ABIVAX Société Anonyme (ABVX) Earnings Call Transcript & Summary

Good afternoon, and welcome to the ABIVAX investor call. [Operator Instructions] As a reminder, this event is being recorded, and a replay will be made available on the ABIVAX website following the conclusion of the call. I would now like to turn the call over to your host, Patrick Malloy, Senior Vice President of Investor Relations. Please go ahead.

Thank you, Sarah, and welcome, everyone, and thank you for joining us this afternoon. Today, we are honored to have with us two esteemed thought leaders in the inflammatory bowel disease state. Joining us today are doctors Marla Dubinsky, who serves as a Professor of Pediatrics and Medicine, the Icon School of Medicine at Mount Sinai Hospital in New York City, and also serves as a Chief Pediatric GI Nutrition at the Mount Sinai Kravis Children's Hospital. Also joining us are Dr. Parambir Dulai, Director of GI Clinical Trials and Precision Medicine and Associate Professor of Medicine at the Feinberg School of Medicine at Northwestern University. During today's program, Dr. Dubinsky and Dr. Dulai will provide an overview of the UC disease state and the market landscape as well as an overview of obefazimod and the unique mechanism of action, followed by an overview of the Phase II data that's been generated to-date. And finally, a discussion around the Phase III design and derisking elements. Following the prepared remarks, we'll move on to a Q&A session, where we'll be joined by our CEO, Marc de Garidel; our CFO, Didier Blondel; our Chief Medical Officer, Sheldon Sloan; and our Chief Scientific Officer, Didier Sherer. As Sarah mentioned, we will move to the Q&A session and first start with the sell-side analyst questions. And following the sell-side analyst questions, we will move to the audience questions. And as a reminder, if you have questions, please go ahead and submit those through the question tab. So with that, I'd like to hand the call over to our CEO, Mark de Garidel. Mark?

Thank you, Pat, and welcome, everyone. As those of you who are familiar with the ABIVAX story now, 2024 is going to be an important year for the company. As we outlined in the press release that we issued a couple of weeks ago, over the next 12 months, we'll be presenting multiple data sets from the obefazimod Phase II program at upcoming congresses, continuing our work on the obefazimod combination therapy program, kicking off the Phase IIb study in Crohn's disease and finally bringing our obefazimod follow on compound forward. However, our #1 priority is the enrollment and execution of our Phase III ABTECT-Program in uterative colitis. With that said, I'm very excited to have the two esteemed thought leaders with us today to provide that perspective on obefazimod and the uptake program. Now I will turn the microphone over to Dr. Dubinsky. Marla?

Great. Thank you, Mark. Hello, everybody. Parambir and I are delighted to be here to speak a little bit about the UC landscape and dig deeper into this asset. So first, I'm going to set the stage by sort of reminding everybody what the burden currently of ulcerative colitis is and a little bit about the background of inflammatory bowel disease. So approximately 2 million to 3 million Americans are impacted by inflammatory balances, but just as a reminder, that encompasses two different diseases, one is Crohn's disease and the other one is ulcerative colitis. Today, we're going to be predominantly focusing on the role of therapies in IBD. Why does this matter? It's because it continues to be an increasing health care expenditure despite all these advances in therapies that have occured really since the '90s, we're still seeing a significant total cost of care spend in inflammatory bowel disease. And also, just a reminder more about, forget necessarily the cost, but also the burden of this disease on individuals who are impacted and the day-to-day life with urgency, even fecal accidents, increased bowel movements, abdominal pain, blood in their stool, et cetera. So the impact of these conditions are really a huge burden, both indirect cost to the individual but and to employers, for example, but also to the total cost of care of managing these individuals. Now despite as noted, there has been really an incredible revolution in the way that we manage IBD patients starting with our original therapies in the antitumor necrosis factor space, most commonly infliximab or adalimumab, moving, therefore, knowing that those targets are specifically focused on a specific inflammatory mediator involved in all things inflammation, realizing we need to go more specific and on target, we moved beyond focusing just on end-stage inflammatory mediators like tumor necrosis factor to trying to address other cytokines with IL-12/23, ustekinumab, IL-23. There's been both mirikizumab and risankizumab approved already. Thinking about other targets. There's been the trafficking therapies, which are what we call the integrin based. We go after the cells that are involved inflammation in -- more so in the bloodstream and then probably the newest kids on the block are really and what we're going to talk more about is oral small molecules and the importance of pills that are actually approved for ulcerative colitis that actually fall into the category of advanced therapies. Most recently, RINVOQ in the JAK space and [indiscernible] and ozanimod as opposing vocipiny in the S1Ps. But despite this immense advance in all of these targets, there still remains a significant unmet need because not everyone responds to all of these therapies, and we haven't quite figured the story out. So there's always room for us being able to get more target and more specific and introduce new mechanisms of actions to the space. So I noted sort of I used the time line of the assets as they were and the actual targets of where these therapies came into play. But this really sets the stage, infliximab even goes back further for Crohn's disease, but in ulcerative colitis, which is what we're focused on here was introduced in 2005. And you could see that there was quite a lag between 2005 and 2012, and then there's been just like a race to the finish line to try and bring even more therapies. If TNFs were the solution, we wouldn't be here today. Clearly, Parambir and I, every day are dealing with individuals who do not respond to already approved therapies, and we can do better. So you could see that there's been this evolution to try and become more targeted and more specific to actually the biology of the individual patient and there's much need for improvement. We have a ceiling. And we barely get above x percentage of response and then x percentage of remission. So our net remission rates, we've got a huge opportunity where there's a plateau. And there's multiple reasons that go into this plateau. But one of them is we just haven't gotten the solution for the biology of everybody and maybe we need to do a new approach to understanding. So -- as we think about, all right, there's all these assets, where is the need, where is the gap in the market, where is the asset fit? And I think probably me sort of explaining a bit more about what goes into decision-making and the fact that really sales of the therapies are dependent on the providers who prescribe them. And what are actually the limitations for patients being prescribed effective therapies, this is really where there's a huge gap actually. It's just an understanding of which drugs when we should be using them and what patient. But probably one of the biggest limitations and I'm going to use the S1Ps as a perfect example. You have a therapy that actually may work first-line approach to inflammation control, a drug that actually causes healing of the intestinal lining and patients want pills. So why is the market as such, recognizing that the minute you either have a black box warning or you're asking me as a physician to do multiple things before I can write a prescription, I am so overburden as a provider that asking me to do one more thing or having my patient do one more thing before I can actually hand them a prescription, really creates a lot of traction and a lot of stickiness in the ability for patients to get on some of our newer therapies. So we shouldn't be using the current market uptake for any of our therapies when we're thinking about the lens to view new therapies. Because if we think about the more I need to do, the extra click, the extra fax, the extra phone call I need to make to get authorization or get my patient have a skin check or an eye check or need to do an EKG automatically, I'm prescribing something that's much easier and requires less work on my staff and my team because it's become difficult to get some of our approvals through. So at the end of the day, even though they're approved based on p-value, efficacy, method significance, then reality kicks in and practicalities of getting a drug into a patient's hand and recognizing who are the limitations or what are the limitations. So as we walk through Parambir is going to sort of remind us about the unique nature of the target that we're here to talk about, but also think about where it fits into the paradigm. So I'll turn it over to Parambir.

