ABIVAX Société Anonyme (ABVX) Earnings Call Transcript & Summary

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

Thank you, Tara. Good morning, good afternoon, and welcome, everyone. We appreciate you taking the time to join us for today's webcast. Fortunate to have joining us today Dr. David Rubin, who serves as the Chief of Gastroenterology, Hepatology and Nutrition and the Director of the Inflammatory Bowel Disease Center at the University of Chicago. With over 500 published articles on the management of IBD, including the 2019 and upcoming 2025 American College of Gastroenterology guidelines for ulcerative colitis, Dr. Rubin's expertise is invaluable to the ongoing advancement of the treatment of ulcerative colitis. Following Dr. Rubin's presentation, we'll move to a Q&A session with both Dr. Rubin and the ABIVAX management team. We'll begin by addressing the questions from the sell-side analysts currently covering ABIVAX. Then if time permits, we'll also take questions that were submitted by investors. Before we dive in, I'd like to turn the call over to our CEO, Marc de Garidel, for some opening comments. Marc, the floor is yours.

Well, thanks, Pat. I want to really to thank David for participating to this special call. We're obviously very excited as we get closer to our readout, as you know, for induction. We plan to have the last patient in the second quarter of this year and followed by the readout induction in Q3 of this year. So great privilege to have David today with us, one of the key thought leaders in the field on a global basis and I'm going to let David take it away. Thanks, David, again.

