Hello, everyone. My name is Marc Le Bozec. I'm the CEO of OSE Immunotherapeutics, which is a listed company on Paris Stock Market. We're very happy and very proud to introduce you to this webinar dedicated to one of our key assets, which is lusvertikimab, an anti-IL-7 receptor monoclonal antibody. We're very proud to have here with us Professor Laurent Peyrin-Biroulet and Dr. Maia Kayal, who will detail results that we have gathered over the years in clinical development. Maybe I will say a few words as an introduction. Our company, which has been listed since 2015, has two lead compounds. Here you have a forward-looking statement because we're a listed company. Here you will see the pipeline of the company, which is part of the pipeline. You will see our clinical assets. Lusvertikimab is clearly a lead asset for us. We have delivered positive readouts in ulcerative colitis last year, and this will be further detailed in this webinar. We're about to launch further clinical trials, in particular in pouchitis, which will be detailed by Dr. Maia Kayal. On top of that, we'll have other compounds, in particular Tedopi. If you can go to the next slide, please. Tedopi, which is an immunotherapy in cancer that has delivered positive readouts in multiple indications, and we're in a registrational phase III for non-small cell lung cancer. We don't have much time to detail other parts of the pipeline that we have. You can see here that we have other clinical assets, which are partner clinical assets, in particular with Boehringer Ingelheim and with Veloxis. I won't spend too much time as an introduction because we have so much information to share with you today. I will pass to our Chief Scientific Officer, Dr. Aurore Morello, who will give you more information regarding the clinical and the scientific rationale for lusvertikimab. Now it's on your plate, Aurore. Thank you so much. Next slide, please. Thank you for the introduction. I'm going to talk about lusvertikimab and the mechanism of action, and why targeting IL-7, IL-7 receptor axis is compelling for targeting IBD patient. Next slide. IL-7 is produced by intestinal epithelial cells. It acts as an upstream signal of the inflammatory cascade by specifically activating effector T cells, and this break the immune balance in the intestinal mucosa, leading to the development of the disease. Multiple preclinical study over 20 years ago actually demonstrate that IL-7 is essential for the development, the persistence, and the exacerbation of the chronic colitis. Next slide, please. In fact, IL-7 creates a loop of chronic inflammation. It activates T cells and activate the production of interferon gamma, which is a pro-inflammatory cytokine. Interferon gamma actually will promote and activate epithelial cells which induce IL-7. This is a loop of chronic inflammation. A key point recently published by Neurath in Nature Reviews Immunology introduced the concept of hungry cells in IBD. Hungry cells are highly pro-inflammatory cells in IBD that drive the molecular resistance to anti-cytokine therapy, such as TNF, IL-12 or IL-23 therapies. What does this matter? Because actually, these therapies act downstream. They are targeting only individual cytokine, IL-23, IL-10, TNF, or it could be also IL-6, and they only block one mechanism at a time. In the system and in the gut, it is not sufficient, where multiple and redundant cytokine can simply take over. Our strategy with lusvertikimab is different. We aim to intervene at the upstream signal by blocking the IL-7 receptor, and we will prevent the activation of the entire inflammatory cascade. It is a different approach compared to the standard of care, and we believe that lusvertikimab is a potent therapeutic option for the patients who are failing to the standard of care. Next slide, please. As shown here, IL-7 and IL- It is okay? As shown here, the IL-7 and IL-7 receptor pathway is clearly dysregulated in IBD patient. On the left, you can see that IL-7 cytokine level is upregulated in both sera and tissue, compared to HC donors. On the right, we observe that there is a massive infiltration of IL-7 receptor positive immune cells in IBD patient compared to HC donors, with a 27-fold increase of T cells, IL-7 receptor positive T cells, and eight-fold increase of IL-7 receptor in eight lymphoid cells. Next slide, please. In addition, we observe that IL-7 receptor and IL-7 receptor pathway is upregulated in non-responder patients. Patients who are not responding to the standard of care in IBD patient, which is TNF, IL-12, 23, or even the anti-integrin, the vedolizumab therapy. This actually position the IL-7 receptor as a marker of treatment of resistance and can highlight the importance of targeting IL-7 receptor pathway for refractory IBD patients. Next slide, please. To antagonize the IL-7 receptor pathway, we have generated at OSE Immunotherapeutics an antibody, the lusvertikimab, which also is called OSE-127. This antibody is designed to specifically target the IL-7 receptor pathway. It is a pure antagonist antibody blocking IL-7 pathway and not TSLP, and I am going to talk about it a little bit later in my presentation. Lusvertikimab is specifically engineered to block memory effector T cells while sparing a specific population, the regulatory T cells. This is essential because lusvertikimab, by blocking only effector T cells, will block the pathogenetic signal and will preserve the regulatory mechanisms to maintain tissue homeostasis. Regarding the mechanism of action, lusvertikimab can suppress the key driver IBD pathogenesis by blocking the activation, the differentiation, the persistence, and the trafficking of pathogenic T cells, and especially the population Th1 and Th17 population. The results of the antibody is one target with multiple inflammatory pathway controlled. Next slide, please. In addition to activate T cells, IL-7 can promote the expression of specific integrins, the alpha-4 and the beta-7 