OSE Immunotherapeutics SA (OSE) Earnings Call Transcript & Summary

Welcome, everybody, to OSE Immunotherapeutics' Key Opinion Leader webinar. In this webinar, we're focusing on OSE's leading immuno-inflammation asset, lusvertikimab, which has completed a Phase II trial in ulcerative colitis or UC. So top line results were reported in July last year, followed by more detailed data in November. More recently, OSE presented multiple abstracts and additional data at the ECCO conference at the end of February. Today's webinar will recap the current clinical status of the program and allow for some valuable insights from key opinion leaders from the field who join us here today. The agenda will be as follows. We're joined by Nicolas Poirier, CEO of OSE Immunotherapeutics, who will provide a more detailed overview of the company's lead immuno-inflammation assets, lusvertikimab. We have Professor, Arnaud Bourreille from CHU Nantes, who will introduce the data presented at ECCO from the Phase II trial. We have Professor, Vipul Jairath from the Schulich School of Medicine and Dentistry, who will share some further insights into the implications of the latest data. And we have Professor, Laurent Peyrin-Biroulet from Nancy University Hospital, who will discuss the current treatment landscape in UC. So to introduce our first presenter, Nicolas Poirier, CEO of OSE. Nicolas holds a PhD in immunology as well as a double master's degree in biotechnology and pharmacology. Nicolas has been a member of the management team of OSE since 2016 and has recently reinforced the leadership team within the company. So to kick things off, Nicolas, can you tell us a little bit about OSE's interest in this area, along with a brief overview of IL-7 in terms of context and differentiation?

Yes, sure. Thank you, Arron. Hi, everyone. So OSE first is a clinical stage biotech. We are dedicated to develop first-in-class immunotherapies by leveraging on our expertise on immunology, what's wrong with the immune system, how we can repair it and leveraging on our also molecular engineering team. So right now, we are developing this diversified pipeline of immunotherapies in both immuno-inflammation in green and immuno-oncology in blue. And today, we will focus more on the immuno-inflammation with our lead program, lusvertikimab targeting at IL-7 receptor for which we are very happy with the meaningful clinical data we will discuss today. So just as a matter of introduction on lusvertikimab, so lus is blocking the IL-7 receptor pathway. And it's a very differentiated new mechanism of actions in chronic inflammation, in particular in IBD, very upstream MOA compared to the classical downstream inflammatory cytokines, where IL-7 is produced by our own tissue, in particular, the epithelial cell in the colon and is at the crosstalk between these epithelial cells and the immune system to sustain locally the survival and expansion of these pathogenic immune cells like T lymphocytes in lymphoid cells and so on. The beauty of this biology is a target of lusvertikimab, IL-7 receptor alpha chain, which is highly expressed by the memory T cells innate lymphoid cells, tissue resonant memory T cells, but very weakly expressed by the Tregs. So it's a quite unique opportunity in IBD and in other inflammatory disease to block the expansions of the bad guys, the pathogenic T lymphocytes and to tip the balance towards more regulation, spare the Tregs and recalibrate this dysfunctional immune system. So this program, lusvertikimab has been first introduced in Phase I in healthy volunteers, where we published very good safety, PK/PD profile in healthy volunteers and then has been introduced first in ulcerative colitis in terms of efficacy studies. Why first ulcerative colitis for IBD? So some of our similar works at the research level on the left highlight that this approach looking at IL-7 receptors is very efficient to control T lymphocyte mediated immune disease, in particular in the colons in humanized animals or in the skin, so in dermatology models in nonhuman primates. And we also illustrated ex vivo with biopsies, fresh biopsies from patients -- ulcerative colitis patients grown ex vivo that these drugs very quickly block the reactivations of T lymphocytes and induce an exertion of these cells. On the right part, we also illustrate that these targets, all the pathway of IL-7 receptors is very overexpressed in the gut mucosa in particular in ulcerative colitis of Crohn's disease patients and more particularly in patients with very severe refractory disease to biological treatment like anti-TNF or vedolizumab at the time we published this work. More recently, our latest research that we disclosed a few days ago at the ECCO conferences highlighted that this target IL-7 receptor is also overexpressed in the gut mucosa of IL-23 or IL-12/23 antagonist treated patients with a very nice correlation between IL-7 receptors and IL-23. We found that IL-7 is a resistant mechanism, it could be a resistance mechanism to anti-IL-23 inhibitors in vitro and in vivo preclinical models, combining these 2 approach deliver very nice preclinical efficacy studies with complete normalization at histological levels, complete inhibition of infiltrates and restorations of all histological lesions. So this was a very good new technical package that highlights the value of this differentiated MOA and that even reinforce our package now with the new positive Phase II data in ulcerative colitis.