All right. Thank you, Marc, and good morning, good afternoon, everybody. I'm pleased to be here with you to do one of the things that I'm most passionate about, which is to raise awareness about ulcerative colitis and to work to find new treatments and better options for our patients. I know some of you are familiar with the IBD space, but allow me to set the stage here. In the United States alone, there's estimated 2 million to 3 million individuals living with Crohn's disease and ulcerative colitis. These are chronic conditions of the intestines that have a progressive or relapsing and remitting course, often diagnosed in young people, lasting a lifetime and with a well-described morbidity, thankfully, a low mortality, but significant effects on quality of life and as you can see, significant costs. The estimated U.S. health care expenditure for IBD is $25 billion to $35 billion annually. A significant amount of that is in the investment and the use of chronic medical therapies, many of which are focused on immune modification. I will make a separate comment to you that the global space of IBD is growing considerably. While we've looked at the Western European space over the years, we now recognize that inflammatory bowel disease is rising everywhere you look. And the fastest rising part of the world is Asia, maybe not surprisingly, and ulcerative colitis leads Crohn's significantly in that part of the world as well. People who have ulcerative colitis have inflammation of their large intestine. That involves the rectum and the colon and when those areas are inflamed, they result in increased stool frequency, bleeding, rectal urgency, which is a very debilitating symptom, and it has a significant impact on their quality of life. People with long-standing uncontrolled ulcerative colitis will require surgery and some end up having cancer, although thankfully, that rate is going down with the advent of some effective therapies. So these are obviously considerable problems. The good news is we've made progress in their management. There are a variety of different advanced therapies that have been developed, and you can see a time line here from the first biological therapy approved for the treatment of moderate to severe ulcerative colitis in adults, which was REMICADE, which is infliximab, an anti-TNF antibody. And you can see subsequently came adalimumab or Humira and Simponi or golimumab. Those are all anti-TNF drugs. We've subsequently developed and been involved in the development of multiple new and different strategies and mechanisms of action. Vedolizumab or Entyvio, I'm hopeful some of you or most of you know a little bit about targets the integrins that are on white blood cells that are trafficking to the gut and is a biological therapy that works in that fashion. STELARA or ustekinumab is a monoclonal antibody that targets a protein called p40, which inhibits 2 cytokines, IL-12 and IL-23 and we have had subsequently biosimilars to the anti-TNFs and a biosimilar group to ustekinumab. Along the line of the monoclonal antibodies, we also have the p19 inhibitors, which are selective to Interleukin-23. I call those second-generation STELARA drugs. That would be SKYRIZI and TREMFYA and Omvoh. But separate from all that are the oral therapies or the small molecules, which have come around more recently. These are targeted synthetic small molecules. The term small molecule means it can be absorbed through the lining of the intestine. That's what makes them oral compared to our monoclonal antibody strategies. And we have 2 classes the Janus kinase inhibitors, which includes tofacitinib or Xeljanz and upadacitinib or Rinvoq and the S1P receptor modulators, which includes both ozanimod, which is ZEPOSIA and etrasimod, which is VELSIPITY. JAK inhibitors work by inhibiting the Janus kinase enzyme that's involved in activating multiple lines of inflammation and S1P receptor modulators work by preventing the escape of activated lymphocytes from lymph nodes. So it's another type of cellular trafficking inhibition. So you see across all of this that we have quite a number of different therapies, and I'm guessing many of you have studied them and understand what they can and can't do. I also wanted to provide you with a brief mention of how we study these therapies. The measures that are routinely used in the registry clinical trials include the Mayo clinical score or the modified Mayo score, and that includes a variety of different categories. Specifically, though, we look at stool frequency, rectal bleeding and the findings by endoscopy, which is a colonoscopy or a limited exam of the sigmoid colon and rectum and then they're graded across different scales, as you can see on the left there. In the Phase III ulcerative colitis trials, the modified Mayo score is used and it's defined as stool frequency that is normal or near normal, no visible blood and an endoscopic score that's either normal or near normal. And so this is a well-defined definition that's used across all of our trials, and it's important to understand that. In Phase II trials, we often use the improvement in the modified Mayo score as a measure and then secondary endpoints are the standard Mayo scores. Now it's not statistically valid to compare trials head-to-head that haven't been performed head-to-head, but looking side by side. But it is relevant to at least have some idea of where we are with this. So I want to point out to you that you can look at the clinical remission after induction, which is the first phase of treatment in ulcerative colitis and look at the different endpoints, whether it's at 6 weeks, 8 weeks, 10 weeks or 12 weeks. And in placebo-controlled trials, you can see not surprisingly the available drugs, albeit placebo. I want to highlight for you a couple of things on this slide. The first one that I want to really drive home is that the Y-axis doesn't even go to 100%, there is a huge gap in our success in managing ulcerative colitis that we have not yet addressed. We often call that the therapeutic ceiling in our field and the recognition that we have yet to identify the cause of colitis or medical cures is a very important priority for our field. It also means that there is great opportunity for us to identify new mechanisms and new therapies that can achieve better control, especially in the early phase of inducing remission. Reminder that on the left here are those monoclonal antibodies of different classes and on the right are those oral or small molecule therapies that we currently have. I'll remind this audience that Jyseleca, which is filgotinib, is not available in the United States, but is available in Europe, and it's a point of reference here for you to see. I want to just highlight for you the other point here, which is the delta over placebo, which you can see varies by drug and by study. And I want to highlight that for you because it does matter what kinds of patients are included in the trial as to what you might expect to see. The other thing that influences placebo rates has to do with geography where in the world some of the studies are performed and separately, whether concomitant therapies are allowed. So for example, when a patient with ulcerative colitis gets into a trial like this, if they're left on corticosteroids, you often see a slightly higher placebo rate, and that can influence that delta between active drug and placebo. The other point I want to make on this slide, and it's important because we'll come back to it, is what we call prior advanced therapies. And that means that how refractory of a patient population was included in the trial. In other words, how many therapies did this patient already fail before they got into a clinical trial. And as you might guess, before people in the United States, especially, but in other parts of