UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported): May 25, 2020

AEGLEA BIOTHERAPEUTICS, INC.

(Exact name of registrant as specified in its charter)

(512) 942-2935

(Registrant’s telephone number, including area code)

(Former name or former address, if changed since last report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

Securities registered pursuant to Section 12(b) of the Act:

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company ☒

If an emerging growth company, 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 13(a) of the Exchange Act. ☒

Item 7.01 Regulation FD Disclosure.

On May 25, 2020, Aeglea BioTherapeutics, Inc. (the “Company”) presented at the 6^th Congress of the European Academy of Neurology (“EAN Congress”) held virtually on May 25, 2020 at 8:15 a.m. Pacific Time. The Company presented an overview of a new 56 week analysis on Arginase 1 Deficiency (“ARG1-D”) patients who have been treated with pegzilarginase from the Company’s completed Phase 1/2 clinical trial and the ongoing Phase 2 open-label extension study. Additionally, on May 26, 2020, the Company issued a press release announcing the new 56 week analysis.

A copy of the press release and EAN Congress presentation are attached as Exhibits 99.1 and 99.2, respectively, to this Current Report on Form 8-K. The EAN Congress presentation is also available on the Company’s website in the Events & Presentations section at www.aegleabio.com.

The information furnished with this report, including Exhibits 99.1 and 99.2, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (“Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any other filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.

Item 8.01 Other Events.

On May 25, 2020, the Company presented the new 56 week analysis on ARG1-D patients who have been treated with pegzilarginase from the Company’s completed Phase 1/2 clinical trial and the ongoing Phase 2 open-label extension study, at the EAN Congress. The presentation included data on 13 patients treated with pegzilarginase who completed the 56 week treatment period (8 weeks Part 2 repeat dosing + 48 weeks open-label extension).

Highlights from the 56 week analysis include:

This current report contains "forward-looking" statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: "anticipate," "intend," "plan," "goal," "seek," "believe," "project," "estimate," "expect," "strategy," "future," "likely," "may," "should," "will" and similar references to future periods. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what the Company expects. Examples of forward-looking statements include, among others, statements the Company makes regarding its cash forecasts, the timing and success of its clinical trials and related data, the timing and expectations for regulatory submissions and approvals, timing and results of meetings with regulators, the timing of announcements and updates relating to the Company’s clinical trials and related data, its ability to enroll patients into its clinical trials, the expected impact of the COVID-19 pandemic on the Company’s operations and clinical trials, success in collaborations, potential addressable markets of the Company’s product candidates and the potential therapeutic benefits and economic value of the Company’s product candidates. Further information on potential risk factors that could affect our business and its financial results are detailed in the Company’s most recent Quarterly Report on Form 10-Q for the quarter ended March 31, 2020 filed with the Securities and Exchange Commission (SEC), and other reports as filed with the SEC. The Company undertakes no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

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Item 9.01 Financial Statements and Exhibits.

(d) Exhibits

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SIGNATURE

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

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Exhibit 99.1

Aeglea BioTherapeutics Announces 1-Year Data for Pegzilarginase in Patients with Arginase 1 Deficiency at the 6^th Congress of the European Academy of Neurology

  Pegzilarginase Showed Durable Clinical Response at 56 Week Analysis

All Patients Demonstrated a Marked and Sustained Reduction in Plasma Arginine

Favorable Safety Profile, Consistent with Previously Reported Results

Austin, Texas, May 26, 2020 - Aeglea BioTherapeutics, Inc. (NASDAQ:AGLE), a clinical-stage biotechnology company developing a new generation of human enzyme therapeutics as innovative solutions for rare and other high-burden diseases, today announced a new 56 week analysis on Arginase 1 Deficiency (ARG1-D) patients who have been treated with pegzilarginase from the Company’s completed Phase 1/2 clinical trial and the ongoing Phase 2 open-label extension study. The data were shared yesterday in a virtual, late-breaking oral presentation at the 6^th Congress of the European Academy of Neurology.

“Arginase 1 Deficiency is a devastating disease that is frequently under diagnosed or misdiagnosed as more common neurological conditions, such as cerebral palsy, due to lack of awareness of this rare condition,” said George Diaz, M.D., Ph.D., division chief of medical genetics in the Division of Medical Genetics and Genomics and Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, New York, NY. “Because of the condition’s progressive nature, it is essential that patients be diagnosed early, and there is an urgent need for a therapy that addresses the underlying cause of the disease and improves clinical manifestations.”