Awesome. Thank you so much, Marla. So I'm going to walk you through the mechanism for obefazimod and help really explain why this is very unique, but the mechanism through which it works is very relevant to achieve some of the long-term sort of efficacy and safety that we're hoping to achieve. So obefazimod enhances the expression of miR-124. And the concept I really want you to understand is that enhancement of miR-124 results in stabilization of what is already a dysregulated inflammatory response. These patients have high cytokine burden, that high cytokine burden results in high trafficking, that increased expression of some of those profiles is what's driving the inflammation. And traditionally, we've used suppressing agents that really push them down, but stabilization is a concept that we really want to introduce with obefazimod and we'll walk through why that's the case and why that's extremely relevant as you think about positioning this. So obefazimod binds the cap binding complex within the nucleus. And I think the most important thing is that there's been a tremendous amount of work done to confirm this, really take detailed images of the protein structure with cryo electron microscopy and know that we're targeting the receptors that we actually think we're targeting. That binding to that cap binding complex induces a selective splicing of a single lung non-coding RNA, which leads to the enhanced expression of MIR-124. That miR-124 then binds to its specific miRNA targets in the cytoplasm and reduces the translation into their respective proteins. One of the basic core concepts of immunology is that these immune cells can't do what they're intending to do if the cytokines aren't being translated from RNA to protein. So blocking that critical step is extremely important. By blocking that translation into the respective proteins, it really hits two key pathways that are relevant. One is MCP-1/CCL2, which is a very relevant pathway for macrophage recruitment and activation and two, STAT3 and IL-6, which are very relevant cytokines that have been traditionally difficult to target because we've been targeting suppression, not stabilization. But by targeting the suppression of these, we actually are able to achieve equilibrium and stabilization in macrophage activation and recruitment and stabilization in Th17 differentiated in those cytokines. That has really three important sort of downstream impacts. One, by avoiding excess immune suppression, we really mitigate a lot of the safety concerns that come with anti-cytokine therapies or anti trafficking agents that some of these things that really push the system down and you can't control or regulate how much of a suppression you have, particularly when patients are getting better. The second concept that's really important here is that by suppressing one pathway traditionally with immune suppressing agents, you do risk compensatory increases in other pathways because the immune system is quite smart and there's some recent work that's been shown to demonstrate why those compensatory mechanisms drive nonresponse to certain therapies like anti-TNF induced increases in IL-23, leading to some of the off-target side effects like psoriasis. And then finally, patient perception and engagement. As Marla talked about, black box warning, pretreatment testing, some of these things that lead patients to believe that there's risks related with treatment. The concept of stabilizing their immune system versus suppressing is something that will resonate extremely well for patient acceptance and uptake of this type of mechanism down the road. So looking at why we feel comfortable making these statements about stabilization. Let's talk about target receptor engagement and then what we've seen in some of the animal models. So one of the unique things about obefazimod that's different from prior studies for biologics and even small molecules is that we've been able to study the target both in the periphery, in the blood and in the tissue. And that's extremely relevant because a lot of the anticytokine or biologic therapies have not been able to be studied in the tissue for target receptor engagement. So we really don't know what that drop-off is. When you look both in the blood and the tissue for miR-124 expression, you can see that all three doses in the Phase II program of 25, 50 and 100 milligrams results in upregulation of miR-124 relative to placebo. And you do see that there's some incremental benefit from 50 and 100 versus 25, but really no difference between 50 and 100. So what this shows us is that in the target tissue of interest, the rectum, where we know that the majority of the inflammation occurs and there's a micro environment, we have demonstrated and observed a shouldering effect for the doses for achieving target receptor impact and really impacting miR-124 expression. So how does that miR-124 enhanced expression translate into changes in these cytokines that I sort of set the stage for very relevant. So to study that, we had 2 separate models. One is a DSS colitis model, very traditional colitis model that's used to induce colitis and two, just normal healthy mice. So when you take a DSS colitis model and study both the colonic tissue and the lymph nodes for these immune cells that are trafficking into the gut. On the left, you can see that when you give a DSS mouse that DSS -- there is a significant increase in CCL2 IL-16 relative to just giving that mouse water as a control. But when you add obefazimod to the DSS, you see that it results in a reduction of CCL2 and IL-6 relative to DSS alone, but it doesn't bring it down to levels that are far lower than what's seen without any induction of colitis. And when you look then at normal mice, you can see that obefazimod really has no impact on CCL2 or IL-6 and normal mice who don't have that induction of the immune response. So that reduction and stabilization and the lack of impact on normal mice is really relevant to demonstrate the stabilization effect. And then finally, when you look at the lymph nodes, you can see there is a change in Th17 cells and Th1 cells with DSS colitis where they do increase, and they're coming into the gut to drive inflammation. And the addition of obefazimod brings them back down to a baseline level that would be expected in both the DSS control mice as well as normal mice who has no impact on them. So this data and this sort of evidence together really shows how the mechanism drives stabilization of these pathways, which should translate into very transformative efficacy down the road. And that's where I'm going to hand it back to Marla to walk you through what we've seen in the Phase II program and how this has translated into our Phase II results.