Europe as well, enter a clinical trial, they often want to be on what is available on the market and what their doctor might give them in advance. You can see across that table on the bottom there that in these trials, there's some variability in terms of the prior advanced treatments patients were exposed to. That's where you see a difference there with the Jyseleca, the filgotinib, where they did one trial where they had all naive patients, and they did another trial where 100% of them had already been exposed to advanced therapies. And you can see the difference there in the drug and placebo rates because of that. You also look at the bottom row of that table and you see how many of the patients in the trial were on 2 or more advanced therapies. So for example, someone gets into a clinical trial, they've already been on infliximab. They've already been on adalimumab, maybe they've already been on vedolizumab, ENTYVIO. And so they've been on 3 drugs or more before they actually get into the trial. That's a really important point as well. Now it doesn't mean that we don't want to be able to treat those refractory patients, but it definitely influences the results that we see when we're interpreting those findings. And I think it's really important to know that a therapy that works well in a refractory patient population is going to work even better when we use it in the real world and start using it earlier in the treatment strategies. Now let's move on to why you're here, which is to learn about Abivax's first-in-class oral therapy. I want to emphasize again, first-in-class. This is a completely new mechanism in my space. So Obefazimod enhances expression of a microRNA called microRNA-124, and it results in stabilization of the dysregulated inflammatory response. What does that mean? Well, let me start by saying that this is completely different than what we currently do. What we currently do with all those therapies I just described to you is we target those therapies against active inflammatory proteins or active inflammatory processes. What this is doing in the way I describe it to my patients when I'm enrolling them in the trial and when I've been educating my colleagues is this is resetting the inflammatory cascade. It's working at the level of the nucleus to actually reset what's going on. So let me walk you through this. This is a small molecule that means, again, that it's oral, binds to something called the cap binding complex, which is inside the nucleus of white blood cells. And it's demonstrated by cryo-electron microscopy. They can actually see this. So they know that, that's actually what it's doing. It induces splicing of a long noncoding RNA. Noncoding RNAs were thought to be meaningless because, of course, we were ignorant. We learned now that these are actually important in different ways and sometimes they end up expressing themselves in different scenarios. So when you splice the long noncoding RNA in this scenario with Obefazimod, it leads to an enhanced expression of a microRNA, which then binds to specific messenger RNA targets in the cytoplasm and shuts down the translation into their protein. So those who remember their biology and who've studied this space separately should appreciate the movement from DNA to RNA to proteins. And what this is doing is it's essentially shutting down some of those proteins. So which proteins are affected by microRNA-124? It's a couple of very important ones, MCP1 and CCL2, which are involved in macrophage recruitment activation and STAT3 and IL-6 receptor which is related to Th17 cell differentiation or regulatory T cell regulation. Now what does that all lead to? Well, it actually down regulates the production of multiple downstream cytokines. So I want to emphasize to you oral novel mechanism and then it shuts down multiple different inflammatory cytokines that we know are related to the acute and chronic nature of IBD, IL-6, IL-23, IL-1, TNF alpha and IL-17, as you can see on the very nice animation here. So essentially, rather than targeting what's already circulating, it's shutting off the faucet at the sink. We'll get back to that. Now if you wanted to know a little bit more, I'm not going to get into the basic science into this, but it's important to know that if you look across time with exposure to the Obefazimod you can see that there's upregulation of that microRNA and it persists as far out as they looked, which is week 96 compared to placebo. So they do know that there's an actual measurable physiologic effect that persists. So it's not that you just shut it down and then something happens and the drug doesn't do anything anymore. That leads to a very nice parallel clinical effect that I'll show you in a moment. Now the primary results that you may have seen previously, and I want to drive home here are the Phase IIb trial design, which is what led to our enthusiasm in moving this to Phase III. This was a multi-center effort. You can see there were 17 countries and 130 sites involved that included 252 patients with moderately to severely active ulcerative colitis. And they specifically enrolled patients who had already been on conventional therapies with mesalamine, thiopurines or steroids and very importantly, or biological and JAK inhibitor therapies, those advanced therapies. Interesting and important to this is that there was no restriction on the number of prior therapies. So you could recruit the most refractory patients to get them into this study. They were allowed to be on steroids, 20 milligrams or less, and they had to stay on that dose through the induction phase. There was a 16-week induction phase, but the primary endpoint was the mean change in baseline modified Mayo score at week 8. You can see that patients were randomized to 1 of 3 doses of Obefazimod or placebo, and then they entered an optional open-label maintenance for up to 2 more years at a single dose, 50 milligrams. So this is an important study design. I will tell you that this is a standard study design for moderate to severe UC and the primary endpoint of a Phase IIb study is exactly what we look at. This is a very important table of the demographics of these patients. These were sick patients with high modified Mayo scores. And I want to highlight for you that they also had a significant amount of disease duration of about 8 years. They also had many of them, the most severe endoscopic findings, meaning severe inflammation when you put a scope in. 75% of these patients had a Mayo score of the scope of 3. And then very importantly, if you look at previous exposure, you can see that 50% of the patients had prior exposure to biologics or JAK inhibitors but that of those, 90% of them had been on 2 or more biologics, including a JAK inhibitor. We have very few trials now that have included prior JAK inhibitor exposure, and 50% of those or even more were primary non-responders, meaning they didn't respond ever and were doing very poorly. Otherwise, they would have gone to surgery. You could also see that about 50% of the patients were on steroids. So, it's very important to understand this is a refractory group of patients who went into this trial. Now, having said all that, you see here that we have statistically significant improvement in the modified Mayo score at week 8, the primary endpoint compared with placebo across all 3 doses of a drug. So very nice to see, clearly works with all 3 doses; active drug better than placebo. You see some placebo response, which is consistent with what we see in all of our Phase II and Phase III trials. And when you look at secondary efficacy endpoints, which are meant to be informative in designing a Phase III, these are the usual endpoints we would look at in Phase III studies. You can see very nicely clinical remission at week 8, clinical response at week 8, and