“The results of this long-term data demonstrate that treatment with pegzilarginase resulted in a durable clinical response, which is a critical factor in effectively treating a life-long, progressive condition,” said Ravi M. Rao, M.B Ch.B PhD, chief medical officer of Aeglea. “We are also pleased to see that the lowering of arginine levels observed in the 20 week analysis were maintained through the 56 week analysis. These results align with the primary endpoint of PEACE, our ongoing pivotal Phase 3 clinical trial, and together with the durable clinical response bolsters our belief that pegzilarginase has the potential to be an impactful treatment for people living with Arginase 1 Deficiency.”

The presentation, titled “1 Year Data from First in Human Study of Pegzilarginase for the Treatment of Arginase 1 Deficiency (ARG1-D),” includes data on 13 patients treated with pegzilarginase who completed the 56 week treatment period (8 weeks Part 2 repeat dosing + 48 weeks open-label extension).

Highlights from the 56 week analysis include:

The presentation is available for download on the Presentations & Events section of the Company’s website.

About the Phase 1/2 and Open-Label Extension Trial

The Phase 1/2, multicenter, single arm, open-label extension study of pegzilarginase enrolled patients aged 2 years and older with Arginase 1 Deficiency in the United States, Canada, and Europe. The trial investigates single ascending doses (Part 1), repeated weekly dosing for eight weeks (Part 2). The trial enrolled 16 adult and pediatric patients and 14 patients rolled over to the open-label extension. The primary endpoint of the trial is safety and tolerability of intravenous administration of pegzilarginase in patients with Arginase 1 Deficiency. The trial also evaluated the pharmacokinetic and pharmacodynamic effects of repeated doses of pegzilarginase on plasma arginine levels, and evaluation of clinical outcomes using several mobility assessments.

Please visit www.clinicaltrials.gov for more information.

About Pegzilarginase in Arginase 1 Deficiency

Pegzilarginase is an enhanced human arginase that enzymatically lowers levels of the amino acid arginine. Aeglea is developing pegzilarginase for the treatment of patients with Arginase 1 Deficiency (ARG1-D), a rare debilitating disease presenting in childhood with persistent hyperargininemia, severe progressive neurological abnormalities and early mortality. Pegzilarginase is intended for use as an enzyme therapy to reduce elevated blood arginine levels in patients with ARG1-D. Aeglea’s Phase 1/2 and Phase 2 open-label extension data for pegzilarginase in patients with ARG1-D demonstrated clinical improvements and sustained lowering of plasma arginine. The Company’s single, global pivotal Phase 3 PEACE trial is designed to assess the effects of treatment with pegzilarginase versus placebo over 24 weeks with a primary endpoint of plasma arginine reduction.

About Aeglea BioTherapeutics

Aeglea BioTherapeutics is a clinical-stage biotechnology company redefining the potential of human enzyme therapeutics to benefit people with rare and other high burden diseases. Aeglea's lead product candidate, pegzilarginase, is in a pivotal Phase 3 trial for the treatment of Arginase 1 Deficiency and has received both Rare Pediatric Disease and Breakthrough Therapy Designation. The Company received approval of its Clinical Trial Application (CTA) for ACN00177 for the treatment of Homocystinuria by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA). Aeglea has an active discovery platform, with the most advanced program for Cystinuria. For more information, please visit http://aegleabio.com.

Safe Harbor / Forward Looking Statements

This press release contains "forward-looking" statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: "anticipate," "intend," "plan," "goal," "seek," "believe," "project," "estimate," "expect," "strategy," "future," "likely," "may," "should," "will" and similar references to future periods. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. Examples of forward-looking statements include, among others, statements we make regarding our cash forecasts, the timing and success of our clinical trials and related data, the timing and expectations for regulatory submissions and approvals, timing and results of meetings with regulators, the timing of announcements and updates relating to our clinical trials and related data, our ability to enroll patients into our clinical trials, the expected impact of the COVID-19 pandemic on our operations and clinical trials, success in our collaborations, the potential addressable markets of the our product candidates and the potential therapeutic benefits and economic value of our lead product candidate or other product candidates. Further information on potential risk factors that could affect our business and its financial results are detailed in our most recent Quarterly Report on Form 10-Q for the quarter ended March 31, 2020 filed with the Securities and Exchange Commission (SEC), and other reports as filed with the SEC. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