Wonderful, amazing, thanks. It's always great to see new sort of new ways of thinking about controlling inflammation. So it's great to be -- you described that. So thank you. So yes, so let's get to what we actually know the data. Focus on the Phase IIb design here, just a couple of key points as a reminder. It was a Phase IIb, the endpoint predominant that we were looking at primary endpoint was mean change from baseline in the actual modified male score, which includes the endoscope, includes the stool frequency and includes rectal bleeding. Three key components to define that we have something that actually changes the outcomes of patients. These were -- there were four arms, they were randomized either 100 milligrams, 50, 25 milligrams once a day or placebo. We had an open-label maintenance as you noted, where everybody, regardless of which arm they were in, went into 50 milligrams once a day. You could see the division across 130 sites, 17 countries, including Europe, Canada and the U.S. The Mayo score, which is how we define the unique minimal inclusion criteria was for what is defined by guidance of moderate to severe inflammation, which means you had to have a score of at least 5 to get into the study. We had obviously patients who were failing conventional. We'll get a little bit into the details around that. on stable dose of steroids and stable dose of immunomodulators, pretty consistent. You'd see that in any sort of protocol that you would know that you would look up in terms of what our studies look like for UC. So a reminder about some key points about this patient population. So as noted here, although I noted 5 to 9, but you can see here, that the majority of the patients fell into 7 to 9, which means they were on this side of the moderate to severe. So if you take 5, 6, 7, 8, 9, you can see 7, 8, 9 was the dominant population here, and you can see the mean score was 7. And also looking at an endoscopic subscore which I think is interesting, although there's no box around it. I would tell you that -- it's a score of 0, 1, 2 or 3. And you could see that, again, at least 2/3 had a score of 3. That is important when you're looking at sort of the more severe population and another way to define disease severity or the population of refractory patients is just look at the exposure to prior advanced therapies, which includes JAK inhibitors. 18% of the population had been exposed to JAK inhibitors. That's the most exposure to a JAK in the trial. And also looking at not just a JAK, but two or more exposure to two or more of either class of biologics or a biologic and inject look at that population, you're talking 90% plus. So you get a feel for the actual refractory nature of this population, which I think is important when you contextualize the outcomes and then say, "Wow, if a huge amount of patients are exposed already when they come to centers like us or the group that they're asking us to help with -- what you can see is that, again, this was the focus of the population, which is where the biggest need is". So I think it's important to think about understanding where the need is in the market when you're thinking about where does this drug fit in? So -- and we'll get to that probably in Q&A. So here is the primary endpoint you could see across the doses. P-values significant. This is, remember, a change in the modified mail, which is rectal bleeding, stool frequency and endoscopic score. I showed you that actually the majority had 3/3 for EndoScore. So again, you're looking at did you achieve a change. You could see across the board, very similar in terms of the delta or the change compared to what placebo, you could see almost a threefold going from 2 to 3, 3.1 from 1.9. So you can see the deltas here of the change. Important week 8, common endpoint, being able to actually assess and you see what we want to see early. Remember, UC is a disease of urgency, rectal bleeding, stool frequency can't get off the toilet. The importance of assessing efficacy early is not lost on us. when we're thinking about when we want to see whether or not patients have achieved outcomes of symptomatic and/or endoscopic improvement. So that was a change, meaning looking at how much did the score change? This is another way of looking at efficacy. And these are secondary efficacy endpoints, primary was the change of the delta over time compared to baseline. This is actually looking at more classically a histogram, how many and what percentage met the endpoint that was defined. This is how you typically see your endpoints in histogram compared to placebo. And what we're showing you here is the delta from placebo. Also highlighting for everybody, clinical remission, which again is defined by stool frequency, rectal bleeding and an endo score. The definition is here on the slide, which is defined as a stool frequency score less than or equal to 1, no blood and an endoscopic subscore of 1 or 0. Remember, you started at 3. So again, this is the definition of clinical remission in current times. It's not just symptoms, it's symptoms plus endoscopy and you could see here the 3 dosing arms and what the delta was compared to placebo. And then you're looking -- and clinical remission is the hardest endpoint, right? The most robust this includes mucosa and clinical. Clinical response, you're really looking at truthfully the symptoms, which are rectal bleeding and stool frequency. Important, again, these are you better with regards to your symptoms and you could see here that. And just a reminder, because you've all seen data slides that when you have a lower bar to reach, placebo patients tend to reach it easier. So that is why the more robust end points are less objective. So just keep in mind that you're going to see placebo rates that are going to go up and down based on how high the bar was. Endoscopic improvement, you can't subjectify your way out of an endoscope. It is either there or it's not, right? So that's why you definitely see when you're looking at endo alone or endo plus symptoms, which is clinical remission, you can see placebo rates are more in line. And that's something you're probably accustomed to seeing and questioning around how do we get such a difference in placebo rates. So just a reminder about the bar out we set. So here, you can see again across the three dosing, you could see the deltas with the placebo. So as you add clinical plus endo, it's a different bar than endo alone or clinical alone. So keep that in mind as you're looking at the end point. And this is looking specifically at the refractory group, looking at endoscopic, objective, cannot subjectify your way out of it. So this is why we're highlighting in here showing you in the naive patients and the bio experience. As a reminder, a naive patient, just like clinical response will always have a higher placebo rate. So that's the point. But as long as the drug arms actually are also higher, you're looking at the deltas, do not look at the height of the bar. That is not how we interpret efficacy of therapies. We look at the delta between active drug and placebo. So you can see across the board. And then yes, there's a higher delta between placebo and dosing typically in any asset you look at, that it's going to be slightly in favor of naive. Great. It did great in naives. But probably where the market is, is look at that placebo rate in those experienced patients, it's almost 0, which is what we expect, the harder to treat patients, but look at those deltas. I think that is where Parambir and I are really excited around the idea that we are getting refractory patients, and we're seeing this kind of delta. So hopefully, we can dig more into that. But this was an important slide to share because it is the most objective and in the most refractory. So when people ask, where is the need? Hello, this is the need. This slide actually details where our needs are in both the objective as well as in the patient population. Of course, we can't talk fairly about efficacy and not mentioned safety, of course, because it's balanced. So here are sort of the key side effect profile to focus on. Obviously, worsening ulcerative colitis gets lumped into a safety slide. That's just because how it is in Table 2 or whatever it's a typical table. But for us, it's less about worsing disease. We know