the objective measure of endoscopic improvement going from a Mayo 2 or 3 down to a Mayo 0 or 1, significantly better than placebo across all of these. You can highlight the delta across these so you can see the difference over placebo. I'll remind you that this was a refractory patient population and that half of them were still on steroids through the entire induction part of the study. But very nice results. This is a very positive signal in our world, and this was very encouraging to all of us who work with patients and who are interested in these trials. Now in a subgroup analysis to look at those who are either naive to advanced therapies or experienced, I've already taught you a bit more about that. You can see even better results in earlier treated populations who had not already failed multiple therapies. But you see a very strong response here looking at that objective endpoint and endoscopic improvement even in those super refractory patients. And I will tell you from experience that this is a very dramatic thing when you see it. And, of course, it correlates to the patient's well-being and other measures as well. So, this is a subgroup analysis. It's not meant to provide you with primary p-values, and you can see the number of patients is smaller. But nonetheless, it gives you a very strong signal, which is why there's been so much enthusiasm in moving this forward to Phase III. Now, if you wanted to compare the obefazimod Phase IIb results to other trials and other drugs, as I've already outlined for you, look all the way to the right on this slide; obefazimod is the last column there. You can see the prior advanced therapies is 48%, which is higher than most of these other trials, not all of them, but most. But you can see that 90% of those prior advanced therapies patients were on more than 2 when they got into the trial, which is substantially more than these other trials. I think that's really important for you to keep in mind refractory patients, yet the drug worked in all the doses studied. Now, the open-label extension was optional for patients but allowed people who wanted to stay on or get drugs to continue with 50 milligrams open-label once daily. You can see how this was designed where we looked at weeks 48 and weeks 96. You can see that there was a 76% 2-year completion rate, that should tell you something about the effectiveness and the tolerability of this therapy. Here are the results of that open-label maintenance study, looking at those who among all patients and then those who are responders. So among all patients, you can see we have 54% at week 48, and 52% at week 96. And among those who responded to the induction phase, you have even higher, which makes complete sense. Patients who do well with drug or on placebo, frankly, in the induction phase, are more likely to continue on with drug and do well and feel well at the end. So that's a predictor of long-term stability, and this is a very nice stable result. If you want to compare to maintenance trials that are available for the other drugs, remember, this was an open-label extension. So, there's not a placebo arm. So they're showing you historical placebo rates based on other trials by adjusting for types of patients. You can see the very nice results with the Phase II open-label all the way on the right there of 66% at week 48 and similar results out to week 96, and we don't even have 96-week results for most of those other therapies. Safety with this drug is actually quite good. I want to start with the bottom of this table to show you there were no serious infections. So whenever we use immune-modifying therapies, we always want to know about that, and there were none. You can see the SAEs across the induction phase were quite low and similar to placebo or even lower than placebo. And you can see that out in maintenance, it's not surprising, there are some SAEs that's when patients end up needing surgery or having their disease progress when they're not as responsive. The one thing that's novel and important to point out here is that patients do have headaches in some cases. You can see that across here, and it looks dose-related. But if you look at the bottom there, I do want to tell you that it is when they start therapy, it resolves within 7 days and does not recur, and they're mild or moderate in severity and discontinuation due to headache was very uncommon. So it is important to know about it, but it's not something that is limiting this therapy for moving forward. Now we're in Phase III currently. You've already heard from Marc that we're expecting the induction data to be released in the third quarter of this year. But I want to just remind you of how this study is designed and what they've done to enhance the study. So they moved forward with 2 doses, 50 and 25, compared with placebo as the FDA usually requires. There are 2 identically designed induction studies. That's the 105 and 106 study, and responders go into a maintenance study where they're randomized to 3 different arms, 2 doses and placebo. Those who are non-responders can go on to a non-responder treatment arm, of course, and a long-term extension is being offered. The primary endpoint in this Phase III study is clinical remission at week 8, and in the maintenance study, it's clinical remission at week 52. And a reminder what clinical remission was at both endoscopy and patient-reported outcomes. They've worked to minimize placebo response in a few important ways here. They're diversifying the geography of this study to include patients from around the world and not have too many overrepresented from one place or another. There are not going to be concomitant immunomodulators, which, by the time people need advanced therapies, don't add anything anyway, and it simplifies this a bit more and will reduce placebo rates in parts of the world where they don't have access otherwise. And the steroid dose has been limited to 15 milligrams, and there's a forced taper, which is a very important thing that we've demanded from our new therapies in IBD, and I'm delighted that they have included that in their design. I want to highlight that they're still including refractory patients. So if I go back to the slide, you look all the way on the left here, you can see their target is 60% of patients will be treatment failure, which is where we need this to work, frankly. But it's oral, it's novel, it's not immune suppressive, and I think that this is going to end up being picked up by patients and clinicians as a preferred option earlier in the disease management. I think that although they're including the most refractory patients, I'm expecting this is going to be something people want to use early. I also want to highlight to you that we do expect this to work. I didn't have to show you a table of what drugs moved on from Phase II to Phase III and succeeded to tell you that I can say that from these results if you ask my colleagues who do what I do, we're all very enthusiastic on this treatment. We're waiting for it to come. I have patients who are asking for it because they're pretty well-informed in my space, and I'm excited to support that otherwise. I also don't routinely do investment calls, but I very much support this, and I believe in what they're trying to do. I hope I've taught you a bit about ulcerative colitis in the disease space and provided you with some context to understand these results. This is an oral first-in-class mechanism that targets a different component of the inflammatory cascade. I'd like to say it resets homeostasis, and it's been shown to be effective at multiple doses in the most refractory patients we have with ulcerative colitis, which is a growing market and a growing need. So I want to thank you for your attention, and I'm, of course, happy to answer some questions.

