DBV Technologies SA Investor Day

May 21, 2014 AM EDT
DBV.PA - DBV Technologies SA
DBV Technologies SA Investor Day
May 21, 2014 / 12:30PM GMT 

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Corporate Participants
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   *  Susanna Mesa
      DBV Technologies - VP - Finance, US IR
   *  Pierre-Henri Benhamou
      DBV Technologies - Chairman, CEO
   *  Lucie Mondoulet
      DBV Technologies - Director - Research Department
   *  David Schilansky
      DBV Technologies - CFO
   *  Charles Ruban
      DBV Technologies - Chief Development Officer
   *  Wence Agbotounou
      DBV Technologies - Director - Clinical Trials
   *  Laurent Martin
      DBV Technologies - Director - Regulatory Affairs
   *  Bertrand Dupont
      DBV Technologies - Chief Technical Officer

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Conference Call Participants
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   *  Franklin Atkinson
      Johns Hopkins Asthma & Allergy Center - Professor and Program Director
   *  Gordon Sussman
      University of Toronto Clinical Immunology and Allergy - Division Head
   *  Jonathan Spergel'
      Children's Hospital of Philadelphia - Chief of Allergy Section
   *  Christophe Dupont
      Necker Hospital - Head of Pediatric-Gastroenterology Ambulatory Dept
   *  Philippa Gardner
      Edison Investment - Analyst

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Presentation
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 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [1]
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 Hi, everyone. Thank you so much for being here. It's a pleasure to seeing most of you. I know most of you. Welcome to DBV Technologies First Investor Day in the United States. My name is Susanna Mesa and I'm DBV's Vice President of Finance, US Investor Relations and Strategy. It's a please to have you here today.

 Before we actually begin, I just wanted to point to our disclaimer which is actually in your agenda, and if you could please read thoroughly through that. You can also refer through our reference document which is list on our website at www.dbv-technologies.com and it leads to all of our risks.

 So today, I actually just wanted to go quickly over the agenda before we start. The day is going to be divided in two different sections. The first section, we're going to try to provide you with a better understanding of what Epicutaneous Immunotherapy actually means and what it is. We'll go through the mechanism of action of our technology and we'll also have the pleasure and honor to have four KOLs with us that will discuss where EPIT fits into the allergy treatments of today.

 Then we'll have a break and we'll reconvene at this same room at about 10.50 and then we'll jump into the second part of our day which will be a deep dive into our pipeline and our strategy for the future. And then we'll close with informal lunch about noon or 12.30 and that will be it for the day.

 So between those sessions, we will have Q&As and we'd hope that all of you guys will participate and if you need anything, you can always pull one of us on the side as well.

 And with that, I would like to introduce our Chairman, Co-Founder and CEO Pierre-Henri Benhamou.

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 Pierre-Henri Benhamou,  DBV Technologies - Chairman, CEO   [2]
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 Thank you, Susanna, and thank you for all, Susanna. She was the person who contribute the -- a lot in this effort, the organization of this meeting. I'm very proud and very happy to welcome you here for this first Investor Day in the US. It's a step for DBV and it's very important for all the team here.

 What we will try to do today is to give you as complete as possible overview of the company when we talk about the science, the clinical development, the different application of the platform, the Viaskin platform.

 As you know we have developed a new method for the treatment of allergy and especially the most severe allergies. The method is completely new because we choose specific immunotherapy, meaning by that it can -- with this method, you can administrate every day, on a regular basis, for a long term one to two years an allergen in order to put the body in the better condition to tolerate this allergen at the end of the treatment.

 But the way of administration is completely new because with this utilization of the immune system of the skin, it is possible to activate the immune system without any passage of the allergen in the bloodstream.

 This method has been fully patented -- excuse me -- this method has been fully patented and in DBV, we have really interesting combination between a new therapeutic method and a new technology. The technology will be explained by Bertrand Dupont in details during this meeting. It will give you all innovation we have developed for the Viaskin and also it's fully patented.

 And beyond the treatment we have developed for allergies especially for the most severe allergies, for the allergy of the youngest children, we have also a platform allowing us to reach the immune system and to treat some immune disease and also to make some vaccination.

 The patch itself, this is the patch with the dressing around, the patch itself -- and you will have somewhere between here and Paris, but they will arrive during the morning hopefully. The patch itself is very easy to use. The patient has to put the patch every day, every morning in the inner part of the arm for the adults and in the back for the children in order to avoid the risk of removing of the patch.

 It's a pharmaceutical product and patient will buy it in pharmacy. And it's self administration and medical prescription.

 The way it works is also a bit special because when we started to develop a patch for allergy, we wanted to put only pure protein on the patch without any adjuvant. It was not possible with the classical method of patch because there is a gel or anything and protein is very unstable and can react with anything and modify structure. So we found this electrostatic method. Meaning by that the central membrane of the patch has been polarized and the protein, pure protein is spread on the patch through an electric field of 20,000 volts.

 And this is very stable. You can keep it at least six months at room temperature. But when you put the patch on the skin, there is a chamber between the central membrane of the patch and the skin, the (inaudible) is perspiration and give -- when I do that, there is a chamber between the membrane of the patch on the skin as periphery of the patch is completely (emetic). It produced some hydration, very rapid hydration.

 In a few minutes, most of the protein is in position, goes through the skin. The skin itself is hydrated and very quickly there is a diffusion of the protein in the superficial layer of the skin and there as Lucie will explain, there is some very interesting antigen presenting cells. That name is Langheran cells and they are among the most heterogenic cell. It ensures harmony of the body with the environment. And these cells are moving very quickly to the immune system in order to activate the immune system.

 This is the development plan of DBV. Our main program dedicated to the treatment of allergy in three indications. The first is the peanut allergy. It's the main program in DBV. We are developing the product under fast-track designation by the FDA. The large part of this development is on US development. And Charles will give you more details on this program and we will see in details all this program.

 The second program is the milk. Milk allergy is the first allergy in life. We will start a large study in the US this summer. And we have also another application of this product with Eosinophilic Esophagitis and Jonathan Spergel from Philadelphia is here and he will give you during the conversation some information on this program.

 The third program concern house dust mite allergy, as you know as I told you this patch can be used very early in life, so it's possible to treat the risky patient with wheezing and house dust mite allergy very early in order to prevent the risk of asthma.

 And this program is the more early program of DBV (inaudible).

 It's clear that co-business of the company is allergy, but we have also other application in different fields with the platform. And if we want to go as far as possible in allergy, we want also to discuss with partnerships concerning the other application of the platform.

 This is for introduction and what I do now is to introduce Lucie Mondoulet. Lucie is Head of Research in DBV and she's working with me for now seven years, I think. She did really incredibly work in -- around the platform and all that -- we are of course all the team of Research and DBV especially (inaudible), an immunologist who is really brilliant who worked on the Langheran cells and the passage of the allergens through the skin.

 In contradiction of EBITDA, I would say that there are three main discoveries in DBV. The first is of course the EPIT TM news route because it allow us to treat without any risk even the most severe allergies and Christophe Dupont will give you move details during the [cowboy] session.

 The second is with the patch. You can expose the skin to the allergen or also they don't, seven days a week and for long period, even until three years. So this is really special because it's a very, very progressive action of the -- in the immune system. And it triggers sustaining effect and it gives us the possibility to change in depth there's immune response.

 And we have, in the next European Academia of Energy communication of epigenetic changed induced by the EPIT. And then the third breakthrough is the extreme safety of the product and its mode of action will allow us to treat very, very young children in order to reduce the risk of allergic diseases, but also to influence what is called allergic march, meaning by that, the different succession of allergic disease during the life.

 So this is a very ambitious program but this platform can allow us to go very, very far and to renew the treatment of allergy as you will see today.

 So Lucie?

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 Lucie Mondoulet,  DBV Technologies - Director - Research Department   [3]
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 So as Pierre-Henri said, I'm Lucie Mondoulet and I'm in charge of the research department at DBV. So I am going to present two major pre-clinical results over the three scientific breakthroughs. So let's start with the importance of treating on intact skin.

 So Viaskin delivers allergens via intact skin result in the passage of the vessel membrane and result any passage into the bloodstream. In this experiment, we use the allergens labeled with the green fluids and probes. And as you can observe, the allergen is only visible in epidermis. And when we observe the fluorescence deeper in the dermis in fact is due to dendritic cells that have captured the antigens in the epidermis and now this migrates to the drain lymph nodes.

 With a larger views of these dendritic cells, we can observe the fluorescence inside the cells and on the phase of the cells, in fact, as an antigens as being captured by the dendritic cenlls and processed for the presentation to the immune systems.

 As the phenotyping of these dendritic cells reveals a surface marker the CD207s is the Langerhans cells as that identifies longer on cells. Longer on cells are truly homogenic dendritic cells. So in this experiment, we demonstrate that epicutanous immunotherapy specifically targets these Langerhans cells.

 How does this Langerhans cells works? In fact Langerhans quickly captures the antigens in the epidermis. After the six hours of applications of the Viaskin, a dramatic decrease of these Langerhans cells, in fact the concord through the migration in the dermis and then the migration is (inaudible) over 24 to 72 hours in the brain lymph nodes. The absence of the passage in the bloodstream was demonstrated in the experiment where we quantify the major peanut allergens the Ara h1 in the blood after the application of the Viaskin on the bloodstream in comparison to subcutaneous injection.

 So with these experiments, we really demonstrated the safety of application of our treatment.

 In these experiments, we would like to analyze distribution of antigens and the differences between intact skin and stripped skin.

 So as we have already observed, when we applied Viaskin on intact skin is that (inaudible) is only visible in the epidermis whereas the same Viaskin applied on stripped skin contract to a large deficient of the antigens all over the skin without any specific targeting of immuno cells and specific targeting of Langerhans cells.

 On this part, in fact underlined that with the application of our Viaskin on intact skin increased some quantity of Regulatory T cells, the injection of this Regulatory T cells lead to 900 immunomodulations with a significant decrease of Specific IgE and a significant increase of Specific IgG2a is the equivalent of IgG4 in humans.

 The same treatment on stripped skin does not induce Regulatory T cells, so it does not modulate the immune response because we enhance the Specific IgE and we have no injection of Specific IgG2a.

 So with this experiments, we underlined that the skin integrity plays a crucial role in the immunomodulations of the immune system.

 After this demonstration of the treatment and the safety of the treatments, we've done a lot of work on the demonstration of the efficacy of our treatments. So the first experiment was performed on mice sensitized to peanuts and challenged by Aerosol to peanuts.

 The epicutaneous treatment was compared in this experiment through the subcutaneous route referenced methods for us at that time. Humoral responses while (inaudible) so just after the sensitization to demonstrate to demonstrate to you sensitization in our animals and after eight weeks of immunotherapy.

 And after the samples for humoral responses, the mice where challenged and hyperresponsiveness was measured by two different methods, an invasive and a non-invasive ones.

 At systemic result, what we could observed is that epicutaneous immunotherapy decreases specific IgEs and induce significant increase of the IgG2a. Similar responses were observed with the subcutaneous route without any differences between EPIT and SCIT.

 After the Aerosol challenges, hyperresponsive measured by the two methods, so the whole body plethysmography and the resistance, we could have found a significant decrease of the Penh index result in differences between EPIT and SCIT. And the second point is -- that's the low variation of response and high growth that demonstrated the robustness of our method of treatment.

 So thus at systemic level and after a challenge, we really demonstrated the efficacy of our treatment.

 As we targeted food allergies we would like to use a method model to evaluate inflammation in the digestive (inaudible). To do that we developed a model of mice, so sensitized peanuts treated by epicutaneous immunotherapy and then expose it to a 10-day peanut regimen in order to induce inflammation in the esophagus.

 So live mice exposed to this peanut regimen does not induce any inflammation. So here we have normal aspect of the mucosa of the esophagus. When sensitized mice were exposed to these peanut regimens, we can observe an inflammation in the esophagus. We see an increase of the sickness of the mucosa and this increase is linked to the infiltration of eosinophils. So eosinophils are visible hereby (inaudible).

 And when mice were treated by epicutaneous route, we can observe that we are at the same aspect as our live mice. So no inflammation in the mucosa and no infiltration of eosinophils. This is confirmed by the specific counting of eosinophil infiltration in the mucosa with a high amount of eosinophils for sensitized and non-treated animals and a significant decrease of eosinophils when mice were treated with epicutaneous route.

 Pig model is the best model to evaluate treatment delivered by epicutaneous route. As for example pig skin is structurally similar to the human skin and is constituted of dermal hair follicles as in human skin. So we decided to develop a model of piglets sensitized to peanuts and then just after the sensitization exposed to the peanuts by the oral route in order to induce inflammation and in this model, we induced inflammation in the stomach.

 As the inflammation was assessed by endoscopy. After the assessment of inflammation, we started the treatment by epicutaneous route for three consecutive month season. The treatment consist of one daily application of the Viaskin loaded with 100 microgram peanut coating extract and it was exactly the same device we use currently in the Phase II clinical trial.

 At the end of the treatment, animals were exposed then to the peanut regimens and the inflammation was assessed by endoscopy and then we can sample different part of the digestive (inaudible). So here you can observe some illustrations from the endoscopy observation. So far the control animal, it's the normal aspect of the stomach. When animals were sensitized to peanuts, here we can observe a severe inflammation of the mucosa and here it's observed an ulcer, so it's a severe lesions of the stomach.

 When animals were desensitized by epicutaneous immunotherapy, we can observe a significant decrease of this inflammation and the modular aspect in the mocusa reveals the recovery of the mucosa.

 This inflammation is already linked to a high infiltration of eosinophils. Here we have counted the eosinophil infiltrations in the mucosa. So far the placebo treated animals, it's really high amongst eosinophils. So this (inaudible) was performed by a veterinary pathologist and it was (inaudible).

 Then after the treatment, what we can observe is really a neutral decrease of eosinophil infitration. I can say this because if you ever look on the scale, it's a low (inaudible) scale, so it's really high decrease of eosinophil infiltration. And you can observe that we're exactly the same between control and EPIT treated animals.

 So with all these experiments in mouse model and piglets, we have demonstrated the efficacy of our treatments and we are convinced that maybe Regulatory T cells could be involved in the mechanisms of actions, but maybe all of those mechanism of action could be involved and now (inaudible) work is done at DBV and (inaudible) mechanism of actions induced by epicutaneous immunotherapy.

 So the first point is to demonstrate the involvement of Regulatory T cells in the mechanism of actions. So in the first experiment, we would like to know if they block the activity of Regulatory T cells. In fact we block the effect of the treatments.

 So in these experiments, we have an additional route treated by epicutaneous route and we add an anti-CD25 antibody that specifically block the activity of Regulatory T cells. And if you just have a look on this additional (inaudible), in the EPIT plus anti-CD25, what we can observe is that we have no effect of the treatment because we can observe the high sickness of the mucosa and the high infiltration of eosinophils and you can observe it is the same when we specifically count the eosinophils, they have exactly the same level of eosinophil infiltrations between Sham treated route and EPIT route plus (inaudible) antibodies.

 These results must confirm in the second experiments. So if we would like to analyze if the protections introduced by EPIT and Tregs could be transferred. So what we've done in fact we sensitized mice to peanuts treated by EPIT. At the end of the treatment, we isolated Regulatory T cells. As these isolated Regulatory T cells were adoptively transferred to a new pool of sensitized animals and then animals who are exposed to the peanut regimen.