that. When you get we're saying disease, obviously, that is an effect, but let's focus on the things that really Parambir and I talk about in the clinic. We don't tell patients that one of the side effects is you don't respond. That's a dumb moment. What we're trying to say is are there other things that may happen. So here you can see headache, across the different both placebo and in the active drug arm, but focused on -- because everyone always asks like, what's more important, the actual event, meaning a percentage of people who have an event or the percentage of people who needed to stop the drug because of that event. That is the more relevant question because that's what Parambir and I get asked every day, is what is a side effect that is going to make me need to stop this drug because why am I going to start it, right? If everybody is stopping it, I don't understand why you're starting it. So it's really important for us to know from our trials, what limitations do these drugs have in terms of us needing to stop and you can see the low number of individuals who actually stop due to headache that we can talk about as well. Other common things, obviously, infections is what everyone wants us to talk about and really what's mostly important is serious infections and serious adverse events. That's where we need to be focused and this line shows you that the 100-milligram dose were the AE is about 5%. So just keeping that in mind when we talk about other things that have been. And here, we just wanted to bring out the headaches bury because I know there's a lot of discussion around the headache story. So we thought we would call out a little bit more about the headache. So it's a treatment initiation, typically transient, most resolved was in 7 days, mild to moderate in severity and managed with or without standard met. So that's the story around the headaches. And so not that I want to spend a lot of time talking about people's headaches, but we did want to bring it out because that is something we've been asked questions about. And then, of course, digging in the treatment adverse events, leading to study discontinuation. We talked a little bit about headaches, but let's dig into what really matters to me and Parambir, when we're sitting in front of a patient, any malignancy warning in any serious infections. That's what stops providers and patients from getting therapies. Those are the things that they really want to be focused on. So just doubling down, no deaths or malignancies reported, no signal for serious infections. There was individual that had an infection due to appendicitis. And the other important thing is because there's a lot of monitoring with a lot of our therapies, but just focusing on, there were no clinically significant changes like liver, leukopenia, which is the white cell [ KOL ]. We're not watching the liver enzymes, et cetera, which we do have to do quite a bit of monitoring or some of our other oral small molecules. So this was just a highlight. Lymphocyte count is a big thing with S1Ps, for example, we just want to highlight that. As of now, based on the Phase II, there was no signal with regards to laboratory parameters. So how do we frame it all? Because again, it's hard to keep track of everything that's out there because you saw that slide after the lull, there was like explosion, which is awesome for Parambir and I, obviously because we have options. But sometimes too many things make it difficult to understand what to use in which patients. So let me just remind everybody on the right is sort of what I just showed you, which is the clinical remission induction efficacy, all over the place between week 6 and 12, 6 is dating back to the interview days or the vedolizumab days and then we went to 8, then we swung to 10, then we swung back to 8, and now we swung to 12. So you really get a sense of across the board that there's many different end points that have been looked at in Phase III. We're focused on the right, looking at the endpoint of Phase II, looking at the clinical remission rates that we talked about, looking at the deltas and I think just in the top bar, looking at the various colors there, you can see across the board, it's within the range of what we know or what we think about when it comes to currently approved both biologics and emphasize oral small molecules because that's the line we're talking in today really, it's about the role of additional oral small molecules in our practice. So wanted to focus. And to double down on how we started this section, which really is about the refractory nature of this patient population. So highlighting that in the Phase II, which the Phase III Parambir is going to get into and sort of detail a little bit more around it in terms of the patient population in Phase III. Just a reminder to everybody on the refractory nature because there is a need for refractory patients who are not responding to traditional currently approved therapy. So this is looking at those patients who failed JAKs and/or biologic or two biologics. And you could see that 90% of that 50%, I'm rounding 48% to 50%, just to make it a total, that means times 90% times 50% you're looking at 45% of the population had literally been refractory to at least two major classes of therapy. That is probably if Parambir can correct me the highest refractory population that we've seen, particularly with 18% being exposed to a JAK. So I think that's a really important point to sort of highlight as we enter into the Phase III design in just a moment. And probably, I think, leading into we're all aware, our maintenance data is open label. Yes, that's quite common that we have this long open-label maintenance arm to our Phase II, these studies. And this is just to really highlight the durability. I think this is important because when you're looking at studying drugs outside of -- in a controlled trial and then having a long-term extension with 4 years later, you're giving the data back on how many people stay on. This gives us visibility into long-term durability of this class or this asset, obviously. And so what we're showing here is these are the clinical remission rates at week 48 and 96 after week 16. So I showed you that the Phase IIb, although the primary was at 8 weeks, it was a 16-week period. And then you're adding 48 and you're adding 96 and on the left is everybody who came in. But then you're actually -- that's and that's really a great durability is that everyone who came in 50% are still on drug at week 48 and at 96 that speaks to the durability and the consistency. But then even taking those week 8 responders because those are the ones we would continue. In real world, if people aren't responding, we tend to move on. So the point of this slide is to say, hey, how about those, forget all comers because you're biased. Let's take just the week 8 induction people, what is happening to them over time. And you could see that those were responsive, you're looking at week 48, which is at the end of maintenance essentially, week 64 you're looking at 66% of patients still on drug and response, right? So this is like an important concept in terms of helping to frame Parambir's part, which is really on the Phase III and to even be creative in the way we think about are we in the zone, right? Are we similar in what we're seeing? And can we interpret that as it relates to currently approved therapies. And what this slide intended is, if you take the Phase IIIs across the board of all those therapies that you're all aware of and/or analyze and/or are approved -- what you're seeing is the placebo rates are pretty consistent across and so granted, 66%, all the caveats, open label, comparing it to historical placebo rates. We get all the caveats around it. But it's to show that it's within the range, right? And that even if you look at some of the other studies when you compare what they found and open compared to what they found in placebo, you're looking at even if there's a delta of 10%, you're still well within the zone of what we've seen across the board for other Phase III. So now that I've sort of walked you through the Phase II understanding what we've had in the maintenance and how we take that into Phase III, I'm going to pass it back to Parambir and he is going to walk us through that.