Great. Thank you, Dr. Rubin, for the outstanding presentation. And Tara, I think we're ready to move to the Q&A session.

Great. Thank you, Pat and Dr. Rubin. [Operator Instructions] So our first question comes from Yatin Suneja at Guggenheim.

Dr. Rubin, thank you so much for educating us on the mechanism and the data. I have maybe 2 questions. First one is on the durability of effect. Could you maybe talk a little bit about the durability effect, how this is -- I know you touched a little bit, but how it is differentiated relative to monoclonal antibodies and other orals, your understanding of the mechanism that is driving it because that's where we think the molecule really stands -- differently stands out. So that's one. And then obviously, the company is running big studies. I'm just curious for you to explain to us what would you like to see from those studies keeping in mind that you have other orals that are being developed, whether it's an IL-23, alpha4beta7 or miR-124.

Thanks for your questions. Let me start with the durability one, which is a really important question and one that I think a lot about. One of the big challenges we have in IBD is secondary nonresponse, which we also say is loss of response. So among patients who respond or who remit to a specific therapy, what's the rate of loss of response over time? And frankly, why does that happen? So I want to highlight a couple of points here. One reason that, that happens with our prior monoclonal antibodies, especially anti-TNF has been due to antidrug antibody formation. So immunogenicity. Now with the newer monoclonal antibodies, those rates are very low. But with our anti-TNFs, it's extremely well described as a reason for loss of response. With small molecules, all of them, including this one, that does not induce immunogenicity. So that's taken off the table right away. The second thing I want to highlight is in older studies where we saw as high as 50% loss of response by the end of 1 year with all of our anti-TNFs, for example, we weren't looking at the same endpoints when we were studying those types of patients. And what I mean by that is we didn't hold them to this bar of remission to look at what happens to them over time, and we didn't look carefully enough at the endoscopic healing because, frankly, we didn't know to do that properly. So when you have the newer therapies that achieve very nice endoscopic results as part of their primary and secondary endpoints, you are looking then downstream and knowing that there's a lower likelihood of loss of response. The third thing that comes up here, though, that's important and relevant to this particular therapy is what we call mechanistic escape. Mechanistic escape is somewhat theoretical, but makes sense and is certainly the best way to describe what we observe. And it means that the body, because we're not treating the underlying cause of colitis, will look for another pathway to drive the inflammation. And when you use a therapy that targets a single cytokine or has a very specific single mechanism, you end up with the possibility of the body just finding a collateral. The human body is quite remarkable in that it has multiple different pathways to drive inflammation because the immune system is there to protect the host. So it's redundant. When you use a therapy like this, however, you're actually resulting in downregulation across multiple different pathways, including cytokines, but also including cellular pathways in the way that the Th17 may be affected. And so I think that it's important to keep in mind and at least the open-label Phase IIb extension gives you some clue to that, that we expect a lower loss of response with a therapy like this for all the different reasons I mentioned. They're looking at the right endpoints. They have multiple targets. We have some preliminary data that support that, and there's no immunogenicity. Now the other question you asked was about other orals and what do I think would be success. In refractory patient population, looking at week 8 remission, I would tell you that I think a delta placebo-adjusted rate of 10% to 12% is considered successful in our space, certainly enough to move that therapy forward into maintenance and to expect that we're going to see that continue. I do think it's really important to know very well and importantly, what's the target and what are we going to get out of it, but also who are the patients. So I emphasize that for a reason here because I'm certainly aware and involved with some of these other oral therapies that are being developed. The oral therapies are just what I would call refined versions of what we already have. This is a first-in-class therapy that offers multiple different targets simultaneously, including IL-23, frankly. So I think that this is a broader strategy that offers a very novel approach. I'll tell you as well that when you explain this mechanism to patients, which I've been doing as part of the recruitment into the trial and what I've done on some investigator calls, it ends up being something that is very easily received by them. It makes sense to them to turn off the inflammation where it's starting than to be tracking and chasing what's already there. I hope that answers those 2 questions.