 And it was possible to observe that this transfer of EPIT TM Tregs protect from the (inaudible) of inflammation in the esophagus.

 In the another experiments, we would like to assess the sustained ability of the effect. So to the result, we do -- we performed the same so work on mice sensitized to peanut treated by EPIT. But for the isolated of Regulatory T cells, we wait for eight additional weeks without any treatment.

 So, the regulatory T cells were isolated eight weeks after the end of the treatment and then transferred to new sensitized mice to peanuts and then exposed the mice to the peanut regimens.

 Sorry. And it was possible to observe that the transfer of Regulatory T cells made (inaudible) for the injection of inflammation of the esophagus. So, adoptive transfer of Tregs generated eight weeks after the end of immunotherapy prevents from the injection of inflammation in the esophagus. So, with this first experiment, we demonstrate at pre-clinicial state the sustainability of the effect.

 We would like also to assess the phenotyping of this Tregs induced by EPIT, to maybe explain the sustainability of the effect. And we took the opportunity of this experiment to compare the Tregs induced by EPIT to the Tregs induced by sublingual immunotherapy.

 So, first, what we could observe? For EPIT, we only induced Foxp3 population of Tregs and at (inaudible) sublingual route. And we have no injection of IL-10+ Regulatory T-cells, the tier one population. Also, epicutaneous immunotherapy induced naive and effector Tregs compared to sublingual immunotherapy at only induced effector Tregs.

 And the last pointer is on this epicutaneous Tregs. We can observe the presence of CTLA-4 that underlines cell-contact mediation of Regulatory T cells induced by EPIT and it was not the case for the Tregs induced by sublingual immunotherapy.

 So, at this stage, we can observe that Foxp3, naive and effector Tregs play a major role in the universal rebalancing of Th1/Th2 immune response.

 As OIT is the most used research for the treatment of food allergies, in our pre-clinical models, we would like to compare the efficacy of epicutaneous immunotherapy to oral immunotherapy. So, all these facts were performed in collaboration with (inaudible) hospital.

 So, they work with mice sensitized to (inaudible) and the treatment was performed for eight weeks with repeat in OIT. And in this model, the assessment of the efficacy was based on anaphylaxis. For a mouse model, anaphylaxis was assessed by the measurement of body temperatures. So, when you observe a drop in temperatures, in fact, you have an anaphylaxis in the mouse.

 So, we have two challenges at the end of the experiment, the challenge one was performed just after the end of immunotherapy to assess the efficacy. And the challenge two was performed four weeks after the end of the immunotherapy to assess the sustainability of the protection.

 So, let's go to the results, so after the first challenge just after the immunotherapy. So, for the naive mice, we have normal body temperatures. For sensitized mice, 30 minute after the overall administration, we can observe a high decrease of the body temperatures. So, we could assess anaphylaxis in sensitized mice. And for mice treated by EPIT and OIT, we have no drop in temperatures, revealing the efficacy and the protection against anaphylaxis. And it was exactly the same between EPIT and OIT.

 The same challenge performed four weeks after the end of the treatments, meaning that for EPIT, we have similar results, so the protection is sustained in four weeks after the end of the treatments. For OIT, what we can observe is really for these four mice -- in fact the four mice dead during the challenge. So, it was not possible to measure the body temperatures because the mice are not dead before the measurement of body temperatures. So, with this first result, we can observe the highest success rate of EPIT compared to OIT in terms of sustainability of the protection.

 In the last fact, we also would like to process the epigenetic modifications that could induced by epicutaneous immunotherapy and could explain maybe the sustainability of the protections induced by our treatment. So, we work with the sensitized mice treated by epicutaneous route and at the end of the treatment, we take a whole spleen and analyze the methylation in the whole spleen cells and the same thing was done eight weeks after the end of the treatment.

 So, results obtained just after the end of epicutaneous immunotherapy. So, we analyze the methylation level of the CpG islands of transcription factor, so GATA-3 into the Th2 transcription factors and the T-BET into Th1 transcription factors. And what we can observe is for the EPIT treated mice, we have an increase of the methylation levels for the GATA-3. This could reveal a modification of the Th2 transcription pathway. And we confirm that with the analysis of the mRNA expression of the GATA-3 and we observe down regulation and the mRNA level.

 We have no modification for the T-BET. And for the Foxp3, we just have a look on the mRNA expression and we can observe an increase of this mRNA expression and this is linked with all the previous results showing that we induced Regulatory Tcells.

 So, same results obtained eight weeks after epicutaneous immunotherapy exactly as the same. We have an increase of methylation levels often for the GATA-3and this was in co-relation with the down regulation of the mRNA expression, so it means that we blocked in fact their Th2 pathway. No modification for the TH1 and again with the injection of mRNA expressions for the Foxp3.

 So, now the equation is out, can we translate this epigenetic modification to the allergic patients. The key points could be as the preventions of the natural cause of allergic disease. So at pre-clinical levels, what we have done in fact, we work with mice sensitized to milk, so the first allergen which children are exposed then treated the mice by epicutaneous immunotherapy to the milk. And at the end of immunotherapy, we try to induce a sensitization to another allergen, so in this case it was the peanuts. And then expose the mice to the peanut regimens in order to assess the injection of sensitization to peanuts.

 So, first result at systemic level, if we just start on the injection of Regulatory T cells, we can observe that this injection is really specific to the treatment because when you reactivated (inaudible) splenosites with milk, you induced Regulatory T cells here in red for the epicutaneous treated routes. And you have no reaction with the peanut.

 And when we have a look on the humoral response to this peanut, we can observe that we block the injection of the specific IgE, but we have a specific injection of IgG2a. So, we have a tolerance response to the peanuts may be due to the previous treatment to the milk.

 After the challenge to the exposition to the peanut regimens, it was the same. We see that we have no injection of eosinophil infiltration for the mice treated by milk and then sensitized to peanuts and exposed to the peanut regimens. So, milk epicutaneous immunotherapy and may prevent for the further sensitization to other allergens, in this case it was peanut, but we have performed other experiments with other allergens and it was exactly the same.

 So, in conclusions, all these pre-clinical results demonstrate also three scientific breakthroughs as I presented to you at the beginning. So more specific keys as the epicutaneous pathway is really crucial point to guarantee the safety of administration and the efficacy by targeting the Langerhan cells, the continuous antigen exposure triggers the sustained tolerization leading to a potential treatment for allergies with injection of Foxp3, naive and effector Tregs and with a deeper epigenetic modifications.

 The original route of treatment and this deeper immunomodulation plays a crucial role in the prevention of allergic disease evolution by allowing an early interventions maybe during the windows of opportunity.

 So, thank you and now I leave the stage to David for Q&A session.



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Questions and Answers
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 David Schilansky,  DBV Technologies - CFO   [1]
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 Thank you Lucie. Good morning everyone, good afternoon for those in Europe and the webcast, we're going to move to the Q&A. We'll have the questions from the room first and I understand we might have questions from the webcast that will take once we have questions from the room (inaudible). Thank you.

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Unidentified Audience Member   [2]
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 Just one quick on the -- on the application itself, do you think you may get variability from patient to patient on skin type?

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 David Schilansky,  DBV Technologies - CFO   [3]
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 Pierre-Henri, will you want to take this one?

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 Pierre-Henri Benhamou,  DBV Technologies - Chairman, CEO   [4]
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 Yes. We have studied, excuse me. We have studied the batch with different conditions, different people, age, origin and there is no difference at all.

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Unidentified Audience Member   [5]
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 Any irritation at all, from the patch itself?

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 Pierre-Henri Benhamou,  DBV Technologies - Chairman, CEO   [6]
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 Yes, it could happen. As with the patch is it contact -- long-term contact with an allergen, so, at the end it could provoke some redness, irritation of the skin. But first if it's too much you can remove the patch before the end of the application and put some (inaudible) on the redness. And most of the time during the treatment, there is progressively decreases of the local reaction.

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 David Schilansky,  DBV Technologies - CFO   [7]
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 Any other question? Are there any questions on the webcast potentially? We're good? We'll move to the round table. Thank you very much.



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Presentation
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 Pierre-Henri Benhamou,  DBV Technologies - Chairman, CEO   [1]
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 Thank you very much. I forgot to introduce David during the introduction. I'm sorry David. David is the CFO of the DBV and he is responsible of this meeting. He did everything around this meeting, so may I apologize.

 We will pass to the second part of our meeting, concerning the Q&A sessions. As you know, DBV has a lot of connection with many scientifics. We have the extreme pleasure to welcome today, some of the most renowned allergists in the world. We will start by Franklin Atkinson. Franklin is working at Johns Hopkins Hospital and he is a great name in allergy field.

 Then, we will let the stage to Gordon Sussman. Gordon is working at the University of Toronto and he is one of the most active center responsible of the center in the VIPES study. And he will give us some feedbacks from the data use of the Viaskin.

 Then, Jonathan Spergel, he is working at Children Hospital of Philadelphia. Jonathan is a member of our study and Franklin Atkinson too and he is one of the world wide specialists of the eosinophilic esophagitis.

 And then, Christophe Dupont, he is my friend. We founded DBV together in 2002. And Christophe, he is the Head of Pediatrics in Hospital Necker in the center of Paris. He is also one of the worldwide key opinion leaders in allergy. And so, we will have after these full presentations, Q&A session. Please Franklin.

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 Franklin Atkinson,  Johns Hopkins Asthma & Allergy Center - Professor and Program Director   [2]
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 Thank you, Pierre-Henri and good morning ladies and gentlemen. My role is to bring to your attention or to remind you, if you are already know these facts about the importance and impact of the growing problem of food allergy, both in the United States and around the world. Could I have my first slide please, let's see. And to do this, we will focus on peanut allergy, which is responsible for more than 80% of the serious food allergic reactions in this country.

 So, here are some facts and figures about food allergy. As I who learn them from my colleague Dr. Robert Wood, Professor of Pediatrics at Johns Hopkins, who was an active investigator in food allergy problems in children.

 It's interesting to have to be reminded even as the practicing allergist, that food allergy is acquired very early in life and that the peak prevalence for food allergy is about one year of age. This reflects early an exposure obviously to the foods that are involved and leads to a differentiation of those who can respond from those who do not respond in a -- with an allergic profile.

 After this peak of prevalence at a year, the prevalence falls slowly over childhood and then, by early adolescence, it reaches a stable state at about 3% to 4% of the general population, so for all Americans, that's maybe 3 million to 6 million have some ongoing problem with food hyper sensitivity that is mediated by this type of allergic antibody.

 The other fact of importance is that the prevalence of food allergy in children in the United States has been documented to have increased substantially over the last several decades. The most commonly quoted data is from a National Health Survey in which 3.5% in 1997 reported problems with food allergy and this had an increase to about 5.1% in the most recent survey conducted in 2011, which represents of 50% increase in food allergy problems over a period of about 13 years.

 This of course, parallels increases in other types of allergic phenomena that are seemed to be -- seen not only in the United States, but worldwide.

 The possibility of food allergy being so widely known in the general population has led of course to an over diagnosis in some case or increased concern on the parts of parents. And surveys have indicated that up to a third of parents believe that they see evidence of food hypersensitivity in one or more of their children during the first year of life. This is not unexpected and increases the demand for both services and potential treatments as more and more patients are shown to be sensitive.

 The top five foods for food allergy in children are milk, egg, soy, wheat and peanut. Not in any particular order, we could be focusing on peanut because of its predominant importance in terms of serious anaphylactic reactions.

 This slide is just to remind us of the most important outcome of food allergy of clinical significance in children and that is the systemic allergic reaction syndrome, that's known as anaphylaxis. And this is a multi-system allergic reaction that involves a in almost to all cases, the airway in terms of bronchospasm and asthma, the skin in term of hives and swelling.

 But also other potential systems as well including in its most extreme form, a collapse of the cardiovascular system leading into life-threatening hypotension and in some cases, a fatal outcome if not properly managed and treated.

 So it's concern for this syndrome that both parents and physicians responsible for children with food allergy are focused on managing and reducing the risk probably.

 Now peanut allergy is the most common source of these types of anaphylactic reactions to foods as I've mentioned. It's the leading cause for presentation to the emergency department for food allergy anaphylaxis. It's the most common trigger for fatal outcomes of anaphylaxis in the United States.

 And about 30,000 emergency encounters for a management of food anaphylaxis are encountered in the United States each year and that's a figure from I think 2009. It could be considerably higher than that now. And about 80% of this, in that survey in 2009, were attributable to peanut allergy itself.

 So as you can see for serious anaphylactic reactions, peanut is far and away the most important food allergen. About 40% of those who have had such a systemic reaction have a history of severe potentially life threatening reactions in the past. So that means that knowing that you are allergic to peanuts doesn't prevent the possibility of you're having a serious and even fatal outcome in the future which is a frightening possibility for parents, children and their physicians.

 And there are more than 100 such fatal outcomes from food induced anaphylaxis each year in this country. Another unique feature of peanut allergy is that it tends to remit or go into spontaneous resolution and less frequently than other food allergy seen early in life, particularly egg and milk as you may hear more about later.

 There is a remission rate and it begins early in childhood. About 6% to 7% a year of resolutions spontaneously through mechanisms we don't fully understand, among sensitized children between the ages of three and six. And as the children grow older, this rate of spontaneous resolution decreases and by the time they are adolescents, it comes down to less than 1% a year. So add all of this up and it's about a 25% remission rate or spontaneous resolution rate for peanut allergy leaving 75% of those who encountered serious problem early in life with a lifelong problem to manage and be aware of.

 Sorry. I hit the wrong the button here. I was trying to go backward. Here we go. Okay. Okay. So the management of this from the medical point of view is essentially to prevent exposure. Its risk mitigation by allergen avoidance which is the primary and most effective treatment for allergy in general, but it turns out to be a very difficult problem for peanuts allergic individuals. A strict peanut avoidance means scrutiny of every food particles that comes in and out of the house or in the house anyway. It means managing exposure to foods and lunchrooms at schools. And it means even public venues can be the source of an occult exposures that can be life-threatening.

 So parents have to be informed and educated about the need to be highly vigilant in looking for sources of peanut in the environment. They also have to be instructed in the early management of inadvertent exposures that lead to reaction so that they can be treated properly with a much higher likelihood of success using first self-injected epinephrine and perhaps with antihistamines followed by emergency room care and management until stability is achieved.

 Schools have to be involved with this process because many of these reactions do occur in the school situation. And there's a common use of calling for emergency treatments through 911 for this purpose.

 So as you can imagine this fear of reactions and occult not easy to avoid to identify or avoid sources of a life-threatening allergen in the environment is a huge impact on the quality of life for families of children who have peanut allergy. Highly disruptive of normal social patterns affects what travel can be undertaken, it affects eating out, even in simple local places certainly the sharing of publicly available food becomes very difficult to comfortably undertake. And then even intimate activities like kissing can be a problem.

 There was a case I think [Rodley] publicized in the media about a year ago of a young adolescent who was hospitalized after treatment for anaphylaxis to peanut as a result of a kiss which she received from her boyfriend. Now, what I didn't see on those reports is whether or not we can hold the French accountable for any part of that story.

 As you can imagine, children, very young children may not be fully aware of their risk and therefore not as anxious as older children can be. But parents more than substitute the anxiety and create a family dynamic that is hugely incapacitating. Some studies have shown that this disease in the family has a greater impact on quality of life than even chronic illnesses like juvenile diabetes which is quite remarkable.