Media Contact:

Kelly Boothe, Ph.D.
Director, Corporate Communications
Aeglea BioTherapeutics
512.399.5458
media@aegleabio.com

Investor Contact:

Joey Perrone

Senior Director, Finance & Investor Relations

Aeglea BioTherapeutics

investors@aegleabio.com

Dr Ravi M Rao, MD PhD Chief Medical Officer, Aeglea BioTherapeutics On behalf of the 101A/102A Investigators and Research Staff  1 Year Data from First in Human Study of Pegzilarginase for the Treatment of Arginase 1 Deficiency (ARG1-D)   Diaz GA1, Bechter MW2, Sloan LS2, Rao RM2, Zori RT3 Exhibit 99.2

Bechter MW, Sloan LS, Rao RM are full time employees of Aeglea BioTherapeutics Diaz GA, Zori RT have performed as consultants and received travel support from Aeglea BioTherapeutics The investigational use of pegzilarginase will be discussed during this presentation Disclosures    

Arginase 1 Deficiency (ARG1-D) Autosomal recessive disorder of arginine metabolism due to ARG1 enzyme deficiency Recent genetic prevalence data suggests > 2500 patients worldwide1  >700 patients in Europe  >250 patients in US  Typically presents at ~2-4 years of age, can be later2,3 Developmental delay with increasing intellectual disability Failure to thrive and short stature Prominent and progressive neurological manifestations4 Impaired mobility due to characteristic spastic diplegia Seizures are a common feature Additional abnormalities due to impairment urea cycle  Hyperammonemia but less prominent than other urea cycle disorders Protein aversion, food refusal and self-restriction of protein Low disease awareness leads to delay in diagnosis2 Suspected cases can be diagnosed reliably Plasma Arginine >300µM5 Red Blood Cell Arginase, Genetic testing6 May be initially misdiagnosed as Cerebral Palsy or Hereditary Spastic Paraplegia7 Video by kind permission of Dr D Carvalho 1. Aeglea Data on File 2. Huemer M, et al. J Inherit Metab Dis. 2016;39:331–340 3.Burrage LC, et al. Hum Mol Genet. 2015;24:6417–6427 4. Carvalho DR, et al. Pediatr Neurol. 2012;46:369–374 5.Haberle J et al J Inherit Metab Dis, 2019, 6.Diez-Fernandez C, et al. Hum Mutat. 2018;39:1029–1050, 7.Carvalho DR et al. Gene 2012; 509(1): 124-130. Video of patient omitted

Current Disease Management Fails To Adequately Control Plasma Arginine Levels Improved catalytic activity and serum stability Substituted metal cofactor (Mn2+ replaced with Co2+ ) Pegzilarginase is Engineered to Robustly Control Plasma Arginine Even with strict dietary restriction, plasma arginine levels ≤200 µM are very difficult to achieve1–3 Diet-related reductions in plasma arginine are not always accompanied by consistent reductions in guanidino compound levels4 Current dietary strategies and use of ammonia scavengers are unable to fully alter disease progression and improve clinical status of patients5,6 ULN, upper limit of normal 1. Burrage LC, et al. Hum Mol Genet. 2015;24:6417–6427; 2. Huemer M, et al. J Inherit Metab Dis. 2016;39:331–340; 3. Diez-Fernandez C, et al. Hum Mutat. 2018;39:1029–1050; 4. Marescau B, et al. Pediatr Res. 1990;27:297–303; 5. Amayreh W, et al. Dev Med Child Neurol. 2014;56:1021–1024; 6. Uchino T, et al. Hum Genet. 1995;96:255–260. Elevated plasma arginine levels in patients with ARG1-D managed with standard of care (n=22) Plasma Arginine(µm)1000 800 600 400 200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 ULN Patient number Catalytic activity 1000 800 600 400 200 0 Kcat/KM (mM-1 s-1 818 44 Pegzilarginase Pegylated native human arginase 1 Serum Stability T1/2 (hr) 40 30 20 10 0 37±3 4.8±0.8 Pegzilarginase Pegylated native human arginase 1