Great to see how lusvertikimab fits into OSE's wider clinical pipeline and learned a bit more about its unique mechanism of action. I'll hand over now to our next key opinion leader, Professor, Arnaud Bourreille. Professor Bourreille is an Associate Professor of Gastroenterology and Head of the Institut des Maladies de l'Appareil Digestif. He specialized in IBD and is currently Head of the Clinical Research team at the Institute. Professor Bourreille recently presented data at the ECCO Congress in Berlin. In fact, his presentation selected from almost 1,800 abstracts was highlighted as one of the top 10 highlights at ECCO. His presentation today will showcase the latest Phase II data for lusvertikimab. So Professor Bourreille, over to you.

Okay. Thank you very much. I'm going to present you the results of this multicenter randomized placebo-controlled Phase II study in patients with ulcerative colitis. So I think that I can go to the design of the study. So patients with moderate to severe active ulcerative colitis, which was defined by a modified Mayo score between 4 and 9 with a Mayo endoscopic subscore above or equal to 2 and rectal bleeding and stool frequency score above 1. And the patients who have failed or were intolerant to steroids, immunosuppressor and biologics were randomized according to a ratio of 1:1:1. In low dose lusvertikimab, high does lusvertikimab or placebo and all the patients received 3 infusions at week 0, 2 and 6. And the end of the induction phase was assessed at week 10 with the evaluation of the primary endpoint. The primary endpoint were the efficacy of lusvertikimab compared to placebo and the reduction of the modified Mayo score. And as you can see, many secondary endpoints were also assessed at the end of the induction phase, clinical endoscopic, histological and biological endpoints as well as the overall safety and adverse events. So the efficacy was assessed on the fast population. The safety and adverse events were assessed in all patients who received any amount of the study drug. The sample sizes of 44 per group were expected to achieve 85% power to reject the null hypothesis of equal means between placebo and the high dose of lusvertikimab, leading to a main difference of minus 1.5 modified Mayo score changes from baseline were analyzed by ANCOVA with treatment baseline score and stratification criteria. And an interim futility analysis was planned after the first 50 patients that completed the induction phase. And if the conditional and the predictive power were less than 20% for one of both doses, the study arm was to be discontinued for futility. So 211 patients were screened and 136 patients responding to the inclusion criteria were randomized in 3 group, placebo, low dose of lusvertikimab and high dose of lusvertikimab. As you can see, only 2 patients were excluded from the analysis because of a major deviation and the diagnosis modification in both low dose and high dose of lusvertikimab. And at the end, 49 patients were analyzed in the placebo group, 35 patients in the low does lusvertikimab and 50 patients in the high dose lusvertikimab. There was fewer patients in the low dose lusvertikimab because this group was dropped after the futility analysis. But importantly, it was later shown to be non-futile. So this is the patient demographic and baseline disease characteristic, baseline characteristic of the patients and the profile was expected with a mean age of 40 years, a mean duration of UC of about 8 years modified Mayo score baseline around 6 points, and modified -- Mayo endoscopic subscore of about -- around 2.5 in each group, where -- but there was a slight imbalance between the low dose lusvertikimab and high dose lusvertikimab, as you can see, there was fewer patients in the low dose lusvertikimab, with higher MMA score, high Mayo endoscopic subscore of 3 and fewer patients were biologic exposed to 1 or 2 biology compared to the high dose of lusvertikimab. Concerning the primary endpoint, the primary endpoint was assessed at week 10 at the end of the induction phase. And as you can see both doses of lusvertikimab decreased significantly compared to placebo, their modified Mayo score in the patients. And if we look at secondary endpoint, clinical secondary endpoint assessed at week 10, you can see that the percentage of patients in clinical remission defined by MMS less or equal to 2 with no subscore above 1 was increased in patients treated by lusvertikimab with a delta of 18% for the low does of lusvertikimab, and 12% for the combined dose of lusvertikimab compared to placebo. Endoscopic parameters were centrally assessed by central readers at the end of the induction phase. The improvement of endoscopic severity was assessed by the names changes in Ulcerative Colitis Endoscopic Index of Severity. And as you can see, there was a decrease -- a significant decrease compared to placebo for both doses of lusvertikimab, the low dose and the high dose of lusvertikimab. And if we look at endoscopic remission with a stringent criteria because endoscopic remission was defined by Mayo endoscopic subscore of 0, you can see that patients treated by lusvertikimab were more in endoscopic remission compared to placebo with a delta of 22% for the low dose and 12% for the combined dose. As for endoscopic parameters, histological parameters were also assessed by central pathologist, independent blinded central pathologist. Histological improvement was defined in the protocol by the Nancy histological index less or equal than 1. And as you can see, both doses of lusvertikimab increase were significantly different compared to placebo with more patients with histological improvement for low dose and high dose of lusvertikimab. And if we look at the histo-endoscopic mucosal improvement, combining the Nancy histological index less or equal to 1 and the Mayo endoscopic subscore plus or equal to 1 you can see also that lusvertikimab increased the percentage of patients with histo-endoscopic mucosal improvement. If we look at other scores of histological improvement, the Geboes score and the Robarts' histological index, you can see that lusvertikimab decreased significantly both scores of activity, histological activity as well as for the Nancy histological index. Concerning the safety, the safety was good with no signal. The table summarized all the adverse events declared for at least 2% of the patients. There was a slight increase of lymphopenia and lusvertikimab compared to placebo, but lymphopenia were always transient, not associated with a higher rate of infections and there was no treatment discontinuation. So in conclusion, lusvertikimab demonstrated clinical endoscopic, histological and biological efficacy versus placebo at the end of the induction phase and the safety was good. The treatment was well tolerated with transient lymphopenia, but without any higher rate of infections.