 Now the limitation of current care is really restricted to the fact that we -- as I've indicated, it's virtually impossible to avoid exposure to peanut in the environment with any certainty. About 50% of children who have a serious life-threatening reaction to food allergy will have another one reaction to a known food allergen within five years and about 70% will sustain another serious systemic reaction to the same food within 10 years, so avoidance is not as easy as it might first appear.

 And what's really amazing statistic I think is that most anaphylactic deaths that's a 100 a year in this country occur in children who are already known to be allergic to the food to which they are reacting in. Most cases this is related to peanuts or other nuts because peanuts and tree nuts are especially hard to avoid because of their widespread use in our diets.

 This slide just illustrates the current approach to management of peanut allergic patients from a clinical point of view. At the bottom here we start with diagnosis, medical history is important, skin pre-test are used with more -- recently a serological measurement of IgE antibody and bladder use because they are predicted profiles for the numbers generated from this test for risk of systemic reaction.

 And then where there's ambiguous response in terms of the risk food challenges are undertaken to define and clearly for the family what can and cannot be tolerated. Family has to be educated in prevention and so inquiries in restaurants, being [to school who prepared] and have an adequate policy to cover the safety of their children looking carefully at all labeling of foods and looking for contaminated products which are very common in a variety of elements within our dietary domain in this country and worldwide, I think.

 And then a recognition of the signs of the impending allergic reactions and their treatment with self-administered epinephrine is important for patients and their siblings and other caregivers to be not only informed about but properly trained in as well.

 And then we have allergen immunotherapy which is always been of interest in this disorder, but as we will has not yet reached a state in which we have a satisfactory program that is safe and effective in ameliorating this problem.

 So here's a little summary of peanut immunotherapy attempts to date. The first thing to be tried was the standard traditional subcutaneous immunotherapy and early attempts at number of fatalities. So it's largely been abandoned as a potentially safe way of inducing immuno regulation that might be of benefit to the patient. More recently anti-IgE treatments in the form of monoclonal antibodies against the IgE have been used and they do tend to attenuate responsiveness to any allergen exposure including foods.

 But they are not disease modifying. So once they are stopped this food sensitivity returns very properly within the matter of weeks. And they have usually been studied in conjunction with other forms of immunotherapy to mitigate against the risk of increasing oral doses for example of foods that are capable of causing allergic reactions themselves.

 Sublingual immunotherapy has limited benefit by current studies is very cumbersome to have to up dose in a combination clinic and home manner to get to satisfactory doses to produce any effect immunologically or clinically. And the maintenance protocols are very unsatisfactory as well.

 Oral immunotherapy allows the achievement of higher doses through the oral route but it's been associated as you've heard with serious allergic reactions in some patients. And the sensitivity appears to rebound even in satisfactory treated patients once the treatment is stopped, so it's certainly not a safe or predictably efficacious approach thus far.

 And interesting mouse model suggested the possibility of getting safety by administering the food allergen rectally but their clinical trial actually was stopped because of safety concerns from systemic reactions. So that's not going to be a viable method for it either

 The goals for ideal immunotherapy for peanut allergy would be certainly beginning with safety and a low risk of systemic reactivity. One would like to see a shift in sensitivity that's clinically meaningful in the sense that we could move patients from a risk of having occult in apparent exposures that can be life-threatening to at least correlation of the like -- of the contamination and low-level exposure that is likely to induce these reactions. That maybe in the order of three or four peanuts, being able to tolerate three or four peanuts or about 1,000 milligrams or so but there's not a universal consensus about that.

 Can I go back? Here you go, one moment, one more back. Okay. So the third bullet here is the persistence of the effect after the therapy had stopped. I've mentioned that even successful models to date have a fall for [going] that effect and nothing really has seemed to persist to a degree that would be desirable. We know this effect persistence of effect can be demonstrated with other forms of immunotherapy for respiratory and (inaudible) allergy so it is potentially achievable.

 Ease of use would be highly desirable property of immunotherapy particularly self-administered because the doses required to achieve tolerance are likely to require frequent dosing rather than infrequent dosing as we'll do for subcutaneous injections for inhaling allergy for example. And the finally as you've heard since the prevalence, these peaks at -- when you're of age, it's important to have a mode of therapy that's going to be practical for administration to young children.

 And then my last slide if I can get it to come forward here. I'm not pointing to the right paragraph. Okay, well all right, so this my last slide and it's just to remind you that the real goal of peanut immunotherapy is to reduce the risk of anaphylaxis. And we might aspire of course for a cure which would make everyone happy, but a more modest goal of being able to move from strict avoidance to controlled avoidance of exposure to inadvertent levels of peanut in the environment that are capable of inducing systemic life-threatening reactions would be a substantial achievement and improvement over what is currently available for these patients and their families at high risk for not only serious allergy problems but also a remarkably all altered quality of life until they achieve better control and better risk reduction that has been possible thus far. Thank you.

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 Gordon Sussman,  University of Toronto Clinical Immunology and Allergy - Division Head   [3]
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 This one in the middle?

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 Franklin Atkinson,  Johns Hopkins Asthma & Allergy Center - Professor and Program Director   [4]
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 The one in the middle.

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 Gordon Sussman,  University of Toronto Clinical Immunology and Allergy - Division Head   [5]
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 I'm afraid to touch this. This one here?

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 Franklin Atkinson,  Johns Hopkins Asthma & Allergy Center - Professor and Program Director   [6]
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 Yes.

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 Gordon Sussman,  University of Toronto Clinical Immunology and Allergy - Division Head   [7]
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 It's my pleasure to address you today. It's my pleasure to follow a true pioneer in allergy and someone who's made major accomplishments. Franklin has developed a lot of new treatments in penicillin and latex and all sorts of other areas, so.

 And it's also my privilege to precede Jonathan Spergel who is developing a new epidemic that we're seeing in allergy which is the Eosinophilic Esophagitis.

 You can see this is my clinical experience. I'm basically an allergist from Toronto. And I try to keep a low profile so I'll go over what we have found.

 Actually in Toronto we have very well-defined large anaphylactic program where I work with Peter Vadas and a few other investigators. And we've had an interest in anaphylaxis for a long time. We've done research probably since the 1980s. But we try to keep a low profile.

 Franklin, this one? So I started in the '80s, actually at Penicillin as a fellow where we looked at minor determinant and then lo behold 1985, a nurse put on a glove which was latex and passed out. It wasn't that difficult to diagnosed latex allergies, she passed out in the operating room. And then after the latex disappeared we had all these people at peanut allergy that we were trying to sort out.

 So that's basically how this whole situation evolved for myself.

 We've also done a lot of research in [urticaria and angioedema], an area that I've always had an interest in and now marijuana which is a pretty common allergy too, so you just couldn't look for another allergen and you'll find a new one every day.

 But peanut is a very important allergen because it potentially is life-threatening.

 There's also a very important psychologic profile and that we have to remember. And I'm going to try to go over the important points. It's difficult for me to state it at 15 minutes, so Franklin, can you tell when I'm getting close?

 I'd also like to commend the people who are in charge of the VIPES study. Wence has done a tremendous amount of work and the research has been designed very well and its well-designed research and they're large studies and we have input into the way the studies are designed and I have to commend the company for doing that.

 So I hope that we'll see the results that we all want to see.

 The VIPES study is important because it was a large study of I think 221 people that have been randomized. So it's a very large study in patients with peanut anaphylactic allergy. This slide shows the study design and if I'm right -- I can't see it. So you can see that this is -- overall there're 221 patients. And in our site alone, we had 36. We could have had 221 at our site because there are so many people that wanted to participate in the research.

 People with peanut allergy really have been looking for a treatment for years. They really don't want to just avoid peanuts and wait for reactions. They would rather be proactive and actually treat the allergy. And this was available and this is possible with venom.

 So for insect venom anaphylaxis, we can actually get immunotherapy and protect the people, but for food allergies, this was never really available. If we did injections, as Franklin said, the reaction would be very severe and life threatening. So the safety of the subcutaneous immunotherapy with peanuts was not really the same as it is with stinging insect venoms.

 The initial part is the screening where we have people with peanut allergy that have high IgE. I'll talk about that a little bit later either by skin test. And the immunoassays that we used in allergy basically just detect sensitization.

 So what we're doing is we're detecting specific IgE. The skin test does it with a size that we see a (inaudible) and a flare, it has to be a specific size. And you can see greater than 8 millimeters actually in the high-end. A lot of studies is just 5 millimeter or greater. And the IgE 0.7 is also more on the high-end.

 But it basically gives a number and does not really mean that people will have serious reactions. The only way we're going to ever know whether people have serious reactions is actually by doing oral challenges. And that's been something that really has only been done the last decade or so.

 You can see that in the study there is a 12-month treatment with three doses, 250 the highest dose, 150 and very important that there is a placebo group. And you can say, 'Well, why would you challenge people with anaphylactic allergy who have no treatment?" And the answer is that we have to randomize so we can get the results and compare because it's important to always have a randomized controlled trial including placebo patients.

 There were two challenges that we did in the study and I'll go through that too; one at the beginning and one at the end of the study. And we finished last week. I think we finished the 24 patients. So all our patients have had pre- and post-challenges and a year of treatment. And now we have 22 of the 24 patients that are in the continuation which is the open label study, so all but two of our patients have continued with the two extra years of immunotherapy.

 I've gone through all I want to say now I can finish right now.

 So to summarize in the next few slides the VIPES which stands for Viaskin Peanut Efficacy and Safety Study I think is a well-designed study. It's a large study which strengthens the study results. There's a rapid gain and knowledge about anaphylactic allergy because we've never really challenged these large numbers of people that have IgEs over 100 anaphylactic reactions and we learn an awful a lot about the disease itself. And I'll go into that as we go along.

 The benefits are very important because patients that are afraid to be challenged with peanuts and some of the screening failures are because people wanted to do the study but they just couldn't go through with the challenge. They were too nervous.

 One patient actually backed out of the study when we're giving him the first dose. So it's a very traumatic experience for people that have avoided peanuts their whole life to actually have to eat them. And it's something that once they do, whether they're treated or not, in my opinion they have psychologic benefit which is important to remember. So even by doing challenges without doing the treatment I believe there's a psychologic benefit.

 So when we see people that have reactions for instance to airborne peanut or in my opinion people that have reactions when you're kissing, or other very rare exposures there's a big psychologic component that's very difficult to weed out and that's why we need large numbers of patients in these randomize trials. We want to have objective evidence of a reaction. We can't just have subject with symptoms.

 So the VIPES study used to challenge matrix which is a chocolate pudding, or moose, or dessert which is disguised with an orange flavor so people cannot distinguish whether this is peanut or whether this is placebo. It's very important in a controlled trial for people not to be able to know what they're getting. And it was double blind so that neither the investigator nor the patient, or the subject would know which group they were in.

 This matrix is used all over the world. So this was an international study done all over the world and basically everyone use the same product. So it was a standard -- we use to challenge all our patients in this research study.

 We used as a protocol that was developed and published in the American Academy in terms of challenges that I'll go into and as I noted there's a placebo group which is important. We used objective symptoms not subjective symptoms to stop the challenge. And we would do a challenge and then once we have objective symptoms, we would treat the patient. So patient, in order to have a positive challenge, would have to have objective symptoms and then have treatment for those objective symptoms.

 And lo and behold it was a pretty safe method. So when we did the challenges in a way we did, we could weed out objective symptoms and not have life-threatening reactions. And we did this at our research center which is not a hospital. So allergists are prepared to deal with anaphylactic allergy, we do that every day when we get into immunotherapy for pollens and we are experienced in dealing with it. There is a going to be a place for doing these oral challenges at centers where they're familiar with the treatment and when they're able to deal with the emergencies that they see.

 I'm going fast, guys. The challenge for safety is shown here and you can see the initial challenge went up to 300 milligram. Oral food challenges, pharmacist prepared the matrix 24 hours before, challenger done first thing in the morning, an IV is established in all patients, experienced emergency room rehearsed, we have experienced staff; two study coordinators. We were over prepared. We were over prepared because we want it to be at this part of the study. And two physicians are readily available to treat reactions.

 The challenge is stopped when there's objective evidence of an allergic reaction. We try to make it comfortable for patients. So if you can see they have a comfortable chair, but you can also see we have a crash cart with an emergency room right in our office prepared to deal with anything; they have IV lines, they have IV fluids, we have the epinephrine antihistamine, steroids and other vasoppressors that are needed to treat any reactions.

 Keen interest from the public; so this study was done with the public already wanting to participate, so in a few months we enrolled 20 -- we've screened 36 patients, enrolled 24 patients and we actually have our recruitment [camp] by the sponsor because we had too many patients.

 You can see that we had all age groups. So the nice about this patched technology is that you can use it in young people and you really wanted to treat people when they're young. And that's an important point. And the other important thing is the patch is very safe and that's another point I'll make in the next few slides.

 You can see when we did the challenges, often people had panic. So the first symptoms that we would see when we challenge was panic and we knew they were having a reaction is subjective but then the next most common is gastrointestinal symptoms. So people would have abdominal cramps, nausea and then eventually they would vomit. So subjectively nausea and cramps would not qualify but if they started at the vomit then that would be an objective symptom. If they just got itchy that wouldn't be an objective symptom but if they broke it in hives that would be an objective symptoms. So that is really what we are looking for, objective symptoms.

 We would see more severe reactions in the adults we challenged. The adults had more severe reactions. I think if we look at it in our group anyways we would give epi more commonly. And the most serious reactions, we would give an epi. We didn't see anything more. Most of the people we treated with antihistamines and oral treatments most people did not actually require epinephrine.

 You can see there's a threshold does too. So the trace amounts most people reacted to via 100 or 150 milligram dose which is roughly a half a peanut. So everyone has a threshold although some people lower, some people higher but it's in the neighborhood of 100 to 150 milligram of peanut protein.

 The past technology is safe and it can be used for long periods of time. You see local reactions you don't see systemic reactions. The problem with oral immunotherapy in my opinion is that you see more reactions because, yes we can do oral desensitization and we can give people three peanuts a day. But in our group we see people have anaphylactic reactions when they exercise, when they have infections, when they have their period. And I think when you look at the number of anaphylactic reactions there's more in the oral than there is in the people that just avoid it. And really that's not the goal. The goal is to prevent and the goal is not to have reactions. So early treatment, long-term treatment, patched safe technology is what I see is being the advantage.

 What we define as a success is 1,000 milligram with peanut protein or tenfold increase in the initial threshold dose. And this would have life threatening -- this would have been life changing implications. So if we could give people three peanuts which is roughly 1,000 milligram that is a significant change in their life.

 The goal of any person who does research is to cure the disease. So obviously, we would like to cure it but if we can't cure it we also would like to be able to tolerate it. And the impressiveness of the patch is it can be used for long periods of time. There's no reason it can't be use for years which is what we're doing in the Phase II or the open-label study.

 Comments from people that have finished the year and have the challenge, and I can't -- because we don't have the results, so we have to wait for the results, but psychologically they feel like they're much better. They feel their life has been changed. They feel they can live easier. They can eat. They can go to restaurants and they can travel. And this is very important because people don't understand that food allergy particularly when you have anaphylactic food allergy is a really a form of a disability and it's something that really alters a person's life.

 So my summary before I go into Jonathan's talk is it's safe, we see local reactions, compliance. We had compliance almost 100% and high expectations. So people once they finished the study wanted to continue in the open-0label study which is another two-year trial using the patch. Thank you.

