therapies, or grant licenses on terms unfavorable to us.

The trading price of our ADSs may be volatile, and you could lose all or part of your investment.

The trading price of our ADSs following this offering is likely to be highly volatile and could be subject to wide fluctuations in response to various factors, some of which are beyond our control, including limited trading volume. In addition to the factors discussed in this “Risk Factors” section and elsewhere in this prospectus, these factors include:

 

   

the commencement, enrollment or results of our planned and future clinical trials;

 

   

the loss of any of our key scientific or management personnel;

 

   

announcements of the failure to obtain regulatory approvals or receipt of warning letters from the FDA, MHRA, EMA or other regulatory agency;

 

   

announcements of undesirable restricted labeling indications or patient populations, or changes or delays in regulatory review processes;

 

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announcements of innovations or new products by us or our competitors;

 

   

adverse actions taken by regulatory agencies with respect to our clinical trials, manufacturing supply chain or sales and marketing activities;

 

   

changes or developments in laws or regulations applicable to our investigational gene therapies;

 

   

any adverse changes to our relationship with licensors, collaborators, manufacturers or suppliers;

 

   

the failure of our testing and clinical trials;

 

   

unanticipated safety concerns;

 

   

the failure to retain our existing, or obtain new, collaboration partners;

 

   

announcements concerning our competitors or the pharmaceutical industry in general;

 

   

the achievement of expected product sales and profitability;

 

   

the failure to obtain reimbursements for our investigational gene therapies or price reductions;

 

   

changes in the structure of healthcare system payment systems;

 

   

manufacture, supply or distribution shortages;

 

   

actual or anticipated fluctuations in our operating results;

 

   

our cash position;

 

   

changes in financial estimates or recommendations by securities analysts;

 

   

potential acquisitions;

 

   

the trading volume of our ADSs on the Nasdaq Global Select Market;

 

   

sales of our ADSs by us, our executive officers and directors or our shareholders in the future;

 

   

general economic, political and market conditions and overall fluctuations in the financial markets in the United States or the United Kingdom; and

 

   

changes in accounting principles.

In addition, the stock market in general, and Nasdaq and biopharmaceutical companies in particular, have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of these companies. Broad market and industry factors may negatively affect the market price of our ADSs, regardless of our actual operating performance. Further, a decline in the financial markets and related factors beyond our control may cause the price of our ADSs to decline rapidly and unexpectedly. If the market price of our ADSs after the completion of this offering does not exceed the initial public offering price, you may not realize any return on your investment in us and may lose some or all of your investment.

Participation in this offering by our existing shareholders and/or their affiliated entities may reduce the public float for our ADSs.

To the extent certain of our existing shareholders and their affiliated entities participate in this offering, such purchases would reduce the non-affiliate public float of our ADSs, meaning the number of ADSs that are not held by officers, directors and controlling shareholders. A reduction in the public float could reduce the number of ADSs that are available to be traded at any given time, thereby adversely impacting the liquidity of our ADSs and depressing the price at which you may be able to sell ADSs purchased in this offering.

Substantial future sales of our ADSs in the public market, or the perception that these sales could occur, could cause the price of the ADSs to decline.

If our existing shareholders sell, or indicate an intention to sell, substantial amounts of our ADSs in the public market after the lockup and other legal restrictions on resale discussed in this prospectus lapse, the trading

 

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price of our ADSs could decline. Upon completion of this offering, we will have 29,229,659 ordinary shares outstanding (or 30,242,159 ordinary shares if the underwriters exercise in full their option to purchase additional shares). Of these shares, only the shares represented by ADSs sold in this offering by us, plus any shares represented by ADSs sold upon exercise of the underwriters’ option to purchase additional shares, will be freely tradable without restriction in the public market immediately following this offering. In connection with this offering, our officers, directors and substantially all of our shareholders have agreed to be subject to a contractual lock-up with the underwriters, which will expire after the end of a lock-up period, described in the sections titled “Shares and ADSs Eligible for Future Sale” and “Underwriting.” If, upon the expiration of the lock-up period, these shareholders sell substantial amounts of our ADSs in the public market, or the market perceives that such sales may occur, the market price of our ADSs and our ability to raise capital through an issue of equity securities in the future could be adversely affected.

The lock-up agreements contain important exceptions that govern their applicability. Moreover, Morgan Stanley & Co. LLC, Goldman Sachs & Co. LLC and Citigroup Global Markets Inc. may, in their sole discretion, permit our officers, directors and other shareholders who are subject to these lock-up agreements to sell shares prior to the expiration of the lock-up agreements.

In addition, ordinary shares or ADSs that are either subject to outstanding options or reserved for future issuance under our 2021 Equity Incentive Plan, to be effective upon the effectiveness of the registration statement of which this prospectus forms a part, will become eligible for sale in the public market to the extent permitted by the provisions of various vesting schedules, the lock-up agreements and Rule 144 and Rule 701 under the Securities Act of 1933, as amended, or the Securities Act. If these additional shares or ADSs are sold, or if it is perceived that they will be sold, in the public market, the trading price of our ADSs could decline.

The rights of our shareholders may differ from the rights typically offered to shareholders of a U.S. corporation.

We are incorporated under English law. The rights of holders of ordinary shares and, therefore, certain of the rights of holders of ADSs, are governed by English law, including the provisions of the UK Companies Act 2006, or the Companies Act, and by our Articles of Association. These rights differ in certain respects from the rights of shareholders in typical U.S. corporations. See “Description of Share Capital and Articles of Association—Differences in Corporate Law” in this prospectus for a description of the principal differences between the provisions of the Companies Act applicable to us and, for example, the Delaware General Corporation Law relating to shareholders’ rights and protections.

You may not receive distributions on our ordinary shares represented by the ADSs or any value for them if it is illegal or impractical to make them available to holders of ADSs.

The depositary for the ADSs has agreed to pay to you the cash dividends or other distributions it or the custodian receives on our ordinary shares or other deposited securities after deducting its fees and expenses. You will receive these distributions in proportion to the number of our ordinary shares your ADSs represent. However, in accordance with the limitations set forth in the deposit agreement, it may be unlawful or impractical to make a distribution available to holders of ADSs. We have no obligation to take any other action to permit distribution on the ADSs, ordinary shares, rights or anything else to holders of the ADSs. This means that you may not receive the distributions we make on our ordinary shares or any value from them if it is unlawful or impractical to make them available to you. These restrictions may have an adverse effect on the value of your ADSs.

Because we do not anticipate paying any cash dividends on our ADSs in the foreseeable future, capital appreciation, if any, will be your sole source of gains and you may never receive a return on your investment.

Under current English law, a company’s accumulated realized profits, to the extent they have not been previously utilized by distribution or capitalization, must exceed its accumulated realized losses, to the extent

 

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that they have not been previously written off in a reduction or reorganization of capital duly made (on a non-consolidated basis), before dividends can be paid. Therefore, we must have distributable profits before issuing a dividend. In addition, as a public limited liability company in England, we will only be able to make a distribution if the amount of our net assets is not less than the aggregate of our called-up share capital and undistributable reserves and if, and to the extent that, the distribution does not reduce the amount of those assets to less than that aggregate.

We have not paid dividends in the past on our ordinary shares. We intend to retain earnings, if any, for use in our business and do not anticipate paying any cash dividends in the foreseeable future. As a result, capital appreciation, if any, on our ADSs will be your sole source of gains for the foreseeable future, and you will suffer a loss on your investment if you are unable to sell your ADSs at or above the initial public offering price. Investors seeking cash dividends should not purchase our ADSs in this offering.

We will have broad discretion in the use of the net proceeds from this offering and may not use them effectively.

Our senior management will have broad discretion in the application of the net proceeds from this offering. Because of the number and variability of factors that will determine our use of the net proceeds, their ultimate use may vary substantially from their currently intended use. Our senior management might not apply our net proceeds in ways that ultimately increase the value of your investment. While we expect to use the net proceeds from this offering as set forth in “Use of Proceeds,” we are not obligated to do so. The failure by our management to apply these funds effectively could harm our business. If we do not invest or apply the net proceeds in ways that enhance shareholder value, we may fail to achieve expected financial results, which could adversely affect our business, financial condition and results of operations, and cause the price of our ADSs to decline.

Your right to participate in any future rights offerings may be limited, which may cause dilution to your holdings.

We may from time to time distribute rights to our shareholders, including rights to acquire our securities. However, we cannot make rights available to you in the United States unless we register the rights and the securities to which the rights relate under the Securities Act or an exemption from the registration requirements is available. Also, under the deposit agreement, the depositary bank will not make rights available to you unless either both the rights and any related securities are registered under the Securities Act, or the distribution of them to ADS holders is exempted from registration under the Securities Act. We are under no obligation to file a registration statement with respect to any such rights or securities or to endeavor to cause such a registration statement to be declared effective. Moreover, we may not be able to establish an exemption from registration under the Securities Act. If the depositary does not distribute the rights, it may, under the deposit agreement, either sell them, if possible, or allow them to lapse. Accordingly, you may be unable to participate in our rights offerings and may experience dilution in your holdings.

If securities or industry analysts do not publish research reports about our business, or if they issue an adverse opinion about our business, the price of our ADSs and trading volume could decline.

The trading market for our ADSs will be influenced by the research and reports that industry or securities analysts publish about us or our business. We do not currently have and may never obtain research coverage by securities and industry analysts. If no or few analysts commence research coverage of us, or one or more of the analysts who cover us issues an adverse opinion about our company, the price of our ADSs would likely decline. If one or more of these analysts ceases research coverage of us or fails to regularly publish reports on us, we could lose visibility in the financial markets, which in turn could cause the price of our ADSs or trading volume to decline.

 

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If we engage in future acquisitions or strategic partnerships, this may increase our capital requirements, dilute our shareholders, cause us to incur debt or assume contingent liabilities and subject us to other risks.

We intend to continue to evaluate various acquisitions and strategic partnerships, including licensing or acquiring complementary drugs, intellectual property rights, technologies or businesses. Any potential acquisition or strategic partnership may entail numerous risks, including:

 

   

increased operating expenses and cash requirements;

 

   

the assumption of additional indebtedness or contingent liabilities;

 

   

assimilation of operations, intellectual property and drugs of an acquired company, including difficulties associated with integrating new personnel;

 

   

the diversion of our management’s attention from our existing drug programs and initiatives in pursuing such a strategic partnership, merger or acquisition;

 

   

retention of key employees, the loss of key personnel and uncertainties in our ability to maintain key business relationships;

 

   

risks and uncertainties associated with the other party to such a transaction, including the prospects of that party and their existing drugs or drug candidates and regulatory approvals; and

 

   

our inability to generate revenue from acquired technology or drugs sufficient to meet our objectives in undertaking the acquisition or even to offset the associated acquisition and maintenance costs.

As a foreign private issuer, we are exempt from a number of rules under the U.S. securities laws and are permitted to file less information with the SEC than U.S. public companies.

We are a “foreign private issuer,” as defined in the SEC rules and regulations and, consequently, we are not subject to all of the disclosure requirements applicable to companies organized within the United States. For example, we are exempt from certain rules under the U.S. Securities Exchange Act of 1934, as amended, or the Exchange Act, that regulate disclosure obligations and procedural requirements related to the solicitation of proxies, consents or authorizations applicable to a security registered under the Exchange Act. In addition, our officers and directors are exempt from the reporting and “short-swing” profit recovery provisions of Section 16 of the Exchange Act and related rules with respect to their purchases and sales of our securities. Moreover, we are not required to file periodic reports and financial statements with the SEC as frequently or as promptly as U.S. public companies. Accordingly, there may be less publicly available information concerning our company than there is for U.S. public companies.

As a foreign private issuer, we will file an annual report on Form 20-F within four months of the close of each fiscal year ended December 31 and reports on Form 6-K relating to certain material events promptly after we publicly announce these events. However, because of the above exemptions for foreign private issuers, our shareholders will not be afforded the same protections or information generally available to investors holding shares in public companies organized in the United States.

While we are a foreign private issuer, we are not subject to certain Nasdaq corporate governance rules applicable to public companies organized in the United States.

We are entitled to rely on a provision in Nasdaq’s corporate governance rules that allows us to follow English corporate law with regard to certain aspects of corporate governance. This allows us to follow certain corporate governance practices that differ in significant respects from the corporate governance requirements applicable to domestic issuers listed on Nasdaq.

We are not subject to Nasdaq Listing Rule 5605(b)(2) because English law does not require that independent directors regularly have scheduled meetings at which only independent directors are present.