Excellent. Thank you very much, Professor Arnaud Bourreille. Great to recap the most recent clinical data for lusvertikimab and hear your thoughts on the efficacy shown by the candidates. Just as a reminder to our attendees, there will be a Q&A session following the presentation today. So please do feel free to send in your questions throughout the event, and we will address them at the end. There should be a panel on the right-hand side of your screen to send those in. For now, we'll move on to our next key opinion leader, Professor Vipul Jairath. Professor Jairath is a Gastroenterologist and Professor of Medicine in the Schulich School of Medicine and Dentistry and holds the John and Susan McDonald Endowed Chair in IBD Clinical Research at Western University, Canada. He leads the IBD Center at University Hospital, and is also a principal investigator for multiple randomized controlled trials in IBD. So Professor Jairath is going to present some additional data that was presented at ECCO, data that showed that lusvertikimab significantly decreased FCP after 10 weeks of treatment in ulcerative colitis patients with active inflammation. So Professor Jairath, the floor is yours.

Okay. Great. Well, thank you very much for the kind invitation to present here, and thanks, everyone, who's joined online. So I'm presenting some additional data that build on the data that you just saw from the ECCO Congress. And we specifically focus in on patients who have had active -- more active UC at baseline, specifically looking at the fecal calprotectin levels at baseline. So if you look at the patients who had a calprotectin at baseline of more than 250, i.e. was elevated at baseline, the slide on the left looks at the absolute change in the fecal calprotectin level in placebo and the 3 groups here. So the placebo group, as you might expect, got slightly worse. There was an 8-point increase in the fecal calprotectin. But if you look at the 3 groups, the 450 milligram, 850 milligram and the combined group, there was anywhere between roughly about 1,000 point to 1,160 point decrease. These are all nominal p-values, which are all highly significant compared to placebo. So telling us that there's an important biomarker response early within 10 weeks. On the right-hand side, we see fecal calprotectin normalization at week 10. Again, this is a population that outcome more than 250 baseline and the endpoint being an outcome of less than 250, that was seen in 18% of patients on placebo, 38% in the -- 45% in the 850 milligram group and 42% at combined group. So delta is over placebo between 20% and 27%, again, all nominally statistically significant and if you look at the p-values. And this data now look at the modified Mayo score improvement and modified Mayo score clinical remission on the right at week 10, again, in the patients with a calpro of more than 250 at baseline. So improvement here on the left in terms of the absolute number of points decrease was 1.4 in placebo and almost double that in the 3 dose groups you can see. Again, these are all highly significant p-values, again, nominal p-values. And on the right-hand side is clinical remission at week 10 in the same population. This was defined as a modified Mayo score of less than 2 points or equal to 2 points and a subscore more than 1. Whenever I see a placebo rate of 0, it tells us we have good internal validity of well-conducted trial. And the highest delta over placebo was in the low-dose group of 28% or 28.3 percentage points over placebo. And look at these again were significant values. We then look at the clinical and endoscopic changes at week 10 according to bio exposure. So here, we present the biologic experience group on the next slide, the bio-naive group. The clinical remission rates at week 10 in the biologic experience group, almost no patients in placebo, 8.4% and approximately 5% in clinical remission in the bio-exposed groups. Again, just to be conscious that these numbers are quite small here because the number of bio-exposed patients was smaller than the bio-naive subgroup. So just bear that caveat in mind. The middle graph looks at endoscopic improvement at week 10 in the biologic experience patients. Again, endoscopic improvement is a modified endoscopic score of 0 or 1. Very few subjects in placebo achieved this just 1.4% and 15.8% in the 850-milligram group and 20.8% in the combined group. So these are giving deltas almost 20% over placebo. And similarly, on the right-hand side, endoscopic remission, which is a more stringent endpoint of Mayo endoscopic subscore 0. Actually, what you can see that the numbers are almost identical to the middle graph because most of these patients actually achieved endoscopic remission. So I think this is consistent with the robust endoscopic remission data we saw in the overall population for this compound. And then this then stratifies the same data by bio-naive subjects on the left -- bottom left, clinical remission at week 10 in the bio-naive subgroup. And you can see the placebo rate 7, again, which is low, and the deltas really range from almost sort of 10% to 20%, 20% on the highest dose for clinical remission, endoscopic improvement, again, which is a Mayo 0 or 1. Again, this is 28% delta over the placebo population, the low dose where it's 48.1 versus 19.6 just at week 10. And in endoscopic remission, which is a Mayo endoscopy score of 0, similar numbers, slightly lower, but 19% in placebo and 38% in the lowest dose where the maximum efficacy was seen over placebo. And this then looks at the endoscopic changes in the patients who are on steroids in the study, which is approximately half of the population overall. This looks at the UCEIS scale. This is another endoscopic scoring tool. It's typically not used as a regulatory endpoint, but a highly ranked secondary endpoint different to the Mayo endoscopy score because it has a broader scaling so you can detect change in small numbers of patients on the scale. And this is consistent with the Mayo clinic score data where you see almost no improvement in the placebo group and up to 2.5% reduction maximally in the low-dose group. And similarly, on the right-hand side, this is endoscopic remission in the patients who are on steroids. This is a Mayo endoscopy subscore of 0 or 1. Again, this is seen in 44% in the low dose and 11% in the placebo group, giving a delta of almost 33%. So thank you.