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 Jonathan Spergel',  Children's Hospital of Philadelphia - Chief of Allergy Section   [8]
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 All right. So thank you, Gordon. Thank you, Franklin. So I'm going to change the topic slightly. We're moving from peanut and we're going to go on to milk. And I'm going to be talking about -- my talk, I'll sort of break then into two parts; milk allergies from an anaphylactic type of milk allergy; then we're going to talk a little bit about EoE.

 So milk allergy. So milk allergy is actually, probably gets lot less play than peanut. Peanut is in the news all the time. So milk allergy is first of all is the most common food allergy anywhere from 2.5% to 6% at the time. Depending on the age, is a typically the first things people see in terms of milk allergy. And we used to always think that people (inaudible) allergy but that actually never happens is showing more and more people probably not growing out of milk allergies as fast as we like.

 And one way we can think about it in terms of natural history is that when you have a higher IgE levels and looking at your manner antibody against milk, the higher it is the more likely you'll outgrow it. And when you look at the slide, so the red lines are people with the highest and you can see, if you have an IgE greater than 50%, less than 60% of the people have persistent IgE. And you can go down even after 10%, when it gets maybe at 10% is a lot of 50%. So a lot of people still are going to outgrow it.

 People (inaudible) milk is not such a big thing. We used to always tell about our peanuts free schools which means one of the silliest things out there because the common reaction in school is milk. Does anyone have heard of a milk-free school? No, okay. It doesn't happen.

 And there was actually a patient, actually a local patient who happens to be my patient who died of milk anaphylaxis. This a patient from New Jersey, so close to the people who are New York here, who died, went to Starbucks and grabbed his brother's -- still getting soymilk, he grabbed his brother's milk and died on Route 1, in New Jersey. Plus they couldn't get the -- parents were stuck in traffic and they didn't bring their epinephrine with them. So milk allergy is serious. It can be fatal. And even though we will talk about other things it's still the number one and more common food allergies out there.

 So when we think of food allergy, it's the same thing we heard about peanut allergies. The treatment of choice is avoidance. That's really the only way. And for milk we think peanut is hard. Think about milk, look at your candy bar, look at the bowls in front of you, there's a lot -- there's milk in that one. There's milk on our table out there. Milk is everywhere. It's one of the most common things we eat and everyone has died all the time from a piece of bread, to a candy, or it could be your tootsie roll, milks all the time. So milk is really, really hard to avoid.

 So the idea of having Viaskin to milk which is the next thing in production is pretty poignant. And we'll be able to again similar to peanut but then protect against severe allergic reactions. The goal is to be able to have more rapid introduction of milk.

 So since milk is such an important part of the diet, kids will be able to grow better, improve quality of life and the idea of be able to do Viaskin since the patch and do oral immunotherapy, and we're doing all the immunotherapy with Omalizumab, with the oral immunotherapy and doing the combinations of sort of doing a little bit of (inaudible), a patch is so much easy to do. It's much easier to do. You can get a patch on a six-month-old.

 It's really tricky to get a young infant to do, only young child to do oral immunotherapy. And it's not really safe because you want the child to tell you what's going on. And if you're doing epicutaneous therapy, you really worry a lot less about that. And it does have this much better theoretically a safety profile.

 So there's a trial called MILES and MILES will be the milk epic trial. And this trial is now under review by the FDA. And hopefully we'll be starting at some point this summer. It will have two phases; the first phase will be Phase I and the part one should be safety which would be three doses versus placebo. The two with the highest tolerated doses then will be continued on to the efficacy study in Phase II which will have three doses -- two doses versus placebo.

 There's a different ratio like in the peanut was much more or less placebo and this one since more kids outgrow milk there's a bigger placebo on. There're challenges similar to VIPES at zero to make sure that you have sort elicit any dose how sensitive they are. Challenging again at 12 months and challenging the open label end at 24 months, looking again how fast kids outgrow it and looking at tolerance. And there'll be total of 150 children and in two large stratification and two large (inaudible) groups with children and adolescence.

 So now, I'm going to jump to my other talk Eosinophilic Esophagitis, also commonly known as EoE or EE. EoE is seen throughout the world, seen in every continent now except for Antarctica so no patients in Antarctica but there are patients now in Africa which was the last continent; seen in every state of the United States basically every country in Western Europe, so it's seen throughout eh world.

 Like the rest of us, as Franklin was saying the rest of the allergy, EoE has risen and it's unclear whether it's rising faster than other allergies or just recognizing it better. This is data from our own institution that we've published several years ago and you can even see there's really rapid rising going to (inaudible) and seeing this -- gaining 100 of patients. So it's really a rapid rise.

 The incident in the United States is just about 1,000 to 2,000 as we've seen in three different ways but looking. We're looking at ICD-9 codes, we're looking at patients reporting in or even questionnaires. However, when they have done sort of random biopsies, in Sweden they did random biopsies have a city in Sweden it was up to possibly as high as 1 in 100.

 So the numbers are probably a lot more common than we think. It's still considered red disease by the FDA plus we're at that cutoff. But maybe in 10 years it actually won't be even considered as a red disease anymore.

 The symptoms of EoE just to give people a sense of who they are it is they present with different age and probably just due to how long those eosinophils are. Eosinophils are cells that normally don't exist in the esophagus. They show up in esophagus from the last of different diseases including reflux. But with EoE they're coming from truly from food allergy and the longer they are there the more dysfunctional and more problems it have causes. And as they are there, they caused more disease.

 So in infants that threats to eat so they don't eat and they get (inaudible) to thrive and they get abdominal pain, they get vomiting because there's a lot of inflammation. As they get older they get used to some of the inflammation. They get just chronic abdominal pain all the time. They come up with what we consider over -- they over chew the food, because they've learned the only way the esophagus doesn't work so well anymore, the only way they can swallow is they over chew.

 So these are the people who chew a lot. It takes them 20 minutes to eat a piece of food plus they really need to get it down to a small size and they drink a lot. And if they don't that quickly, they'll end up with food impaction, they get their food stuck.

 In the adult world, the most common way this disease presents is food impaction and that half of the food impaction that were sent to an emergency room are due to Eosinophilic Esophagitis.

 So as we know it's different and EoE doesn't seem to be at all outgrown and probably less than 5% and as the longer you have the disease the more fibrotic you are. The esophagus comes really schematic and really gets into the chronic disease state. And this graph, this shows you over time, you're getting -- more likely you're getting stenosis.

 All right. So what do we know? What can we treat it with? What do we know from the basic science side? As you heard earlier, we conduced it in mice and pigs, you can play with mice models, you can knock out IgE, we talked about IgE for peanut allergy, milk allergy, it's probably the key role, but for EoE, probably not the key role, at least we published that out of -- our institution when we knock out IgE in mice, it makes no difference.

 So it's probably a distant pathway, but nonetheless, when they looked in mice and pigs, they can cure -- cute [on quote], the inflation, the inflammation goes away after you treat it.

 So why do we know -- we think in humans it's not IgE, is based on two basic theories, this is from the clinical side. This is a patient who had milk allergies, this is a little girl who had milk allergies, so had hives to milk. The kid was not eating milk a lot, so had (inaudible) wasn't growing. So this end up having this what we see here, this is actually normal looking esophagus, no inflammation.

 So at basically 18 months, the kid had a negative skin test, got small -- this is skin test size, so that decreased, so we did a food challenge that Gordon was talking about, did a food challenge, and now -- it could outgrow the milk allergy. Great. This is one of the patients who actually outgrown milk allergy. So started drinking more and more milk, but at the same time, started developing classic symptoms of eosinophilic esophagitis, having belly pain, a lot of reflux, not responding to medication in reflux, some of those got worse and worse and worse.

 So at five, ended up getting another endoscopy, now it has EoE. But skin test is completely negative, so skin test is completely gone, we take milk back out of the diet, everything goes away, so this kid actually end up having both IgE mediated reactions to milk and a non-IgE mediated reaction having EoE to milk. So this young girl had two things to milk.

 So when we think of treating EoE, there's really two ways you have to treat it. The first, like anything else, you got to diagnose the patients, you got to make sure they have the right disease. And there are two basic therapies. One is, this is a food allergy in almost all patients, you can take foods out, and the other is sort of pharmacological therapy.

 And the main reason why we do pharmacological therapy is off label use of topic steroids. And when we think of topical steroids you can use systemic steroids like oral prednisone, works great, it cures them. But as soon as you stop it, everything comes back. And we never put people on oral -- long term use of oral steroids, lots of side effects, of course growth problems, bone problems, [immuno-suppression], really not the best thing to do.

 Topical steroids is probably the most common way to do it, people use -- off label use of almost any topical steroid, the most common one people use are fluticasone, and budesonide, you basically make them and you swallow it, you take your medicines really [poorly]. And when you stop it, it comes back. You see oral [candidiasis] in about 10% to 15% of the patients knows what the long term growth suppression in these doses. We worry about growth suppression because these doses would cause growth suppression if we did it in asthma, but we don't know with EoE because no one really looked long enough yet.

 So what about food allergy? What did we prove with food allergy? There's a lot of ways to know, but one thing we know, (inaudible) when they have done it and [Hopkins] back in the 1990s, they were able to show more people on an elemental formula. You take the food, almost everyone gets better. Work done by lots of people including us, but this is a work -- a nice paper published by [Mimi Gonzales] out of [North Westin], is when they put these patients on what we call the -- they call it six food elimination diet, sort of a [funny] way that you think -- and I presume -- hope there's no gastroenterologist listening or on the audience that can count to six. It's milk, egg, wheat, soy, peanut. So all peanuts, all fish -- all shellfish, so that's at least eight, but they call that six. But that's the six elimination diet.

 You put the patients on the diet, everyone gets better, you introduce the food, all the inflammation comes back, really just sort of filling cause -- [partially] the food cause the disease.

 So why -- so the question is, okay, here, we know what's causing it, can we just do regular oral immunotherapy? The sublingual or the oral? The interesting thing, if you look at the literature, about 10% to 15% failed, and they fail because they'll develop EoE. And this is sort of the prime, this is a great case of it.

 And if you look at this, this is a young child who ate egg and had hives. At four, had what we really worry about, had an accidental exposure -- had anaphylaxis. So went under oral immunotherapy for egg at 10 years of age. After two months, great success eat a whole egg, however, seven months later, now is having bad esophageal symptoms, has now developed EoE.

 So they take, they diagnosed EoE, and they take the egg out, everything goes back to normal. So if you look at the literature, it's about 10% to 15%. It depends with the -- last [QUAD ii] meeting and I was talking about giving a press conference on for that last patient, that one who came, that had EoE, and [Hugh Samson] and [Wesley Brook] were talking about their oral immunotherapy and they tell me it was 15% in their studies.

 So it really happens, they see it a lot. So this is one of the reasons that I worry about oral immunotherapy. But hopefully, we won't see this with EPIT. So -- one slide too far. There we go. So why we care about milk?

 Milk is the most common cause of EoE, seen about 70% of the patients, you can prove it by biopsy or by symptoms, these are number -- reactions, I just -- but milk is by far the most common cause.

 So the idea was, since we know EoE is [inflammatory] disease, milk is the primary allergen, and we have not real treatment out for you. Can we do EPIT? So when doing EPIT for desensitization. So we're doing a trial that will happen sometime, hopefully late this year, early 2015, depending on FDA and (inaudible) study called SMILEE. And this is the study of efficacy and safety for milk, Viaskin Milk for treating EoE.

 It is a study we're going to be doing in 20 subjects, it's going to be randomized since it's with placebo. They get EPIT -- and it's easiest to see looking at it this way. So we give them milk, we showed that they have EoE induced milk, we take milk out, it shows that removing milk ends, get rid of the disease. We put them on EPIT treatment, we re-expose them to milk and we see it -- the biopsy -- will it be normal now back on -- after being treated.

 So just to conclude, milk allergy is really common. It's probably the most common cause of IgE mediated reaction, the most common cause of non IgE mediated reactions.

 Milk allergy is serious. People die from it, (inaudible) is so common. EoE, we have no treatment. It's a (inaudible) disease. Nothing out there works right now, we've been treating symptoms, or we can do avoidance. So the idea of EPIT, we may be able to treat things for milk for a big reason for both IgE and non IgE reactions. And now, I will hand it back to Dr. Dupont. Dr. Dupont will be talking about EPIT.

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 Christophe Dupont,  Necker Hospital - Head of Pediatric-Gastroenterology Ambulatory Dept   [9]
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 My name is Christopher Dupont. I'm Professor of Medicine in Paris. Actually, I'm (inaudible) I focus on food allergy and I've been working with food allergy treatment for now -- for more than 20 years, I think.

 I would like to make a brief overview of what we did actually when we started this study 10 years ago with my friend, (inaudible) was an engineer who was responsible for the design of this [patch]. It's quite difficult because we've got -- I've got only -- I've got 15 minutes to summarize what we did in 10 years.

 But I would like to just end the line what seems for me is essential in this study. Skin has been used for 100 years now -- where's the -- I'm sorry.

 Okay, so skin is being used for 100 years now and it's being used usually with what we call skit, the injection of the allergen below the skin. And as you see, this is something that you cannot use when you are dealing with food, on this, specially peanuts are difficult, it's too dangerous.

 So when we started thinking about that, we thought that one of the major points was to have safety. And for us, safety was using the skin, applying the allergen onto the skin and not below the skin. And with this safety, we thought that we could expect something that could be good, but basically without putting the children at risk of any anaphylaxis for example because of the use of only the application onto the skin.

 So what we did, I think that the first invention that we had was to use the application on the skin. And also, we wanted to act on the intact skin, we didn't want to have a technique that could be dangerous, and we applied on the intact skin and at that time, we could not foresee what we saw later on that was detailed by [Lucy] when we were using the intact skin, we were targeting the Langherans cells and now, we know that these Langheran cells are very potential -- have got a very potent activity in terms of action against allergy.

 And also, we thought that since we're acting on the intact skin just applying the allergen onto the skin, we probably would be obliged to use a long term continuous application to get these anti-allergenic effect. And this is what we did. And now, we know that using this long term, continuous application, we have actually a very important in-depth immonomodulation.

 And basically, I think that what we have to recognize now that with the idea to use intact skin and long term continuous application is the thing that was probably more important when we started this study.

 So if we want to try to summarize what we did in 10 years, perhaps we can organize that in three different chapters that we'll go -- we'll call them as breakthroughs. And those breakthroughs, I'm going to detail them.

 The first one is that, we use what we call now the epicutaneous [test] pathway using this pathway is just applying the patch on the skin, onto the skin, above the skin, and not under the skin.

 When you do that, and this was shown before, you apply the allergen onto the skin, and the allergen is taken up by specific cells, the Langheran cells, and the allergen is not transferred into the bloodstream. This is what you see when you apply the patch on the skin, and once you inject the allergen under the skin by subcutaneous injection.

 When you do that, then you've got the delivery of the allergen into the bloodstream and this is the interest. When you put the allergen in the patch, and when you apply the patch on the intact skin, you do not have any passage of the allergen inside the bloodstream.

 So that whatever you do, it is not dangerous because you do not have any delivery of the allergen into the bloodstream. And now, we know, and this was shown that actually, the allergen is taken up by this cell, and this cell is migrating them to some immuno-components of the body, and the action comes from the ability of the Langheran cells to take up this allergen.