 

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Similarly, we have adopted a remuneration committee, but English law does not require that we adopt a remuneration committee or that such committee be fully independent. As a result, our practice varies from the requirements of Nasdaq Listing Rule 5605(d), which sets forth certain requirements as to the responsibilities, composition and independence of compensation committees. English law requires that we disclose information regarding compensation of our directors for services as a director of an undertaking that is our subsidiary undertaking and as a director of any other undertaking of which a director is appointed by virtue of our nomination (directly or indirectly) but not other third-party compensation of our directors or director nominees. As a result, our practice varies from the third-party compensation disclosure requirements of Nasdaq Listing Rule 5250(b)(3). Additionally, we are not subject to Nasdaq Listing Rule 5605(e) because, under English law, director nominees are not required to be selected or recommended for selection by either a majority of the independent directors or a nominations committee comprised solely of independent directors.

Furthermore, English law does not have a regulatory regime for the solicitation of proxies applicable to us, thus our practice varies from the requirement of Nasdaq Listing Rule 5620(b), which sets forth certain requirements regarding the solicitation of proxies. In addition, we have opted out of shareholder approval requirements for the issuance of securities in connection with certain events such as the acquisition of stock or assets of another company, the establishment of or amendments to equity-based compensation plans for employees, a change of control of us and certain private placements. To this extent, our practice will vary from the requirements of Nasdaq Listing Rule 5635, which generally requires an issuer to obtain shareholder approval for the issuance of securities in connection with such events. In addition, while we intend to adopt a code of business conduct and ethics, English law does not require us to publicly disclose waivers from this code that have been approved by our board within four business days. We expect to report any such waivers in the subsequent Annual Report on Form 20-F. As a result, our practice varies from the requirements for domestic issuers pursuant to Nasdaq Listing Rule 5610.

In accordance with our Nasdaq listing, our audit committee is required to comply with the provisions of Section 301 of the Sarbanes-Oxley Act of 2002, or the Sarbanes-Oxley Act, and Rule 10A-3 of the Exchange Act, both of which are also applicable to Nasdaq listed U.S. companies. Because we are a foreign private issuer, however, our audit committee is not subject to additional requirements applicable to Nasdaq listed U.S. companies, including an affirmative determination that all members of the audit committee are “independent,” using more stringent criteria than those applicable to us as a foreign private issuer, subject to certain phase-in requirements permitted by Rule 10A-3 of the Exchange Act.

We may lose our foreign private issuer status which would then require us to comply with the Exchange Act’s domestic reporting regime and cause us to incur significant legal, accounting and other expenses.

As a foreign private issuer, we are not required to comply with all of the periodic disclosure and current reporting requirements of the Exchange Act applicable to U.S. domestic issuers. We may no longer be a foreign private issuer as early as June 30, 2021 (the end of our second fiscal quarter in the fiscal year after completion of this offering), which would require us to comply with all of the periodic disclosure and current reporting requirements of the Exchange Act applicable to U.S. domestic issuers as of January 1, 2022. In order to maintain our current status as a foreign private issuer, either (a) a majority of our securities must be either directly or indirectly owned of record by nonresidents of the United States or (b)(i) a majority of our executive officers or directors cannot be U.S. citizens or residents, (ii) more than 50% of our assets must be located outside the United States and (iii) our business must be administered principally outside the United States. If we lose our status as a foreign private issuer, we would be required to comply with the Exchange Act reporting and other requirements applicable to U.S. domestic issuers, which are more detailed and extensive than the requirements for foreign private issuers. We may also be required to make changes in our corporate governance practices in accordance with various SEC and Nasdaq rules. The regulatory and compliance costs to us under U.S. securities laws if we are required to comply with the reporting requirements applicable to a U.S. domestic issuer may be significantly higher than the cost we would incur as a foreign private issuer. As a result, we expect that a loss of foreign private issuer status would increase our legal and financial compliance costs and is likely to make some activities

 

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highly time-consuming and costly. We also expect that if we were required to comply with the rules and regulations applicable to U.S. domestic issuers, it would make it more difficult and expensive for us to obtain director and officer liability insurance, and we may be required to accept reduced coverage or incur substantially higher costs to obtain coverage. These rules and regulations could also make it more difficult for us to attract and retain qualified members of our board of directors.

We are an emerging growth company within the meaning of the Securities Act and the reduced disclosure requirements applicable to emerging growth companies may make our ADSs less attractive to investors.

We are an “emerging growth company,” or EGC, as defined in the Jumpstart our Business Startups Act of 2012, or the JOBS Act. We will remain an EGC until the earliest of: (i) the last day of the fiscal year in which we have total annual gross revenues of $1.07 billion or more; (ii) the last day of the fiscal year following the fifth anniversary of the date of the completion of this offering; (iii) the date on which we have issued more than $1.0 billion in nonconvertible debt during the previous three years; or (iv) the date on which we are deemed to be a large accelerated filer under the rules of the SEC, which means the first day of the year following the first year in which the market value of our ADSs that are held by non-affiliates exceeds $700 million as of June 30. For so long as we remain an EGC, we are permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that are not emerging growth companies. These exemptions include:

 

   

the provisions of Section 404(b) of the Sarbanes Oxley Act requiring that our independent registered public accounting firm provide an attestation report on the effectiveness of our internal control over financial reporting;

 

   

being permitted to provide only two years of audited financial statements in this initial registration statement, in addition to any required unaudited interim financial statements, with correspondingly reduced “Management’s Discussion and Analysis of Financial Condition and Results of Operations” disclosure;

 

   

the “say on pay” provisions (requiring a nonbinding shareholder vote to approve compensation of certain executive officers) and the “say on golden parachute” provisions (requiring a nonbinding shareholder vote to approve golden parachute arrangements for certain executive officers in connection with mergers and certain other business combinations) of the Dodd-Frank Wall Street Reform and Consumer Protection Act, or the Dodd-Frank Act, and some of the disclosure requirements of the Dodd-Frank Act relating to compensation of our executive officers; and

 

   

the requirement to provide detailed compensation discussion and analysis in proxy statements and reports filed under the Exchange Act and instead provide a reduced level of disclosure concerning executive compensation.

We may choose to take advantage of some, but not all, of the available exemptions. We have taken advantage of reduced reporting burdens in this prospectus. In particular, we have not included all of the executive compensation information that would be required if we were not an EGC. We cannot predict whether investors will find our ADSs less attractive if we rely on certain or all of these exemptions. If some investors find our ADSs less attractive as a result, there may be a less active trading market for our ADSs and our ADS price may be more volatile.

In addition, the JOBS Act provides that an EGC may take advantage of an extended transition period for complying with new or revised accounting standards. This allows an EGC to delay the adoption of certain accounting standards until those standards would otherwise apply to private companies. We have elected to avail ourselves of this exemption from new or revised accounting standards and, therefore, we will not be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies.

 

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If we fail to establish and maintain proper internal controls, our ability to produce accurate financial statements or comply with applicable regulations could be impaired. As a result, shareholders could lose confidence in our financial and other public reporting, which would harm our business and the trading price of our ADSs.

Section 404(a) of the Sarbanes-Oxley Act, or Section 404(a), requires that beginning with our second annual report following our initial public offering, management assess and report annually on the effectiveness of our internal control over financial reporting and identify any material weaknesses in our internal control over financial reporting. Although Section 404(b) of the Sarbanes-Oxley Act, or Section 404(b), requires our independent registered public accounting firm to issue an annual report that addresses the effectiveness of our internal control over financial reporting, we have opted to rely on the exemptions provided in the JOBS Act, and consequently will not be required to comply with SEC rules that implement Section 404(b) until such time as we are no longer an EGC.

We expect our first Section 404(a) assessment will take place for our annual report for the fiscal year ending December 31, 2022. The presence of material weaknesses could result in financial statement errors which, in turn, could lead to errors in our financial reports, delays in our financial reporting, which could require us to restate our operating results or our auditors may be required to issue a qualified audit report. We might not identify one or more material weaknesses in our internal controls in connection with evaluating our compliance with Section 404(a). In order to maintain and improve the effectiveness of our disclosure controls and procedures and internal control over financial reporting, we will need to expend significant resources and provide significant management oversight. Implementing any appropriate changes to our internal control may require specific compliance training of our directors and employees, entail substantial costs in order to modify our existing accounting systems, take a significant period of time to complete and divert management’s attention from other business concerns. These changes may not, however, be effective in maintaining the adequacy of our internal control.

If either we are unable to conclude that we have effective internal control over financial reporting or, at the appropriate time, our independent auditors are unwilling or unable to provide us with an unqualified report on the effectiveness of our internal control over financial reporting as required by Section 404(b), investors may lose confidence in our operating results, the price of our ADSs could decline and we may be subject to litigation or regulatory enforcement actions. In addition, if we are unable to meet the requirements of Section 404, we may not be able to remain listed on the Nasdaq Global Select Market.

Our disclosure controls and procedures may not prevent or detect all errors or acts of fraud.

Upon completion of this offering, we will become subject to certain reporting requirements of the Exchange Act. Our disclosure controls and procedures are designed to reasonably assure that information required to be disclosed by us in reports we file or submit under the Exchange Act is accumulated and communicated to management, recorded, processed, summarized and reported within the time periods specified in the rules and forms of the SEC. We believe that any disclosure controls and procedures or internal controls and procedures, no matter how well conceived and operated, can provide only reasonable, not absolute, assurance that the objectives of the control system are met. These inherent limitations include the realities that judgments in decision making can be faulty, and that breakdowns can occur because of simple error or mistake. Additionally, controls can be circumvented by the individual acts of some persons, by collusion of two or more people or by an unauthorized override of the controls. Accordingly, because of the inherent limitations in our control system, misstatements or insufficient disclosures due to error or fraud may occur and not be detected.

We will incur significant increased costs as a result of operating as a company whose ADSs are publicly traded in the United States, and our management will be required to devote substantial time to new compliance initiatives.

As a U.S. listed company, and particularly after we no longer qualify as an EGC, we will incur significant legal, accounting and other expenses that we did not incur previously. The increased costs may require us to

 

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reduce costs in other areas of our business. The Sarbanes-Oxley Act, the Dodd-Frank Wall Street Reform and Consumer Protection Act, the listing requirements of the Nasdaq Global Select Market and other applicable securities rules and regulations impose various requirements on non-U.S. reporting public companies, including the establishment and maintenance of effective disclosure and financial controls and corporate governance practices. Our senior management and other personnel will need to devote a substantial amount of time to these compliance initiatives. Moreover, these rules and regulations will increase our legal and financial compliance costs and will make some activities more time-consuming and costly. For example, we expect that these rules and regulations may make it more difficult and more expensive for us to obtain director and officer liability insurance, which in turn could make it more difficult for us to attract and retain qualified senior management personnel or members for our board of directors.

However, these rules and regulations are often subject to varying interpretations, in many cases due to their lack of specificity, and, as a result, their application in practice may evolve over time as new guidance is provided by regulatory and governing bodies. This could result in continuing uncertainty regarding compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices.

Pursuant to Section 404, we will be required to furnish a report by our senior management on our internal control over financial reporting. However, while we remain an EGC, we will not be required to include an attestation report on internal control over financial reporting issued by our independent registered public accounting firm. To prepare for eventual compliance with Section 404, once we no longer qualify as an EGC, we will be engaged in a process to document and evaluate our internal control over financial reporting, which is both costly and challenging. In this regard, we will need to continue to dedicate internal resources, potentially engage outside consultants and adopt a detailed work plan to assess and document the adequacy of internal control over financial reporting, continue steps to improve control processes as appropriate, validate through testing that controls are functioning as documented and implement a continuous reporting and improvement process for internal control over financial reporting. Despite our efforts, there is a risk that we will not be able to conclude, within the prescribed time frame or at all, that our internal control over financial reporting is effective as required by Section 404. If we identify one or more material weaknesses, it could result in an adverse reaction in the financial markets due to a loss of confidence in the reliability of our financial statements.

Our Articles of Association to be effective in connection with this offering will provide that the courts of England and Wales will be the exclusive forum for the resolution of all shareholder complaints other than complaints asserting a cause of action arising under the Securities Act and the Exchange Act, and that the U.S. federal district courts will be the exclusive forum for the resolution of any shareholder complaint asserting a cause of action arising under the Securities Act and the Exchange Act.