integrins. Those integrins are really key for the migration of the T cells in the gut. Our in vitro data, shown on the right, demonstrate that lusvertikimab blocks the trafficking effector T cells into the gut by blocking the expression of alpha-4 and beta-7 on the T cells. This has been shown in vitro and also in vivo, showing a decrease of infiltration of T cells into the colon. Next slide, please. Next, we validated the efficacy of lusvertikimab at preclinical level. As shown on the left, we demonstrated a significant efficacy of reducing the inflammation in humanized IBD mouse model and on the right in a skin inflammatory model in a monkey model. By comparing the lusvertikimab, which is a pure antagonist antibody, we have demonstrated a high efficacy to decrease inflammation compared to other antibody, anti-IL-7 receptor monoclonal antibody, that could be antagonist but have also partial agonist activity. This antibody shown in red is not efficient in skin inflammatory disease in this model. Can you put the next slide, please? Thank you. One key challenge today is the resistance of the current therapy and the resistance of the anti-IL-23 therapy in IBD patients. We have evaluated the role of IL-7 in this context. As shown on the left, we used the guselkumab, which is an anti-IL-23 antagonist antibody. This antibody is known to block the secretion of the IL-7 cytokine. When we add the IL-7 cytokine into the media, which mimics actually the inflammatory microenvironment where you have a lot of cytokine, we observe that the guselkumab is not able anymore. [audio distortion] Well-positioned for the treatment of IBD and IBD-related conditions such as chronic pouchitis, which Maia will present after. Lusvertikimab can be also interesting for other pathology driven by IL-7 or Th1, Th17-mediated inflammation to block the upstream IL-7 signal, which is a differentiated therapeutic approach for the treatment of inflammatory disease. Next slide. Thank you. We are first evaluated in phase I in healthy volunteer patients. It is a phase I randomized double-blind placebo-controlled clinical trial. We have demonstrated that lusvertikimab is well-tolerated, with no evidence of cytokine release syndrome and no significant lymphopenia. Regarding the receptor occupancy, we have high receptor occupancy with a saturation level maintained over 100 days, and we have confirmed the target engagement of the antibody, with a significant decrease of the IL-7 induced gene signature post-treatment in lusvertikimab. Thank you for the attention. Now we switch to Laurent. I have just one question. Are we still live? I think that we experienced some troubles regarding microphones or something like that. We had echo. Hopefully, we can move forward. Professor Laurent Peyrin-Biroulet, can you please now take the lead of this presentation? Hopefully, it works. That is the beauty of live presentations. It works very well, at least for me. Thank you. Fantastic. Thank you so much, Marc Le Bozec. Thank you all for being here. We are developing many drugs in the field of IBD, but it's not so often that there is something so exciting with such encouraging results, and we are all the IBD community is talking about it. I am delighted to present this phase II data for this drug with a new, which is a first in class. It happens to have a first in class. But what matters, it's a first in class with very good results in the phase II, which then makes the drug very rare, and in that case, quite unique. Let's move to the next slide. Thank you. Just as a reminder, but you probably know that because you all know and you all like IBD and immunology. You know that IL-7 is something that for decades we know is produced by epithelial and stromal cells, that it will be sustaining T-cell survival and driving Th1 and Th17 differentiation. It's expressed on T lymphocyte, the receptor. What is interesting is that many data showed for sure it's animal, but it's always interesting. If it doesn't work, then it would be a problem. It was showing that IL-7 receptor A blockade was preventing and protecting against experimental colitis. This was promising, I would say the first step, but sometimes it happens that you can see something promising. We are all waiting, and all the community were looking for the data of a phase II trial, especially after, as I said, Aurore, that it was showing the safety and very PK, PD, all these fantastic results in the phase I study with ascending doses up to 10 milligram per kg. Next slide. If we are looking at this slide, this was tested in moderate to severe UC. What is important is the first thing is that the sample size, the sample size was 150 patients, and it is interesting because now it is considered something that is good. Before we had a lot of trials with 30 patients per arm, and the total number of patients was more 90 patients. I would say that nowadays, what we consider that is good, it is having at least 30, 40 patients per arm. This is what we got, and we are very happy. There was IV infusion, week 0, week 2, week 6. Two doses were tested, 850 milligram and 450 milligram. We can already tell you that both doses are working, but clearly, which is nice, 850 milligram looks even more promising, and this is the drug. When you look at patients entering the open label extension, which is nice, it is close to 100%. Then what is important is that all patients were treated with a dose that we think we know, we expect. I would say as a kind of IBD expert, I do not like this term, I am pretty sure that it will be working. It will be open label extension with 850 milligram. Next slide. What is interesting is that when you look at demographics and disease characteristics, there was not really something special, except that when you are looking at previous exposure to biologics, you see that at least around, roughly, I would say half of patients were exposed to two biologics at least. But interestingly, when you compare, even