 What we did not expect also was that there is -- there seems to be with EPIT, we have labeled this technique, EPIT, a specific mode of action. This is quite complicated. See in the slide that it has been published very recently, describe the differences between oral immunotherapy, sublingual immunotherapy and EPIT.

 You see here that the system going to [desensitization], may have some modulation ,and the modulation may come from oral immunotherapy and sublingual immunotherapy. But when you look at this, you see that there are some (inaudible) acting on this pathway, and you see that with EPIT, it looks like it is different. One, the allergen is taken up the Langheran cells, then it induces t-regulators, the cells which are very important to refrain the allergy process, and the action of the t-reg is that they directly on this -- [TH2] pathway, but through the interaction with another cell, the antigen (inaudible) cell, if you see here. And it looks like it's quite different. And for us, it is something which is very important because it might explain why we have such a potent activity that we saw.

 Now this important -- this point of safety, I would like to go back again to it because this was at the very beginning of the study. And as you know now, this patch allows -- depositing the allergen onto the skin, and since there is no blood passage, then with this technique, treat any kind of allergy even if the allergy is severe, you do not have any passages into the bloodstream.

 You can treat any patient. The youngest patient, the severely asthmatic patients, for the youngest patient, it is very important because you just apply the patch, do not ask the patient to swallow the patch or to have the patch -- the allergen through -- to swallow the allergen, or to have the allergen deposited sublingually, below the tongue. And you can do that whatever the danger that you have with the allergen.

 This very important because this is the only treatment that can be considered when the dangerous effect is sick, and Jonathan just talked this problem of eosinophilic esophagitis, you know that when you swallow the allergen, you may have from time to time, this inflammation of the esophagus because of the contact of the allergen with the mucosa of the esophagus. But in this situation, you have contact only with the skin so that you can do the immunotherapy without any alteration of the digestive track.

 I would like to go to the next one please. Okay. So the second breakthrough is that with this patch, we use the intact skin and we have a continuous antigen exposure.

 It was our feeling from the beginning that if we were to use the intact skin, the medium to administer the patch, we were obliged to administer the antigen all the day long. And this is the basics of the continuous antigen exposure.

 And we have actually good results. And this is the paper that we published 10 years ago -- three years ago. And it was basically the first study showing that we could do something using this kind of patch applying to the skin. We did that with children with cow's milk allergy, we applied this patch for three month, continuously. There was milk inside the patches for the peanut. And we did a clinical trial with double blind placebo control design, and we were able to see that with this patch, after three months, we had in some children, a very nice increase of the amount of milk that was tolerated during our double blind placebo controlled food challenge.

 We published the results in the Journal of Allergy and Clinical Immunology. We analyzed the situation after six months of treatment, we saw that we have much better results after six months, and this was for us, the first perception that we have about the kinetics of the desensitization.

 It appeared for us that if we wanted to have this kind of desensitization, probably starting after three months, but we had much better results after six months. And this is one of the reason why when we designed the other studies, we analyzed the children only after six months, and even for the [live study], after one year.

 What we saw also with some of the clinical trial that we did, and this is the [Arachild] study in children allergic to peanut. What we saw was that using this patch, we have a very important immune response and very important modification of the levels of IgE which are responsible for the reaction for IgG4 which are responsible for protection against reaction to peanut.

 What you see here is that when you start applying the patch, you have a very interesting and very important increased specific IgE against peanut which indicates that there is a strong immune stimulation based on the patch.

 And what you see also is that from the beginning, you've got an increased in these IgG4 which are protective against the allergy to peanut. And what you see is that we sustained the stimulation of the skin because of the patch being applied for everyday for months, you see that at some point, you have, with the Ig, the peak and then the Ig spefic Ig going down, but still the specific IgG4 still go up so you go to a point where you've got a decrease of specific Ig, there's still an increase of IgG4 which are protective, and this is something which is for us, very important because you get the kind of protection that you have with EPIT because of this decline of IgE and increase in IgG4.

 One important point was also the analysis of the sustainability of the response. You see that it was said before that when you do -- try to desensitize children with oral immunotherapy for example, at some point, when you start the treatment, then the child becomes allergic again, and may still have a reaction. And what's -- one to do when you try to desensitize anybody, you want for the effect to be permanent when you stop the treatment.

 And we have now some data that probably may give some indication as a potential sustainability of this treatment. This was shown by Lucy before. You know that if you want to try to go to sustainability, probably, it is important to see if you modify the action of the gene. And if you want to modify on the long term, the action of the gene, what you need to do is to go to epigenetic modification, epigenetic modification are the mutilation of the gene basically, if there is an increase mutilation of the gene, then you have a decreased [action] of the gene, and a decreased expression of the gene. This is what you see here for example, (inaudible) you see here, an increased mutilation of the gene and decreased expression of the production of the protein depending on that.

 And this is important because it is an epigenetic modification and you know that epigenetic modification, these are the kind of modification that you can see for example, transmitted from one generation to another, which means that you've got a very, very prolonged action with this kind of modification.

 So this is important and we have now some evidence that in children, when you stop the treatment, you still have the protection. And this is a child that we published in France recently. This child, how [he] was -- been treated in the Arachild study, 8 years old, was able in the beginning to (inaudible) approximately 100 milligram of peanut (inaudible) and left to treat after 12 months -- 18 months of treatment, he was able to multiply by 10, the amount of protein that was triggering a reaction. Then he stopped the treatment. And then after one year, he still did the challenge and there was a big increase in the amount of protein that was reacted during the food challenge which means that the protection that he got was maintained and even increased after one year -- one year after stopping the treatment.

 It looks like this treatment is probably also protecting against anaphylaxis. It is something which is new, and I would like to thank Lucy for providing these slides showing that now, we have a new data concerning the protection against anaphylaxis. This looks like complicated, but it's not really complicated.

 You see, you got here mice, you sensitize the mice to milk and then you treat the mice that have been sensitized to milk, with (inaudible), which means no treatment, and then you collect the t-regs from these mice, and then you've got t-regs, actually, explain the site, you got t-regs from mice that have been treated with EPIT and mice which have not been treated by EPIT. Then you take [live] mice and you transfer to these [live] mice the t-regs, coming from mice which have been treated with EPIT or mice which have been treated to (inaudible). Then you sensitize these mice through -- of [albumin] and then you do an intravenous challenge with -- of albumin, and you see if your modification of body temperature, body temperature modification the equivalent of the anaphylaxis in humans.

 And what you see here is that when you have -- when you try to reproduce the anaphylaxis in these mice, which have been treated with EPIT, you do not see any drop in temperature which means that just using the t-regs that have been collected in mice that have been treated with EPIT, when you transfer those t-regs in other mice, then you prevent the anaphylactic shock.

 And it is my experience now in the Arachild study that when the child has been treated for a sufficient amount of time with EPIT, you do not see any more this symptoms of anaphylaxis.

 You still see some symptoms, but you do not see anymore the symptoms of anaphylaxis. So that it is my feeling now that with this kind of treatment, we probably have got a good indication that we might protect against anaphylaxis.

 Then I would like to go through the third breakthrough of this presentation and this relates to the fact that you can use it in very early -- children -- okay, speed up the process. I like talking about that, I'm sorry.

 What you can do with this patch is that you can use the patch from [birth] because you do not have to ask the child if he wants to swallow or not. And this is very important because if you can target the children, then you can do something which probably interferes with what we call the allergic [match]. You are probably familiar with the allergic match. You know that when a child starts allergy, sometimes it disappears spontaneously, and sometimes, you may have this -- you may go, you must know the allergic match and this child will have eczema and so on and so on.

 With the patch, you may interfere at this level. And Lucy showed to you that when you desensitize with a mice, with allergy -- we start to desensitize these mice, then you prevent further sensitization. And since pediatrician now looking for a technique that might interfere with this allergic -- I think that the data that were provided by Lucy indicates that it is probably something that can be developed further.

 This intervention during this window of opportunity when the child is very young and when the only technique that can be used is this kind of technique, that patches that we apply on the skin.

 So I would like just to summarize these. We can treat children very young and with very severe allergy. We know now that we have got a sustained effect and we know that we have potentially a prevention of the allergic match. And I would like to finish this presentation just to say that it was -- we started this study 10 years ago, and now, it's really a pleasure for me, I'm a pediatrician, to see children who have been very allergic to -- peanut, being able to chew M&Ms with a big smile. And this is really a great achievement.

 Thank you very much.

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Unidentified Company Representative   [10]
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 Thank you very much. Thank you all of you and it's time for questions. Please, if you have any question, we'd really be happy to answer. He is arriving.



==============================
Questions and Answers
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Unidentified Audience Member   [1]
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 I was wondering if you could, if you have any indications from the same point of view, have one child who is allergic to any of these things, peanuts, or whatever, is there an increased likelihood that as sibling is allergic? Or is there any data about kind of among siblings or in a family group?

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Unidentified Company Representative   [2]
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 So in terms of family risk, we don't know a genetic marker that says one of the other. But if there's a sibling, there is definitely an increased risk for that food as well as probably other foods as well. The exact number depends on the food and the study, but there's definitely an increased risk for siblings -- of the food allergies.

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Unidentified Audience Member   [3]
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 For the larger studies and as you guys advance, what do you see as a primary endpoint as far as FDA and that type of --

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Unidentified Company Representative   [4]
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 I'll pass along. So you never know what FDA wants, we'll leave it at that, but I think this -- so my interactions with the FDA always been, they want a patient -- something that affects the patients. So I think they're -- in my mind, this 10-fold increase is probably actually a real thing because that's sort of hey, I can tolerate a lot more . The FDA obviously was willing to accept this as part of -- in this initial Phase II trial. So I would -- I never can predict what the FDA wants, but I think that's a reasonable endpoint.

 As a parent of a kid with food allergies, I want my kid to have none. Okay? I hope so. I want my kid to have actually zero which is, as a parent, safety is important, but I really want the [pie in the sky]. I want zero, but anyone else who wants --

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Unidentified Company Representative   [5]
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 We will discuss at this point, in the second part of the meeting in details because we will talk about the clinical development.

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Unidentified Audience Member   [6]
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 I guess two questions. First, how much intra-patient variability over time is there in the reactive testing? So over a period of months for instance if you test the same patients. And with regard to that, how well does that correlate with clinical symptoms and in particular, the risk of anaphylaxis?

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Unidentified Company Representative   [7]
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 That's a very good question because there is patient variability. The placebo controlled trial will hopefully, in a large trial, address those issues because one threshold dose at the beginning and the end, may be different from placebo versus treated patients and hopefully, we'll be able to define whether it is a treatment effect or whether it's not. And that's really what we're trying to do.

 The other thing is, with the reactions that we're seeing, we're waiting for objective symptoms so you know, you want objective symptoms without having life threatening reaction. So we're dealing with real disease and we're really dealing with real reactions. And again, that will be something that is going to allow you to address those two issues.

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Unidentified Company Representative   [8]
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 Other questions? Perhaps -- okay, so we will take a break and -- 15 minutes. We are not exactly on time. So if you can be here in 10.50, it would be perfect.

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Unidentified Company Representative   [9]
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 Is there any questions on the line now? No? We're good? Okay.

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Unidentified Company Representative   [10]
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 And if you want to ask questions to any of us, I'm sure we'll -- I'm staying around and you can ask.

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Unidentified Company Representative   [11]
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 Thank you, guys. Thank you for being here.

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Unidentified Company Representative   [12]
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 Thank you, all of you.

 (Break)

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Unidentified Company Representative   [13]
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 Thank you. So we'll start. So we're entering into the second part of the day dedicated to the technology and the regulatory and critical development of Viaskin Peanut. And it's a pleasure to ask Bertrand Dupont, Co-Founder of the company, Chief Technical Officer to present the Viaskin and [electrospray] technologies. Bertrand.

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 Bertrand Dupont,  DBV Technologies - Chief Technical Officer   [14]
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 Good morning everybody, I'm Bertrand Dupont, I'm the Chief Technical Officer of DBV Technology, and I manage all the development of the technology of DBV Technology. My presentation will address those (inaudible) three points the Viaskin, electrospray and the manufacturing technology. And you will see that the technology [is so special in new device skin] because the treatment and the technology has been developed together.

 So as I said, the Viaskin Patch. The way it works and [the active trouble of] the patch. The way to put [the proteins] in the patch which is electrospray and [thus] the manufacturing [tool]. Before starting I think it's interesting to say again what we wanted to achieve at the beginning of the development of the technology [at the] beginning of the [DBV]. First we wanted the flexibility in the patch. We wanted the patch to be able to be developing clinical trials. So to [add the] different doses in it.

 We wanted obviously stability of the proteins, stability of the API. We wanted [delivery onto] the skin, meaning that we wanted that the API was able to go everywhere in the skin under the patch. We wanted reproducibility for industrial reason. And in addition, we wanted bioavailability. We wanted spontaneously being able to be dissolve under the skin.

 And this is the pharmaceutical development that we wanted in all these things. First of all the Viaskin patch. The principle of [the way affection] the Viaskin patch has been developed before. But it's [just full to] have a closer look at it. Actually Viaskin Patch works with water. And together this water under patch, we need -- we need condensation chamber. This condensation chamber is from between the backing --

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Unidentified Company Representative   [15]
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 (Inaudible -- microphone inaccessible)

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 Bertrand Dupont,  DBV Technologies - Chief Technical Officer   [16]
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 This is the backing. This is the adhesive crown and this is the skin and the condensation chamber is in between. And this condensation chamber [together with the] water that comes out from the skin, the skin swells a bit, becomes very hydrated and after the water condensates on the backing and is able to dissolve the proteins. And after we have the proteins onto the skin and there, they are able to go into the skin in the upper layer.

 Here you have the sketch of the patch, the adhesive crown, the backing, it's a PET [politer] film with thin layer of titanium to be able to be conductive, this is [going to] electrospray technique. And at the top of that -- on the top of that we have breathable over-adhesive in order to hold the patch onto skin all day long. And with this over-adhesive, you are able to have a shower, you have to -- even to swim and it's very useful for the patch. Here you can see (inaudible) here you can see the condensation chamber just here.

 Let move to the electrospray technique. You see electrospray technique is the technique we have developed to fill the patch with proteins. Medically what is electrospray? This is a machine to produce droplets, but these droplets are very small and they are electrically charged. For that you need a pump to have the regulated flow and in constant flow. You need a nozzle, a capillary nozzle and the flow go through the nozzle, you need the ground. In our case this the patch, this is the backing of the patch. And you need high voltage. And when you wire the nozzle to the high voltage, you create [this spray] that we call electrospray.

 How electrospray works? First of all, we start without electrical field, without electricity. We have only a nozzle and a regular flow of liquid. And this is like a dripping [depth]. You got droplets falling down each after the other.

 What is the equilibrium, the mechanical equilibrium of the water? There is this (inaudible) [many course] excuse me, at the tip of the nozzle. Gravity is pulling the water down. And the surface tension holds the water together [will then share constraints]. So surface tension is a pressure that holds the water together [in order to have] this meniscus and you got drops. But this drops are not [macrometric], they are [milimetric]. This is quite large drops.

 When you wire the nozzle to the electrical, to the -- to the high voltage, you create between the meniscus and the patch around an electrical field. This electrical field split the electrical charges into the liquid between the positive charges and negative charges. And the negative charges accumulate on the surface of the meniscus. And the electrostatic pressure created by this positive charges [come to] surface tension so we can get this clinical shape of the meniscus. And at the tip of the meniscus, the electrical field pull the positive charges, create a jet and after at the tip of the jet, it splits in a very tiny droplets which are macrometrics.