Awesome. Thank you so much, Marla. So I'm going to walk you through the Phase III program, and I want to highlight some specific aspects of how we designed this trial to make sure that we maximize probability for success for bringing what we think is going to be a transformative agent to practice and to sort of routine use. So just to level set, I want to sort of remind everybody about the prior trials that Marla did a great job of going over in terms of efficacy, but really, really focusing on the design. The majority of trials have used a responder rerandomization design for maintenance studies. So induction with rerandomization of responders. And that's the type of design we're going to use here. Well, we've done some very unique things to try to help maximize the amount of data and the value of data we can gain from this study, and we'll walk through that specific aspect now. So first, thinking about the population that we're going to recruit, consistent with regulatory requirements in our prior study, these are moderately to severely active UC modified Mayo score of 5 to 9. We are allowing for prior failures of conventional biologics, JAK inhibitors and S1Ps, and there's no limit on the number of prior treatment failures. We wanted to keep this study as similar to our Phase II program, where Marla did a great job of highlighting how refractory they were and the high efficacy rates we had in those refractory patients. And we are -- that's why we are targeting about 60% of these patients to have treatment failures. There's two separate induction studies randomized to placebo, 25 milligrams or 50 milligrams with a week 8 assessment for the primary endpoint of clinical remission. Marla did a great job of setting the stage for why clinical remission is the primary endpoint. It's relevant for us clinically and from a regulatory perspective. And I think the week 8 time point, it fits within the landscape of what other studies have done, helps to minimize the placebo rates, probably saw from the prior slides with Marla, those 15% placebo rates were only seen when you went out to about week 12. So we minimize those placebo rates by using a week at induction. And we know that the drug, small molecule, not really influenced by pharmacokinetics, can achieve those outcomes in that time frame. Then patients who are responding are rerandomized to placebo, 25 milligrams or 50 milligrams, and we'll look out to week 52. But what's really important is that those nonresponders at week 8 actually enter a blinded active treatment arm, which means we have the opportunity to study the incremental efficacy of continued treatment beyond week 8 in nonresponders and the ability to study what happens at patients relapse during the maintenance study and go into a blinded active treatment arm to see what happens. And this unique design allows us to really capture some data points to study the totality of efficacy across different populations and scenarios that are relevant for our routine practice. So when we really think about the two big components that we want to think about within a Phase III program. It's how do we minimize placebo response rates so we can show maximum delta efficacy and make sure our trial is successful for an induction time point and our maintenance and how do we drive that consistency between what Marla just showed you and what we anticipate will be a consistent amount of efficacy or possibly more in our Phase III program. So the three points we did to sort of really highlight for minimizing placebo response. In the prior Phase II program, three out of the eight placebo responders came from one site that recruited a total of 8 patients. So what we've done in this program is we've made sure that we have a much more diverse inclusion of trial sites and no single region can account for more than 25% of the patient population to avoid any potential regional or site variation in placebo response rates due to practice patterns or the use of concomitant therapies. When we think about the concomitant therapies that are often a major source of placebo response rates, the two things that we've specifically done for the Phase III program is we are not allowing concurrent treatment with immunomodulators. This was allowed in the prior Phase II program and was something that was seen in some of the placebo responders. And two, we're limiting the upper dose of the concomitant corticosteroids to 15 milligrams versus 20 milligrams because this is another factor that really dramatically influences placebo response rates. So I think this part of it will help us to at least at minimum carry forward those response rates in placebo, so we have a good understanding of efficacy. And then finally, how are we going to drive consistent reproducibility for obefazimod efficacy in the Phase III program. The majority of the dropout that's been seen historically from Phase II to Phase III programs. This is because they've had to shift to including more refractory patients for optimizing recruitment success in those Phase III programs. What you saw in our trial design is, we had a very refractory population in Phase II, and we're mimicking that population for Phase III. So we don't expect that to be a major impact. And evidence of that is the recent RINVOQ Phase II, Phase III programs, where they studied the same population in terms of percentages that were refractory and got pretty consistent results between those two, and that's why we're also going to be targeting a similar consistent population to what we had in the Phase II program. So with that, I'd like to thank you, and I'll hand it back over to Patrick.