Excellent. Thank you very much for those additional insights and helping us understand what the data means in a wider context. We're doing pretty well for time here today. Everyone is keeping to their time schedule. So there's going to be plenty of time for Q&A. So as a reminder, do please keep sending those questions in. We've got a few already. So it would be good to see some more come through throughout the remainder of the presentation portion of the webcast. And that then brings me on to introduce our last presenting key opinion leader, Professor Peyrin-Biroulet. Professor Peyrin-Biroulet is a Professor of Gastroenterology at Nancy University Hospital and an internationally recognized expert in Inflammatory Bowel Disease. He is currently the principal investigator of several dozen ongoing clinical trials, and he's also developed several indexes for IBD, such as for measures of severity and disability. So to wrap things up with the presentation portion of this webcast, Professor Peyrin-Biroulet is going to give us some discussion around the burdens associated with the disease, the instance and epidemiology as well as an overview of the therapeutic landscape. So without further ado, Professor Peyrin-Biroulet, over to you.

Thank you so much. Hello, everyone. I must say that when a drug is changing something, you have to change the agenda. So this is the reason why I'm speaking now because initially, we are thinking that I would start, but I was thinking, okay, it's a game changer. We are so excited. So let's talk after all my friends to talk about where we are in terms of ulcerative colitis and IBD in general. So if you look at the next slide, I think this is our biggest challenge. What is our biggest challenge. We are far from a cure. What is a cure? The cure is that no disease and a patient who is feeling in great shape. This is summarized on this slide. It's very funny because I made this slide maybe -- I don't know, maybe 10 or 15 years ago, and it's still valid. This is still -- when everybody is asking me what is the ultimate therapeutic goal in IBD, I say this is that. The next slide, if we go to epidemiology, just to remind you because we talk a lot about new drugs, but still the incident is rising. It's still endemic. It started a long time ago, we reported the first UC case almost 1 century ago. And now you see that it has increased everywhere in Western industrialized country, but still now in newly industrialized country, it is also rising a lot. When you talk about the current prevalence and incidence, what is very interesting on this slide, maybe you can do again, which is very easy. You can just look at your country. Just try to find your country on this slide. And you will see that if I take the example of France, this means that almost 1 out of 10 people in France will have IBD. This is a disaster. This means that we need to do for sure, more research. But when I started IBD 20 years ago, a long time ago when Professor Jairath was still at high school, when I started my medicine studies, and when I started working on IBD, everybody was saying me what is IBD? It's a rare disease. No, we know that, it's not anymore the case because this is very frequent disease like psoriasis, diabetes and so on. If you look at the next slide, where we are coming from in terms of drugs, they were showing you new drugs, new MOA, which is very nice, very exciting, but we need to look back to see what has been achieved, what has changed in our practice. We started with steroids a long time ago, as I chopped in, then the revolution started 25 years ago with the arrival of infliximab. Infliximab was a start of a new story and was really fantastic. In terms of drugs, this was 25 years ago. And then when Professor Jairath was advancing regarding his medicine studies, you could see that there were a lot of drugs that were tested. Success or failure, we were quite fortunate at the end because even if we say, okay, at some point, a lot of drugs have failed, look at all the drugs that have been approved at some point and that now are available in routine practice. This is starting to be very impressive to be honest. This is where we were, I would say, the last 2 decades, now this is where we are with JAK coming, IL-23 inhibitors, but still we need more drugs for these patients. When you look at the natural history of IBD, this is a paper that we published a few days ago in Lancet Gastro, which I think is probably one of a very important topic. I think it's one of the biggest topic today. It's how to treat our IBD patient. No overtreatment, no under treatment. If you look at the natural history of these people, when you look at 10 years, you see that some patients will never need an advanced therapy. We have sometimes overtreated this patient because we were so excited to have