 So at the end, we have macrometric droplets and we have also an effect of evaporation very effective because the surface of the droplets are very high regarding the size of the droplets [and the vaporization] is very rapid. So (inaudible) we have electrically charge droplets so that we can direct the droplets directly into the patch.

 Now, you can see the [electrospray projection] this is the [little movies] where we can see again this projection [that] given to you. The dripping mode, large droplets, then the high voltage with the electrical [film] from the meniscus to the [round] and the creation of the electrospray.

 There is a little animation to show how the droplets are formed by the electrical field. You can see the meniscus, the clinical meniscus the jet and the split and the formation of the droplets. And this is a picture showing how the droplets are formed from the -- from the jet. We call that "The cone jet mode" cone jet mode.

 This picture another thing, we can act on the size of the [biometer] of the deposits that we make onto the patch. Thank you. So you we can -- you can see that with electrospray we can have [a numerous] deposits because we can direct the droplets directly onto the patch and be sure that the deposit is very homogeneous. We can have adjustable mass deposited into the patch because we can regulate the flow and have exactly the flow we want. We can have [electro steps adjustable] size of the deposit because of the electrostatic lens that we have [just under the movie], we have an instant drying of the liquid making a dry deposit on the patch. And we have a high soluble deposit as well because the droplets which arise on the patch forms like a [granular] deposit and the water is able to dissolve the deposits very easily.

 Next, it doesn't work. Yes. Both the technology of the patch itself of the Viaskin and the electrospray are patented. Let's move now to the manufacturing tools of the DBV Technology and from the Viaskin. One advantages I have talk about is the scalability of the electrospray. You see that we can have a nozzle making a deposit, the dry deposit on the patch. But we can have several nozzles working together to increase the [throughput] of our machine.

 Please, yes. We started at the beginning with one nozzle. This is the nozzle in which we have developed electrospray. After we move to 10 nozzles working together, then 18 now that are working together. And this is the spray head, the first machine we have developed, [again, 3.1] machine that we have in the [South of France] and to which -- with which we manufacture the clinical batches. And we are now moving to 54 nozzles. And this is one module, there will be nine of them to form a head, the spray head of 54 nozzles.

 Here [a movie] about this GEN 3.1 machine. Please. You can see the chamber with the deposit on it. This is the dry coating, the dry layer. The control of the machine, the spray head. Nozzles working together, the ring which acts like electricity [clans], the control of the current and the [whirl] machine working. This is [the front]. This machine works in a clean chamber in a pharmaceutical laboratory who manufactures the patches for DBV.

 We are now building GEN 3.2 machines. This machine will be dedicated to the phase III clinical trial. And we will be manufacture large batches for this clinical trial. It's -- the machine is in construction and it will be ready to use in September 2014. You can see the machine in construction.

 And this is the prototype for the GEN 4 machine. Then GEN 4 machine will be the commercial manufacturing machine. It's not the GEN 4 machine but it's only a prototype to test the principles of new technology we are going to use in this machine. You can see that we have some components to guide [this trip and the liner and the backing -- the backing]. And here there is a box with the control for controlling the batches. And this machine has to be ready on -- at the end of 2015 in order to manufacture the clinical trial batches.

 Yes, okay. So we are now on the -- we are obviously now on the -- in the industrial stage of the development of the tools. The GEN 4 machine will constructed and the -- with some specific principle with the in-house techniques [with are the] modular components. And we will build an industrial platform in order to manufacture each machine we will need for our manufacturing for our clinical trial and for the commercial batches.

 Thank you very much.

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Unidentified Company Representative   [17]
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 Thank you, Bertrand Dupont, for this presentation. My name is Charles Ruban, I am the Chief Development Officer of the company. I joined the company two years ago, and I have the great pleasure, the great honor to actually be -- to lead all development aspect of the company, meaning, CMC, clinical development, regulatory affairs and so on, with an exceptional team. I'd like to say that we are very [fortunate] company on our development, and that we try to make it real for the patient, all the [denies] innovation that there has been developed in the last decade by DBV.

 I think I will first start my talk by talking about the -- our portfolio, our program portfolio. I think it's important that you understand that we are very focused company. We are actually concentrate 95% of our energy on three key program that actually address high unmet medical need in [RRG], the first of which are of course peanut. We [will be] talking a lot of peanut in this session, but also milk which has been very nicely presented by Jonathan Spergel.

 We have a third program which is also the house dust mites in ours dust mite just two words about that and I will not be talking anymore about this program. It's moving forward pretty. We end -- we are at the outside, the non-clinical stages. And it's important to say that we are really targeting very young children as Pierre said in order to prevent of onset of asthma in patient who are -- who are highly sensitive to house dust mite and who have a chance to develop asthma.

 Coming back on peanut and milk, it's important to say that peanut is the most advance program. We are at some months to have the key clinical results of the vipes study. We are eager to have this -- those data. And we look forward to moving forward into phase III, in registration process after that. Milk is the same, we are pushing very, very hard to actually have these dose for patient in the clinical trial. And it's really a true motivation for all the development teams to move -- to move ahead.

 Coming back on the peanut development program, it's important to understand that we are fully driving this development program. It's a fully [flexible] from coming from the phase I, phase II and phase III for which we have the resources and the capabilities to conduct every clinical step and also to perform the registration of the program.

 It is the biggest clinical development ever conducted in peanut [energy]. It is a very optimized clinical development because [if trend continues to], meaning it addresses those population, European and US population and North American population. And it also fits -- we make it fit the regulatory -- the regulatory requirements in both the US and in Europe as you would see [we will talk later] on.

 Together with that development plan, we have very, very good and very fruitful academic collaboration. We talked a little bit about [the outside] previous -- previously which [is a trial that] has been conducted by the French hospitals group which is the [Hospital Public of the Pari] and Christophe Dupont is -- has been the principal investigator of that trial which actually demonstrates the efficacy of the product in a -- in the children population, it's a very promising data.

 On the top of that, we have a very fruitful collaboration with the COFAR, the COFAR, the consortium from food, energy research which is a group of center of expertise I would say in food around here in the US. We have a program named COFAR 6 which is handed by [Hue Samson at] Mount Sinai, which actually studies Viaskin Peanut in two dosage against placebo. The clinical trial is ongoing [through completing] right now. There are a lot of patient wanting to be involved in the trial. And really this collaboration will help us better understand the mechanism of action of the product as well as defining additional biomarkers.

 This is a chart showing you how many [patient years] will have at the time of filing. We believe that we'll have more than 1,000 to 1,500 patient years including in our data set that will actually document the efficacy and the safety of the product. At this time, again, it's the biggest clinical development ever conducted in peanut allergy.

 We are studying every single -- every patient population. Those patients no matter what their age, if they are severe or highly synthesized patient I would say suffering from peanut allergy are eligible to the treatment and that's why we actually include them upfront in our clinical development.

 So we do not do that sequentially, we do not start at the adult, then the children since the children unmet need is so high, we actually include children upfront in our clinical trial. It's important to see [and use] that in each and every efficacy study that we will be conducting, we will actually stratified the population in our phase II and phase III. You see the importance of the children below 12 years old, the unmet need is really obvious.

 Jumping into milk, so the milk I'm really happy that Jonathan Spergel had the time, the opportunity to present to you the milk opportunity, because the milk as such is a platform. The Viaskin Milk product of course our first objective is to de-synthesize the patient, help them better tolerate the milk and possible to reintroduce the milk in their diet. That's the first offers objective. You have understood that there is an additional indication for Eosinophilic Esophagitis that is conducted through an investigator-sponsored trial by Jonathan about to start. And I hope it will be this year Jonathan. We're doing what we can to do that.

 And finally, as milk is the first energy in life, this product has the potential to actually influence the allergic march because you know that [dose food] allergic patient actually have multiple energy. So I mean, acting on the first energen, it may drive and change the course of the energy status later in the years. And we have some ideas about [but give up in case].

 And we have the same for the milk, we have the capabilities and the skills actually to conduct the full clinical development it will be a clinical development that is fully held by DBV. We are about to start this phase I and II, Jonathan had actually provided the -- I'm sorry, the design ways. And after that we'll be able to jump in phase III. We have very positive actions (inaudible) on this trial. And we are really about to start.

 A few words to say that of course 95% of our efforts are concentrated on the industry programs, but the 5% of the rest actually do explore the versatility of the platform. I think it's really important to understand how many application we can actually treat with this product. And in some allergic or non-allergic disease [in clinical disease] in vaccines, so let's -- and for example [I like] just to insist on the very advanced [purchases] boost vaccine program we are in together with the University of Geneve. [We have approve of] concept in human that is about we hope to start in couple of months or end of this year or early next year.

 We have a program with Stallergenes, which actually came to us, asking us actually to develop a Viaskin program with the recombinant protein of the major allergen of the [breast] which is [all but we want]. So we are developing this program together with the Stallergenes teams. And of course I'd like to emphasize the very fruitful collaboration we have with the Mount Sinai on the crohn's disease.

 Every single application of Viaskin is patented. So every time we really try hard to protect all those innovation and every single application of Viaskin is patented. So this was it for this -- for the program portfolio. I think you have a better overview of this.

 Now, for the rest of the talk we'll be focusing especially on peanut really. And I [reading that we have] the -- I will have the pleasure to do that together with Wence and Laurent. Of course I will be -- I'll be explaining to you what is the [fair particular value] of peanut.

 I think it's really important to really understand what Viaskin Peanut provide as a value to the patient. What are the specifics of that? And then we'll have Wence explaining you how we have design [in the clinical] development and as well we have design the CMC and regulatory pathway with the Laurent.

 So Viaskin Peanut value proposition, it really has some specifics. So you understand [what we are] talking about, a very severe allergy, the life threatening allergy and the high unmet need. What are the specifics of that? The first specific is that actually it base it's specificity on a unique mechanism of action. So this key you're seeing here as the gateway to the immune system and as such it has unique proprietary to actually activate this immunological cascade, are the one that matters for the patients.

 And here in our development, we are really trying to make it clear cut, easy simple for the patients so that it's a treatment that will be -- that will actually be real and treat -- that will treat a lot of patients.

 Of course, what are the patient expectations? First is to lower the risk of life -threatening anaphylactic reaction, that's their first expectation. Second, as Franklin Atkinson said earlier, is to guarantee the sustained and tolerogenic effect. So once you've taken the patient out of the zone of risk you have to guarantee that this patient actually has maintained its level of desensitization.

 Third part but very, very important, this product is non-invasive. So it's really easy to treat, you can see -- I mean some of compliance, it's really an exceptional product because the parents can see on the back of their children that the children who actually put the patch did not enter a vial in the sink, they do not hide the peanut under the mattress, they don't do that.

 It's really safe; so safety is really key in that kind of therapy, it actually enables and eventually provide you with some very good compliance rates about -- and drop out -- and every interesting drop our rates in the trial. This is actually due to the high safety and non-invasiveness of the product.

 And finally, it is adapted to every kind of population. And here we are talking a lot about treating adults, adolescent, but also very young patient and really this promise to conform, really has this distinct advantage to be able to treat patient as young as four, three, two years old; we hear with it which is out of reach of any allergen (inaudible) anyhow. It is the first in class treatment, it would be registered as a pharmaceutical drug in the US and in Europe.

 So if we put ourselves in the shoes of the peanut allergic patients, I think Jonathan --I think you mentioned -- it was very good, to stay well. We have looked everywhere and that's almost the same, we have looked everywhere and for those patient it's really actually the avoidance strategy are very, very complex, very -- they know that they are allergic to peanut but they are able to really avoid peanuts and they are only, I would say tools to do that is their own awareness about avoidance and in the proper management of the peanut frame. That's the only two they have.

 If you ask those patients or if you ask patient association about that to -- if you ask them, so what does a cure mean for you? They would not say my (inaudible) is to eat the peanuts, that's not their purpose. Here the (inaudible) for this patient is to actually -- to be out of the danger zone and the danger zone they are in right now, the life-threatening zone is the one for which the victim not control any element of the environment. So taking thus patient to a level of where for instance we -- the traces of peanut in the food will be actually tolerated by the patient, it's a very clinical element for [code raise] for this patient.

 Again, these patients they don't want to eat 20 peanuts, that's not their purpose, they just want to be taken off the life-threatening zone of the food allergy. And that's how we see, a clear thing, we believe that some patient will actually progressively de-risk their own profile and you'll be able to move from strict avoidance to controlled avoidance, we know that they would be able to reintroduce a may contain products for instance and for this patient we're also able to move a step forward, they would be able to reintroduce if they wish the peanut in their diet.

 But the question is how to de-risk or reduce the risk of anaphylaxis for this patient? And this is basically reflected in the way we construct the design of our clinical trial and you see that it's a long treatment, it lasts three years but it's a soft effect on the immune system.

 We basically have to -- the idea of this treatment is actually to take patient who are basically in the red zone and to drive them to up to a zone where their level of risk is significantly lower, we do actually recognize the fact that the patient will be a good entry.

 We will have as a topline, it shows you here, we have a very good responders up front. I mean, after one year, we do have some page turn who will actually be able to already tolerate 1000 milligram. 100 milligram is four peanut, it's really significant and for those patient, I start the example how we -- after three year, it will pass the challenge. They will not be reactive to peanut anymore.

 There will be other patient for which I may need to progress after the first year will be a 10 X in identification by 10 of the initial dose it was reacting to a baseline which is a significant progress and which also shows that it's on the right way to be further desensitized.

 So this patient is also a responder and we will also have patient who will (Audio Gap) we ruled out and our challenge today is actually to identify the means and then two, to actually select those patients very early in the treatment and I don't know if you have the opportunity to look into the actual data, we already have some good candidates that actually help us predict the patient who will actually respond to the treatment and the patient who will not respond to the treatment. It's important for the patients, it is important for the regulators, it is important for the payers.

 So, a second point I want to you to raise your attention about is that not all the patient are equal versus a peanut allergy. Some of them are very, very allergic; what I'm saying very allergic that is to say they react to very, very tiny dose of peanut allergen.

 They are the one on the left side of this curve which is actually very well long enough years, basically it means that there were 10 milligrams of peanut butter, you have somewhat 10% of the patient who are reacting to that dose. Those patient are the lowest at risk patient, those patient cannot tolerate traces at all and they came to anaphylactic shock at any point in time rather than come through traces of peanut.

 100 milligrams, those patients are a bit less at risk but still in the red zone and the actually basically represent 50% of the patient. At 1000 milligram, they are 90% of the patient that are responding to a -- 905 of the patient are actually having a dose that is lower or equal to 100 milligram.

 So the more you're going to left on this graph, the more at risk you are; the more you're going to the right of this graph, the less at risk you are. And the value of our treatment today is to actually shift this curve to the right. After one year and after three years, to actually have a significant chunk of the population we are treating the de-risk up to the right of the treatment -- of this scheme.

 It's taken key feature of the program and I think we have some very good presentation this morning by Lucie especially and also as recalled by Christophe about the capability of the treatment to maintain its efficacy while off-treatment.

 That's the very, very important point and that is the differentiated feature. It's of course -- this experiment is included when I think of the bottom plan, you will that with Wence later on but it's really important to actually have provide a patient with a guarantee that his level of desensitization will be actually maintained.

 Nobody want this patient -- has been very responder to our treatment or if he only actually crossed the 100 milligram, I mean this patient is desensitized but what is important is that he maintains his level of de-risking.