Our Articles of Association to be effective in connection with this offering will provide that the courts of England and Wales will be the exclusive forum for resolving all shareholder complaints other than shareholder complaints asserting a cause of action arising under the Securities Act and the Exchange Act, and that the U.S. federal district courts will be the exclusive forum for resolving any shareholder complaint asserting a cause of action arising under the Securities Act and the Exchange Act, including applicable claims arising out of this offering. This choice of forum provision may limit a shareholders’ ability to bring a claim in a judicial forum that it finds favorable for disputes with us or our directors, officers or other employees, which may discourage such lawsuits. The enforceability of similar exclusive forum provisions (including exclusive federal forum provisions for actions, suits or proceedings asserting a cause of action arising under the Securities Act) in other companies’ organizational documents has been challenged in legal proceedings, and there is uncertainty as to whether courts would enforce the exclusive federal forum provisions in our Articles of Association. Additionally, our shareholders cannot waive compliance with the federal securities laws and the rules and regulations therefore. If a court were to find either choice of forum provision contained in our Articles of Association to be inapplicable or unenforceable in an action, we may incur additional costs associated with resolving such action in other jurisdictions, which could adversely affect our results of operations and financial condition.

 

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Claims of U.S. civil liabilities may not be enforceable against us.

We are incorporated and have our registered office in, and are currently existing under the laws of England and Wales. In addition, certain members of our board of directors and senior management are nonresidents of the United States, and all or a substantial portion of our assets and the assets of such persons are located outside the United States. As a result, it may not be possible to serve process on such persons or us in the United States or to enforce judgments obtained in U.S. courts against them or us based on civil liability provisions of the securities laws of the United States. As a result, it may not be possible for investors to effect service of process within the United States upon such persons or to enforce judgments obtained in U.S. courts against them or us, including judgments predicated upon the civil liability provisions of the U.S. federal securities laws.

The United States and the United Kingdom do not currently have a treaty providing for recognition and enforcement of judgments (other than arbitration awards) in civil and commercial matters. Consequently, a final judgment for payment given by a court in the United States, whether or not predicated solely upon U.S. securities laws, would not automatically be recognized or enforceable in the United Kingdom. In addition, uncertainty exists as to whether English courts would entertain original actions brought in the United Kingdom against us or our directors or senior management predicated upon the securities laws of the United States or any state in the United States. Any final and conclusive monetary judgment for a definite sum obtained against us in U.S. courts would be treated by English courts as a cause of action in itself and sued upon as a debt at common law so that no retrial or re-examination of the issues would be necessary, provided that certain requirements are met. Whether these requirements are met in respect of a judgment based upon the civil liability provisions of the U.S. securities laws, including whether the award of monetary damages under such laws would constitute a penalty is an issue subject to determination by the court making such decision. If an English court gives judgment for the sum payable under a U.S. judgment, the English judgment will be enforceable by methods generally available for this purpose. These methods generally permit the English court discretion to prescribe the manner of enforcement.

As a result, U.S. investors may not be able to enforce against us or our senior management, board of directors or certain experts named herein who are residents of the United Kingdom or countries other than the United States any judgments obtained in U.S. courts in civil and commercial matters, including judgments under the U.S. federal securities laws.

If we are a “passive foreign investment company,” or a PFIC, in the year of the offering or in any future year, a U.S. shareholder may be subject to adverse U.S. federal income tax consequences.

Under the Internal Revenue Code of 1986, as amended, or the Code, we will be a PFIC for any taxable year in which, after the application of certain look-through rules with respect to our subsidiaries, either (i) 75% or more of our gross income consists of passive income or (ii) 50% or more of the average quarterly value of our assets consists of assets that produce, or are held for the production of, passive income (including cash). Passive income includes, among other things, dividends, interest, certain non-active rents and royalties, and capital gains. Based on our operations, income, assets and certain estimates and projections, including as to the relative values of our assets and the treatment of amounts in respect of refundable tax credits from governmental entities we received, or are or may become entitled to receive, as gross income that is not passive income, we do not believe that we were a PFIC in 2020 and do not expect to be a PFIC for our 2021 taxable year. However, the determination whether we are a PFIC is a fact-intensive determination that must be made on an annual basis applying principles and methodologies that are in some circumstances unclear, and whether we will be a PFIC in 2021 or any future taxable year is uncertain because, among other things, (i) we currently own, and will own after the closing of this offering, a substantial amount of passive assets, including cash, (ii) the valuation of our assets that generate non-passive income for PFIC purposes, including our intangible assets, is uncertain and may depend in part of the market price of our ordinary shares or ADSs from time to time, which may fluctuate substantially, (iii) the treatment of amounts in respect of refundable tax credits from governmental entities we received, or are or may become entitled to receive, as gross income that is not passive income is uncertain, and

 

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(iv) the composition of our income may vary substantially over time. Accordingly, there can be no assurance that we will not be a PFIC for any taxable year, and our U.S. counsel expresses no opinion with respect to our PFIC status, or with respect to our expectations regarding our PFIC status in 2021 or any future taxable year.

If we are a PFIC for any taxable year during which a U.S. investor holds our ordinary shares or ADSs, we would continue to be treated as a PFIC with respect to that U.S. investor for all succeeding years during which the U.S. investor holds our ordinary shares or ADSs, even if we ceased to meet the threshold requirements for PFIC status, unless certain exceptions apply. Such a U.S. investor may be subject to adverse U.S. federal income tax consequences, including (i) the treatment of all or a portion of any gain on the disposition of our ordinary shares or ADSs as ordinary income (and therefore ineligible for the preferential rates that apply to capital gains with respect to some U.S. investors), (ii) the application of a deferred interest charge on such gain and the receipt of certain dividends on our ordinary shares or ADSs and (iii) compliance with certain reporting requirements. We do not intend to provide the information that would enable investors to make a qualified electing fund election, or a QEF Election, that could mitigate the adverse U.S. federal income tax consequences should we be classified as a PFIC.

For further discussion, see “Material Income Tax Considerations—Material U.S. Federal Income Tax Considerations for U.S. Holders.”

Because we believe we are currently a controlled foreign corporation for U.S. federal income tax purposes, there could be adverse U.S. federal income tax consequences to certain U.S. holders who own, directly, indirectly or by attribution, ten percent or more of our ADSs or ordinary shares.

Each “Ten Percent Shareholder” (as defined below) in a non-U.S. corporation that is classified as a “controlled foreign corporation,” or a CFC, for U.S. federal income tax purposes generally is required to include in income for U.S. federal tax purposes such Ten Percent Shareholder’s pro rata share of the CFC’s “Subpart F income,” investment of earnings in U.S. property, and “global intangible low-taxed income,” even if the CFC has made no distributions to its shareholders. Subpart F income generally includes dividends, interest, rents, royalties, gains from the sale of securities and income from certain transactions with related parties, and “global intangible low-taxed income” generally consists of net income of the CFC, other than Subpart F income and certain other types of income, in excess of certain thresholds. In addition, a Ten Percent Shareholder that realizes gain from the sale or exchange of shares in a CFC may be required to classify a portion of such gain as dividend income rather than capital gain. A non-U.S. corporation generally will be classified as a CFC for U.S. federal income tax purposes if Ten Percent Shareholders own, directly, indirectly or constructively (through attribution), more than 50% of either the total combined voting power of all classes of stock of such corporation entitled to vote or of the total value of the stock of such corporation. A “Ten Percent Shareholder” is a United States person (as defined by the Code) who owns or is considered to own 10% or more of the total combined voting power of all classes of stock entitled to vote of such corporation or 10% or more of the total value of the stock of such corporation. The determination of CFC status is complex and includes attribution rules, the application of which is not entirely certain. In addition, the TCJA repealed Section 958(b)(4) of the Code, which prohibited “downward attribution” from non-United States persons to United States persons for purposes of determining CFC status.

As a result of (i) the ownership of 50% or more of our stock by Syncona, which we understand also owns 50% or more, directly or indirectly, of one or more U.S. corporations, and (ii) the repeal of Section 958(b)(4) of the Code, we believe that we are, and each of our non-U.S. subsidiaries that is a corporation for U.S. federal income tax purposes is, currently a CFC, and, depending on the future ownership of our stock by Syncona or other shareholders, may continue to be a CFC in the future. While our status as a CFC will generally not have any U.S. federal income tax consequences for U.S. Holders (as defined below under “Material Income Tax Considerations—Material U.S. Federal Income Tax Considerations for U.S. Holders”) of our ADSs or ordinary shares who are not Ten Percent Shareholders, U.S. Holders of ADSs or ordinary shares should consult their own tax advisors with respect to the potential adverse tax consequences of becoming a Ten Percent Shareholder in a

 

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CFC. If we are classified as both a CFC and a PFIC (as discussed above), we generally will not be treated as a PFIC with respect to those U.S. Holders that meet the definition of a Ten Percent Shareholder during the period in which we are a CFC.

We may be unable to use net operating loss and tax credit carryforwards and certain built-in losses to reduce future tax payments or benefit from favorable UK tax legislation.

As a UK tax resident company, we are subject to UK corporate taxation. Due to the nature of our business, we have generated losses since inception. As of December 31, 2020, we had cumulative carryforward losses of $80.4 million. Subject to any relevant restrictions, we expect these to be available to carry forward and offset against future operating profits. As a company that carries out extensive research and development activities, we benefit from the UK research and development tax credit regime for small and medium-sized companies, whereby we are able to surrender the trading losses that arise from our qualifying research and development activities for a payable tax credit of up to 33.35% of eligible research and development expenditures, which includes a 130% enhancement to the standard 14.50% tax credit rate. Qualifying expenditures largely comprise employment costs for research staff, consumables and certain internal overhead costs incurred as part of research projects. Certain subcontracted qualifying research expenditures are eligible for a cash rebate at a discounted rate. This is restricted to 65% of total contractor costs and has an effective tax rebate of 21.68% applied to these costs. The majority of our pipeline research, clinical trials management and manufacturing development activities are eligible for inclusion within these tax credit cash rebate claims. We may not be able to continue to claim payable research and development tax credits in the future when we become a public company because we may no longer qualify as a small or medium-sized company.

We may benefit in the future from the United Kingdom’s “patent box” regime, which allows certain profits attributable to revenues from patented products to be taxed at an effective rate of 10%. We are the exclusive licensee or owner of several patent applications which, if issued, would cover our investigational gene therapies, and accordingly, future upfront fees, milestone fees, product revenues and royalties could be taxed at this tax rate. When taken in combination with the enhanced relief available on our research and development expenditures, we expect a long-term lower rate of corporation tax to apply to us. If, however, there are unexpected adverse changes to the UK research and development tax credit regime or the “patent box” regime, or for any reason we are unable to qualify for such advantageous tax legislation, or we are unable to use net operating loss and tax credit carryforwards and certain built-in losses to reduce future tax payments then our business, results of operations and financial condition may be adversely affected.

Shareholder protections found in provisions under the UK City Code on Takeovers and Mergers, or the Takeover Code, will not apply if our place of central management and control remains outside the United Kingdom (or the Channel Islands or the Isle of Man).

We believe that, as at the date of this prospectus, our place of central management and control is not, and is not expected to be, in the United Kingdom (or the Channel Islands or the Isle of Man) for the purposes of the jurisdictional criteria of the Takeover Code. Accordingly, we do not consider that the Takeover Code applies to us and, as a result, our shareholders will not be entitled to the benefit of certain takeover offer protections provided under the Takeover Code, including the rules regarding mandatory takeover bids. In the event that this changes, or if the interpretation and application of the Takeover Code by the Panel on Takeovers and Mergers, or Takeover Panel, changes (including changes to the way in which the Takeover Panel assesses the application of the Takeover Code to English companies whose shares are listed outside of the United Kingdom), the Takeover Code may apply to us in the future. The Takeover Code provides a framework within which takeovers of companies are regulated and conducted. The following is a brief summary of some of the most important rules of the Takeover Code:

 

   

In connection with a potential offer, if following an approach by or on behalf of a potential bidder, the company is “the subject of rumor or speculation” or there is an “untoward movement” in the

 

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company’s share price, there is a requirement for the potential bidder to make a public announcement about a potential offer for the company, or for the company to make a public announcement about its review of a potential offer.

 

   

When a person (a) acquires, whether by a series of transactions over a period of time or not, interests in shares carrying 30% or more of the voting rights of a company when taken together with shares in which persons acting in concert with that person are interested (which percentage is treated by the Takeover Code as the level at which effective control is obtained), or (b) acquires an interest in any other shares which increases the percentage of shares carrying voting rights in which he is interested when they are, together with persons acting in concert with them, already interested in shares which carry not less than 30% of the voting rights but do not hold shares carrying more than 50% of such voting rights, they must make a cash offer to all other shareholders at the highest price paid by them in the twelve months before the offer was announced.