Inclusion criteria: Diagnosis of ARG1-D >2 years old Exclusion criteria: Severe, uncontrolled hyperammonaemia Key Objectives Primary endpoint: Safety and tolerability Secondary endpoints: Effect on: Plasma arginine (p[Arg]) Plasma guanidino compound (GC) levels Evaluation of clinical outcome assessments including: 6 Minute Walk Test GMFM Part D (standing) GMFM Part E (walk, run, jump) A clinical Responder was defined as showing a 1 MCID or greater improvement in one of: 6MWT, GMFM Part D or Part E Open-Label, Multi-Centre Phase 1/2 Study of Pegzilarginase in ARG1-D (101A and 102A Studies) ARG1-D = arginase 1 deficiency; IV = intravenous; QW = weekly; Q2W = every 2 weeks ARG1-D = Arginase 1 Deficiency; IV = intravenous; QW = weekly; Q2W = every 2 weeks; MCID = Minimal Clinically Important Difference, GMFM = Gross Motor Function Measurement, 6MWT = Six Minute Walk Test Part 1 Single Ascending Dose (Q2W) N=16 0 ~10 Weeks 101A Completed Part 2 8 Repeat Doses (QW) 0 8 Weeks N=14 N=15 20 Week Analysis [8wks Part 2 + 12wks OLE] 56 Week Analysis [8wks Part 2 + 48wks OLE] 24 48 0 Weeks Weeks Open-Label Extension (QW, IV SC at week 24) 12 N=13 ongoing 102A Ongoing Up to 3 Years Previously Reported Clinical Assessments Weeks 8 Week Analysis

Baseline Characteristics (n=16) *Values are median (range) unless stated otherwise. Arg, arginine; ARG1, arginase 1; BL, baseline; NH3, ammonia; 6MWT, 6-minute walk test; GMFM-D/E, Gross Motor Function Measure Part D/E; Pt, patient ** 1 patient non-assessable (wheelchair bound) Safety Summary Pegzilarginase has a favorable safety profile in ARG1-D patients More than 750 doses administered in 101A and 102A   Approximately 500 intravenous doses Most treatment-related adverse events were mild The frequency of treatment-related adverse events decreased over time Hypersensitivity and hyperammonaemia were the most common treatment-related serious adverse events; expected and manageable Mobility Assessments 88% (14 of 16) had at least one mobility deficit at baseline 6MWT 13 of 15** GMFM-D 8 of 16 GMFM-E 9 of 16 Age*, years (range) 15 (5-31) Sex, female, n 11 (69%) Race white, n 11 (69%) Height, <10th Centile, n 12 (75%) Weight, <10th Centile n 3 (19%) p[Arg]*, µM (40-115) 389 (238-566) NH3*, µM (range) 38 (9-77)

Baseline p[Arg] on standard disease management was markedly elevated Significant and sustained reductions in p[Arg] were achieved from baseline to week 1, week 8, week 20 and week 56 At the week 56 analysis: the median p[Arg] was 99µM (40-115µM) 10/13 patients achieved a p[Arg] within normal range (40-115uM) 13/13 patients achieved a p[Arg] within target range (<200uM) p[Arg] reductions accompanied by expected decreases in plasma Guanidino Compounds Pegzilarginase Markedly Reduces and Sustainably Controls Plasma Arginine  Plasma Arginine in Response to Pegzilarginase Arginine (µM) 700 600 500 400 300 200 100 0 389 *p<0.001 for CFB 171 127 112 99 BL Part 1 1 Week Analysis 8 Week Analysis 20 Week Analysis 56 Week Analysis 200 µM 115 µM 40 µM p[Arg] Normal Range 40-115 µM p[Arg] Target Treatment Range <200 µM

Clinically Impactful Improvements at Patient Level with Pegzilarginase Assessment Normal Population Baseline 20 Week Analysis 56 Week Analysis Plasma arginine 40 - 115µM  363µM 108.5µM* 88.2µM* 6MWT 310 - 664m 174m 176m 209m* GMFM-D Max = 39 21 27* 28* GMFM-E Max = 72 27 35* 34* Teenage girl diagnosed at age 1 (presented with hyperammonaemia) Developed severe lower limb spasticity, speech delay, intellectual disability Treated with severe protein restriction, essential amino acids, and ammonia scavengers Persistent hyperargininaemia Progressive worsening of lower extremity diplegia, walked with arm crutches at baseline (GMFCS II) Patient 5: Baseline Patient 5: 20 Week Analysis Unable to cross legs and dependent on walking aid Able to cross legs and less dependent on walking aid * Achieved MCID: 6MWT = 16m; GMFM-D = 3.3; GMFM-E = 2.8   Images by kind permission of Dr GA Diaz