so many drugs that we said at IBD diagnosis, let's start with a drug just to see what happens. Let's start with a drug with an advanced therapy for everybody at IBD diagnosis. This is a risk of over treatment. In IBD, in ulcerative colitis at least 20% of patients just need 5 visit. In Crohn's disease, 50%, 60% of patients does not have complication, disease complications that have lower damage and maybe can be treated with simple drugs. If you look at STRIDE-II, it's a very famous slide, but I think this slide is just illustrating and I would like to remind people that STRIDE-II is about routing practice, not clinical trials. When you look at STRIDE-II, what matters is where we are going. We are always more ambitious. We want [indiscernible], we want ulcerative colitis -- we want histological healing in ulcerative colitis. Ulcerative colitis, you have a verdict trial that is ongoing and led by Professor Jairath, that will be a very important trial. He moved from high school to now very innovative and very big trial that probably I think will be published in the New England and that we are all waiting to see what is the ultimate therapeutic goal. And this trial that is ongoing will tell us whether we need this drug. But what I can anticipate is that the rate of complete disease control or disease clearance will be at the end relatively low. So this means that once again, we need new MOA such as the compound that we are discussing tonight. And you see, and this is a slide for Vip, now that -- now he is growing, I'm even taking his slide. This is just the concept that to tell you, we are more and more and more and more and more ambitious. Now we are looking at disease clearance, which means we want no inflammation, no symptoms. We think it's the best way to change the natural history of ulcerative colitis, no symptoms, endoscopic remission, histologic remission, and so on. When you look at this trial, I told you the verdict is ongoing. We'll get the final results very soon. Everybody is looking for it. This will tell us where we should go. Because a target does not mean anything by itself. What means the target? It's simple, interesting, if it is associated to a change in the natural course of the disease. This is what is exciting. A target by itself does not mean anything. You have patient perspective where patients want to feel better. And whether you can change the natural course of the disease in ulcerative colitis, preventing hospitalization, preventing surgery and so on. How can we break the therapeutic ceiling? So this is a slide that was done by [ Dr. Raine and Professor Daniele ] just to say that this is what we are exploring, this is what we want to do. We are dreaming about that because we want to be close to a cure. We are very far. Only 20% of patients will achieve full remission with current advanced therapy. How can we do that? And I think it's very important, and it's something that is changing. It's probably with combination therapy. I think, and it was quite surprising despite we have to be very cautious because this is very small sample size, so we have to be cautious regarding the interpretation of this trial. But when you put 2 drugs together, it's better. So I would not say that 1 plus 1 is 2, but at least it's close to 2. It's not like in genetics. In genetics, when you do 1 mutation plus 1 mutation, it's 1.1 Here, it's very impressive. And maybe we are close to a clinical remission rate that we have never seen. It's almost doubling the remission rate, which is something that is very nice. So we have been started very far and where we are today is very exciting. And I hope that in the near future, this will be top of the top with all these new compounds. It's not only this one that will combine, and we'll see where we can change patient life and change disease course. And this is the last slide to tell you that where we are going. I don't want to put take-home messages. I just want to let you know that this is for me a very important slide. It is summarizing what we have learned since decades of work. It looks very simple. And I remember when we did that for gastroenterology. And it's very funny because it's even -- I did this slide because it's something I have in mind. Everybody is always asking me, Laurent, but what is the ultimate target? The target is first to control the disease and the symptoms; second, to achieve deep remission. The level of deep remission should be discussed transmural healing, histological healing, endoscopic healing, and then to change the course of the disease with disease modification. With that, I would like to thank you for your attention. And I don't think that it's Nicolas who will speak after me because you already spoke. So thank you so much for your attention, and now probably we can continue. Thank you.