 Finally, I will -- my last words and just to summarize what I've been talking about, it's the -- everything is summarized in the target product profile. I think it is important to understand first that we using a modality of the treatment are very, very simple. It's one patch, one dose, every day, you remove the patch; it's a three year treatment duration. It's simple, it's (inaudible) under the adult supervision.

 The target population is of course, children, adult and adolescent patient who are highly sensitive to peanuts. At launch the indication will have the prevention of anaphylactic risk occurrence in these categories of patients and one we'll be able to document further the clinical effect of the product and especially with a sustaining responsiveness I was talking about will have this disease modifying treatment indication that will be attached to the product.

 We do actually conduct an extensive research on biomarker to help us select and monitor the efficacy and sustainability of the treatment. It will be of course part of the labeling of the new product.

 So, this is what -- the end of my talk, I'll be handing it over to Wence of the Clinical Development and then Laurent for the regulatory and CMC. Wence, you're first.

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 Wence Agbotounou,  DBV Technologies - Director - Clinical Trials   [18]
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 Thank you, Charles. My name is Wence Agbotounou, I'm the Chief Clinical Trial Officer at DBV Technology and I am leading all the clinical trials at DBV Technology for six year now and it's my pleasure to honor to guide you through the Viaskin Peanut Clinical Trials, those that we have conducted, that we are preparing now. Also from the Phase III up to the registration.

 These clinical program has been designed to obtain registration in North America and European. We started with the Phase 1 study four years ago entirely conducted in the US where we have been able to show that it was safe to apply the Viaskin peanut up to the dose of 500 micrograms on the scheme of patient highly sensitive to peanut.

 We also even showed that for our subject who have shown severe reaction to peanut in the past, we could apply the patch on their skin safely. After the success of the Phase 1 study we have been able to conduct or construct the Phase IIB study which is currently ongoing, it is called the VIPES study. This study is a one-year treatment study where we want to show the efficacy of Viaskin Peanut in peanut allergy subject. This study is conducted in North America, so US, Canada and also in Europe and at the end of this one year treatment in the VIPES study, our goal is to move to a Phase III study where the subject will again be treated for one year and at the end of that one year treatment in the Phase III we will be able to apply for registration for Viaskin in the US, Canada obviously and also in Europe.

 However, the program is also constructed to treat the subject for longer period of time and also to study the sustained effect and that will be done for -- it's actually currently being done for the subject that have completed the VIPES study, who have already started the follow up study which we call OLFUS-VIPES, that stands for Open Label Follow Up Study and we'll be doing the same for the subject in the Phase III study.

 So let's get a little bit into details about the VIPES and OLFUS-VIPES study design. This VIPES study is very unique and is the largest study ever conducted in peanut allergy subject worldwide. We constructed this Phase IIB study with a very important goal in our mind which is to move to a Phase III study at the end of it.

 This is a true growth finding study controlled by placebo, we have three doses of Viaskin Peanut, 50micrograms, 100 micrograms and 250 micrograms of peanut proteins. We have randomized 221 subjects, the goal was to randomize 220 so we are above expectations and we've randomized both pediatric and adult population.

 The subject are treated for one year and we have a second challenge after one year of treatment and then at the end the on year treatment we have built the OLFUS-VIPES study so that the subject that are willing to continue its treatment for an additional two years are offered that opportunity. And they are treated at the highest dose of 250 micrograms at the moment which has been shown during the first year of treatment to be safe for all patient population.

 So the efficacy, how do we analyze or measure that efficacy, we basically used the double-blind placebo controlled food challenge and to ensure that we have solid results we have built these procedure to be as solid as a possible and as robust as possible.

 So we are -- we have used standardized metrics that we have sent to all sides of all subject, the 221 are being controlled with this challenge which is standardized. We are using best practices for conducting this food challenge and we are using the PRACTALL practices that are published by the [QOL] among which Officer Hugh Samson.

 The way for grading the reactions during the food challenge is also made as using a standardized published protocol, so each side will be grading the same reaction, the same way and again, one of the challenge to be stopped only on the -- when an objective symptom has appeared.

 An objective symptom is a symptom that a physician can evaluate which is different from subjective symptom that the patient feels but that the physician cannot evaluate. So Gordon has spoken about these challenges that he has been -- that's used and he's using actually currently at his site. And we have a 3 milligrams pretty rapid way of increasing the dose in this challenge moving from 1 milligram to3 milligrams, 10 milligrams, 30 milligrams, 100 milligrams and 300 milligrams at entry. So it's a similarly gradually increased and this help us better catch the sensitivity of the subject and we use this grading system for grading the reactions.

 So what is -- what are the patient population that we have in the VIPES study and the criterion success that we are using and the size of it. In terms of study population, Charles already explained that we are covering all the ranges of patient population starting from the children to the adolescent and adults.

 And again, this makes the VIPES study unique indeed, then these studies are conducted either studying adults or children and we are able to study the whole range of patient age in the VIPES study.

 Obviously we are interested in peanut allergy subject, we were interested in those that are actually highly sensitive so they have to show a certain level of IgE specific to peanut, they have to have a positive Skin-Prick test and most importantly their reactive dose was cut to 200 milligram peanut protein at entry; in other words, they have to react to lower dose of peanut protein to be in the study. And if they have not reacted at that dose of 200 milligram which is the highest dose during the challenge, then they are screen-failed.

 The primary efficacy endpoint, we wanted the subject to jump the gap from reacting to below 300 milligram protein to reacting only at 1000 or above; so it's an important gap for them to jump. Or to have a 10 X as compared to their initial level in the -- during their initial challenge after 12 months of treatment. And this was obviously discussed and agreed with the FDA and also some European authorities where the study is conducted.

 To calculate the sample size, we just took the 30% absolute difference response rate in a treated group versus placebo and we have estimated 10% response rate in the placebo group so we did it 40% as a minimum, the response rate in the active groups.

 The risk was chosen to be 5% and we powered -- we have a high power in this study at 90% to show any statistical significant difference. The sample size calculated with this barometer gave 47 subject and taking to consideration that we could have up to 15% drop out rate, the actual sample size of 55 subjects.

 So we follow to this study in five countries, 22 sites in total and the enrollment was pretty satisfactory. In total we screened 315 subjects of those 94 have screen failed and it's getting -- the screen failures are those subject as I said that were not sensitive enough to be in our study, either they have IgE level that were lower than our threshold of 0.7 kU/L or their skin -prick test didn't give a read of 18 (inaudible) or they screen-failed the challenge which means for that they have not reacted even to the 300 milligram dose at entry.

 We finally randomized 221 subject, of those half were children and it was actually easier and quick and fast to recruit the 113 children than the other patient population. So the child population is really -- and their parents are very willing to doing the studies. We had -- in the second half, two-third, adolescent and one-third of adults. And as Gordon explained previously subject and their families were very, very motivated to be in the VIPES study.

 So that is shape of the baseline peanut sensitivity of the patients, so the subject were given the doses of 1 milligram, 3 milligrams, 10 milligrams, 30 milligrams, 100 milligrams and 300 milligrams and we have the number of subject that have reacted to each of these dose. And so the median reactive dose was 100 milligram peanut protein and this graph is pretty consistent with the sensitive peanut allergic subjects.

 Where are we now in the VIPES study, out of the 221 subject randomized, 149 have now completed the study as of yesterday, probably we have 150; 60 subject are still under treatment as of yesterday and all those 60 subject have already passed 10 months of treatment. So they have less than two months to go and we know that the last subject is expected in VIPES for the 9th of July approximately. The subject can change their dates but it's on the 9th of July.

 And what was really amazing that I would like to draw your attention on is the low dropout rate that we have in this study. As of yesterday, we have 12 subject that have dropped from the study, we have forecasted 32 by the end of the year, of the study. So this is also very good point that we have noticed in this study.

 So the subject are truly motivated to be on the study as shown by this low dropout rates. We forgot to mention the compliance on this slide but the compliance is also very high and Gordon already spoke about almost 100% compliance in his 24 subjects. Just to mention that in the 231 subject, we have the 24 subject that Gordon has spoken about earlier today.

 So VIPES really is about [true to end] and we are currently working hard to have the results available in October and we have put in place some action plan knowing that the last subject is completed in the study on the 9th of July, we have several steps to clean the database and make the results available and reviewed by the Data and Safety Monitoring Board on VIPES. So that would take approximately two and a half months to have the result available. So their results for a few more months to get the result in October this year and then we would be able to have the final study report in Q1 2015.

 Some safety information on the VIPES study, so far there have been 15 serious adverse events in the VIPES study and none of them were related to this study drug actually. The majority -- 11 of them were -- occurred during the challenges, either the challenges that we cut up at entry in the study or the challenges that have taken place after 12 months of treatment and I already said that we have 149 who have passed this challenge.

 There were a few SAEs for subject who consume peanut accidentally and ended up in the emergency department. There are 12 subjects who have dropped prematurely, two of them have dropped because of adverse event related to the study drug and the high majority of them actually withdrew their consent.

 Very important and safety wise, we have three Data and Safety Monitoring Board that have taken place throughout the VIPES study life, all of them have concluded that there were no safety concerns. The last meeting took place in 24th of February this year and all the subject were randomized at that time and all of them had at least received six months of treatment and still there was no safety concerns. So Viaskin Peanut shows a very satisfactory safety profile in highly peanut sensitive subjects.

 When you apply the patch on the skin, there will be local reactions and that is expected, 90% of the subject in the study have reported at least one local reaction and all of the 70,000 doses that have been applied as of now, we know that 40% of those doses did not trigger any local reactions. Another 40% have triggered mild reactions, 16% have triggered moderate reactions and we have four doses that have triggered severe reactions.

 The local severe reactions are generated pruritus, when you applied the patch, that will generate a pruritus that can be heavy in a few cases and -- however, because you have applied a patch when you -- when those subject experiences severe local reactions the recommendation is to remove the patch.

 You remove the patch, you remove the allergen. It is also something that is far from the other immunotherapy when you have OIT or sublingual for instance, if you have a local reaction then you have to deal with that local reaction. With the patch you have local reaction that is severe, you remove the patch and you remove the allergen and you stop the reaction.

 You can also adjust the daily application of the patch so the patch is to be applied for 24 hours, you can reduce that application for a certain duration during the treatment so that the subject gets used to applying the patch for longer period of time over time and after certain duration of treatment you can apply the patch and keep it for a longer period of time.

 The local reactions can be treated with topical corticosteroid or antihistamines if necessary and these -- even for those subject with sever local reaction, that did not systematically conclude or result in patient withdrawing because we have had only two subject who withdrew because of local reactions.

 We spoke about the OLFUS-VIPES study which is the follow up study of the VIPES. So we are offering an additional 24 months of treatment to the subject who have completed the VIPES study and the subject are being treated at 250 microgram the highest dose.

 We have been very surprised by the high rollover rate that's probably definite, from subject completing the VIPES study and moving into the OLFUS -VIPES study. We have up to 86% of them rolling over into OLFUS-VIPES study. So out of the 149 who completed the VIPES study, we have 128 currently in the OLFUS-VIPES study and that actually is pretty much consistent with the side of Dr. Gordon Sussman with 22 subjects who rolled over out of 24 and this is very high.

 In terms of timelines, we are expecting the last subject to enroll into OLFUS-VIPES when he completes VIPES so that will be in July 2014. We will analyze -- e conduct a challenge every year in the OLFUS-VIPES study so we will be able to analyze the data and gather data out of -- for subjects who have been treated for two years and then we will have the final result in Q4 2016 and yes, what is really amazing is the strong patient motivation who even after one year of treatment in VIPES, wants to continue and I can say that I am receiving constant phone calls or emails from sites that want their subject to roll over into OLFUS-VIPES when they should not actually qualify for OLFUS-VIPES, so the demand is very high from subject and parents.

 So, we believe we will have successful VIPES study that will allow us to move through the phase III, the pivotal phase III confirmatory study. Its design may be very close to the VIPES study design with the difference that there will be the placebo group versus just one dose of Viaskin Peanut which will be the optimal dose from the VIPES study.

 The subject will be treated for one year and we will analyze the data after one year and register after that. And again, for the phase III, the subject will be offered an additional two years of treatment and at the end of the three years of treatment if you combine, and I forgot to mention that in the OLFUS-VIPES study. At the end of the OLFUS-VIPES study, after the additional two years of treatment, we will be studying the sustained unresponsiveness, i.e. those subject that were desensitized up to a certain point after three years of treatment when they are taken off of treatment they're maintaining their unresponsiveness that will be also studied in the OLFUS-VIPES study and I forgot to mention that previously. Sorry for that. And we will be doing that for the Phase II subjects as well.

 In the phase III study, we are contemplating studying at two years of age for the subject, so we are really willing to treat subjects as early as possible if they are allergic to peanut. The sample size is 300 patients at the moment and the primary endpoint will be similar to VIPES.

 In conclusion about the clinical development of Viaskin Peanut, I would like to stress that this is a sound and consistent clinical development program with studies well powered allowing us to move to one step to the other normally and especially for the VIPES study, the results that we are expecting should allow us to move to a pivotal phase III study very soon.

 And that concludes my thoughts of today and I will hand it over to my colleague Laurent Martin to speak about the CMC and regulatory pathway.

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 Laurent Martin,  DBV Technologies - Director - Regulatory Affairs   [19]
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 So, thank you, Wence. I am Laurent Martin. I am leading the regulatory group at DBV for the last six years. I'm very pleased to lead that group because we have very exciting programs.

 So, first of all, I would like to start discussing the CMC strategy for Viaskin Peanut. So, what we want to ensure is to be able to keep all important aspects of the API for the active ingredient and final product under our control and that's the key point.

 So, we have internalized all process development, process optimization activities as well as test method development and test method optimization. But of course, at this stage of development, we want to continue outsource the GMP activity to well known and first class CMOs, to ensure both flexibility and use of limited investment in manufacturing infrastructure. But of course, we keep strong supervision of those CMO.

 When we file and obtain the BLA, we will secure the supply chain of Viaskin Peanut and we will, of course, proceed to dual sourcing of the API and the final product and we will consider also internalizing part of the manufacturing of control activities.

 So, as of today, what are our GMP partnership? So, with regard to the raw peanut or the peanut that we use to produce our patch, so we have a supply agreement with US producer of peanut. We are very focused on high quality of peanut with food [possibility] and we are very happy with this supplier and we will keep this supplier to the registration of the product.

 Then, when you have the raw peanut, you need to process this raw peanut first in a source material, i.e. defatted peanut flour and then from this peanut flour you extract the peanut protein which is the active ingredient and both processes, for the source material process and the active ingredient process are performed currently by SANOFI in a French site which is already approved by FDA and a successful quality track record. We will keep this agreement with SANOFI up to the registration of the product.

 For the final product, we currently have our equipment, our Electrospray equipment that was discussed by Bertrand located in clinical CMO. This clinical CMO is suitable to produce all clinical treatment for our program but of course, for the commercialization of Viaskin Peanut, we will need to get commercial CMO able to handle FDA inspection and we have already started the process to selecting this commercial CMO.

 So, we have a clear picture of the main activity for the CMC activity up to the filing of the BLA in the next two, three years. So, for the active ingredient supplier as well as for the final product supplier, we will have a key milestone which are the process optimization, the process validation and then move on to the pre-approval inspection on due time at the time of the BLA filing.