All right. Great. Thank you, Parambir, and thank you to both you and Marla for a fantastic presentation. As I mentioned in my opening comments, I will now move to the Q&A session. And for the Q&A session, we'll be having our management team, which will include Mark de Garidel, you might -- previously as well as our CFO, CMO and Chief Scientific Officer. As far as the order of the questions, we're going to go to the sell-side analyst first, who has [indiscernible] audio. And then we'll move to the questions that are being submitted. I know we have about 20 minutes, a little bit less than 20 minutes, so we'll try and get to as many questions as possible. Sarah, can you go ahead and queue the questions.

Thank you, Pat. At this time, we'll begin conducting our Q&A session. [Operator Instructions] So at this time, we'll kick it off with our first question from Thomas Smith at Leerink.

I guess first for Dr. Dubinsky and Dr. Dulai. If I could just ask you to kind of take a step back and put the totality of the clinical data into context and just help us understand how you expect to use a drug like obefazimod in your clinical practice, assuming the Phase IIb profile translates in a similar fashion into the Phase III results? And specifically, if I could ask you to quantify to the extent that you can, the proportion of advanced therapy naive and experienced patients, you would think would be ideal candidates for obefazimod?

Yes, I think that's a great question. So I think when thinking about that question, you have to think about sort of the practice location a little bit. So Marla and I are tertiary academic referral centers, we deal with that population that we referenced quite a bit, two or more advanced therapy failures, some of whom have failed JAK therapies, and we really need something before offering them the need to go to colectomy. And I think that's an immediate spot where this would take -- to be taken up pretty quickly if the data translates. Now when you start shifting out to regional community centers or true community practices where you start seeing maybe one advanced therapy failure or the bio-naive population, what drives use of therapies in those populations. One is safety. So the fact that there's very limited concerns about safety currently. We have the headaches, but mesalamine has a 5% rate of headaches and remains the most prescribed medication for both UC and Crohn's. And then two, convenience because I think getting it into patients' hands and getting it in a convenient format that's easy for them to use will result in a large uptake of the drug across those positions as well. So the small molecule nature safety profile that looks like it should be better, sort of at least less than what we've seen with others and the anticipated lack of safety signal issues and the efficacy that's at least on par with those other oral small molecules in that space. I anticipate there's going to be a high uptick in the community where there's the biggest gap. And then for us in the academic centers, we really would be leveraging this to sort of rescue a lot of our patients that are failing several therapies.

Yes, I think you sort of just to add some thoughts for how we think about it is that really you have -- I'll give you a historical, so when risankizumab came out for Crohn's, what everyone was attracted to in the Crohn's market is that it worked for refractory and it also worked very well for naive. We do not have that with our current sort of UC landscape right now for everybody to just remember and the orals were focused on, you have to fail and anti-TNF to get a JAK in the S1Ps, for example, 69%, Chris may correct me, he'll say 70%. 69% of the patients in the etrasimod study were bio-naive, so it's really important to understand the population that -- and the data that we have is that we have those patients who were refractory, which means Parambir and I are going to have a solution that is an oral small molecule for a refractory population that you don't have to fail another drug. Okay, important because that's what him and I contend with every day. And then you have the population in the community who actually want to use a drug where as I started the conversation where I have to do 1,000 things on my checklist and monitor this and monitor that, I just would like to hand the script for a therapy that I can just give them like I would give 5 ASAs? That's important. So the dual nature of it, I think, is what is relevant at the current moment based on the Phase II data.

Got it. That's super helpful. Yes, I appreciate the perspective. And then maybe just a follow-up question, if I could, for the company. I know the focus of this event is on the UC opportunity. But last week, you disclosed some changes to the design of your Phase II Crohn's program based on FDA feedback. I was wondering if you could walk through the rationale for the updated trial design to maybe comment on the dose selection in that study and the decision to explore the 12.5 milligram dose?