 

   

When interests in shares carrying 10% or more of the voting rights of a class have been acquired for cash by an offeror (i.e., a bidder) and any person acting in concert with it in the offer period (i.e. before the shares subject to the offer have been acquired) and the previous twelve months, the offer must be in cash or be accompanied by a cash alternative for all shareholders of that class at not less than the highest price paid by the offeror in that period. Further, if an offeror or any person acting in concert with them acquires for cash any interest in shares during the offer period, the offer for the shares must be in cash or accompanied by a cash alternative at a price at least equal to the highest price paid for such shares during the offer period.

 

   

If, after a firm offer announcement is made, the offeror or any person acting in concert with it acquires an interest in shares in an offeree company (i.e., a target) at a price higher than the value of the offer, the offer must be increased to not less than the highest price paid for the interest in shares so acquired.

 

   

The offeree company must appoint a competent independent adviser whose advice on the financial terms of the offer must be made known to all the shareholders, together with the opinion of the board of directors of the offeree company.

 

   

Favorable deals for selected shareholders are not permitted, except in certain circumstances where independent shareholder approval is given and the arrangements are regarded as fair and reasonable in the opinion of the financial adviser to the offeree.

 

   

All shareholders must be given the same information.

 

   

Those issuing takeover circulars must include statements taking responsibility for the contents thereof.

 

   

Profit forecasts, quantified financial benefits statements and asset valuations must be made to specified standards and must be reported on by professional advisers.

 

   

Misleading, inaccurate or unsubstantiated statements made in documents or to the media must be publicly corrected immediately.

 

   

Actions during the course of an offer by the offeree company, which might frustrate the offer are generally prohibited unless shareholders approve these plans. Frustrating actions would include, for example, lengthening the notice period for directors under their service contract or agreeing to sell off material parts of the target group.

 

   

Stringent requirements are laid down for the disclosure of dealings in relevant securities during an offer, including the prompt disclosure of positions and dealings in relevant securities by the parties to an offer and any person who is interested (directly or indirectly) in 1% or more of any class of relevant securities.

 

   

Employees of both the offeror and the offeree company and the trustees of the offeree company’s pension scheme must be informed about an offer. In addition, the offeree company’s employee representatives and pension scheme trustees have the right to have a separate opinion on the effects of the offer on employment appended to the offeree board of directors’ circular or published on a website.

 

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We could be subject to securities class action litigation.

In the past, securities class action litigation has often been brought against a company following a decline in the market price of its securities. This risk is especially relevant for us because pharmaceutical companies have experienced significant securities price volatility in recent years. If we face such litigation, it could result in substantial costs and a diversion of management’s attention and resources, which could harm our business.

You may not have the same voting rights as the holders of our ordinary shares and may not receive voting materials in time to be able to exercise your right to vote.

Except as described in this prospectus and the deposit agreement, holders of the ADSs will not be able to exercise voting rights attaching to the ordinary shares represented by the ADSs. Under the terms of the deposit agreement, holders of the ADSs may instruct the depositary to vote the ordinary shares underlying their ADSs. Otherwise, holders of ADSs will not be able to exercise their right to vote unless they withdraw the ordinary shares underlying their ADSs to vote them in person or by proxy in accordance with applicable laws and regulations and our Articles of Association. Even so, ADS holders may not know about a meeting far enough in advance to withdraw those ordinary shares. If we ask for the instructions of holders of the ADSs, the depositary, upon timely notice from us, will notify ADS holders of the upcoming vote and arrange to deliver our voting materials to them. Upon our request, the depositary will mail to holders a shareholder meeting notice that contains, among other things, a statement as to the manner in which voting instructions may be given. We cannot guarantee that ADS holders will receive the voting materials in time to ensure that they can instruct the depositary to vote the ordinary shares underlying their ADSs. A shareholder is only entitled to participate in, and vote at, the meeting of shareholders, provided that it holds our ordinary shares as of the record date set for such meeting and otherwise complies with our Articles of Association. In addition, the depositary’s liability to ADS holders for failing to execute voting instructions or for the manner of executing voting instructions is limited by the deposit agreement. As a result, holders of ADSs may not be able to exercise their right to give voting instructions or to vote in person or by proxy and they may not have any recourse against the depositary or us if the ordinary shares underlying their ADSs are not voted as they have requested or if such shares cannot be voted.

Holders of ADSs are not treated as holders of our ordinary shares.

By participating in this offering you will become a holder of ADSs with underlying ordinary shares in a company incorporated under English law. Holders of ADSs are not treated as holders of our ordinary shares, unless they withdraw the ordinary shares underlying their ADSs in accordance with the deposit agreement and applicable laws and regulations. The depositary is the holder of the ordinary shares underlying the ADSs. Holders of ADSs therefore do not have any rights as holders of our ordinary shares, other than the rights that they have pursuant to the deposit agreement. See “Description of American Depositary Shares.”

Holders of ADSs may be subject to limitations on the transfer of their ADSs and the withdrawal of the underlying ordinary shares.

ADSs are transferable on the books of the depositary. However, the depositary may close its books at any time or from time to time when it deems expedient in connection with the performance of its duties. The depositary may refuse to deliver, transfer or register transfers of ADSs generally when our books or the books of the depositary are closed, or at any time if we or the depositary think it is advisable to do so because of any requirement of law, government or governmental body, or under any provision of the deposit agreement, or for any other reason, subject to the right of ADS holders to cancel their ADSs and withdraw the underlying ordinary shares. Temporary delays in the cancellation of your ADSs and withdrawal of the underlying ordinary shares may arise because the depositary has closed its transfer books or we have closed our transfer books, the transfer of ordinary shares is blocked to permit voting at a shareholders’ meeting or we are paying a dividend on our ordinary shares. In addition, ADS holders may not be able to cancel their ADSs and withdraw the underlying ordinary shares when they owe money for fees, taxes and similar charges and when it is necessary to prohibit withdrawals in order to comply with any laws or governmental regulations that apply to ADSs or to the withdrawal of ordinary shares or other deposited securities. See “Description of American Depositary Shares.”

 

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We are entitled to amend the deposit agreement and to change the rights of ADS holders under the terms of such agreement, or to terminate the deposit agreement, without the prior consent of the ADS holders.

We are entitled to amend the deposit agreement and to change the rights of the ADS holders under the terms of such agreement, without the prior consent of the ADS holders. We and the depositary may agree to amend the deposit agreement in any way we decide is necessary or advantageous to us or to the depositary. Amendments may reflect, among other things, operational changes in the ADS program, legal developments affecting ADSs or changes in the terms of our business relationship with the depositary. In the event that the terms of an amendment are materially disadvantageous to ADS holders, ADS holders will only receive 30 days’ advance notice of the amendment, and no prior consent of the ADS holders is required under the deposit agreement. Furthermore, we may decide to direct the depositary to terminate the ADS facility at any time for any reason. For example, terminations may occur when we decide to list our ordinary shares on a non-U.S. securities exchange and determine not to continue to sponsor an ADS facility or when we become the subject of a takeover or a going-private transaction. If the ADS facility will terminate, ADS holders will receive at least 30 days’ prior notice, but no prior consent is required from them. Under the circumstances that we decide to make an amendment to the deposit agreement that is disadvantageous to ADS holders or terminate the deposit agreement, the ADS holders may choose to sell their ADSs or surrender their ADSs and become direct holders of the underlying ordinary shares, but will have no right to any compensation whatsoever.

ADSs holders may not be entitled to a jury trial with respect to claims arising under the deposit agreement, which could result in less favorable outcomes to the plaintiff(s) in any such action.

The deposit agreement governing the ADSs representing our ordinary shares provides that, to the fullest extent permitted by law, holders and beneficial owners of ADSs irrevocably waive the right to a jury trial of any claim they may have against us or the depositary arising out of or relating to the ADSs or the deposit agreement.

If this jury trial waiver provision is not permitted by applicable law, an action could proceed under the terms of the deposit agreement with a jury trial. If we or the depositary opposed a jury trial demand based on the waiver, the court would determine whether the waiver was enforceable based on the facts and circumstances of that case in accordance with the applicable state and federal law. To our knowledge, the enforceability of a contractual pre-dispute jury trial waiver in connection with claims arising under the federal securities laws has not been finally adjudicated by the U.S. Supreme Court. However, we believe that a contractual pre-dispute jury trial waiver provision is generally enforceable, including under the laws of the State of New York, which govern the deposit agreement, by a federal or state court in the City of New York, which has nonexclusive jurisdiction over matters arising under the deposit agreement. In determining whether to enforce a contractual pre-dispute jury trial waiver provision, courts will generally consider whether a party knowingly, intelligently and voluntarily waived the right to a jury trial. We believe that this is the case with respect to the deposit agreement and the ADSs. It is advisable that you consult legal counsel regarding the jury waiver provision before entering into the deposit agreement.

If you or any other holders or beneficial owners of ADSs bring a claim against us or the depositary in connection with matters arising under the deposit agreement or the ADSs, including claims under federal securities laws, you or such other holder or beneficial owner may not be entitled to a jury trial with respect to such claims, which may have the effect of limiting and discouraging lawsuits against us or the depositary. If a lawsuit is brought against us or the depositary under the deposit agreement, it may be heard only by a judge or justice of the applicable trial court, which would be conducted according to different civil procedures and may result in different outcomes than a trial by jury would have had, including results that could be less favorable to the plaintiff(s) in any such action, depending on, among other things, the nature of the claims, the judge or justice hearing such claims and the venue of the hearing.

No condition, stipulation or provision of the deposit agreement or ADSs serves as a waiver by any holder or beneficial owner of ADSs or by us or the depositary of compliance with any substantive provision of the U.S. federal securities laws and the rules and regulations promulgated thereunder.

 

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As an English public limited company, certain capital structure decisions will require shareholder approval, which may limit our flexibility to manage our capital structure.

English law provides that a board of directors may only allot shares (or rights to subscribe for or convertible into shares) with the prior authorization of shareholders, such authorization stating the aggregate nominal amount of shares that it covers and being valid for a maximum period of five years, each as specified in the articles of association or relevant shareholder resolution. We have obtained authority from our shareholders to allot additional shares for a period ending April 1, 2026, which authorization will need to be renewed upon expiration (i.e., at least every five years) but may be sought more frequently for additional five-year terms (or any shorter period).

English law also generally provides shareholders with preemptive rights when new shares are issued for cash. However, it is possible for the articles of association, or for shareholders to pass a special resolution at a general meeting, being a resolution passed by at least 75% of the votes cast, to disapply preemptive rights. Such a disapplication of preemptive rights may be for a maximum period of up to five years from the date of adoption of the articles of association, if the disapplication is contained in the articles of association, or from the date of the shareholder special resolution, if the disapplication is by shareholder special resolution but not longer than the duration of the authority to allot shares to which the disapplication relates. In either case, this disapplication would need to be renewed by our shareholders upon its expiration (i.e., at least every five years). We have obtained authority from our shareholders to disapply preemptive rights for a period ending April 1, 2026 which disapplication will need to be renewed upon expiration (i.e., at least every five years), but may be sought more frequently for additional five-year terms (or any shorter period).

English law also generally prohibits a public company from repurchasing its own shares without the prior approval of shareholders by ordinary resolution, being a resolution passed by a simple majority of votes cast and other formalities. Such approval may be for a maximum period of up to five years. See “Description of Share Capital and Articles of Association.”

