OSE Immunotherapeutics SA (OSE) Earnings Call Transcript & Summary

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 Weiner dedicated to one of our key assets, which is Lusvertikimab, an entire IL-7 receptor monoclonal antibody. We are very proud to have here with us Professor Laurent Peyrin-Biroulet, who will -- and Maia Kayal, who will detail results that we have gathered over the years. in clinical development. And maybe I will say a few words as an introduction. So 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. So 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 a positive readout in ulcerative colitis last year, and this will be further detailed in this webinar. And we're about to launch further clinical trials, in particular in Purchase, which will be detailed by Dr. Maia Kayal. On top of that, we 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 and cancer. We don't have much time to detail other pipelines of the part of the pipeline that we have. You can see here that we have other clinical assets, which are partner clinical assets, in particular, with [indiscernible] with Veloxis. So I won't spend too much time as an introduction because we have so much information to share with you today, and I will pass to our Chief Scientific Officer, Dr. Aurore Morello, who will give you more information regarding the clinical and the anti rationale for Lusvertikimab. And now it's on your plate, Aurore. Thank you so much.

Thank you for the introduction. So I'm going to talk about Lusvertikimab and the mechanism of action. And why targeting IF IL-7 receptor axis is compelling for the -- for targeting IB patient. Next slide. So IL-7 is produced by intestinal epithelial cells. It acts as an upstream signal of the inflammatory cascade by specifically activating effect accepts. And this breaks the immune balance in the intestinal mucosa leading to the development of the disease. So 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. So in fact, IL-7 creates a loop of chronic inflammation. It activates T cells and activate the production on [indiscernible], which is a pro-inflammatory cytokine. And [indiscernible] actually will promote and activate epithelial cells, which induce IL-7. So this is a loop of chronic inflammish. So a key point recently published by Neurath in Nature Review Immunology, introduced the concept of angry cells in IBD. So angry 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. So what does this matter? Because actually, these therapies are downstream. They're targeting only in the individual cytokine, [indiscernible] or it could be also IL-6, and they only block 1 mechanism at a time. And in the system and in the gap, it's not sufficient, where multiple and redundant [indiscernible] can sickly take over. So our strategy with Lusvertikimab is different. So we aim to intervene at the upstream signal by blocking the IL-7 receptor. And we will prevent the activation of the anti entire inflammatory escape. So it's 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 on here, [indiscernible] and IL-7 receptor pathway is clearly disregulated in IBD patients. So on the left, you can see that IL-7 cytokine level is upregulated in both sea and tissue compared to [indiscernible]. And on the right, we hope that there is a massive infiltration of IL-7 receptor positive immune cells in IBD patients compared to LC donors with a 2-fold increase of T cells IL-7 receptor positive T cells and increase of IL-7 receptor in a life. Next slide, please. In addition, we observed that IL-7 receptor and IL-7 receptor pathway is upregulated in nonresponder patients. So patients who are not responding to the standard of care in IBD patients, which is IL-12/23 or even the anti-integrin [indiscernible] therapy. So this actually positioned the IL-7 result 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. So to [indiscernible] the IL-7 receptor pathway, we have generated at [indiscernible], an antibody, the Lusvertikimab, which also is called -- so this antibody is designed to specifically target the IL-7 receptor pathway. So it's a pure antagonist antibody blocking IL-7 pathway and not CSLP. And I'm going to talk about it a little bit later in my presentation. So Lusvertikimab is specifically engineered to block memory effector T cells while sparing a specific population, the regulatory set. So this is essential because Lusvertikimab by blocking on the effect of T cells will block the bactogenic signal and will preserve the regulatory mechanisms to maintain tissue on stasis. 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 C1 and Th17 population. So the results of the antibodies on target with multiple inflammatory pathway control. Next slide, please. So in addition to activate T cells, IL-7 can promote the expression of specific integrate, the alpha 4 and the beta even [indiscernible] are really key for the migration of the T cells in the gut. So in vitro data, shown on the right demonstrate that blocks the [indiscernible] effect of T cells into the gut by blocking the expression of alpha 4 EBITA on the T cells. This has been shown in vitro and also in vivo showing a decrease of infiltration of T cells into the color. Next slide, please. So next, we validated the efficacy of Lusvertikimab at preclinical level. And 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 the monkey model. So 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-7ceptor monoclonal antibody that could be antagonist, but have also partial agonist activity. And this antibody shown in red is not efficient in skin inflammatory disease in this model. Can you put the next slide, please. So one key challenge today is the resistance of the cure therapy and the resistance of the anti-I23 therapy in IBD patients. So we have evaluated the role of IL-7 in this context. And as shown on the left, so we used the Lusvertikimab, which is an T23 antagonist antibody. This antibody is known to block the secretion of the IAS-17 cytokine. When we add the IL-7 cytokine into the media, which means actually the inflammatory [indiscernible] [Technical Difficulty] Such as chronic [indiscernible], which Maia will after, Luzertikimab can be also interesting for other pathology driven by L7, our [indiscernible] mediate inflammation to block the upstream IL-7 signal, which is a differentiated therapeutic approach for the treatment of inflammatory disease. Next slide. Thank you. So we are first evaluated in Phase I in LC volunteer patients. It's a Phase I randomized dubbing placebo-controlled clinical trial. And we have demonstrated that Lusvertikimab is water related with no evidence of cytokine rely syndrome and no significant lymphopenia. So regarding the receptor occupancy, we have high receptor occupancy with a situation level maintained over 100 days, and we have confirmed the engagement of the antibody with a significant decrease of the IL-7 indies gene signature post-treatment in Lusvertikimab. Thank you for the attention.