Yes, very good. One more, if I may. Just -- it's regarding the endpoint time point. So the induction endpoint is at 8 weeks, given the mechanism, given the durability that we see, do you think 8 weeks is appropriate? And I think the uptake you think the mechanism is able to capture the delta that you're talking about at 8 weeks?

A lot goes into thinking about our endpoints, but some of it is predefined and predetermined by the way the studies were designed for other therapies in the space. I've actually been an advocate that we can look earlier and have go/no-go signals on novel therapies, but we don't know that about the particular pharmacodynamics of this therapy in this refractory group of patients. Challenge is always if you look too soon, you underestimate effect. And if you look too long, you miss an opportunity to gain control in someone who's quite sick. So week 8 is standard these days in ulcerative colitis. And what is also well described across all of the new therapies is what's called delayed response and delayed remission. So one of the nice things that we don't have the data yet for or at least I haven't seen is the delayed response rate. So after you get to week 8 and you look at your primary analysis, patients are still getting therapy. What percentage did you pick up in delayed response so that you're not leaving things on the table. But the challenge is, as you might hopefully imagine, somebody with rectal urgency and bleeding, having them go 4 months waiting for induction is not a practical approach to the management. So 8 weeks is completely standard. I favor it over 12. And I think waiting 12 weeks, 3 months for somebody to demonstrate response is waiting a bit too long. We have other options that work fast and faster.

Our next question comes from Sam Leach at Piper Sandler.

Two for me. So when we think about we're getting induction data this year and then longer-term maintenance data next year, when you and your colleagues start to get data from new programs, can you just contextualize the difference in expectations between these 2 data sets? Do you think you and your colleagues are laser-focused on the induction data? Or do you think people tend to look at the induction data and then wait to see what maintenance looks like? Or is it really the combination of both that guide your overall opinion on what a new program might be like and who might be best for it? And then our second question, so how important is the oral route of administration? And do you feel like you often get patients come in who are just really trying to avoid an injection?

I will say to you that, in general, when we get the induction readout, we can tell what's going to happen in maintenance, especially when we have such a well-designed Phase II study that has informed us. I think that the folks at ABIVAX, who designed that trial, were very thoughtful about it. So we already have a sense for based on what we see in induction is going to help us understand maintenance. I like the idea that in maintenance here, they're going to explore 2 doses, 50 and 25, because I do have -- my bias is that people who are in endoscopic remission after induction probably need less drug for maintenance. And so it would be very interesting to see that. I'm outspoken against placebo withdrawal studies for drugs we already know how they work. But I'm really interested in the maintenance placebo arm here because this mechanism is so novel that I want to try to understand more about what the relapse rate may really be if you reset homeostasis and will it allow us to think about a new paradigm. But to answer your question directly for an investor, I think the induction response rates over placebo would be considered a very positive signal and maintenance is going to succeed. And my colleagues and I will be very happy to be supporting this and moving it forward because we desperately need better therapies, and this is a new one. Now the other question was about how many patients really want oral versus something that's less frequent that would be injectable or infusible. And when you explain to a patient that the primary reason for a parenteral therapy, injection or infusion is because the molecule is too big and you're just getting it into their body and that the oral therapy is delivering orally because of the size of the molecule, it helps them understand why they might need those other options. But the future of management of our conditions, I really think is oral. I've described treatment revolutions in our field. And I'll share with you very briefly that the first revolution in ulcerative colitis was the recognition we could use corticosteroids to treat these conditions. That was in the 1950s. The second revolution didn't come until anti-TNF, which was all the way in the 2000s, early 2000s. The third revolution was the oral small molecules, which this falls into, but this also bridges into the fourth revolution, which is reestablishing homeostatic control as opposed to just tamping down active inflammation otherwise. So I really think this is going to usher in an era where we start thinking differently about how we do this, and that's one of the reasons I'm so enthusiastic about it. And yes, patients want oral. They would pick oral over injectables whenever possible. The only people who don't feel that way are people who've already been through multiple therapies and are stable on an infusible or an injectable, and they are nervous about switching. But if you started with any patient who walks in the door who's going to need some treatment, they would always choose oral over other options initially.