 

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SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This prospectus contains forward-looking statements that involve substantial risks and uncertainties. In some cases, you can identify forward-looking statements by the words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue” and “ongoing,” or the negative of these terms, or other comparable terminology intended to identify statements about the future. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. The forward-looking statements and opinions contained in this prospectus are based upon information available to us as of the date of this prospectus and, while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. Forward-looking statements contained in this prospectus include, but are not limited to, statements about:

 

   

our recurring losses from operations and our estimates regarding expenses, capital requirements and needs for additional financing;

 

   

the development of our investigational gene therapies, including statements regarding the timing of initiation, completion and the outcome of clinical studies or trials and related preparatory work, the period during which the results of the trials will become available and our research and development programs;

 

   

our ability to design and implement successful clinical trials for our investigational gene therapies;

 

   

the potential for a pandemic, epidemic or outbreak of an infectious diseases in the United States, United Kingdom or European Union, including the COVID-19 pandemic, to disrupt our clinical trial pipeline;

 

   

our failure to demonstrate the safety and efficacy of our investigational gene therapies;

 

   

the results obtained in earlier stage clinical testing may not be indicative of results in future clinical trials;

 

   

our ability to enroll patients in clinical trials for our investigational gene therapies;

 

   

the potential advantages of our investigational gene therapies;

 

   

the possibility that one or more of our investigational gene therapies or Orbit SDS may cause serious adverse, undesirable or unacceptable side effects or have other properties that could delay or prevent their regulatory approval or limit their commercial potential;

 

   

the timing and our ability to submit applications for, and our ability to obtain and maintain regulatory approval of, our investigational gene therapies in the indications for which we plan to develop them, and any related restrictions or limitations imposed by regulators;

 

   

our limited manufacturing experience which could result in delays in our development or commercialization of our investigational gene therapies or Orbit SDS;

 

   

the possibility that contamination in our manufacturing process, shortages of raw materials or failure of any of our key suppliers to deliver necessary components could result in delays in our clinical pipeline;

 

   

our ability to identify or discover additional investigational gene therapies, or failure to capitalize on programs or investigational gene therapies;

 

   

our ability to contract with third-party suppliers and manufacturers and their ability to perform adequately;

 

   

the scalability and commercial viability of our manufacturing methods and processes, including our intentions to develop and implement plans to establish and establish our own in-house manufacturing operations and facility;

 

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our dependence on a limited number of, or sole suppliers, for some or all of our components and materials used in our investigational gene therapies and Orbit SDS;

 

   

our commercialization, marketing and manufacturing capabilities and strategy;

 

   

the success of competing therapies that are or may become available;

 

   

the rate and degree of market acceptance and clinical utility of our investigational gene therapies, in particular, and gene therapy, in general, and Orbit SDS;

 

   

the impact of Brexit on our business and operations;

 

   

our ability to obtain, protect and enforce our intellectual property and to maintain patent protection for our current investigational gene therapies, Orbit SDS, any future investigational gene therapies or devices we may develop and our technology;

 

   

our continued compliance with obligations under our intellectual property licenses with third parties;

 

   

our ability to commercialize our investigational gene therapies and Orbit SDS without infringing, misappropriating or otherwise violating the intellectual property rights of others;

 

   

potential claims relating to our intellectual property and third-party intellectual property;

 

   

whether we are classified as a passive foreign investment company, or PFIC, for the current year or future periods;

 

   

the increased time and costs associated with operating as a public company;

 

   

other factors discussed under “Risk Factors” and elsewhere in this prospectus; and

 

   

our plans, objectives, expectations and intentions contained in this prospectus that are not historical.

The preceding list is not intended to be an exhaustive list of all of our forward-looking statements. The forward-looking statements contained in this prospectus speak only as of the date of this prospectus. You should refer to the section titled “Risk Factors” for a discussion of important factors that may cause our actual results to differ materially from those expressed or implied by our forward-looking statements. As a result of these factors, we cannot assure you that the forward-looking statements in this prospectus will prove to be accurate. Furthermore, if our forward-looking statements prove to be inaccurate, the inaccuracy may be material. In light of the significant uncertainties in these forward-looking statements, you should not regard these statements as a representation or warranty by us or any other person that we will achieve our objectives and plans in any specified time frame, or at all. We undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

You should read this prospectus and the documents that we reference in this prospectus and have filed as exhibits to the registration statement of which this prospectus is a part completely and with the understanding that our actual future results may be materially different from what we expect.

 

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USE OF PROCEEDS

We estimate that the net proceeds from the sale of ADSs in this offering will be approximately $127.8 million, or $147.6 million if the underwriters exercise their option to purchase additional ADSs in full, based on an assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, and after deducting the underwriting discounts and commissions and estimated offering expenses payable by us.

Each $1.00 increase or decrease in the assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range listed on the cover page of this prospectus, would increase or decrease the net proceeds to us from this offering by $6.3 million, assuming that the number of ADSs offered by us, as set forth on the cover page of this prospectus, remains the same, after deducting the underwriting discounts and commissions and estimated offering expenses payable by us. We may also increase or decrease the number of ADSs we are offering. An increase or decrease of 1,000,000 in the number of ADSs we are offering would increase or decrease the net proceeds to us from this offering by $19.5 million, assuming the assumed initial public offering price remains the same, after deducting underwriting discounts and commissions and estimated offering expenses payable by us. We do not expect that a change in the initial price to the public or the number of ADSs by these amounts would have a material effect on the uses of the proceeds from this offering, although it may accelerate the time at which we will need to seek additional capital.

We intend to use the net proceeds from this offering, together with our existing cash, to advance our clinical pipeline, including, specifically:

 

   

approximately $90.0 million to $130.0 million to advance our lead product candidate, GT005, including to fund our ongoing Phase I/II FOCUS clinical trial, ongoing Phase II EXPLORE clinical trial and our ongoing Phase II HORIZON clinical trial;

 

   

approximately $10.0 million to $20.0 million to advance our product candidate, GT011; and

 

   

the balance for the development of our other preclinical programs and general corporate purposes, including general and administrative expenses and working capital.

We may also use a portion of the net proceeds from this offering to acquire or invest in complementary products, technologies or businesses, although we have no present agreements or commitments to do so.

Based on our current operational plans and assumptions, we expect that the net proceeds from this offering, combined with our current cash and cash equivalents, including the net proceeds from the Series C Financing, will be sufficient to fund operations through mid-2023, but we expect that we will need to raise additional capital in order to develop and commercialize our investigational gene therapies, including any potential future trials that may be required by regulatory authorities. Our expected use of net proceeds from this offering represents our current intentions based upon our present plans and business condition. As of the date of this prospectus, we cannot predict with certainty all of the particular uses for the net proceeds to be received upon the completion of this offering or the actual amounts that we will spend on the uses set forth above. We believe opportunities may exist from time to time to expand our current business through the acquisition or in-license of complementary product candidates or programming technologies. While we have no current agreements for any specific future acquisitions or in-licenses at this time, we may use a portion of the net proceeds for these purposes.

The amounts and timing of our actual expenditures will depend on numerous factors, including the progress of our clinical trials, the potential for achieving accelerated regulatory approval and the amount of cash used in our operations. We therefore cannot estimate with certainty the amount of net proceeds to be used for the purposes described above. We may find it necessary or advisable to use the net proceeds for other purposes, and we will have broad discretion in the application of the net proceeds.

 

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Pending these uses, we plan to invest these net proceeds in short-term, interest bearing obligations, investment-grade instruments, certificates of deposit or direct or guaranteed obligations of the United States. The goal with respect to the investment of these net proceeds is capital preservation and liquidity so that such funds are readily available to fund our operations.

 

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CORPORATE REORGANIZATION

Gyroscope Therapeutics Holdings plc was incorporated as Gyroscope Therapeutics Holdings Limited, a private company with limited liability incorporated pursuant to the laws of England and Wales on December 17, 2020. Gyroscope Therapeutics Holdings Limited was incorporated with nominal assets and liabilities for the purposes of becoming the ultimate holding company for Gyroscope Therapeutics Limited and consummating the corporate reorganization described herein. Gyroscope Therapeutics Limited was incorporated as a private company with limited liability under the laws of England and Wales on April 18, 2016. In December 2020, we incorporated Gyroscope Holdings (UK) Limited, as a wholly owned subsidiary of Gyroscope Therapeutics Holdings Limited. Gyroscope Therapeutics Holdings plc and Gyroscope Holdings (UK) Limited are holding companies which have not conducted any operations prior to this offering other than activities incidental to their formation, the corporate reorganization, the Series C Financing and this offering.

Prior to the completion of this offering:

 

   

Gyroscope Therapeutics Holdings Limited incorporated Gyroscope Holdings (UK) Limited as a wholly owned subsidiary.

 

   

Gyroscope Therapeutics Holdings Limited acquired all of the issued share capital of Gyroscope Therapeutics Limited pursuant to a share-for-share exchange as described below.

 

   

Gyroscope Therapeutics Holdings Limited re-registered as a public limited company and changed its name to Gyroscope Therapeutics Holdings plc.

 

   

Gyroscope Therapeutics Holdings plc has four direct and indirect subsidiaries: Gyroscope Holdings (UK) Limited, Gyroscope Therapeutics Limited, Orbit Biomedical Limited and Gyroscope USA, Inc.

Therefore, investors in this offering will only acquire, and this prospectus only describes the offering of, ADSs representing ordinary shares of Gyroscope Therapeutics Holdings plc.

The corporate reorganization will take place in several steps, some of which will be completed following the completion of this offering. We refer to the following steps, which are discussed in more detail below, as our “corporate reorganization”:

Prior to completion of this offering:

 

   

Adjustment of the nominal value and redesignation of the share capital of Gyroscope Therapeutics Holdings Limited: the share capital of Gyroscope Therapeutics Holdings Limited was (i) adjusted by way of an issue of one more additional share in the capital of Gyroscope Therapeutics Holdings Limited and a consolidation of the share capital into a share with a nominal value that is the same nominal value as the shares issued in the following step and (ii) with effect immediately prior to the completion of the next step, was redesignated into a share with the same rights attached to an E ordinary share of Gyroscope Therapeutics Limited.

 

   

Exchange of Gyroscope Therapeutics Limited Shares for Gyroscope Therapeutics Holdings Limited Shares: All shareholders of Gyroscope Therapeutics Limited exchanged each of the shares held by them for shares of Gyroscope Therapeutics Holdings Limited to result in them holding the same number and class of newly issued shares of £1.75 nominal value each of Gyroscope Therapeutics Holdings Limited and, upon completion of the transfer of the shares in Gyroscope Therapeutics Limited, Gyroscope Therapeutics Limited will become a wholly owned subsidiary of Gyroscope Therapeutics Holdings Limited.

 

   

Reduction of capital of Gyroscope Therapeutics Holdings Limited: Gyroscope Therapeutics Holdings Limited reduced its issued share capital pursuant to Chapter 10 of Part 17 of the Companies Act.

 

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Re-registration of Gyroscope Therapeutics Holdings Limited as a public limited company and change of name to Gyroscope Therapeutics Holdings plc.

 

   

Reorganization of separate classes of shares of Gyroscope Therapeutics Holdings plc (other than deferred shares) into a single class of ordinary shares: The different classes of issued share capital of Gyroscope Therapeutics Holdings plc (other than deferred shares) will be reorganized into a single class of ordinary shares.

Following completion of this offering:

 

   

Reorganization of the deferred shares of Gyroscope Therapeutics Holdings plc: The deferred shares of Gyroscope Therapeutics Holdings plc may be transferred, consolidated, subdivided and/or cancelled and deferred shares may be issued for the purposes of simplifying our share capital and to ensure compliance with the applicable requirements of the Companies Act.

 

   

Reorganization of separate classes of shares of Gyroscope Therapeutics Limited into a single class of ordinary shares: The different classes of issued share capital of Gyroscope Therapeutics Limited will be reorganized into a single class of ordinary shares.

 

   

Transfer of Gyroscope Therapeutics Limited shares to Gyroscope Holdings (UK) Limited: Gyroscope Therapeutics Holdings plc will transfer the entire issued share capital of Gyroscope Therapeutics Limited to Gyroscope Holdings (UK) Limited in exchange for the issue of shares in Gyroscope Holdings (UK) Limited and, as a result, Gyroscope Therapeutics Limited will become a wholly owned subsidiary of Gyroscope Holdings (UK) Limited, which, in turn, will be a wholly owned subsidiary of Gyroscope Therapeutics Holdings plc.

 

   

Reduction of capital of Gyroscope Holdings (UK) Limited and Gyroscope Therapeutics Limited: Gyroscope Holdings (UK) Limited and Gyroscope Therapeutics Limited are expected to reduce their issued share capital pursuant to Chapter 10 of Part 17 of the Companies Act.

Adjustment of the nominal value and redesignation of the subscriber share of Gyroscope Therapeutics Holdings Limited

Gyroscope Therapeutics Holdings Limited was incorporated with share capital of a single ordinary share of £1.00 nominal value. Prior to the effectiveness of the registration statement of which this prospectus forms a part, the initial shareholder of Gyroscope Therapeutics Holdings Limited (i) subscribed for one additional ordinary share of £0.75 in the capital of Gyroscope Therapeutics Holdings Limited and approved a consolidation of the share capital of Gyroscope Therapeutics Holdings Limited into a share with a nominal value of £1.75 and (ii) approved with effect immediately prior to the completion of the next step, a redesignation of the ordinary share in issue into a share with the same rights attached to an E Ordinary share of Gyroscope Therapeutics Limited.