So now we switch to Laurent. I have just one question. Do we are -- are we still live because I think that we experienced some troubles regarding microphones or something like that. We had eco. Hopefully, we can move forward. So Professor Laurent Peyrin-Biroulet. Can you please now take the lead of this presentation. Hopefully, it works. That's the beauty of live presentation.

Very well at least for [indiscernible]. Thank you so much, Marc. Thank you all for being here. We are developing many drugs in the field of IBD, but it's not so often, but there is something so exciting with such encouraging results and we are all the ibd communities talking about it. So I'm delighted to present this Phase II data for this drug with 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 very -- the drug very, very rare and in that case, quite unique. So let's move to the next slide. Thank you. So just as a reminder, but you probably know that because you all know and you all like IBD and immunology. So you know that IL-17 is something that for decades, we know is produced by PTL and small cells, but it will be sustaining T-cell survival and driving TH1 and Th17 differentiation. It's expressed on [indiscernible], the receptor -- and 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-17 receptor alpha blockade was preventing and protecting against experimental collective. So this was promising, I would say, the first step, but sometimes it happens. It happens that you can see something promising, but we are all waiting and all the community were looking for the data of the Phase II trial, especially after, as I said, Aura, that it was showing the safety and very PPD, all these fantastic results in the Phase II study with ascending doses up to 10-milligram per kg. Next slide. So if we are looking at this slide, so this was tested in moderate to severe UC. What is important is the first thing is that the sample size. So the sample size was 150 patients, and it's interesting because now it's 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's adding at least 30, 40 patients per arm. So this is what we got, and we are very happy. So there was IV infusion with 2 doses were tested. So 850 milligrams and 450 milligrams. We can already say I can already tell you that both doses are working, but clearly, 850, which is nice, 850 milligrams looks even more promising, and this is a drug. So when you look at patients entering the open label extension, which is nice, it's close to 100%. And then what is important is that all patients were treated with the dose that we think we know, we expect. And I would say as a kind of IBD expert, I don't like this term, I'm pretty sure that it will be working. It will be open label extension with 850 milligram. Next slide. So what is interesting is that when you look at demographics and disease artistic, 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 2 biologics at least. But interestingly, when you compare an mean,if was randomized, but it can happen when it relatively when it sample size is like this. It was 40% of patients with severe ulcerative connected versus 2/3 of patients. So the population treated with 100 -- sorry, 50-milligram was more severe, so more difficult to treat. And despite that, you will see that the results are very good. Next slide. So now it's time to see the results. So you know that the endpoint and everything is changing, and I believe it is the beauty of IBD, the endpoint, we have come every 6 months, we are learning, seeing something different. But what is important is to have a consistent story. When we are looking -- when we try to get an overview of the result of the trial, what matters is that everything is consistent. And what we found and what has been observed, which was very nice. It was that all 3 doses, all to those history were working, 450 and 850, you see with a premier endpoint, which is a modified Myocore improvement at week 10. And what is interesting is that for sure, when you are pulling the data, you could see that it was interesting. And 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. So it's numerical difference. It's interesting treatment effect. And it is reaching statistical significance with this mix. Then when you are looking at the clinical remission week 1, which is quite early for such robust standpoint, you see that it was significant. It was almost significant, but I would say it was superior for 850, but it is quite early as we know. So this is not telling you everything and the clinical remission is tough. The 450 was statistically significant versus placebo in this patient. But what matters is that when you were treating these patients up to week 4, sorry, from week 1 to week. So all patients, as a reminder, were treated with open-label extension with 850. 