if it was randomized, but it can happen when it is sample size is like this. It was 40% of patients with severe ulcerative colitis versus two-thirds of patients. The population treated with 80, 100, sorry, 850 milligram was more severe, so more difficult to treat. Despite that, you will see that the results are very good. Next slide. Now it is time to see the results. You know that the endpoint and everything is changing in IBD. This is the beauty of IBD. The endpoint, the outcome every six months, we are learning, seeing something different. What is important is to have a consistent story. When we try to get an overview of the result of a trial, what matters is that everything is consistent. What we found and what has been observed, which was very nice, it was that all three doses, all two doses, sorry, were working, 450 milligram and 850 milligram. You see we have a primary endpoint, which is a modified Mayo score improvement at week 10. What is interesting is that for sure when you are pulling the data, you could see that it was interesting. Interestingly, when you were comparing versus placebo, it was statistically significant. I'm not sure that it's always the most important thing to be statistically significant in such a phase II, but if it was not, it would have been a problem for everyone. It's numerical difference, it's interesting treatment effect, and it is reaching statistical significance, which is nice. When you are looking at the clinical remission at week 10, which is quite early for such robust endpoint, you see that it was significant. It was almost significant, but I would say it was superior for 850 milligram. But week 10 is quite early, as we know. This is not telling you everything and the clinical remission is tough. 450 milligram was statistically significant versus placebo in this patient. What matters is that when you were treating this patient up to week 34, from week 10 to week 34, all patients, as a reminder, were treated with open label extension with 850 milligram. You see that there was, and it's something interesting because this is something that we are all working on. We are still capturing and increasing the benefit over time. It means that at week 10, it's not the end of the story. This is what we call late responders. You have initial responders and you are adding after initial responders, you are adding late responders to reach in terms of sustained benefit. It was two-thirds of patients after week 34. Next slide. We all like to see everything about endoscopy and histology. Histology will come later. What was interesting is that I would say usually we don't look so much at endoscopic remission at week 10 because it's too early. We are mostly looking at endoscopic remission at six months or one year. What we are looking at is endoscopic improvement at week 10. Interestingly, you see that both doses were statistically, I would say, superior to placebo with at least a 10% difference, reaching statistical significance with 450 milligram. When you are merging, when you are doing a pooled analysis of both active arms, you see that there was a 20% treatment effect versus placebo. As we always say, when you are reaching 15%-20% treatment effect, this is a game changer in the field of IBD. It was also superior when you are looking at endoscopic remission at week 10 already, while it's a very important, very tough endpoint, and if you are looking at other drug development program, endoscopic remission at the end of induction is very difficult to reach, even for some drugs that were later developed in a phase III trial or approved. When you are looking at the change in the UCEIS, because theoretically this is a political story, I could tell you more, but I'm just telling you, UCEIS is a more robust instrument than Mayo. But it's politics, strategy, and many things in the IBD world. You could see that there was a very good effect in favor of this drug. Next slide. Histology. Histology, which is very interesting because it's even more difficult to achieve, but it's a more robust endpoint. We still do not know whether in routine practice we should reach histology for all patients. What is interesting is that histology is more robust, and the indexes that we are using are more robust than endoscopy. The histological improvement at week 12, you could see that for all doses it was statistically significant versus placebo, which with, I would say, because you should never compare with other trials, because every trial is different and we should not do indirect comparison, but look at the treatment effect and the delta. The delta is between 20% and 35%, which is huge for such a drug. When you are looking at HEMI, endoscopic mucosal improvement, we like to be creative with new terms in the field of IBD. You could see that once again there was a statistical difference versus when you are doing a pooled analysis or looking at 450 milligram, there was a difference versus placebo and it was confirmed with change in histology index. Next slide. To keep on time, I will go a little bit faster. Fecal calprotectin, when it works with endoscopy, when it works with histology, it has to work with fecal calprotectin. If it does not work with calprotectin, it is not a consistent signal. It is game over. Here, the entire story is the same. Symptoms, clinical remission, endoscopy, histology, calprotectin, whatever we are looking at, the drug is working very well. This is very nice. Even when you are looking at fecal calprotectin normalization, look at the delta, 20%- 27% treatment effect. Next slide. Now it is time to look at safety. For sure, it is not the end of the story. I would say it is 30 patients, but if you have an alarming signal, you can see it very early. Here it was nice making, and I think it is very important, the fact that the risk-benefit profile of a drug is interesting and encouraging. It is a competitive field. There are many drugs, and what I like here is that