Excellent. Thank you very much, Professor Peyrin-Biroulet for that overview. Very nice to hear how the prevalence of ulcerative colitis has evolved over the years and how the treatment landscape has developed up to today. Thank you very much to our attendees as well for bearing with us with the last-minute change of order. But that concludes the presentations for now. So thank you very much to all of our key opinion leaders for your insights. I think we're all going to join me on screen now, and we're going to proceed to the Q&A session. So as a reminder, to ask a question, please type it into the Q&A tab on the right-hand side of your screen. And just while we let some of those come through, I'll kick the conversation off with an initial question, perhaps best suited to Professor Laurent Peyrin-Biroulet, actually. So could you provide, just from your perspective, perhaps a bit more color on where you believe lusvertikimab might fit into the current treatment landscape for ulcerative colitis?

I think, to be honest, it's always too early to draw any conclusion about that. I could say it's fantastic, gamechanger, changing everything, and we use it in any patient. I think what is important, you have to keep in mind 2 messages is that, first of all, it's a new MOA, and we need new MOA. So it will allow new combination for these patients. Probably, combination with IL-23 will be big in the near future. So I think this is advancing the field. Where it would fit? I don't think that it's a question of efficacy only. It's probably a question of risk benefit. If the safety is confirmed to be very good, it's a very good point, then this means that the risk/benefit could be very interesting, whether it will be in every moderate-to-severe, it also depends on the country. In France, you need head-to-head for reimbursement and so in the U.S., you can get access to drug. So it also depends on the country. So we have to see. But to be honest, it's quite early. I don't want to be too -- I want to be very honest.

Understandable. A question now for Professor Arnaud Bourreille. Looking at the Phase II data, we saw an interesting dose response between 450...

I think Arnaud has maybe frozen. Maybe just to add to that, just while we have a pause. I think one of the things that stood out for me in the data was the endoscopic and histological data. Many trials now have 12-week endpoints. Most ulcerative colitis trials have 12-week endpoints. And we know with time, you get typically greater efficacy. So this was a 10-week endpoint. And I think what really stood out to me was the objective marker of efficacy. So even the endoscopic remission, which was Mayo 0 after 10 weeks, was seen in over 1/3 of subjects. So I think that's as good as most things that we've seen. So I echo what Laurent said that obviously, we need additional MOAs because, unfortunately, there's a group of patients who cycle through therapies, and they get immune escape mechanisms that do need an MOA. So this looked in a similar ballpark to other modalities we have, accepting it's Phase II, and we need a Phase III trial. But the early data would suggest that. And I think ultimately, as Laurent says, I think really to shift the needle of where do you take a very effective agent like this, which presumably will have a good safety profile and match it up with another agent, and you really get to north of 60%, 70% efficacy rate. So I think that's where we would see the landscape going eventually with a single agent with the objective data certainly looked robust in a relatively small Phase II.

Excellent. Yes, thanks for that, Vipul. Thanks for bearing with us as well. I think we've got Arnaud was just frozen, but I think we're back now. So Arnaud, if I can direct a question to you. We're just looking at the Phase II data and thinking about the dose response in between the 450- and the 850-milligram doses. I wonder if you could comment on how we should go about interpreting this.

Yes. I think it's difficult to conclude about the dose response with lusvertikimab because, in fact, with the results of the Phase II study, the low dose seems to be more efficient than the high dose. But as I show you, there was a slight imbalance between the low dose and the high dose of lusvertikimab, and it was a consequence of the futility analysis, because at the beginning of the study, both of the patients were less severe and less biologically exposed. And the placebo rate was very high, explaining why the low dose of lusvertikimab was shown as futile after the futility analysis. But at the end of the trial, when we have analyzed all the patients treated with the low dose, it appeared that the low dose was not futile. So to satisfy the stratification criteria of biologic exposed patients, we were forced to include, after the modification of the protocol, more patients biologically exposed in the high-dose lusvertikimab and more severe patients. And of course, it's very difficult in a Phase II study with a low number of patients to demonstrate efficacy in subgroup of patients. But I think that there are -- the protocol, the study was positive for the primary and for many stringent secondary endpoints for both doses of lusvertikimab. And it's difficult to assert that there is a difference between the high and low dose of lusvertikimab.

Excellent. Thank you. A question for Vipul. You kind of touched upon it, but just thinking back to some of the safety outcomes. It's obviously a really important component, particularly...