So our next question comes from Julian Harrison at BTIG.

First, Dr. Rubin, I wanted to get your reaction to the ANTHEM-UC data shared last week. What do we know? What do we not know yet? And what are maybe some important differences to highlight with obefazimod?

Sure. I am aware of it as well, of course. And I think it's of interest and certainly exciting to know that we might have an oral IL-23 therapy, at least one that works on the IL-23 receptor effectively. I think that the results are promising and encouraging. What we don't know from their press release and from the data that is available are which types of patients were included? Were they more naive patients? Or were they the more refractory types? We know a lot about IL-23. So I can tell you that we know that inhibiting IL-23 is an effective strategy when it's dosed right. And then we also know that, as you saw in the summary slides I had where I had studies lined up next to one another, we're not expecting that an oral IL-23 is going to work better than what we already have as IV and injectables, but we're enthusiastic about new options like this. It's a single target. It's IL-23. And in psoriasis, that's great because 90% of people with plaque psoriasis are IL-22 driven and IL-23 inhibition works. In IBD, it's not the same. There's a lot of patients who don't respond to IL-23 or who have partial responses. So I'm enthusiastic about it. I just don't know what the patient population was. I suspect that -- and I didn't write their press release, obviously, but I suspect that if it was a really refractory type of patient population, they might have shared some of that in their initial release, but they didn't. So I can't tell you that. I also don't know what the differences were between the doses. They describe benefit at the different doses and then they only show us the highest dose remission rates. So there are some things we'd like to figure out, and I'd like to learn more. I also know that patients with severe colitis have very high inflammatory burdens. So you want to understand more about how severe were these patients and did this really work in those individuals, which are the tough ones. That's all I can tell you.

Got it. That's helpful. And then a follow-up, if I may. On the topic of activity in biologic and/or JAK experienced patients, wondering if you could talk more about how much of a success factor you view that for obefazimod? And then looking at data reported to date of obefazimod, how persuasive is the activity in that segment specifically?

Can you repeat the first question? I didn't quite understand it.

Sure. How important is activity in biologic and/or JAK experienced patients for obefazimod?

Got it. Sorry. If you look across the U.S. market and you look at the majority of prescribers who are not IBD experts, which is the majority of gastroenterologists and advanced practice nurses, you'll see that they still rely on the drugs that they know and the ones that have the longest time on market. That would be, of course, Humira and the adalimumab biosimilars. It would be the ENTYVIO, vedolizumab and then infliximab. So you're going to have a large number of people who are already getting exposed to those drugs as a matter of practice before they might go to this. On the other hand, after this has been around for a while and people become comfortable and what I say to my colleagues is after you try it, you're going to see what it does and then it will make it more -- you'll be more comfortable using it and understanding it, you'll see it get picked up. But where we need the most advances in our space is in novel therapies that address refractory patients, first and foremost, because people want to avoid surgery for obvious reasons. And then backing it up, what I'm trying to do in my research and in my influence is to move everyone to a healed bowel, which has downstream benefits to the rest of your health. So we're moving the whole field that way. But you definitely -- if you start with the most refractory patients and demonstrate such nice efficacy and safety, then you can imagine that people become more comfortable using it earlier in the management strategies. But with any new mechanism, you always deal with that barrier to prescribing upfront. So people need to learn about it and then they need to embrace it. And then once they understand the mechanism, they'll use it more. I think you know that. But that's my general take on this. I will say that the JAK inhibitors, despite the fact that I remain very enthusiastic about them, and I've been excited to use mostly upadacitinib these days, Rinvoq, there remains this black box hanging over them that makes people very nervous about prescribing. So it's not infrequent that our colleagues send their patients to us and they're afraid to prescribe those drugs. So we need safer options that make sense. This appears to be one and it's not going to have any restriction or pretesting that's going to be required before people can get on it. And I think that will go through that. The S1Ps have been hindered by people's in GI, people's concerns about macular edema, needing to get an EKG. I'll tell you that when I educate on those, I say that you guys are over-reading this. That's nothing. It's a safe drug, but it still hasn't had any uptake. So this could be the one that breaks through as an oral therapy that people are ready to use earlier and later because it makes sense and the mechanism is so novel.

Our next question comes from Thomas Smith at Leerink.