both are very good with a good risk-benefit profile. Next slide. We just take a little bit about molecular and immunology. This was confirmed. We need to read the basic sciences to explain everything, but as I do a few things, I will do my best. I also did a few things in my career. Just to tell you that there was a confirmation. You want to look at what happens at the intestinal tissue, whether you have a target blockade, whether you have something reflecting target engagement, and everything is nice. When you are looking at placebo responders, you do not see what you will see with responders. When you are looking at the IL-7 pathway, it is really blocked effectively. When you are looking at decline in mucosal T cells, innate lymphoid cells, and total inflammatory cells, also very nice. It works with statistical impact, I would say, at the molecular level. Next slide. We are also looking at precision medicine. It is just the start. This is a biomarker that has been analyzed, but you have to start somewhere with AI, combining AI, histology, molecular transcriptomics. It is a very interesting approach that I like very much. Still, the road we know that biomarker is long, but it's a competitive field, and everything that you add makes your drug more attractive and more interesting. We are all looking at precision medicine if we want to break the therapeutic ceiling. Can we break the therapeutic ceiling? Look at the clinical remission based on the biomarker. You see that when there is no biomarker, there is no difference, no efficacy versus placebo. When you are using the biomarker, it's positive, it's 22 patients, but still there is a 50% effect and 60% efficacy in terms of clinical remission. You are breaking the therapeutic ceiling. So safety, efficacy, histology, endoscopy, biomarker precision medicine. It's a very nice list. Just to conclude my last slide. Next slide, please. I'm sorry. Just to summarize, because now you will know everything about pouchitis and where we go. IL-7. We know that it's a key target and it's the first non-internalizing pure antagonist with no antagonist activity on TSLP, which is nice. It's very specific, modern, targeted precision medicine. Everything is positive. Clinical, endoscopy, histology, biology, fecal calprotectin. It's safe, which is very nice. Just transient lymphopenia, but we know that we don't care. Clearly this is showing that we need to do something for phase III. My feeling is that now it will be discussed by people. My long neighbor from New York will tell you what we need to do now in pouchitis. Thank you. Many thanks, Laurent. Many thanks for that. Dr. Kayal, we are very passionate to hear you about pouchitis. Yes. Thank you so much for the invitation, and I'm very excited to speak to all of you today about pouchitis, because that is certainly where lusvertikimab might have a great potential role. Let's get started. Next slide, please. Let's take a step back, because we spent a lot of the first part of the conversation discussing ulcerative colitis. But despite all of our amazing medical therapies now, still about 15% of patients will need surgery for their medically refractory ulcerative colitis. The ideal surgery is something called the staged restorative proctocolectomy with ileal pouch-anal anastomosis. This is a surgery that preserves GI continuity and allows patients an alternative to a permanent end ileostomy. Next slide. The surgery is performed in three stages. The first stage is removal of the colon and a temporary ileostomy. That involves an external ostomy appliance. The second stage is removal of the rectum, construction of the pouch itself, and a temporary diverting ostomy. Again, a temporary external ostomy appliance. The third stage is an ostomy takedown. This is done over the course of six months and is typically performed in this staged approach to reduce postoperative complications. Next slide, please. Let me tell you a little bit more about the pouch itself, because even for some physicians, it's a little bit of a confusing concept. Because removal of the colon is the only surgical therapy that is available for patients with bad ulcerative colitis, t he idea in the '70s came about to create a pouch from small intestine to essentially serve as an internal reservoir for stool so that patients don't have to have an external ostomy appliance. The pouch itself, to get into a little bit more detail, is actually constructed from the distal 40 centimeters of small intestine. The surgeons bring the small intestine, after removing the colon, into the pelvis. They fold the intestine onto itself and then open it onto itself so that you're essentially creating a reservoir. This is known as the pouch or the J pouch because it's shaped as a J. This entire small intestine now is anastomosed or connected to the anus and then is also sealed off at the top. In this way, the patient now has gastrointestinal continuity. It's a very important advancement in surgical therapy for patients with ulcerative colitis. The pouch, of course, is small. It's only about 15- 20 centimeters in length with a diameter of about 4 centimeters and can carry a volume of about 200 milliliters. Next slide, please. Unfortunately, we are not curing ulcerative colitis when we perform this surgery because ulcerative colitis has no cure. We know that a significant proportion of patients, up to 80% actually, will have an episode of pouchitis after their surgery. That is inflammation of the pouch. These symptoms include increased stool frequency, urgency, bloody bowel movements, pain, very reminiscent of their ulcerative colitis, unfortunately. Most frequently, patients will not only have one episode of acute pouchitis, they will have multiple episodes of acute pouchitis. In fact, at least 60% of patients will have at least one recurrence pretty soon after their first episode of pouchitis, and then up to 20% of patients will develop chronic pouchitis. As you can see