Pegzilarginase Demonstrates Sustained Improvements in 6 Minute Walk Test 6MWT by Patient at 56 Week Analysis Mean Change from Baseline in 6MWT Change from Baseline (m) 6MWT – Six Minute Walk Test; MCID=9% 8 Week Analysis Mean Change from Baseline (m) 20 Week Analysis 56 Week Analysis Individual Patient Number R R R R R R R R R * * * p<0.01 R = ≥1MCID Improvement 50 40 30 20 10 0 6 32* 45* 150 100 50 0 151 112 86 68 43 35 32 30 29 28 7 -3 -34 16 11 9 14 10 5 8 12 1 2 15 7 6

GMFM-D Change from Baseline 56 Week Analysis (n=6) GMFM-E change from Baseline 56 Week Analysis (n=6) Patients in GMFCS Levels II and III also Show Improvement in Mobility MCID for GMFM Part D is 3.3 and 1.5 for GMFCS Levels II and III, respectively; MCID for GMFM Part E is  2.8 and 1.8 for GMFCS Levels II and III, respectively.   Maximum values for GMFM-D and GMFM-E are 39 and 72, respectively. R = ≥1MCID Improvement Patient Change from Baseline Patient Change from Baseline R R R R R R R R R R 8 7 6 5 4 3 2 1 0 6 5 1 9 8 7 8 7 6 6 3 0 16 12 8 4 0 7 8 9 5 1 6 17 17 14 7 4 3

Pegzilarginase Demonstrates Durable Clinical Response at 56 Week Analysis *MCID for 6MWT = 9%; MCID for GMFM Part D is 2.4, 3.3, and 1.5 for GMFCS Levels I, II and III, respectively; MCID for GMFM Part E is 4.0, 2.8, and 1.8 for GMFCS Levels I, II and III, respectively.  Maximum values for GMFM-D and GMFM-E are 39 and 72, respectively. Patient 1 Patient 2 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12 Patient 14 Patient 15 Patient 16 Overall Combined Response 29m 28m 35m (34m) (3m) 32m 86m 43m 112m 30m 68m 8m 151m 6MWT Week 48 6 2 7 8 0 3 6 2 0 0 0 Week 48 4 3 7 3 17 17 14 3 0 1 0 GMFM-D GMFM-E Week 48 R R R R R R R R R R R BL III I II II III II II I I I I I I GMFCS Not assessed <1 MCID increase Responder (≥1 MCID Increase) ≥1 MCID decrease data not available Clinical Responder defined by achievement of in one or more of three mobility assessments   Overall clinical response rate: 20 Week Analysis: 11/14 (79%) 56 Week Analysis: 11/13 (85%) 56 Week Analysis (Change from Baseline)

Conclusions Arginase 1 Deficiency (ARG1-D) is a debilitating, progressive, inherited, metabolic disease driven by the accumulation of arginine and its metabolites, which results in prominent neurological manifestations including progressive spastic diplegia and early mortality Delays in diagnosis are common with some cases initially diagnosed as Cerebral Palsy or Hereditary Spastic Paraplegia Pegzilarginase was highly effective in sustainably lowering plasma arginine levels with a favorable safety profile and is now being further evaluated in an active Phase 3 study. Plasma arginine reduction was accompanied by improvements in disease manifestations within 8 weeks and a durable clinical response rate of 85% at 56 Week Analysis These marked improvements in important disease-related manifestations with pegzilarginase on a background of standard treatment suggests the potential for a substantial clinical improvement over current management of patients with ARG1-D 

The 101A/102A Investigators and Research Staff wish to acknowledge and thank the Patients, their Families, and Caregivers for their dedication to these studies Acknowledgements Information on the ongoing Phase 3 Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints (PEACE) Study for patients with Arginase 1 Deficiency is available at ARG1Dstudy@aegleabio.com