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. So it means that at week 10, it's not the end of the story. This is what we call late responders. So you have any call responders and you are adding after initial responders, you are adding late responders to reach in terms of sustained benefit, it was 2/3 of patients after week 34. Next slide. So we all like to see everything about endoscopy and histology to log will come later. What was interesting is that I would say, usually, we don't look so much at endoscopy commission at week 10 because it's too early. We are mostly looking at endoscopy commission at 6 months or 1 year. What we are looking at is endoscopic improvement at week 10. And interestingly, you see that both doses were statistically where, I would say, superior to placebo with at least a 10% difference reaching statistical significance with 450. And when you were merging when you were doing a pooled analysis of both active arms, you see that there was a 20% treatment effect versus possible. And as we always say, when you are reaching 15% to 20% treatment effect, this is a game changer in the field of IBD. Then it was also superior when you are looking at endoscopic remission at 1 already, while it's a very important, very tough end point. And if you are looking at other drug development program, endoscopies at the end of induction. It's very difficult to reach even for some drugs that we are later developed in a Phase III trial or approved. And when you are looking at the change with -- in the UCIS because theoretically, this is a political story. I could tell you more, but I'm just telling you, you CIS is a more robust instrument than by, but it's policy strategy, many things in the BD world. You could see that there was a very good effect in favor of this drug. Next slide. Histology. So 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 a voting practice, we should reach histology for all patients. But 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 possible with, I would say, because you should never compare with other trials because every trial is different and we should not do in the 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 any store endoscopic cost improvement, we'd 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 million, there was a difference versus placebo and it was confirmed when we've changed in [indiscernible]. Next slide. To keep on time, I will go a little bit faster. So fecal protecting when it works with endoscopy, when it works with histology, it has to work with fecal protecting. If it doesn't work with [indiscernible], it's not a consistent signal. It's 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. So this is very nice. And even when you are looking at fecal protected normalization, look at the delta, 20% to 27% [indiscernible]. Next slide. So now it's time to look at safety, for sure. It's not the end of the story. I would say it's 30 patients. But if you have an [indiscernible] you can see it very early. And here, it was nice, making -- and I think it's very important the fact that the risk-benefit profile of the drug is interesting and encouraging. We have to -- it's 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 and we just take a little bit about molecular immunology. This was confirmed. So this you need to read basic scientists to explain everything, but as industrial things I will do my best. I also did a few things in my career. So just to tell you that there was a confirmation, you want to look at what happens at the intestinal issue, whether you have a target blockade, whether you have something reflecting target engagement and everything is nice. And when you are looking at placebo responders, you don't see what you are looking, what you will see with responders. When you are looking at the IL-17 pathway, it is blocked, really blocked effectively. And when you are looking at decline in mucosal cells, [indiscernible] and total inflammatory cells, also very nice. It works with statistical impact, I would say, at the molecular level. Next slide. And we are also looking at precision medicine. It's just the start. This is a biomarker that has been analyzed, but you have to start somewhere with AI, combining AI, histology, molecular [indiscernible]. So it's 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 [indiscernible] and can we break the therapeutic selling, 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 efficacy in terms of clinker remission. So you are breaking therapeutic selling. So safety, efficacy, histology, endoscopy, biomarker precision medicine. So it's a very nice list. And just to conclude my last slide, just to tell you that -- so next slide, please, I'm sorry, just to summarize, because now you will know everything about Process and where we go. IL-7. So we know that it's a key target and it's the first noninternalizing pure antagonist with no antagonist activity on TSLP, which is nice. So it's very specific modern targeted precision medicine, everything is positive clinical endoscope histology, biology, [indiscernible] protected, it's safe, which is very nice. Just [indiscernible], we don't care. So clearly, this is showing that we need to do something for Phase III. And my feeling is that now it will be discussed by people, by long neighbor from New York. We'll tell you what we need to do now in [indiscernible]. Thank you.

Many thanks, Laurent. Many, many thanks for that. Dr. Kayal, we are very invested you about [indiscernible].