here, this is how we currently frame the thinking behind pouchitis, that it's a spectrum of disease. Along the lines of inflammatory bowel disease, somewhere in between ulcerative colitis and maybe Crohn's disease. It starts with acute pouchitis. Patients are treated with antibiotics. Some patients will develop antibiotic-dependent pouchitis. Many of those patients will go on to antibiotic refractory pouchitis, where they no longer respond to antibiotics. A proportion of patients will develop Crohn's-like disease of the pouch. Which doesn't mean that they have Crohn's disease, they just have manifestations that are similar to traditional Crohn's disease. Next slide, please. In this slide, we can see in a little bit more detail what these phenotypes look like. With acute pouchitis, there is inflammation that is limited to the pouch itself. With antibiotic-dependent and antibiotic refractory pouchitis, we see a similar manifestation of inflammation limited to the pouch itself. But here, patients either require constant antibiotics or no longer respond to antibiotics. In Crohn's-like disease of the pouch, again, not a phenotype that represents a misdiagnosis of Crohn's, but a phenotype that represents a true diagnosis of ulcerative colitis that is now presenting with symptoms or signs that are typical of traditional Crohn's disease, such as strictures and fistulae, and proximal small intestine inflammation. Next slide, please. It's important to understand, again, that despite all of our improvements in our therapy, we haven't really changed the rate of colectomy in a significant way. We're still sending the same proportion of patients to surgery. Unfortunately, what we are seeing is that the incidence of pouchitis is increasing in these patients. There is some thought, in fact, that the therapies that we are exposing our patients to before surgery is having an impact on the rate of pouchitis after surgery. We are seeing increasing signals of an increasing incidence of pouchitis in these patients. Next slide, please. There is a significant unmet therapeutic gap in these patients, in fact. Our current management of pouchitis is largely based on our overall management of inflammatory bowel disease. There are no unique therapies that have been developed specifically for pouchitis. We essentially borrow therapies that have been approved more broadly for ulcerative colitis and Crohn's disease, such that when a patient presents with acute pouchitis, our first approach is to treat them with antibiotics. Some patients will respond, but in fact, up to 35% of patients will not respond, and these patients are labeled antibiotic refractory pouchitis. These patients are then started on a biologic, and most of the time, we try to avoid recycling the same biologic or small molecule therapy that they were on pre-surgery. Because we have shown data that these patients are unlikely to respond if we give them the same therapy pre-surgery, post-surgery for their pouchitis. In these patients who don't respond to antibiotics, when we start a biologic or a small molecule, we are choosing something that they have not been exposed to before. Unfortunately, we know that up to 50% of patients, in fact, will not have a response, and then we start to cycle them to the second and third and fourth-line therapy. The issue at hand, however, is that we don't have that many therapies in ulcerative colitis or Crohn's disease to start with. If you've used many therapies pre-surgery, you can imagine that post-surgery, you don't have many options left for these patients. This is a significant unmet medical need for this patient population. Next slide, please. Now let's talk about, given that baseline and that reference, why lusvertikimab can have a potential role in pouchitis. Next slide, please. The beginning part of this session, we spoke a lot about. Next slide, please. We spoke a lot about the pathogenesis of ulcerative colitis and the significant role of T-cell driven inflammation in IL-7. We see that this is actually a similar pathogenic process, both in ulcerative colitis, in pouchitis, where they're driven by similar inflammatory mechanisms, including a predominance for T-cell driven inflammation and a dysregulation of the IL-7 pathway, both in ulcerative colitis and pouchitis. You can imagine both from this group and other groups, that these shared pathways might suggest a shared response to similar therapeutics. In fact, more broadly, one of the only therapies that are approved for pouchitis is vedolizumab, which has actually been shown to be quite effective in ulcerative colitis. We share that idea that if disease processes are driven by the same mechanisms, then perhaps they would respond to the same therapeutics. Next slide, please. In pouchitis specifically, we see that there is a predominance for T-cell driven inflammation, both in mRNA expression and also immune cell expression. We see that T-cells are the major population that is infiltrating the pouch during inflammation, and that there is similarly high expression of IL-7 and IL-7R in the pouch. In fact, in both scenarios, a higher extent in the pouch and in pouchitis compared to ulcerative colitis. Again, speaking to the idea that perhaps a therapy that targets these mechanisms of action could be quite effective in pouchitis. Next slide, please. I spoke to you before that our current management of pouchitis is really focused on not reusing the therapies that we invoked for patients pre-surgery. Unfortunately, this puts us in a difficult situation when our patients have already been exposed to all of these therapies. Hence, we are constantly looking for opportunities for new mechanisms of actions and new therapies for these patients with pouchitis. This is where lusvertikimab poses an exciting potential. This is a product and a mechanism of action that patients have not been exposed to pre-surgery, such that positioning it uniquely post-surgery in patients with a