Yes, I got it. I think -- so we actually -- so we had a I think submitted the IND in the end of the year, and we actually got feedback from the FDA to get a green light to go ahead with our Phase IIa study. They also provided comments that was illustrated -- illustrative for helping get to Phase III. I think from our previous design, we felt comfortable that we have a lot of information from our IIa study. They were -- they felt that the data from the UC study was independent of what dose we would select for our Crohn's study. So they recommended that we actually follow dose-ranging study prior to doing it -- to starting our Phase III. So that's the rationale. We elected to go with that suggestion. Again, that was our choice. That was their suggestion. It wasn't mandated. Why did we pick a 12.5? Well, we know that from our Phase IIb study in UC and Marla already pointed out, the adverse event profile with 100 milligrams increased. And so we knew we were going to do a dose ranging study with a higher dose. And so we elected to go with three doses of 50, 25, and 12.5. And why didn't we go with the lower dose, we felt that this was a good range of doses to really see what the dose response would be amongst those three doses. And that was a company decision as well, not an FDA mandate.

The next question comes from Samuel Slutsky at LifeSci Capital.

Great. Thanks for the questions and for hosting the event. A couple for me. I guess, first for Dr. Dubinsky and Dr. Dulai. So assuming a consistent safety profile with the Phase II study, what placebo-adjusted remission rates, would you want to see with obefazimod in Phase III for both the naive and biologic failure patients to get excited about the treatment. And then second one would be what clinical endpoints are really most relevant to as you think about prescribing drugs, whether it's endoscopic or remission response, et cetera?

Yes. So I'm going to take the refractory because I sort of showed you the 3-point something, that's well within. It's around 3% to 5% is with a plus or minus 2.5% or 5%, let's say, 7.5% versus 2.5%. You're sort of looking at that. We would expect similar. It's a similar population. It's the refractory population. I showed you, particularly around the endoscopic outcome. For the clinical, again, within 7 to 10 plus or minus 2.5% up or down, confidence interval. That's on the exposed -- I mean, the refractory. Parambir, what do you sort of walk away in terms of your naive expectations? Knowing what we showed here, it's a little bit complicated with the naive population.

Yes. I think with the naive population, I mean, even something that sort of 12% delta are higher is sort of on par with what we've seen with other therapies in that -- in general. And I think would be enough given the convenience and safety to be able to use this confidently in that population. I think the maintenance part of it is the other part of it that's extremely relevant for a bio-naive population because the durability of a lot of the drugs that we use first line is quite low. And to have something where we can really sort of help our community colleagues get them on the right drug first, where they do well over the long term. And I think that maintenance delta difference of about maybe 20% between placebo and drug would be more than enough to help really feel confident that we could push this as a first-line agent.

Okay. And then just on endpoints that are kind of most relevant to you as you think about...

Yes, right. So I would say clinical remission is by far sort of the primary endpoint that most of us really focus on because it takes into account both things that impact the patient, rectal leading stool frequency and things that are much more objective, which we've linked to long-term risks for hospitalization, colectomy, colon cancer. And then endoscopic data would be the second most important in terms of the endpoint. So clinical remission and then the endoscopy subscore are probably the two for me. Marla if you have any differences in thoughts here.

Yes. And so when you approach them, recognizing UC even more than Crohn's, urgency rectal bleeding are priority. That's what keeps them away from getting off the toilet and going to work. So it's really important to also understand sort of why symptom improvement and the speed of it is also very important, which we'll also get a little bit more of when we see the Phase III data. But rectal bleeding means there's inflammation 90% of the time. So that's why Parambir and I also use rectal bleeding as a surrogate to say we're heading in the right direction. Patients have voted that rectal bleeding is the most impactful on their quality of life, I think, because they mean -- they're tracing having blood as being they are sick. So we try and also sort of bump that with pain, rectal bleeding and urgency are really the key focus in UC patients. That's the immediate need. We then say we also want mucosal inflammation improvement quickly, but that we can also know and you see by the presence or absence of blood. So that's why symptoms for UC is mission-critical as first line.

Got it. Okay. And then for the ABIVAX's team, just because we've got a few questions on it. Could you just remind me the proposed mechanism for the transient headaches with obefazimod? Is it thought to be on target for miR-124 upregulation or is it potentially something else?

Yes, indeed, we don't have data to show that it's MOA related. The only thing we can say when we look at the timing of the occurrence of the headache, it either occurred during the first couple of weeks of treatment, and when we look at the exposure, the PK profile of the drug, we know that the PK, the exposure is at its highest during the same time period. And we know that obefazimod is crossing the blood-brain barrier. So this seems to be a correlation between the timing of occurrence of the headaches and the time when the exposure to the drug is at it's highest. So it may be a link here. On the other hand, this drug was originally developed for HIV, and we know also that most of the anti-HIV treatment induce headache and nobody knows why actually. So that's the two ways we're looking at the headache right now. But I think what we have to keep in mind is those headache are transient, they occur in the first couple of weeks of treatment, and they don't seem to reoccur during chronic treatment and they can be treated with OTC most of the time.

The next question will come from Vikram Purohit from Morgan Stanley.

We have two. So first is building on the questions regarding real-world use. One follow-up I had for the KOLs is, how are you thinking about the potential for obefazimod combination therapy? Sorry if this was discussed and I missed it because my audio cut off for a moment. But would you anticipate using obefazimod primarily as a monotherapy? Or if the Phase III data looks like the Phase IIb, do you think there are specific therapies that you're currently using that could be a good combination use case here? And then secondly, on safety, just based on the Phase IIa, Phase IIb data you've seen and your understanding of the MOA and the cytokine profile you're hitting. Are there any particular safety signals you're watching out for in the Phase III study beyond just the headache signal you've already discussed during the presentation.