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. So let's get started. Next slide, please. So 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. And the ideal surgery is something called the [indiscernible]. This is a surgery that preserves GI continuity and allows patients an alternative to a permanent and ileostomy. Next slide. surgeries performed in 3 stages. The first stage is removal of the colon and a temporary ileostomy, so that involves an external ostomy appliance. The second state is removal of the rectum construction of the pouch itself and a temporary diverting ostomy. Again, a temporary external ostomy planes. And then the third stage is an ostomy takedown. This is done over the course of 6 months and is typically performed in this staged approach to reduce postoperative complications. Next slide, please. Now 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. The 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 -- 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 moving the colon into the pelvis they fold the intestine onto itself and then open it out to 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 anastomos or connected to the ANS and then is also sealed off at the top. And in this way, the patient now has gastrointestinal continuity. And so it's very important advancement in surgical therapy for patients with ulcerative colitis. The pouch, of course, is small. It's only about 15 to 20 centimeters in length with a diameter of about 4 centimeters and can carry a volume of about 200 milliliters. Next slide, please. Now unfortunately, we are not curing ulcerative colitis when we perform the surgery because ulcerative colitis has no cure. And 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. And these symptoms include increased stool frequency, urgency, bloody bowel movements, pain, very reminiscent of their ulcerative colitis, unfortunately. Now most frequently, patients will not only have one episode of acute arthritis, they will have multiple episodes of acute paltitis. And in fact, at least 60% of patients will have at least one recurrence pretty soon after their first episode of paucitis and then up to 20% of patients will develop chronic pouchitis. And 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. And so it starts with acute pouchitis. Patients are treated with antibiotics. Some patients will develop antibiotic dependent [indiscernible] many of those patients will go on to antibiotic refractory patois where they no longer respond to antibiotics and a proportion of patients will develop chronic disease at 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. And 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 patch itself. But here patients either require constant antibiotics or no longer respond to antibiotics and then it comes like disease of the pouch. Again, not a phenotype that represents a misdiagnosis of current, 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 stricter and fistula and proximal small intestine inflammation. Next slide, please. Now with -- it's important to understand, again, that despite all of our improvements in our therapy, we haven't really changed the rate of collect me in a significant way. And so we're still sending the same proportion of patients to surgery. But 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. And so we are seeing increasing signals of an incident of an increasing incidence of pouchitis in these patients. Next slide, please. And 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 [indiscernible]. 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 presurgery because we have shown data that these patients are unlikely to respond if we give them the same therapy pre-surgery post surgery for the pathitis. And so in these patients who don't respond to antibiotics, when we start a biologic or a small mace, we are choosing something that they have not been exposed to before. But 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 class or Crohn's disease to start with. And if you've used many therapies pre-surgery, you can imagine that post surgery, you don't have many options left for these patients. And so this 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. And 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 presurgery because we have shown data that these patients are unlikely to respond if we give them the same therapy presurgery, post surgery for their pouchitis. And so 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. But 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. And if you've used many therapies presurgery, you can imagine that post surgery, you don't have many options left for these patients. And so this is a significant unmet medical need for this patient population. Next slide, please. And so now let's talk about, given that baseline and that reference, why Lusvertikimab can have a potential role in puchitis. 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. And we see that this is actually a similar pathogenic process, both in ulcerative colitis and 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. And so you can imagine both from this group and other groups that these shared pathways might suggest a shared response to similar therapeutics. And in fact, more broadly, one of the only therapies that are approved for palptitis is vedolizumab, which has actually been shown to be quite effective in ulcerative colitis. And so 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. So 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. And 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 presurgery. And 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. And this is where Lusvertikimab poses an exciting potential because this is a product and a mechanism of action that patients have not been exposed to presurgery, such that positioning it uniquely post surgery in patients with about 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 review you the last party in the conference. We don't like to reuse the same therapies. And so this is a rare opportunity to trial therapy that our patients have not been exposed to within a significant unmet medical need. Next slide, please. So this leads us to the current study design for Lusvertikimab in patients with pouchitis. This is a proof-of-concept study. They would be a double-blind randomized study with a total of 47 patients with a 3:1 randomization strategy, 3 for Lusvertikimab and went for placebo. The idea here is that the study is built against failure, which is great. It's a 2-stage Phase II single-arm Simon 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 1 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. And if there are greater than 4 responses, the study will be declared positive and the next phase will proceed. All patients, of course, will receive induction at via intravenous at 0 to 6, 10 weeks. And 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. And so we do expect to see a significant difference at the early time point. After that, patients will continue in the open-label maintenance study and then secondary and exploratory end points will be examined at week 38. Next slide, please. I believe that's it. So we're excited to take any questions that you may have.