Exchange of Gyroscope Therapeutics Limited shares for Gyroscope Therapeutics Holdings Limited shares

The share capital of Gyroscope Therapeutics Limited is divided into the following classes: B ordinary shares, C ordinary shares, D ordinary shares, E ordinary shares, series A preferred shares, series B preferred shares, series C preferred shares and deferred shares. Prior to the effectiveness of the registration statement of which this prospectus forms a part, the shareholders of Gyroscope Therapeutics Limited exchanged each of these shares of Gyroscope Therapeutics Limited for shares of Gyroscope Therapeutics Holdings Limited to result in them holding the same number and class of shares of £1.75 nominal value each, with the same rights, in Gyroscope Therapeutics Holdings Limited. As a result, Gyroscope Therapeutics Holdings Limited will become the sole shareholder of Gyroscope Therapeutics Limited.

 

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Reduction of capital of Gyroscope Therapeutics Holdings Limited

Gyroscope Therapeutics Holdings Limited reduced its issued share capital pursuant to Chapter 10 of Part 17 of the Companies Act by way of the reduction of the nominal value of shares issued and outstanding. Such reduction of capital was approved by special resolutions passed by the shareholders of Gyroscope Therapeutics Holdings Limited and the reserve arising upon completion of such reduction of capital will be credited to Gyroscope Therapeutics Holdings Limited’s reserves that are available for distribution.

Re-registration of Gyroscope Therapeutics Holdings Limited as a public limited company and change of name to Gyroscope Therapeutics Holdings plc

Following the steps described above and prior to the completion of this offering, Gyroscope Therapeutics Holdings Limited re-registered as a public limited company and changed its name to Gyroscope Therapeutics Holdings plc. A special resolution was passed by the shareholders of Gyroscope Therapeutics Holdings Limited to approve the re-registration as a public limited company, the name change to Gyroscope Therapeutics Holdings plc and the adoption of new articles of association for Gyroscope Therapeutics Holdings plc appropriate for a public company.

Reorganization of separate classes of shares of Gyroscope Therapeutics Holdings plc (other than deferred shares) into a single class of ordinary shares

Pursuant to the terms of the articles of association of Gyroscope Therapeutics Holdings plc prior to the closing of this offering, each class of shares of Gyroscope Therapeutics Holdings plc (other than deferred shares) will be reorganized into one class of ordinary shares of Gyroscope Therapeutics Holdings plc. The ratio for the redesignation of each class of shares of Gyroscope Therapeutics Holdings plc into ordinary shares of Gyroscope Therapeutics Holdings plc will be determined based on the final price per ADS in this offering. Assuming an initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover of this prospectus, each such class of shares of Gyroscope Therapeutics Holdings plc outstanding on the date of this prospectus (other than deferred shares) will be redesignated as follows:

 

   

Each B ordinary share will be redesignated as 1.00 ordinary share;

 

   

Each C ordinary share will be redesignated as approximately 0.57 ordinary share;

 

   

Each D ordinary share will be redesignated as approximately 0.57 ordinary share;

 

   

Each E ordinary share with a threshold amount of £0.60 will be redesignated as approximately 0.74 ordinary share;

 

   

Each E ordinary share with a threshold amount of £1.00 will be redesignated as approximately 0.57 ordinary shre;

 

   

Each E ordinary share with a threshold amount of £1.40 will be redesignated as approximately 0.40 ordinary share;

 

   

Each series A preferred share will be redesignated as 1.00 ordinary share;

 

   

Each series B preferred share will be redesignated as 1.00 ordinary share; and

 

   

Each series C preferred share will be redesignated as 1.00 ordinary share.

Following the reorganization into a single class of ordinary shares as described above, such ordinary shares will be consolidated and subdivided to reflect an approximately 1 for 0.155 reverse split of such ordinary shares and the balance of any ordinary shares will be redesignated as deferred shares prior to completion of this offering.

Such reorganization will involve (without limitation) the redesignation of classes of shares and the consolidation and/or subdivision of shares pursuant to the terms of the articles of association of the Company in effect at such time as described above. The number of shares that each current shareholder of Gyroscope Therapeutics Holdings plc receives will be rounded up or down to the nearest whole share. Therefore, upon

 

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consummation of the corporate reorganization and prior to the completion of this offering, the current shareholders of Gyroscope Therapeutics Holdings plc will hold an aggregate of approximately 22,479,659 ordinary shares of Gyroscope Therapeutics Holdings plc.

Reorganization of deferred shares of Gyroscope Therapeutics Holdings plc

Following completion of this offering, the deferred shares of Gyroscope Therapeutics Holdings plc may be transferred, consolidated, subdivided and/or cancelled and deferred shares may be issued for the purpose of simplifying our share capital structure and to ensure compliance with the applicable requirements of the Companies Act.

Reorganization of separate classes of shares of Gyroscope Therapeutics Limited into a single class of ordinary shares

Pursuant to the terms of the articles of association of Gyroscope Therapeutics Limited in effect at such time, each class of shares of Gyroscope Therapeutics Limited will be reorganized into one class of ordinary shares as follows:

 

   

Each B ordinary share will be redesignated as one ordinary share;

 

   

Each C ordinary share will be redesignated as one ordinary share;

 

   

Each D ordinary share will be redesignated as one ordinary share;

 

   

Each E ordinary share will be redesignated as one ordinary share;

 

   

Each series A preferred share will be redesignated as one ordinary share;

 

   

Each series B preferred share will be redesignated as one ordinary share;

 

   

Each series C preferred share will be redesignated as one ordinary share; and

 

   

Each deferred share will be redesignated as one ordinary share.

Transfer of Gyroscope Therapeutics Limited shares to Gyroscope Holdings (UK) Limited

Following the reorganization of the share capital of Gyroscope Therapeutics Limited, Gyroscope Therapeutics Holdings plc will transfer the entire issued share capital of Gyroscope Therapeutics Limited to Gyroscope Holdings (UK) Limited in exchange for the issue of shares in Gyroscope Holdings (UK) Limited. As a result, Gyroscope Therapeutics Limited will become a wholly owned subsidiary of Gyroscope Holdings (UK) Limited, which, in turn, will be a wholly owned subsidiary of Gyroscope Therapeutics Holdings plc.

Reduction of capital of Gyroscope Holdings (UK) Limited and Gyroscope Therapeutics Limited

Gyroscope Holdings (UK) Limited and Gyroscope Therapeutics Limited will reduce their issued share capital pursuant to Chapter 10 of Part 17 of the Companies Act by way of reduction in the nominal value of shares issued and outstanding and/or reduction of the amounts credited to each company’s share premium account or other permitted undistributable reserves. Any such reduction of capital will be credited to each company’s reserves that are available for distribution.

 

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CAPITALIZATION

The following table sets forth our cash and cash equivalents and capitalization as of December 31, 2020 on:

 

   

an actual basis;

 

   

a pro forma basis to give effect to (i) our corporate reorganization (including the approximately 1-for-0.155 reverse split of all our ordinary shares prior to completion of this offering) as described under “Corporate Reorganization” and (ii) the consummation of the Series C Financing and our receipt of net proceeds therefrom; and

 

   

a pro forma as adjusted basis to give effect to (i) our corporate reorganization (including the approximately 1-for-0.155 reverse split of all our ordinary shares prior to completion of this offering) as described under “Corporate Reorganization,” (ii) the consummation of the Series C Financing and our receipt of net proceeds therefrom and (iii) the sale of 6,750,000 ADSs in this offering.

The pro forma as adjusted calculations assume an initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, after deducting the underwriting discounts and commissions and estimated offering expenses payable by us. The pro forma information set forth in the table below is illustrative only and will be adjusted based on the actual initial public offering price and other terms of this offering determined at pricing.

You should read this information together with our audited financial statements and related notes appearing elsewhere in this prospectus and the information set forth under the sections titled “Presentation of Financial and Other Information,” “Selected Financial and Other Information,” “Use of Proceeds” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations.”

 

     As of December 31, 2020  
     Actual     Pro Forma     Pro Forma As
Adjusted(1)
 
    

(in thousands except share

and per share data)

 

Cash and cash equivalents

   $ 20,915     $ 142,510     $ 270,545  
  

 

 

   

 

 

   

 

 

 

Shareholders’ equity:

      

Preferred shares, nominal value £0.00001 per share; 135,974,285 shares authorized, 69,934,047 shares issued and outstanding, actual; 135,974,285 shares authorized, none issued and outstanding, pro forma; 135,974,285 shares authorized, none issued and outstanding, pro forma as adjusted

     1       —         —    

Ordinary shares, nominal value £0.00001 per share; 400,000,000 shares authorized, 9,445,037 shares issued and outstanding, actual; 400,000,000 shares authorized, 22,479,659 shares issued and outstanding, pro forma; 400,000,000 shares authorized, 29,229,659 shares issued and outstanding, pro forma as adjusted

     —         1       29  

Additional paid-in capital

         112,682       265,527       393,284  

Accumulated other comprehensive loss

     (874     (874     (874

Accumulated deficit

     (108,805     (114,627     (114,627
  

 

 

   

 

 

   

 

 

 

Total shareholders’ equity

     3,004       150,027       277,812  
  

 

 

   

 

 

   

 

 

 

Total capitalization

   $ 3,004     $     150,027     $ 277,812  
  

 

 

   

 

 

   

 

 

 

 

(1)

Each $1.00 increase or decrease in the assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, would increase or decrease the pro

 

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  forma as adjusted amount of each of cash, total shareholders’ equity and total capitalization by $6.3 million, assuming that the number of ADSs offered by us, as set forth on the cover page of this prospectus, remains the same, and after deducting underwriting discounts and commissions. We may also increase or decrease the number of ADSs we are offering. An increase or decrease of 1,000,000 in the number of ADSs offered by us, as set forth on the cover page of this prospectus, would increase or decrease the pro forma as adjusted amount of each of cash, total shareholders’ equity and total capitalization by $19.5 million, assuming no change in the assumed initial public offering price per ADS and after deducting underwriting discounts and commissions.

The number of ordinary shares outstanding on a pro forma as adjusted basis in the table above excludes:

 

   

336,533 ordinary shares issuable upon the exercise of options outstanding as of December 31, 2020 with a weighted-average exercise price of $6.33 per share;

 

   

2,294,243 ordinary shares issuable upon the exercise of options outstanding after December 31, 2020 with a weighted-average exercise price of $14.79 per share;

 

   

1,040,946 deferred shares outstanding as of December 31, 2020 and any other deferred shares issued and outstanding as of the date of this prospectus;

 

   

3,361,411 ordinary shares authorized for future issuance under the 2021 Equity Incentive Plan (including 2,288,108 ordinary shares reserved for future issuance under our Series C Share Option Plan that will be transferred to our 2021 Equity Incentive Plan upon its effectiveness and including the grants of options to be made in connection with this offering described below) to be adopted in connection with this offering;

 

   

292,297 ordinary shares authorized for future issuance under the Sharesave Plan to be adopted in connection with this offering;

 

   

292,297 ordinary shares authorized for future issuance under the 2021 ESPP to be adopted in connection with this offering; and

 

   

the expected grant of options to purchase approximately 1,315,335 ordinary shares (based on an amount equal to 4.5% of the ordinary shares outstanding after this offering) to our directors, officers and other employees in connection with this offering, with an exercise price equal to the initial public offering price.

 

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DILUTION

If you invest in our ADSs in this offering, your ownership interest will be immediately diluted to the extent of the difference between the initial public offering price per ADS in this offering and the pro forma as adjusted net tangible book value per ADS after this offering. Dilution results from the fact that the initial public offering price per ADS is substantially in excess of the net tangible book value per ADS. As of December 31, 2020, we had a historical net tangible book value of $(2,170), or $(2.36) per ordinary share (equivalent to $(2.36) per ADS). Our net tangible book value per share represents the amount of our total assets less our total liabilities, excluding goodwill and other intangible assets, divided by the total number of ordinary shares outstanding at December 31, 2020.