pouch, where we've seen that there is overlapping mechanisms and pathogenesis in ulcerative colitis, could provide the opportunity for a drug that has not been used before and could really yield significant efficacy. Because again, we don't like to reuse therapies. Yes, we don't like to reuse the same therapies, and so this is a rare opportunity to trial a therapy that our patients have not been exposed to, within a significant unmet medical need. Next slide, please. This leads us to the current study design for lusvertikimab in patients with pouchitis. This is a proof of concept study. It would be a double blind randomized study with a total N of 47 patients with a 3 to 1 randomization strategy, three for lusvertikimab, and one for placebo. The idea here is that the study is built against failure, which is great. It's a two-stage phase II single arm assignment design. In the first stage, 17 patients will be enrolled and randomized, and the study will be considered futile if there is less than or equal to one response to therapy, which we don't expect to happen. In the second stage, an additional 18 subjects, for a total of 35, will be randomized and included. If there are greater than four responses, the study will be declared positive and the next phase will proceed. All patients, of course, will receive induction via intravenous at 0 to 6 to 10 weeks, and then the primary endpoint will be at week 14 and will be an endoscopic endpoint because we know, and Laurent has spoke to you earlier, the objective markers are key in our endpoints for these clinical trials. Now week 14 was chosen specifically because we expect patients with a pouch, if they will respond, to have an early time point of response. We do expect to see a significant difference at that early time point. After that, patients will continue in the open label maintenance study. Then secondary and exploratory endpoints will be examined at week 38. Next slide, please. I believe that's it. We're excited to take any questions that you may have. Thank you so much, Dr. Kayal. We have a first question. We experienced some technical issues with the various conferences which are open. Sorry about that. The first question is, how can we explain the differences between the 450 milligram dose and the 850 milligram dose? Is there a biological rational, like receptor occupancy saturation or some exposure response effect? Or is that simply a noise in a small exploratory subgroup? Maybe Silvia, Dr. Silvia Comis, our Chief Medical Officer, will answer to this question. Silvia? Thank you, Marc. This is a very important question, of course. We believe, in fact, that the patients treated with 850 were more severe, had a more severe disease compared the group of patients treated with 450, and this could have played a role in the results seen. On the other side, we fully agree that this is a proof of concept study with a small sample size, and this could also have an impact. On the other side, the question is also linked to the selection of the dose for the next pouchitis study. We will use the 850 milligrams. And why? Because we saw a higher probability of achieving full receptor occupancy in the tissue with the 850 compared to 450 based on some simulation work that was done months ago. We saw better efficacy for the primary endpoint with 850 when the patients with mMS ≤4, so with less severe disease, were excluded from the analysis. In addition, histological improvement when measured with Robarts or Geboes was better with 850 than the 450. In addition, we saw a rapid increase in symptomatic remission when the patients who received 450 during induction were switched to 850 for the OLE part. They achieved a rapid increase in symptomatic remission with one single dose of the 850. Based on those considerations, we decided to adopt the 850 for the next pouchitis study. Many thanks for that, Silvia. The next question is for Aurore. Aurore, given the preclinical data showing that the IL-7 drives resistance to IL-23, what proportion of patients in your phase II CoTikiS trial expressed this high IL-7 receptor signature, and does OSE plan to actively pursue clinical development of an upfront IL-23 combination strategy? Aurore? Yes, thank you for the question. Actually, in the phase II clinical trial, when we analyzed the effect of lusvertikimab, we demonstrated that we significantly decreased the IL-7 signature in patient in peripheral blood T cells. It's not all patient because we didn't have all specimen. But all of them, actually, from what we analyzed, decreased the IL-7 signature after treatment with OSE-127 with both dose. Regarding the combination, actually, as I shown before, we demonstrated that we have really high efficacy by combining the IL-23 and IL-7 receptor. We also have a combination efficacy with anti-TL1A and showing a synergistic activity. We demonstrate actually that IL-7 can drive the resistance. That's why probably we have even better efficacy with the lusvertikimab as a treatment in combination. Today, the combination is probably the future for IBD, and combination treatment can increase actually the therapeutic ceilings. Today, a lot of patients and a lot of, sorry, biotech actually are constructing a bispecific molecule to target two different signaling. We are actually also trying bispecific molecule, but we have also observed by combination that we have even better effect by combinating than bispecific molecule for the treatment of combining anti-IL-7 receptor with an anti-IL-23, for example. Thank you for that, Aurore. We have a question from Arron from Edison, and probably for Laurent. Looking across the CoTikiS data set as a whole, for you, Laurent, what aspects of the efficacy signal stand out most? Is there any histological, clinical remission? What is the most important to you? This is a key point. As always, we need to look beyond symptoms, but I would say two things. First of all, the story has to be consistent. What is nice is