 Now, I would like to discuss more in detail the regulatory pathway for Viaskin Peanut. So, first of all I want to make clear that we have a combination product made of an innovative delivery system of Viaskin patch and biological product which is the allergen peanut protein extract. So, this product will be regulated in the US by FDA, and CBER or so it is considered as a drug, medicinal product in Europe.

 So, globally, we want to have a global development for this first-in-class drug. With clinical trial conducted everywhere through North America and Europe but with clear focus on US, our key market for Viaskin Peanut. And so, priority is given to constructive and positive interaction with FDA. And we try our best to fulfill their expectation in terms of CMC development, non-clinical development and clinical development.

 As an example of positive interaction that we have with FDA so we have, for instance, a successful end-of-phase I meeting before starting the phase II trial and of course, end-of-phase I meeting are not granted to every company so we were happy to have a face-to-face meeting with FDA to discuss the phase II clinical program and we extensively discuss this clinical protocol, the endpoints, the primary and secondary endpoint. We discussed the size of the study as well as the statistical assumptions.

 So, based on these positive interaction, we really can now shape the phase III clinical trial based on the strong development rationale and that's key for us. We have also key interaction with European Medicines Agency for the pediatric investigation of plant and also we have French and other agency with no major issue raised so far on the development of our product.

 And as part of the recognition of the Viaskin Peanut program, I would like to mention that DBV has been invited by FDA and the Paul-Ehrlich Institut, the leading European agency for the evaluation of allergen. So, DBV has been invited by both agency to discuss the Viaskin Peanut program during the next Paul-Ehrlich seminar which will take place in October this year. And this seminar is very important, it takes place only every three years and it is a regulatory forum where regulators meet industry and all the key stakeholder and discuss in details all scientific and regulatory aspect of allergen immunotherapy. So, we are very happy to be part of this meeting this year invited by FDA and Paul-Ehrlich Institut.

 Then, for the US approach of further registration of the Viaskin Peanut, I would like to stress that we will use all tools available to DBV to expedite development and registration of this first-in-class product which will address important unmet medical need.

 So, of course, before conducting the phase II clinical trial, we have request a Fast Track status that we obtained quite easily because of this unmet medical need and being granted Fast Track, we will be able to envision, anticipate holding solution for this dossier and we will plan to submit first the CMC and then clinical section of the BLA.

 Then, so in October of this year, we will get the result of the VIPES study and when we will get this result, we will evaluate the opportunity to ask breakthrough therapy with FDA so we'll contemplate that at the time of that result. We will also have a very important meeting, the end-of-phase II meeting next year when we will get the final report of VIPES study and of course during this end-of-phase II meeting, we will discuss in details the phase III program but we intend to conduct this phase III program under SPA. And I think that the division people we talked at FDA are very willing to help us to get an SPA and so if we get it, we think that it will be of course as you know, increase the likelihood of positive BLA filing at the end.

 Finally, at the time of BLA filing, we will ask for priority review to speed up the review process of the BLA for Viaskin Peanut.

 Finally, I want to discuss the EU regulatory approach. So, the EU is second priority for the DBV and we think that the US registration of Viaskin Peanut will pave the way for a successful European registration and we will submit the registration file in Europe when the phase III trial will be completed. We will go centrally in Europe, meaning that we will submit the dossier to the European Medicines Agency directly and not to the authority of each member state in Europe. So, we will file centrally and the evaluation of the Viaskin Peanut dossier by EMA should lead to a quick approval within nine to 12 months and access to all EU member states at the same time because it's a European marketing authorization that we will get at the end.

 So, thank you very much for your attention and I will leave the floor to Susanna.



==============================
Questions and Answers
------------------------------
 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [1]
------------------------------
 Thank you, thank you, guys and I hope everybody, that was helpful. We are going to open it up for Q&A, so do we have a first question on the floor? Question over here. Thank you, thank you.

------------------------------
Unidentified Audience Member   [2]
------------------------------
 Yes, a couple of questions from my side. First one, maybe on the dose selection. Could you elaborate, maybe, on the dosage on the VIPES study and the underlying question is whether you think we can see a plateau in terms of the efficacy for the doses. So, one question on the rest of the pipeline outside the core project, could you, maybe, share with us which are the most enthusiastic projects in your view, maybe, pick two projects on the outside of the core project and last one, I know it's a little bit early, but you could you share with us your thoughts and your mindset currently regarding potential commercialization and what other strategic option that you are looking at right now. Thank you.

------------------------------
 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [3]
------------------------------
 Wence, you want to start with the first part and then Charles, you follow?

------------------------------
 Wence Agbotounou,  DBV Technologies - Director - Clinical Trials   [4]
------------------------------
 It is very difficult to anticipate how the three doses will respond, the 50 micrograms and 250 micrograms in VIPES. I wouldn't like to make any assumptions here. Hopefully, we will have a dose-finding effect, that's what we are expecting and the results will tell us what's the truth so I'm afraid I will invite you to bear with us up to October. We are all very eager to know about the results but I won't make any assumptions on what we are expecting at the moment.

------------------------------
 Charles Ruban,  DBV Technologies - Chief Development Officer   [5]
------------------------------
 Maybe, another comment on your point, first on the dose selection, how did we, maybe to your question, how did we select the 50 microgram, 100 microgram, 250 microgram in the VIPES. Sorry, that's the jet lag, maybe. I think it's important that this comes out of a process of selection that comes from phase I, okay? So, actually, what we've been doing is really in line with what regulators are expecting. We are actually targeting the dose, the highest dose possible and we even know that the 500 dose that was not tested in VIPES could even be tested later on in the population and especially in adults. It is important to state that we wanted to combine both population in the single trial to really expedite the development that actually -- we had to make choices and that's how those doses were selected.

 In my previous time, I worked for Stallergenes and we know and there has been a lot of development on allergen immunotherapy trial and the dose effect exists. You're right. I mean, there might be a plateau to which the -- where, I mean, I think an additional dose would not give any gain. So far, we'll see what the VIPES results. I think it's obvious it will also be driven by the safety profiler product. So far the safety profiler product is really excellent. So I don't know if the 250 microgram is as good as 100 microgram. I mean, we'll choose, basically, the optimal dose. That's the idea.

 Your second question was --

------------------------------
 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [6]
------------------------------
 On fiber core.

------------------------------
 Charles Ruban,  DBV Technologies - Chief Development Officer   [7]
------------------------------
 Outside the quorum, maybe you want to take that question, [Kelly]? Two interesting projects. I think they are listed; several ones in the pipeline. I mean, it's very difficult to pick up the key one vaccines this is very -- the participation is very well-advanced and the collaboration with the University of Geneva is really tremendous and there is great hope on this side. On the other end, working on the Crohn's disease, it's really a very strong point. It's not as advanced as for the vaccine. But I think it's a great opportunity also.

 So I think those are the two among others. But I don't know what any other comments we can make regarding on that.

------------------------------
 Pierre-Henri Benhamou,  DBV Technologies - Chairman, CEO   [8]
------------------------------
 Just a very brief comment. This is the platform and the potential of the platform is really very large because the immune response we can induce by the vaccines is completely different than all other method of immunotherapy.

 We know that for vaccination, for example, profile it's not only the protection then and just the production of antibodies we see in any moment in vaccination, but it's also the profile of the response, which is really new and interesting. And in whooping cough, we have this project with the University of Geneva on the boost, which is a big issue. We have puritanical results, really incredible. And we think it would be a very, very nice project. We will start a clinical study at the end of the year.

 And we have also other very, very early stage project. And especially one in Crohn's disease in collaboration with Mount Sinai Hospital.

------------------------------
 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [9]
------------------------------
 Thank you. And then we're missing the commercialization question, right? Charles?

------------------------------
 Charles Ruban,  DBV Technologies - Chief Development Officer   [10]
------------------------------
 Oh, yes. So I think the first point is that we're making everything to make this product on markets. And really, everything in the current development plan aims at registering the product and taking to account every market access, features, upfront now. So we are really reflecting on that. So that's the first point.

 I think, on the commercialization, everything is really open to date. It's really, really in DBV's reach to really commercialize in this market. We're not talking about a target physician that is really numerous; we are talking about the 5,000 physicians here in the US to a very specialized physicians, and it's really in DBV's reach to get it commercialized. So we don't have any -- we are very open to that.

------------------------------
 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [11]
------------------------------
 Any other questions in the audience? I think we have a question. Oh, question right here. Yes.

------------------------------
Unidentified Audience Member   [12]
------------------------------
 Is there a potential for compassionate use post Phase II based upon the protocol that you guys designed similar to Phase III study?

------------------------------
 Wence Agbotounou,  DBV Technologies - Director - Clinical Trials   [13]
------------------------------
 Compassionate use could be contemplated, of course. We need to discuss with authorities soon in Europe and in the US. There is always pro and cons for such an approach. I give that in the path for [Offendrig], because I was involved in the Offendrig business previously. I would say that there is a potential, but we need to first focus our attention on the successful Phase III trial.

------------------------------
Unidentified Audience Member   [14]
------------------------------
 And then just one last question on submitting to EU. Can you just go over quickly again what the plan was there? To submit for approval, would you go to top countries? Maybe Sweden for --

------------------------------
 Wence Agbotounou,  DBV Technologies - Director - Clinical Trials   [15]
------------------------------
 As explained, we should go to centralized procedure in Europe. So we need one single dossier to the European Medicine Agency located in London, and when they make the evaluation of the product, and when they grant it approval, the marketing authorization will be automatically granted in all EU member states. So we will have access to all EU markets at the same time.

------------------------------
 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [16]
------------------------------
 Any questions here before we go on the phone? I think we can get the webcast question now.

------------------------------
Operator   [17]
------------------------------
 Thank you. If you would like to ask a question over the phone line, press star one on your telephone keypad. We will take our first question from Philippa Gardner from Edison. Please go ahead.

------------------------------
 Philippa Gardner,  Edison Investment - Analyst   [18]
------------------------------
 Oh, hi there. I've got a couple of questions if I could, please. Just in terms of the plans for initiating treatment once the product is approved, is there any plan to have the first patch or maybe complete patches done in the physician's office? Or will it be that the patients will just be given a prescription and off they go and just apply the patch at home?

 And then I also had a question, if possible, relating to some of the things discussed in the earlier presentations. Just about peanut allergy, what is the thinking or thought behind why patients with peanut allergy don't sort of outgrow this allergy? Why is that less common amongst peanut allergy? And then, also perhaps related to that, why is there more rebound in peanut allergy after-treatment than we perhaps see with a various peanut allergies? Thank you.

------------------------------
 Charles Ruban,  DBV Technologies - Chief Development Officer   [19]
------------------------------
 Maybe for the first question, about how this product will be prescribed. So it's a prescription product, definitely. And the safety of the treatment allow the patient to actually apply the treatment on their skin. Of course, it will be performed under an adult supervision. And one question that will be discussed is about the treatment initiation, whether the first application of the patch will be performed at the physician's office. That will be discussed with the US regulatory, I think. But, really, the treatment is meant to be applied at home and renewed by the patient every day.

------------------------------
 Laurent Martin,  DBV Technologies - Director - Regulatory Affairs   [20]
------------------------------
 Maybe I can complete how the treatment of the patch is induced or started. In the current studies, what we do is that on the first day of application, obviously the investigators are explaining to the subject how to apply the patch and will apply the patch at site, and the subject stays at site for observation for a couple of hours. And if everything is okay then the subject goes home with his patches to apply them at home. That's how we are currently doing it, and that's probably how we will be doing that after the subject is on the market.

------------------------------
 Charles Ruban,  DBV Technologies - Chief Development Officer   [21]
------------------------------
 Oh, yes. Go ahead. (Inaudible-microphone inaccessible)

------------------------------
 Gordon Sussman,  University of Toronto Clinical Immunology and Allergy - Division Head   [22]
------------------------------
 Second of your question, we were just talking, I'm not sure if anyone -- why people don't outgrow peanut allergy compared to milk allergy. I don't think we know. Anyone else?

------------------------------
 Charles Ruban,  DBV Technologies - Chief Development Officer   [23]
------------------------------
 No.

------------------------------
 Gordon Sussman,  University of Toronto Clinical Immunology and Allergy - Division Head   [24]
------------------------------
 No. I will agree, we have no idea. And more rebound from peanut -- the answer is I don't think there's more -- I'm not sure what you mean by rebound, but if you think when you stop any -- the only ones we've had so far is when you say the oral immunotherapy, when you stop it, it's sort of desensitization. So when you stop something, the patients have been only desensitized and not really tolerate it, which is I don't think it's the same thing for any allergen we see. I don't think it's more specific for peanut versus milk or egg; it's still all in immunotherapy. We see this all the time for drug allergy. We've been doing desensitization for drug allergies for decades and you see the exact same thing. So I don't think there's any more specific for peanut.

------------------------------
 Jonathan Spergel',  Children's Hospital of Philadelphia - Chief of Allergy Section   [25]
------------------------------
 True immunotherapy is immune [marginal regulatory] so you really want to change the immune system; desensitization is not. And they're completely different. Some people develop allergies later on. Some people, like -- shellfish allergy is one that's developed in adulthood more than in childhood, so it's just a natural history and people generally don't outgrow peanut allergy and they do outgrow egg and milk allergy.

------------------------------
 Franklin Atkinson,  Johns Hopkins Asthma & Allergy Center - Professor and Program Director   [26]
------------------------------
 I would just add that one reason that it may appear that patients on peanut oral immunotherapy relapse more rapidly as it is -- as we discussed earlier, peanut doesn't have -- once you're in adolescence, doesn't have a remission rate of any appreciable size and therefor -- unlike other food allergies. So that works against any apparent but not real reduction in sensitivity that might be attributable to the treatment. So that may be an artifact of the natural history of these different food allergies.

------------------------------
 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [27]
------------------------------
 I have one --oh, go ahead.

------------------------------
 Pierre-Henri Benhamou,  DBV Technologies - Chairman, CEO   [28]
------------------------------
 To say, in our point of view, DBV, we have a lot of -- of course, the treatment is new and we haven't the long follow-up on that. What we know is, first, in animal model, it seems that the tolerance we can induce is really clear and when you compare these long-term effect of EPIT's with the other methods, it's clear that we can induce some epigenetic changes and we can induce a very long-term protection.

 And this is -- I think we will explore in the future. And it will probably change the modified indication of the product because when we will be able to prove this long-term efficacy, we will have a real disease-modifier treatment. We have a lot of data making us very confident for this long-term effect of EPIT's.

------------------------------
 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [29]
------------------------------
 There's one more question.

------------------------------
Operator   [30]
------------------------------
 Thank you. There are no further question on the phone queue at this time.

------------------------------
 Susanna Mesa,  DBV Technologies - VP - Finance, US IR   [31]
------------------------------
 All right. With that, Henri, would you close everything out?

------------------------------
 Pierre-Henri Benhamou,  DBV Technologies - Chairman, CEO   [32]
------------------------------
 Okay. I would like to thank you very warmly. It was a very heavy half-day talking about DBV. I hope you will have a clear view of this wonderful project, I think. I'm very proud of all the team of DBV. I think we had a very long preparation of this meeting.

 But to do that, we were very happy to show you this image of our company. I think this is what we wanted to say -- it's a real breakthrough in the treatment and it makes possible to treat patients unable to be treated and with a very poor quality of life all their life long.

 So, really, I would like to thank you, everybody. I would like to thank you, our key opinion leaders, and to thank you to be with us today. Thank you very much. And there is some lunch outside.




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