After giving effect to our corporate reorganization as described under “Corporate Reorganization” (including the approximately 1 for 0.155 reverse split of all our ordinary shares prior to completion of this offering) and the Series C Financing, our pro forma net tangible book value at December 31, 2020 would have been $6.44 per ordinary share (equivalent to $6.44 per ADS). After giving further effect to the sale of 6,750,000 ADSs in this offering at an assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, and after deducting the underwriting discounts and commissions and estimated offering expenses payable by us, our pro forma as adjusted net tangible book value at December 31, 2020 would have been $9.44 per ordinary share (equivalent to $9.44 per ADS). This represents an immediate increase in pro forma as adjusted net tangible book value of $3.00 per ADS to existing investors and immediate dilution of $11.56 per ADS to new investors. The following table illustrates this dilution to new investors purchasing ADSs in this offering on a per ADS basis:

 

Assumed initial public offering price per ADS

     $ 21.00  

Historical net tangible book value per ADS as of December 31, 2020

   $ (2.36  

Increase in net tangible book value per ADS attributable to our corporate reorganization and the Series C Financing

     8.81    

Pro forma net tangible book value per ADS as of December 31, 2020

     6.44    

Increase in net tangible book value per ADS attributable this offering

     3.00    

Pro forma as adjusted net tangible book value per ADS as of December 31, 2020

       9.44  
    

 

 

 

Dilution per ADS to new investors purchasing ADSs in this offering

     $ 11.56  
    

 

 

 

The dilution information discussed above is illustrative only and will change based on the actual initial public offering price and other terms of this offering determined at pricing. Each $1.00 increase or decrease in the assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, would increase or decrease our pro forma as adjusted net tangible book value as of December 31, 2020 after this offering by $0.21 per ADS, and would increase or decrease dilution to new investors by $0.79 per ADS, assuming that the number of ADSs offered by us, as set forth on the cover page of this prospectus, remains the same, and after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us. We may also increase or decrease the number of ADSs we are offering. An increase of 1,000,000 in the number of ADSs we are offering would increase our pro forma as adjusted net tangible book value as of December 31, 2020 after this offering by $0.33 per ADS, and would decrease dilution to new investors by $0.33 per ADS, assuming the assumed initial public offering price per ADS remains the same, and after deducting the underwriting discounts and commissions and estimated offering expenses payable by us. A decrease of 1,000,000 in the number of ADSs we are offering would decrease our pro forma as adjusted net tangible book value as of December 31, 2020 after this offering by $0.36 per ADS, and would increase dilution to new investors by $0.36 per ADS, assuming the assumed initial public offering price per ADS remains the same, and after deducting the underwriting discounts and commissions and estimated offering expenses payable by us.

If the underwriters exercise their option to purchase additional ADSs in full, the pro forma as adjusted net tangible book value per ADS after the offering would be $9.44, the increase in net tangible book value per

 

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ADS to existing shareholders would be $3.33 and the immediate dilution in net tangible book value per ADS to new investors in this offering would be $11.23.

The following table summarizes, on the pro forma as adjusted basis described above as of December 31, 2020, the differences between the existing shareholders and the new investors in this offering with respect to the number of ordinary shares, including ordinary shares represented by ADSs purchased from us, the total consideration paid to us and the average price per share, including ordinary shares represented by ADSs, based on an assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover page of this prospectus, before deducting underwriting discounts and commissions and estimated offering expenses payable by us.

 

     Ordinary Shares Purchased
from Us(1)
    Total
            Consideration             
    Average Price
per Ordinary
Share
 
     Number      Percent     Amount      Percent        

Existing shareholders

     22,479,659        76.9   $ 259,250,525        64.7   $ 11.53  

New investors

     6,750,000        32.1       141,750,000        35.3       21.00  
  

 

 

    

 

 

   

 

 

    

 

 

   

 

 

 

Total

     29,229,659        100   $ 401,000,525        100   $ 13.72  
  

 

 

    

 

 

   

 

 

    

 

 

   

 

 

 

 

(1)

Including ordinary shares underlying ADSs.

Each $1.00 increase or decrease in the assumed initial public offering price of $21.00 per ADS, which is the midpoint of the price range on the cover page of this prospectus, would increase or decrease the total consideration paid by new investors by $6.3 million and, in the case of an increase, would increase the percentage of total consideration paid by new investors by 1.1 percentage points and, in the case of a decrease, would decrease the percentage of total consideration paid by new investors by 1.1 percentage points, assuming that the number of ADSs offered by us, as set forth on the cover page of this prospectus, remains the same, and after deducting the underwriting discounts and commissions and estimated offering expenses payable by us. We may also increase or decrease the number of ADSs we are offering. An increase or decrease of 1,000,000 in the number of ADSs offered by us, as set forth on the cover page of this prospectus, would increase or decrease the total consideration paid by new investors by $19.5 million and, in the case of an increase, would increase the percentage of total consideration paid by new investors by 3.2 percentage points and, in the case of a decrease, would decrease the percentage of total consideration paid by new investors by 3.6 percentage points, assuming no change in the assumed initial public offering price per ADS.

If the underwriters exercise their option to purchase additional ADSs in full, the percentage of ordinary shares held by existing shareholders will decrease to 81.4% of the total number of ordinary shares outstanding after the offering, and the number of shares held by new investors will be increased to 7,762,500, or 18.6% of the total number of ordinary shares outstanding after this offering.

The table and discussion above exclude:

 

   

336,533 ordinary shares issuable upon the exercise of options outstanding as of December 31, 2020 with a weighted-average exercise price of $6.33 per share;

 

   

2,294,243 ordinary shares issuable upon the exercise of options outstanding after December 31, 2020 with a weighted-average exercise price of $14.79 per share;

 

   

1,040,946 deferred shares outstanding as of December 31, 2020 and any other deferred shares issued and outstanding as of the date of this prospectus;

 

   

3,361,411 ordinary shares authorized for future issuance under the 2021 Equity Incentive Plan (including 2,288,108 ordinary shares reserved for future issuance under our Series C Share Option Plan that will be transferred to our 2021 Equity Incentive Plan upon its effectiveness and including the grants of options to be made in connection with this offering described below) to be adopted in connection with this offering;

 

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292,297 ordinary shares authorized for future issuance under the Sharesave Plan to be adopted in connection with this offering;

 

   

292,297 ordinary shares authorized for future issuance under the 2021 ESPP to be adopted in connection with this offering; and

 

   

the expected grant of options to purchase approximately 1,315,335 ordinary shares (based on an amount equal to 4.5% of the ordinary shares outstanding after this offering) to our directors, officers and other employees in connection with this offering, with an exercise price equal to the initial public offering price.

Following the reorganization into a single class of ordinary shares as described above, such ordinary shares will be consolidated and subdivided to reflect an approximately 1-for-0.155 reverse split of such ordinary shares and the balance of any ordinary shares will be redesignated as deferred shares prior to completion of this offering.

Such reorganization will involve (without limitation) the redesignation of classes of shares, the consolidation and/or the subdivision of shares pursuant to the terms of the articles of association of the Company in effect at such time as described above. The number of ordinary shares that each current shareholder of Gyroscope Therapeutics Holdings plc receives will be rounded up or down to the nearest whole share. Therefore, upon consummation of the corporate reorganization and prior to the completion of this offering, assuming an initial public offering price of $21.00 per ADS, which is the midpoint of the price range set forth on the cover of this prospectus, the current shareholders of Gyroscope Therapeutics Holdings plc will hold an aggregate of approximately 22,479,659 ordinary shares of Gyroscope Therapeutics Holdings plc. In the event of a $1.00 increase in the assumed initial public offering price per ADS to $22.00 per ADS, the current shareholders of Gyroscope Therapeutics Holdings plc will hold an aggregate of approximately 22,504,077 ordinary shares of Gyroscope Therapeutics Holdings plc. In the event of a $1.00 decrease in the assumed initial public offering price per ADS to $20.00 per ADS, the current shareholders of Gyroscope Therapeutics Holdings plc will hold an aggregate of approximately 22,451,130 ordinary shares of Gyroscope Therapeutics Holdings plc.

To the extent that options are issued under our 2021 Plan and our 2021 ESPP, or we issue additional ordinary shares or ADSs in the future, there will be further dilution to investors participating in this offering.

We also may choose to raise additional capital due to market conditions or strategic considerations even if we believe we have sufficient funds for our current or future operating plans. To the extent that additional capital is raised through the sale of equity or convertible debt securities, the issuance of such securities may result in further dilution to our shareholders.

 

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SELECTED FINANCIAL AND OTHER INFORMATION

The following tables present our selected financial data as of the dates and for the periods indicated. We derived the selected consolidated statements of operations and comprehensive loss data for the fiscal year ended January 31, 2020 and the fiscal year ended December 31, 2020 and the selected consolidated balance sheet data as of January 31, 2020 and December 31, 2020 from our audited financial statements included elsewhere in this prospectus. Commencing with the fiscal year ended December 31, 2020, we have modified our fiscal year to end on December 31. Accordingly, our historical results for the fiscal year ended January 31, 2020 are not directly comparable to the fiscal year ended December 31, 2020, for which we had an 11-month fiscal year. We prepare our financial statements in accordance with U.S. GAAP.

Our historical results are not necessarily indicative of our future results. You should read this data together with our financial statements and related notes appearing elsewhere in this prospectus and the information under the sections titled “Capitalization” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations.”

We maintain the financial statements of each entity within the group in its local currency, which is also the entity’s functional currency. Monetary assets and liabilities denominated in currencies other than the functional currency are translated into the functional currency at rates of exchange prevailing at the balance sheet dates. Non-monetary assets and liabilities denominated in foreign currencies are translated into the functional currency at the exchange rates prevailing at the date of the transaction. Exchange gains or losses arising from foreign currency transactions are included in other expense, net in the consolidated statement of comprehensive loss.

For financial reporting purposes our financial statements have been presented in U.S. dollars, the reporting currency. The financial statements of entities are translated from their functional currency into the reporting currency as follows: assets and liabilities are translated at the exchange rates at the balance sheet dates, revenue and expenses are translated at the average exchange rates and shareholders’ equity is translated based on historical exchange rates. Translation adjustments are not included in determining net loss but are included as a foreign exchange adjustment to other comprehensive loss, a component of shareholders’ equity.

The following tables and notes thereto have not been retroactively adjusted to reflect our corporate reorganization (including the approximately 1-for-0.155 reverse split of all our ordinary shares prior to completion of this offering) as described under “Corporate Reorganization.”

 

     Fiscal Year Ended
January 31,

2020
    Fiscal Year Ended
December 31,

2020
 
     (in thousands, except for share and per share data)  

Consolidated Statements of Operations and Comprehensive Loss Data:

    

Revenue

   $ 2,966     $ 864  

Cost of revenue

     1,053       112  
  

 

 

   

 

 

 

Gross profit

     1,913       752  

Operating expenses:

    

Research and development

     24,844       41,307  

General and administrative

     16,998       24,389  
  

 

 

   

 

 

 

Total operating expenses

     41,842       65,696  
  

 

 

   

 

 

 

Loss from operations

     (39,929     (64,944
  

 

 

   

 

 

 

Other income (expense), net:

    

Other expense, net

     (144     825  

Interest expense, net

     (9     (174

Benefit from R&D tax credit

     6,264       10,857  
  

 

 

   

 

 

 

Total other income, net

     6,111       11,508  
  

 

 

   

 

 

 

 

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     Fiscal Year Ended
January 31,

2020
    Fiscal Year Ended
December 31,

2020
 
     (in thousands, except for share and per share data)  

Loss before income taxes

     (33,818     (53,436

Income tax benefit

     283       264  
  

 

 

   

 

 

 

Net loss

   $ (33,535   $ (53,172
  

 

 

   

 

 

 

Other comprehensive income (loss)

    

Foreign exchange translation adjustment

     1,956       (1,965
  

 

 

   

 

 

 

Total comprehensive loss attributable to ordinary shareholders—basic and diluted

   $ (31,579   $ (55,137
  

 

 

   

 

 

 

Net loss per share attributable to ordinary shareholders—basic and diluted

   $ (12.89   $ (11.15
  

 

 

   

 

 

 

Weighted average ordinary shares outstanding—basic and diluted

     2,602,516       4,767,392  
  

 

 

   

 

 

 

 

     As of January 31,
2020
     As of December 31,
2020
 
     (in thousands)  

Consolidated Balance Sheets Data:

     

Cash and cash equivalents

   $ 12,640      $ 20,915  

Working capital(1)

     14,144        (6,644

Total assets

     29,955        48,387  

Total liabilities

     8,258        45,383  

Total stockholders’ equity

     21,697        3,004  

 

(1)

We define working capital as current assets less current liabilities.

 

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MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS

You should read the following discussion and analysis of our financial condition and results of operations together with section entitled “Selected Consolidated Financial Data” and our consolidated financial statements and related notes appearing elsewhere in this prospectus. Some of the information contained in this discussion and analysis, including information with respect to our plans and strategy for our business and our expectations with respect to liquidity and capital resources, includes forward-looking statements. These forward-looking statements are subject to numerous risks and uncertainties, including, but not limited to, those risks and uncertainties described in “Risk Factors” and “Special Note Regarding Forward-Looking Statements” in this prospectus. Our actual results could differ materially from the results described in or implied by these forward-looking statements.