I'm going to Parambir give you the true scientists, and then I'll give you the practicalities of combos. So go ahead.

Yes. So I can start. So I think one thing to just think about is there's a push towards combination therapy so that we can target two different cytokine pathways, which are thought to be synergistic. What we've demonstrated to you in the translational data is that obefazimod actually hits multiple cytokine pathways, so in some ways, it is in itself already a combination pathway drug. But if you're thinking about how you might consider using other immune suppressing agents alongside this immune stabilizing agent, I think I would use obefazimod probably as the backbone just because it looks like it has a pretty safe profile, efficacy is good, long-term immune stability. And there may be patients that are extremely severe, where you need an added amount of immune suppression upfront with anticytokine agent or another small molecule like a JAK inhibitor to really induce that remission and then maintain that remission with something like obefazimod that keeps the immune system stable without allowing for a lot of compensatory changes. So I think that's how I really think about the combination component. And then in terms of safety signals. STAT3 and IL-6 have been traditionally the hardest pathways to target mechanistically because previously, we really focused on suppression of STAT3 or IL-6 when they've tried to target it as a therapeutic consideration. Excess suppression of STAT3 can lead to off-target considerations for infection risk because there is an immune regulatory component of having enough STAT3 to respond to certain things. So I think infections would be the one that we'd be watching out for. But like I said, the mechanism would not translate into that. And we didn't see that in the Phase II program to really be worried about it just because we're not seeing that suppression of the immune system.

Yes. And so I'll just talk about someone who is very excited around combination therapy and does a lot of it and have published around this. I would say that what we do know now is adding something after something has been a partial or a failure. That is different than combination therapy in real-world practice, where Parambir has also written about that at UCSD. But the reality is there's two types of combinations that do start two things off at once because you're complementary like what we're doing in the DUET studies with Janssen and their 23 and their [ TNF ] using mouse to decide that there's overlap -- nonoverlapping gene expression, et cetera. Is that reality? And does everybody need that. So I think what's going to happen is we're going to have to figure out and do a lot more work before we start saying, this is everybody's combination. Even within DUET, figuring out who actually needs to versus who needs what. There's a lot more work to be done. And I wouldn't say that this is sort of near term. So what I think ABIVAX needs to focus on is exactly what Parambir said. Does it as a monotherapy what is it role in practice and use true biology to make a distinction, what are the pathways we may be missing and what would make sense as a combination and not just because some company has two assets and it makes sense to combine them. That's not a combination therapy. So I think it's sexy and I'm obsessed with it, but the reality and the practicalities have to be important for us to understand the biology behind what we're asking.

I think we have time for one more question if there's another, Sarah if there is somebody else on the line?

Yes. So the next question will come from Sebastian [indiscernible].

I'm wondering whether you could expand on the proportion of patients who received concurrent -- more later during the Phase II study. And -- to what extent is actually influence not only the placebo rate, but also the treatment response. And I'm also wondering regarding the [indiscernible] population Phase III study, if you could expand on whether a proportion of these patients received S1P inhibitors.

Sheldon, maybe you want to take that? I'm not sure if you want to address the population.

Yes, I can address the population. I'm just trying to get the data out really quickly, Sebastian. I had it in front of me and lost it. I don't have the analysis in front of me of the response. But with those taking the immunomodulators, it was about 15% across the populations in the Phase IIb study. And I don't have the response of that subgroup per arm.

Parambir, do you foresee biologically taking thiopurines because really what else is really typically being used? Is there any sort of aspect of the way thiopurines work sort of in -- with this asset?

Right. So I think we know that the thiopurines aren't going to work well after a couple of advanced therapy failures. And so if you just focus on that population, we can very clearly see that it's unlikely to have influenced the efficacy of obefazimod. Where I think the concomitant immunomodulators and as a field for clinical trial design is becoming a question is oftentimes in the bio-naive population. You get these patients who are started on a low-dose thiopurine with moderate to severe activity. They end up then being allowed to screen in because they qualify for disease activity, and you have a latency of onset of effect for that thiopurine during the induction phase. And I think that's what the design is really trying to focus on avoiding is the single sites or centers that have traditionally done that where they start a low dose of an immunomodulator to get them to qualify, that low dose doesn't kick in during screening. They remain qualified for the trial, and then it kicks in during induction and drives placebo response rates. But mechanistically, there's no good reason why immunomodulators would be synergistic or anything specific to obefazimod. And if you look just in the refractory population, you can see that clearly balance out because of the randomized nature of the trial, those immunomodulator exposed patients would be balanced across sort of throughout the study sort of cohort. So I don't anticipate it affected obefazimod. I do anticipate the concomitant immunomodulators impacted the placebo rates which is something we've seen even in recent meta analyses that we've done looking at all the prior studies that have been put together.

Yes. And just to add to that, Sebastian. two out of the seven placebo remitters actually were on immunomodulators. But again, I don't know if that exactly answers your question.

No, this is very insightful. Thank you guys. It's really clear.

Pat, I think you're muted.

Okay. Great. Well, first of all, I just wanted to thank again Dr. Dubinsky and Dr. Dulai for the presentation and sharing their perspective on the markets, the obefazimod ABTECT-Program program and thank everybody for joining us today. We look forward to keeping the market informed on updates going forward, and I wish everybody a great rest of your day. Thank you.

Thank you.

Thank you.