that all endpoints are consistent. This is a very, very important point. If there is a discrepancy or something that is not consistent, it is always an issue. So calprotectin symptoms, endoscopy, histology, and so on. This is my first comment. Second comment is that the treatment effect is very important also. The treatment effect, it is something that we are looking at now, especially because we have many options, and we see that the treatment effect is very encouraging. Last but not least, as always, even if the focus of the FDA is always symptoms plus endoscopy and clinical remission and so on, still, we know that the most reliable tool, because, for instance, the Mayo score has never been fully validated. The UCEIS is better but not always used. Its histology and what we see for histology is really impressive, and telling us clearly. I would say this sentence may be it looks stupid, but what we know is that I cannot predict the treatment effect during the phase III, but we know that the studies that will be done with phase III pouchitis, whatever, can be only positive because all the stories like that. This is at least what we know from here. We have never seen something that was so positive in phase II that was negative after that. There is only one compound, which was etrolizumab, because we did a mistake with many small study, and it was a big mistake. So it cannot happen that, at least what we know today is that we cannot happen, but the drug does not work. Many thanks for that, Laurent. Another question for Aurore. Given IL-7's role in memory maintenance, what gives you, Aurore, confidence that chronic treatment will not impair long-term immune competence? Thank you. It is an important question. What we have seen in phase I healthy volunteers and also in the phase II, we do not have any lymphopenia. We do not have modification of the lymphocytes. We have analyzed also the repertoire, the T-cell repertoire and the B-cell repertoire of the patient treated with lusvertikimab. What we have seen is we do not have any modification in the T-cell and the B-cell repertoires, meaning that we will have the same clonality and the same capacity of T-cell to respond to any infection or any infection cancer cells or any damage to eliminate any damaged cells. This is actually associated also in clinic with we do not have any occurrence of infection post-treatment at short-term and long-term. Actually, we think that with the dysregulation of IL-7 in IBD, we will target the colon, and we will target the T cells and the dysregulation in the colon, and we will not affect the memory T cells for infection or future response to other pathogens. Many thanks, Aurore. Another question regarding toxicity. Maybe Laurent, if you can give your answer. Our friend, Abivax, reported the cancer cases in their phase III. Did you see similar outcome in CoTikiS? Can you say a few words maybe on the safety profile of lusvertikimab that is of the essence, of course, for patients? Yeah. It is a good point. When you look at Abivax, first of all, recently the pool analysis was published and was negative, but still there was this signal with these randomized cases. Whatever they are claiming, for sure, the main problem is that it was dose dependent, which for me it was a bigger problem because it was dose dependent. Here we do not see anything. I think it is mostly related also to the mechanism of action because with microRNA, we still do not know how it works. It will interfere many organs, many things. It has a systemic effect. I do not say that there is an increased risk of malignancy, but it is different here because it is targeted, because we know the role, because we know the biological, because we know that it is pro-inflammatory, all these things. I am not worried for this, to be honest. I don't think it's an issue. We need hundreds of patients and more patients. As always, I have to say that from a medical point of view. But if I had to bet and to predict, I would not be worried at all. Yeah. Thank you for that, Laurent. Dr. Kayal, a question for you. Is the IL-7 receptor biomarker work in UC expected to inform development in pouchitis as well? Or do you view the pouchitis opportunity as independent of patient selection? I think this is a great question. I'm going to throw in the caveat that pouchitis is a very understudied patient population in patients more broadly within IBD. We like to think that we can borrow the biomarkers that have been seen both in ulcerative colitis and Crohn's disease and apply them to a certain extent in pouchitis. But it hasn't been done in a comprehensive way. It's not fully clear that we'll be able to see that same biomarker signal apply in patients with pouchitis. But I don't think that the decision to proceed with lusvertikimab in this setting is based on that angle alone. I think it's more based on the fact that there is a shared pathogenesis with ulcerative colitis that we see quite strongly, and more specifically, that this patient population has really an absence of available therapies, especially when they've been exposed to all the mechanisms of action prior to surgery, such that a novel mechanism of action really has an opportunity to play a big role in these patients. I think it is independent of using the biomarker to select a group of patients that we expect to respond more and more to see how the therapy plays out in this group. Thank you so much for this answer, Dr. Kayal. Maybe a question for you, Silvia. In the design of the further trial in pouchitis, you have chosen with all the experts, and in particular with Dr. Kayal, a 14-week analysis. Why that? Why the difference between the 10-week induction phase in UC study in CoTikiS versus a 14-week in the pouchitis study? First, what we saw in the OLE was that symptomatic remission continued to improve in patients who received 850 during induction. We believe that especially for the most severe patients, we need more