On December 17, 2020, Gyroscope Therapeutics Holdings Limited was incorporated under the laws of England and Wales to become the ultimate holding company for Gyroscope Therapeutics Limited pursuant to our corporate reorganization. See “Corporate Reorganization.” Prior to this offering, Gyroscope Therapeutics Holdings Limited has only engaged in activities incidental to its formation, the corporate reorganization and this offering. Accordingly, a discussion and analysis of the results of operations and financial condition of Gyroscope Therapeutics Holdings Limited for the period of its operations prior to the corporate reorganization would not be meaningful and are not presented. Following the corporate reorganization, the historical consolidated financial statements of Gyroscope Therapeutics Holdings plc will be retrospectively adjusted to include the historical financial results of Gyroscope Therapeutics Limited for all periods presented.

Share and per share amounts discussed in this “Management’s discussion and analysis of financial condition and results of operations” do not reflect the 1-for-0.155 reverse split of all our ordinary shares prior to completion of this offering.

Overview

We are a global clinical-stage gene therapy company developing gene therapy beyond rare diseases. Our mission is to preserve sight and fight the devastating impact of blindness. Our science is grounded in the genetic understanding of patients with serious eye diseases to make medicines designed to have a meaningful impact. Our initial focus is age-related macular degeneration, or AMD, one of the leading causes of irreversible blindness, affecting more than 196 million people worldwide. We are developing a differentiated pipeline of recombinant adeno-associated virus, or rAAV, gene therapy candidates targeting genetic variants in the complement pathway that we believe to be key drivers of AMD. Our investigational gene therapies are designed as one-time treatments. Our lead investigational gene therapy, GT005, is advancing in an ongoing Phase I/II clinical trial and is being evaluated in Phase II clinical trials in two different genetically defined patient populations with geographic atrophy, or GA, an advanced form of dry AMD. We have received Fast Track designation from the U.S. Food and Drug Administration, or the FDA, for GT005 for the treatment of GA secondary to AMD.

Genetically-defined therapeutics have been successfully developed for rare inherited diseases of the eye. However, unlike other disease areas such as oncology, ophthalmology has yet to experience the proliferation of treatments specifically tailored towards a person’s genetics. We are aiming to change this with development of our gene therapies, as we believe one-time gene therapies could fundamentally change the way people suffering vision loss are treated and the outcomes they achieve. We have assembled a world-class team that has deep expertise in genetics, gene therapy, the complement system and ophthalmology, and have established the critical operations that we believe are required to deliver medicines to patients, including research, clinical development, scalable manufacturing and delivery technology. By bringing together the right people with the right expertise focusing on the right challenge, we aim to deliver on our promise to patients: Vision for Life.

Our initial focus is AMD, which causes progressive and permanent vision impairment leaving many people not only with devastating vision loss, but also loss of their independence as they lose the ability to read, drive or

 

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even recognize the faces of loved ones. There are two forms of AMD known respectively as dry AMD and wet AMD, with dry AMD representing 85-90% of the 196 million global AMD cases.

Since our inception in April 2016, we have devoted substantially all of our resources to conducting preclinical studies and clinical trials, organizing and staffing our company, planning our business initiatives, raising capital and establishing our intellectual property portfolio. Our Orbit SDS device has been cleared for commercial use, but we do not have any gene therapies or other products approved for sale. We have funded our operations to date primarily with proceeds from the sale of preferred shares and convertible loan notes. Through December 31, 2020, after giving effect to the consummation of the Series C Financing and our receipt of proceeds therefrom, we had received cash proceeds of $259.3 million from sales of our preferred shares and convertible loan notes.

We have incurred operating losses since inception, including a net loss of $33.5 million and $53.2 million for the fiscal year ended January 31, 2020 and the fiscal year ended December 31, 2020 respectively. As of January 31, 2020 and December 31, 2020, we had an accumulated deficit of $55.6 million and $108.8 million, respectively. These losses have resulted primarily from costs incurred in connection with research and development activities and general and administrative costs associated with our operations. We expect to continue to incur significant expenses and recurring increasing operating losses for the foreseeable future as we advance our investigational gene therapies through preclinical and clinical development, seek regulatory approval and pursue commercialization of any approved investigational gene therapies. Our operating losses stem primarily from our internal R&D activities, and they will continue to increase with our growth initiatives as we increase our headcount and progress our investigational gene therapies through clinical trials. Furthermore, following the closing of this offering, we expect to incur additional costs associated with operating as a public company, including significant legal, accounting, investor relations and other expenses that we did not incur as a private company. As a result, we will need substantial additional funding to support our continuing operations and pursue our growth strategy. Until such time as we can generate significant revenue from product sales, if ever, we expect to finance our operations through the sale of equity, debt financings or other capital sources, including potential collaborations with other companies or other strategic transactions. Our inability to raise capital as and when needed could have a negative impact on our financial condition and ability to pursue our business strategies. There can be no assurances, however, that the current operating plan will be achieved or that additional funding will be available on terms acceptable to us, or at all.

We expect that our cash and cash equivalents of $20.9 million as of December 31, 2020, together with the net proceeds of $146.6 million from the Series C Financing that closed in March 2021 and with the expected net proceeds from this offering, will enable us to fund our operating expenses and capital expenditure requirements through mid-2023. See “—Liquidity and Capital Resources—Funding Requirements” below.

The development of our investigational gene therapies could be disrupted and materially adversely affected in the future by a pandemic, epidemic or outbreak of an infectious disease, such as the recent COVID-19 pandemic. The spread of COVID-19 has impacted the global economy and has impacted our operations, including the interruption of our preclinical and clinical trial activities and potential interruption to our supply chain. For example, the COVID-19 pandemic has delayed enrollment in the first half of 2020 for our ongoing Phase I/II and Phase II clinical trials for GT005. If the disruption due to the COVID-19 pandemic continues, our additional planned Phase II clinical trial for GT005 also could be delayed due to government orders and site policies on account of the pandemic, and some patients may be unwilling or unable to travel to study sites for treatment or follow-up visits, enroll in our trials or be unable to comply with clinical trial protocols if quarantines impede patient movement or interrupt healthcare services, which would delay our ability to conduct preclinical studies and clinical trials or release clinical trial results and could delay our ability to obtain regulatory approval and commercialize our investigational gene therapies. In addition, as a result of the recent U.S. government-mandated COVID-19 vaccine development and production orders related to Operation Warp Speed, we may experience delays in the testing, development and manufacturing of our investigational gene therapies due to the potentially restricted capacity of our third-party service providers. Furthermore, COVID-19 could affect our employees or the employees of research sites and service providers on whom we rely as well as those of companies with which we do business, including our suppliers and CMOs, thereby disrupting our business operations. Quarantines and travel restrictions imposed by governments in the jurisdictions in which we and the

 

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companies with which we do business operate could materially impact the ability of employees to access preclinical and clinical sites, laboratories, manufacturing sites and offices. We have implemented work-at-home policies or new working practices requirements for laboratory and facility employees who continue to work on site, and may experience limitations in employee resources. Our increased reliance on personnel working from home may negatively impact productivity, or disrupt, delay, or otherwise adversely impact our business.

We are still assessing our business plans and the impact the COVID-19 pandemic may have on our ability to advance the testing, development and manufacturing of our investigational gene therapies, including as a result of adverse impacts on the research sites, service providers, vendors, or suppliers on whom we rely, or to raise financing to support the development of our investigational gene therapies. We cannot presently predict the scope and severity of any potential business shutdowns or disruptions, but if we or any of the third parties on whom we rely or with whom we conduct business, were to experience shutdowns or other business disruptions, our ability to conduct our business in the manner and on the timelines presently planned could be materially and adversely impacted.

Change in fiscal year

Commencing with the fiscal year ended December 31, 2020, we have modified our fiscal year to end on December 31. Accordingly, our historical results for the fiscal year ended January 31, 2020 are not directly comparable to the fiscal year ended December 31, 2020, for which we had an 11-month fiscal year. We have included in this prospectus our audited consolidated financial statements at and for the fiscal year ended January 31, 2020 and fiscal year ended December 31, 2020 prepared in accordance with U.S. GAAP.

Foreign Currency Translation

We maintain the financial statements of each entity within the group in its functional currency. The majority of our expenses are incurred in pounds sterling, and the majority of our cash and cash equivalents are held in a combination of pounds sterling and US dollars. Monetary assets and liabilities denominated in currencies other than the reporting currency are translated into the reporting currency at rates of exchange prevailing at the balance sheet dates. Non-monetary assets and liabilities denominated in foreign currencies are translated into the reporting currency at the exchange rates prevailing at the date of the transaction. Exchange gains or losses arising from foreign currency transactions are included in other expense, net in the consolidated statement of operations and comprehensive loss.

For financial reporting purposes, the financial statements have been translated into the U.S. dollar. Assets and liabilities are translated at the exchange rates at the balance sheet date, revenue and expenses are translated at the average exchange rates and shareholders’ equity is translated based on historical exchange rates.

Translation adjustments are not included in determining net loss but are included as a foreign exchange translation adjustment to other comprehensive loss, a component of shareholders’ equity.

Components of Our Results of Operations

Revenue

Revenues are primarily derived from license of Orbit SDS technology, products and related services which is recognized over the term of the license with product sales and training services recognized as they are delivered and incurred respectively. License fees are billed in advance and recorded as deferred revenue. Deferred revenue represents consideration received for which services have yet to be provided.

Cost of Revenue

Cost of revenue primarily consists of direct material costs and personnel costs such as training expenses, travel and meals.

 

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Gross Profit

Our gross profit consists of revenue less cost of revenue.

Operating Expenses

Research and Development Expenses

Research and development expenses consist primarily of costs incurred in connection with the research and development of investigational gene therapies and medical devices, Research and development expenses consist of:

 

   

expenses incurred under agreements with contract research organizations, or CROs, contract manufacturing organizations, or CMOs, as well as investigative sites and consultants that conduct our clinical trials, preclinical studies and other scientific development services;

 

   

manufacturing development and scale-up expenses and the cost of manufacturing preclinical and clinical materials;

 

   

expenses to acquire technologies to be used in research and development;

 

   

employee-related expenses, including salaries, related benefits, travel and share-based compensation expense for employees engaged in research and development functions;

 

   

costs of outside consultants, including their fees, share-based compensation and related travel expenses;

 

   

the costs of laboratory supplies and acquiring, developing and manufacturing preclinical study and clinical trial materials;

 

   

costs related to compliance with regulatory requirements;

 

   

lab facility-related expenses, which include direct depreciation costs and allocated expenses for rent and maintenance of facilities and other operating costs; and

We expense research and development costs as incurred. We recognize external development costs based on an evaluation of the progress to completion of specific tasks using information provided to us by our service providers. Payments for these activities are based on the terms of the individual agreements, which may differ from the pattern of costs incurred, and are reflected in our consolidated financial statements as a prepaid expense or accrued research and development expenses.

Our direct research and development expenses consist primarily of external costs, such as fees paid to outside consultants, CROs and CMOs in connection with our preclinical development, manufacturing and clinical development activities. License fees and other costs incurred after an investigational gene therapy has been selected that are directly related to an investigational gene therapy are also included in direct research and development expenses for that program. License fees and other costs incurred prior to designating an investigational gene therapy are included in other R&D expense. We use internal resources primarily to oversee the research and discovery as well as to manage our preclinical development, process development, manufacturing and clinical development activities. These employees work across multiple programs and, therefore, we do not track their costs by program.

Research and development activities are central to our business model. Investigational gene therapies in later stages of clinical development generally have higher development costs and resources than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials and related product manufacturing expenses. As a result, we expect that our research and development expenses will continue to increase over the next several years as we (i) continue the clinical development and seek to obtain marketing approval for our lead investigational gene therapy GT005; (ii) initiate additional clinical trials for our

 

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investigational gene therapies, including GT005; (iii) improve the efficiency and scalability of our manufacturing processes and supply chain; and (iv) build our in-house process development, analytical and manufacturing capabilities and continue to discover and develop additional investigational gene therapies, increase personnel costs and prepare for regulatory filings related to our investigational gene therapies. We also expect to incur additional expenses related to milestone, royalty payments and maintenance fees payable to third parties with whom we have entered into license agreements to acquire the rights related to our product candidates.

The successful development and commercialization of our investigational gene therapies is highly uncertain. This is due to the numerous risks and uncertainties associated with development and commercialization, including the following:

 

   

completing research and preclinical development of our investigational gene therapies and identifying new gene therapy investigational gene therapies;