Yes, I would agree. I think the stringency across all the endpoints speaks to that. And I think the other thing that stood out is that we've seen a number of clinical trials recently with anomalously erroneously high placebo rates, which we don't fully understand and gave me some faith to see this trial with placebo rate operating at sub-5%, which is where they should be for some of these endpoints. So it was obviously a very well-conducted Phase II trial, so credit to whoever was responsible for that.

We'll move on now to a question for Nicolas. Nicolas, could you share an overview of what the next steps for the program might look like?

Yes, sure. So I think first part of the answer, short term, we are analyzing the open-label extension periods. So the last patient last visit was end of January, a few weeks ago. And now we're analyzing this data with additional 24 weeks treatment in terms of safety and also patient response. So this will be an important piece of additional data that we will communicate at the upcoming medical conferences, hopefully to reassure on their safety and efficacy for longer duration of treatment. So that's the first part, let's say, really short term. Then second, in parallel, we are evaluating the best strategic opportunities for this program and for the company. We have very strong confidence of lusvertikimab. We are very confident with the data we have generated. It's potentially diamonds, let's say. So in parallel of progressing of our development strategy in ulcerative colitis, we are also exploring broader opportunities in additional therapeutic areas. We know that there is very strong biological translational rationale in other therapeutic space in I&I with high unmet needs, very great market opportunity. So we're working on it, and we look to maximize the value for both the patients and the shareholders of the company. So we are looking forward to sharing more information on the development plan in the coming months in the future.

Okay. Excellent. Thank you very much. Just as a reminder to our audience, please do feel free to keep sending your questions in using the Q&A tab. We'll endeavor to answer as many of them as possible. An open question now for any of our key opinion leaders. Quite a general one, but how do you see this field evolving in the years to come?

Very well. No, I think, you have good and bad things. The bad thing is that when you look at the pipeline compounds and so on, to be honest, I don't see a compound that could lower or at least envision a cure. This is a negative, pessimistic view. I don't think that there is a compound for cure. The good point is that with combination and so many new MOA to treat these patients in routine practice with positioning, sequencing, clinical personalized medicine, and also this will be fantastic for our patients.

Thank you very much. Our next question comes from -- we've kind of touched upon it a little bit already. But in terms of the better efficacy with a lower dose, I suppose could we just maybe get a bit more color on whether this might be due to patient characteristics at baseline, so perhaps elements of biologically exposed patients?

Yes. I think that the imbalance between the high dose and the low dose lusvertikimab for clinical baseline characteristic of the patient could explain the difference of the efficacy of the treatment. But, of course, the high-dose lusvertikimab was also efficient and demonstrated its efficacy in the primary endpoints and in endoscopic and histologic endpoints. So I think that it's impossible to conclude that the low dose was better than the high dose because we don't have enough patients to analyze subgroup of patients and the disequilibrium between the 2 groups of patients impaired the analysis at the end.

Thank you very much. Our next question, perhaps best suited to you, again, Arnaud. Could you please explain the interim analysis, which led to the futility? How do you explain response, which I think we've already covered, but...

Yes. The futility analysis was planned at the beginning in the protocol of the study. And the first 50 patients included in the study treated by placebo, low and high dose of lusvertikimab were analyzed on the MMS, on the changes of the modified Mayo Score. And as I said, patients at the beginning of the study were mostly biologic-naive patients and less severe. And, of course, the placebo rate of efficacy was high in this subgroup of patients bio-naive and less severe and explained that there was no difference for the 51st patient between the low-dose lusvertikimab and the placebo. So at this time, the low-dose lusvertikimab group was closed, and the protocol was modified to include patients only in placebo and high-dose lusvertikimab. But at the end of the study, we have analyzed all the patients in the low-dose lusvertikimab, the patients of the futility analysis, but also the patients who were ongoing and treated by lusvertikimab low dose. And at the end, the final analysis of the study demonstrated that the low dose was not futile at all. So it explains why we have the efficacy for the low and the high-dose lusvertikimab at the end of the study for both primary and secondary endpoints.

Thank you very much. Our next question, please, could you comment on the imbalances in baseline characteristics between the study arms.

Yes. It's always the same answer because there was less patients with severe MMS and severe Mayo Endoscopic subscore and less patients with exposure to 1 or 2 biologics compared to the high dose. But it was always due to this -- it was necessary after the futility analysis to include more severe patients and more bio-exposed patients, and we had only 2 groups, placebo and high dose. And at the end, it explained the disequilibrium, the imbalance between the 2 groups.

Excellent. Thank you very much. Our next question, which I believe is directed at Nicolas. Would you have any element to share with us about the maintenance phase after 24 weeks? Or when do you plan to share information with the market about this subject?