Thank you so much, Dr. Kayal. So we have a first question. We experienced some technical issues with the various conferences, which are open, sorry about that. So the first question is how can we explain the differences between the 450-milligram dose and the 850-milligram dose? Is there biological rationale, like receptor occupancy saturation or some exposure response effect? Or is that simply a noise in a small exploratory subgroup. So maybe Sylvia, Dr. Sylvia Comis, our Chief Medical Officer, will answer to this question. Sylvia?

Thank you, Marc. This is a very important question, of course. So we believe, in fact, that the patients treated with 50 were more severe and a more severe disease compared the group of patients with 40, 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 an impact. On the other side, the question is also linked to the selection of the dose for the next [indiscernible] study. We will use the 850 milligrams. And why? Because we saw a higher probability of achieving foreset occupancy in the tissue with 850 mg compared to 450 mg based on some simulation of board that was done months ago. We saw better efficacy for the primary endpoint with the 1050 when the patients with MS for with less severe disease were excluded from the analysis. In addition, histological improvement with -- when measured with robots or [indiscernible] was better with 850 mg than the 450 mg. And in addition, we saw a rapid increase in symptomatic remission when the patients who received 450 during induction were switched to 850 for the OLED part. They achieved a rapid increase in symptomatic remission with 1 single dose of the 800 things. So based on those considerations, we decided to adopt the 850 for the next PoC study.

Many thanks for that, Sylvia. So the next question is for Aurore. So given the preclinical data showing that the IL-7 drives resistance to I-23. What proportion of patients. In your Phase II otitis trial expressed this high IL-7 receptor signature. And those OE plan to act pursue clinical development of an upfront IL-23 combination strategy.

Yes. Thank you for the question. So 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. So it's not all patients because we didn't have all by specimen. But we -- all of them actually from what we analyze decreased the IL-7 signature after treatment with OS127 with both those -- with posters. Regarding the combination. So actually, as I showed before, we demonstrated that we have really high efficacy by combining the T23 and IL-7 receptor. We also have combination efficacy with NTTL 1A and showing a synergistic activity we demonstrate actually that IL-7 can drive the resistance. So that's why probably we have even better efficacy with Lusvertikimab as a treatment in combination today, the combination is probably the future for IBD and combination treatment can increase actually the therapeutic sellings. And today, a lot of patients and a lot of -- sorry, biotech actually are constructing a bispecific molecule to target 2 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 NT-L7 receptor with non-CLL23, for example.

Thank you for that, Aurore. We have a question from Aaron from Edison and probably for Laurent. Looking across the Cotys data set as a whole, for you, Laurent, what aspects of the efficacy signal stand out most. Is there any -- is the logical clinical remission? What is the most important to you?

Yes. So this is a key point. As always, we are -- we need to look beyond symptoms, but I would say two things. First of all, the story has to be consistent. And 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's always an issue, [indiscernible], symptoms, endoscopically and so on. So this is my first comment Second comment is that the treatment effect is very important also. And the treatment effect is something that we are looking at now, especially because we have many options, and we see that the treatment effect is very encouraging. And last but not least, as always, even if the focus of the FDA is always symptoms plus [indiscernible] and cancer remission and so on. Still, we know that the most reliable tool because, for instance, the [indiscernible] has never been fully validated. The US is better, but not always used is histology. And what we see for histology is really, really, really, really impressive and telling us clearly, I would say the sentence maybe 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 purchases whatever, can be only positive because all the stories like that. So this is at least what we know from here. We have never seen -- We have never seen something that was so positive in Phase 2 that was negative after that. There is only one compound which was Lusvertikimab 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 your confidence that chronic treatment will not impair long-term in competence.

Thank you. It's an important question. So what we have seen in Phase I healthy volunteers and also in the Phase II that we don't have any [indiscernible]. So we don't have modification of the life of set -- so we have analyzed also [indiscernible], the T cell repair to and the B-cell repat of the patient treated with Lusvertikimab. And what we are seeing is we don't have any modification in the T cell and the B cell repair to us, meaning that will have the same clonality and the same capacity of T cells to respond to any infection or in infection cancer cells or any damage to eliminate in DM cells. So this is actually associated also in clinic, we don't have any occurrence of infection post treatment at short term and long term. So actually, we don't -- we think that with the gas regulation of IL-7 in IBD, we will target the column, and we will target the T cells and the disregulation in the column and will not affect the memory T cells for infection or future response to other paresis.