time, as Professor Laurent Peyrin-Biroulet said, that we need more time for a product to show efficacy. On the other side, we know that the mechanism of action is on the cells, on T cells, and this requires time to show efficacy as well. We should not forget that we have a product registered in pouchitis in Europe with the EARNEST study where the primary endpoint was measured at week 14. I do not know, Maia, if you want to add anything, but- I agree. I agree with everything you said, Silvia. I think it is tricky in patients with a pouch in that we cannot apply the same exact endpoints that we apply more broadly in ulcerative colitis because we do not actually know for sure that endoscopic remission is ever fully plausible or feasible in these patients. We know in general, based on our internal data and data that has been published more broadly, that patients with a pouch do take a little bit longer to achieve that remission. I think the choice of week 14 is appropriate in this situation because although we are invoking the idea that the disease processes share a similar underlying mechanism, the manifestation of that process is very unique in patients with a pouch. Adopting a week 14 endpoint is more appropriate in this situation. Thank you for that. Dr. Kayal, given the lack of FDA-approved products for this specific indication, what primary endpoint would be required by the regulators in your views? This is a good question. I am actually going to bring Laurent into this answer as well because I think he has a lot of expertise in more broad randomized control trials. I think this is a conversation we had not that long ago in the spring about what would be the most appropriate endpoint. I think we are moving towards having an objective endpoint is a must, right? Especially because we know that clinical and endoscopic disease often doesn't align one-to-one. We really need an objective endpoint. I do think the primary endpoint of endoscopic remission is important. Trial duration, I think if we have a primary endpoint at week 14 and then we follow patients up to week 52, I think that would be adequate. Ultimately, in a field where there is no other therapy other than vedolizumab, which most of our patients have been exposed to pre-surgery, and is not an ideal option because of that, most of these therapies would be readily approved by regulatory authorities recognizing it is an orphan indication. Laurent, I would be interested to hear your opinion on this as well. Can you please repeat the question, Maia? What would be the best primary endpoint and trial duration to allow for expedited approval for a therapy in pouchitis? Yeah. I think it is still a moving target. But recently, there was the ATLANTIS. In fact, it is always the same. You have historical ones and new ones. The historical one, for instance, in histology is Geboes, but it is not a good one. The historical one in endoscopy you see is Mayo. It is not a good one. But the time to admit and to be approved by the FDA, so UCEIS, Robarts, San Francisco for histology, and now the Atlantic Pouchitis Index, it always takes a lot of time because we have no reference and it is a moving target. I think we should assess everything. For sure, endoscopy will be the key. You have to see something for endoscopy, and it will be very important. But I think we need to look at historical pouchitis index, plus the new one that has been released a few months ago in CGH. Then we will see, as always, we will see if everything is consistent. We will know that if histology, endoscopy, pouchitis index and ATLANTIS and everything consistent, then clearly it is a big success for patients. Thank you so much, both of you, for your answers. I have a last question, or let us say, series of questions regarding, let us say strategic level, future of lusvertikimab in ulcerative colitis. For sure, we want to move forward in ulcerative colitis. You all know that it is very expensive. It takes quite a lot of time. It requires large clinical trials and large population. We want to move in that direction. The key question will be can we afford to do that by ourselves, or do we have to partner with someone else? We want to be in a position in 2027 to make a choice between moving by ourselves or signing a deal with a large partner. For that, we have developed a subcutaneous formulation, which is of the essence today, because patients can now access oral formulation or subcutaneous formulation. For the moment, lusvertikimab is only available in IV formulation. We have developed that. It will be validated clinically. The readout is June 27th. Starting June 27th, we will have further discussions with a series of big names, big players that you know, to figure out if we move forward with them as partners or if we decide to raise the amount of money which are required to do that by ourselves. There will be a key question regarding also combination. We already have started discussion with some of those big names regarding those combination. That is a key question that Aurore, our Chief Scientific Officer, addressed in this presentation, is that do we anticipate that the bispecific would be the right answer? This is not necessarily what we see at in vitro and in vivo level in our research team. We try to convince the big names that bispecific are not necessarily the best scenario, in particular regarding safety. We have discussions ongoing in combination. We trust that the future for UC will also be a combination of various mechanism of action. That's where we stand today. Thank you so much to everyone to have participated in this webinar. Please feel free, all the participants, to ask further question. The team, Silvia, Aurore, everyone in the company will be super happy to answer all your question. Professor Laurent Peyrin-Biroulet and Dr. Maia Kayal, thanks again. Many, many thanks for your participation. That's the end of this webinar. Bye-bye. Congratulations. Thank you. Bye. Bye.