Yes, we have no information yet, as I said previously. So the last patient last visit was end of January, so just a few weeks ago. So then we need to clean the database, database lock, et cetera. And the team are currently analyzing these additional safety elements and clinical response for the patients after 24 weeks. So we will have complete reports in a few days or weeks now, and then we will share these information at the next upcoming medical conferences.

Excellent. Thanks very much, Nicolas. Our next question, again, touching upon the doses there. We may have already covered this, but we've just been asked if we can touch on the severity of disease for patients in the 850 versus the 450 mg arms.

Can you repeat your question, excuse me, Arron?

Sure. We've been asked if we could touch on the severity of disease for patients in the 850 versus the 450 mg arms.

I'm sorry, but I don't understand your question.

That's okay. Perhaps we can move on from that one.

Maybe the question was why -- how do you explain that we have more severe patients? Is it okay? These questions are...?

Because, of course, when you -- yes, it's a supposition. I don't have the firm conclusion about that. But at the beginning of the study, investigators included their patients and most of the patients were bionaive. I don't have a clear explanation about that, but it's typical in this kind of Phase II study, you include all your patients, all your active patients in the Phase II and the patient could be treated or not with biologics. And at the beginning, patients were bio-naive, and it explained the disequilibrium between the 2 doses of lusvertikimab.

Thank you very much. Our next question is directed at Vipul. Vipul, if you can, maybe just from your point of view, could you just summarize what you believe some of the key takeaways are from the most recent data?

Okay. Sorry, I think, unfortunately, I can't hear any of the questions coming through. But I think the question I've been asked is in the chat here, summarize the key takeaways from the data. So look, this is a Phase II trial. It's about -- it's an adequate sample size for Phase II trial. It was a well-conducted study, and you can see that from the placebo rates that we've seen in the study. I think overall, the efficacy rates are for a Phase II compound in keeping with pretty much any other asset that we have in the clinic today, there are good clinical remission rates. I think the objective endpoints of endoscopist pathology and the combined endpoints, particularly are robust. And I think it has a clean safety profile. Of course, the numbers are small. There's a 10-week endpoint, and you'd have to see something very major in safety, but there are no red flags there. So I think this really -- I think what I see from these data really supports the target #1, supports the development of this into the next phase. So really, those are the key takeaways for me.

Excellent. Thank you very much. And apologies for the technical difficulties there, but thank you for asking out our questions. Our next question, perhaps directed at Nicolas. Could you comment on the potential of lusvertikimab and any indications beyond UC, which is obviously the current lead program?

Yes, that's quite confidential for the moment, let's say, we have some competitors in the space. So we don't want to provide too much information before it's officially public. But what we can say in terms of beyond IBD or beyond UC for CD is a very high interest in Crohn's disease, of course, for the same reasons and the same preclinical and translational package. Then there is other therapeutic space in I&I like in dermatology with many different possibilities where this type of molecule should provide benefit in monotherapy with good market opportunities and that's the same, let's say, nearly all sorry to be technical Th1 or Th17 mediated chronic inflammatory disease in rheumatology, in neuroinflammations, type 1 diabetes. So there's a lot of literatures. And I'm sorry, I will not give exactly the precise indications we have in mind today. We will inform later on with the development plan.

Excellent. So I believe this will be our final question of the day, and I believe this is directed at Nicolas. Do you have any biomarker data for which -- any data that might help select appropriate patients for subsequent clinical trials?

Yes, that's a very important question indeed. So of course, during this study, we collected samples in patients pre and post treatment over the duration of treatments. And now we are currently analyzing this using the multi-omics approach, proteomics, transcriptomics, microbiomics, et cetera, to understand I think with 2 objectives. Do we have -- what are exactly the molecular change impact in the tissue and therapy with these treatments. So in order to very well characterize the mechanism of actions in patients now this time in the tissue, first objective. Second one potentially is to identify any predictive biomarkers that could be of interest to predict clinical remissions of the patients that are likely to be enriched with clinical remissions. This is work that is ongoing, and we will be very happy to share more at the next upcoming conferences or the other one in addition to the open-label extension package.

Excellent. Thank you very much, Nicolas, and thank you very much to all of our presenters today. That's going to conclude our Q&A session. So thank you very much, everybody, for joining us today and for your questions. If you'd like to access more information on the company, please don't hesitate to visit our website, oseimmuno.com, and you can also freely access Edison's research on [email protected]. A recording of this webinar will be made available in the coming days. So all that's left to say is thanks very much to everyone for dialing in. Thanks to our presenters, and have a good day.