First for Dr. Rubin, just on safety. I know you alluded to this in your presentation, but can you comment on the headache signal and your experience treating patients with obefazimod? I know the discontinuation rates are quite low, but can you describe how much of an issue, if any, this has been for the patients you've enrolled into the study? And then for the Abivax team, you've previously commented on some of the enrollment and patient trends that you're seeing in ABTECT on a blinded basis. I was wondering whether you could provide an update on what you're seeing with respect to the type of patient being enrolled, biologic experience versus biologic naive. And also with respect to the treatment discontinuation rates, how have these aspects trended relative to your Phase II experience and your expectations for the Phase III?

So the headache is mild, at least my experience with it and my understanding being part of their steering committee and reviewing all this. But also, what I say to patients is that you may have a headache. There's a 1 in 5 or 1 in 3 chance you're going to have a mild headache. It will last a week. You can take Tylenol. It shouldn't result in you needing to stop the therapy, and it's not associated with anything worse that you need to be worried about. So this is a manageable AE, and I want to emphasize the majority of patients don't have it. In fact, out in maintenance, the rate is much lower as you follow patients out. So when it occurred, it was limited and went away. And I don't think we know the mechanism of it. It's a common AE in general, but it's worth calling out because it was distinct with this therapy. I don't expect that, that's going to be an issue in rolling it out to patients. I think most people who have rectal urgency and are bleeding when they go to the bathroom will put up with a mild headache for 7 days. I'll let the Abivax folks answer your questions about the current Phase III.

Thank you, Dr. Rubin. Marc, do you want to comment maybe at a high level on the trends that we're seeing?

So maybe the first question was, is there a difference in population between Phase III currently in the Phase IIb between bio- experience and bio-naive. So actually, we are at 48% year-to-date for both Phase IIIs in terms of bio- experience. So you saw on the slide that presented that was exactly where we are in the Phase IIb. So I think the population is going to be very similar. Again, I'd like to remind you that one way we did it is that in the Phase IIb, we had 1/3 of our patients were in, let's say, Western Europe and in the U.S., and most of it was 2/3 in Eastern Europe. We think that in the Phase III, at least again, based on a year-to-date basis, percentage of patients coming from Eastern Europe is going to be much lower, more in the range of, I think, 35%. So it be a fairly dramatic decrease. So that's the first part. I think the second question you had is what are you seeing in the blinding data. Again, blinding data is blinding data, so it has its limitation. In terms of related to the safety and the headaches, the discontinuation rate in the Phase IIb was 12.5%. And currently, again, when we look at the combined Phase IIIs, 105 and 106, we see a discontinuation rate around 10%, so slightly lower. So overall, again, we are pretty encouraged by that. And then the last thing also we indicated in the past is one measure we track are the number of patients or the percentage of patients who move from the current 105 and 106 study into the maintenance. And that's been characterized by essentially the responders and not remission, but the responders. And we see the same percentage as before in the Phase IIb, so 53% for both studies. So overall, we are tracking.

I just want to clarify, I know you said it correctly, but I want to drive home the point that discontinuation is not due to the headaches and the doses moved forward into Phase III, that was only 4 patients total who ended up stopping related to headache. And that's not the main reason that, that happened. So the rate that Marc mentioned to you all is what we see in these trials. That's completely consistent with people who get worse colitis and move on to surgery and other things.

Our next question comes from Sam Slutsky at LifeSci Capital.

Dr. Rubin, just as you mentioned, obefazimod has potential to be used across lines of therapy, particularly as physicians get more comfortable with a new mechanism. When you think of use in later-line patients, though, do you see this potentially slotting in front of JAK inhibitors given the safety profile? And then the second question I just have is for maintenance data. Obviously, it's open-label, but just given the magnitude of effect and the duration of effect, what's the likelihood of this not being a strong treatment effect and something due to the open-label aspect of it?

Thanks for your questions. I just want to say, in general, I'm not surprised, but the questions are all great. Let me start by reminding you that in the U.S., JAK inhibitors are positioned only after inadequate response or intolerance to anti-TNF. So you already have to go through another therapy before you can get to the oral JAK inhibitor. So if this therapy comes to market as we hope it will, it will not be positioned that way based on what we know. And therefore, it will be an obvious oral choice before we have to go through monoclonal antibodies necessarily. And certainly, before JAK inhibitors, which I mentioned already, have some concerns from our colleagues for safety. And the S1Ps have similar, even though we could argue they're safe and they'd be easy to use. People have been very hesitant and the market uptake on those have unfortunately been slow. There's a niche for this in the early phase of management that I think will be surprisingly fast in uptake once people understand it and knowing that it works in the most refractory patients means you don't end up forgetting about it later, and that will be where people use it early, as you know, when a new drug comes to market. So I think that, that's going to be very nice to see and a lot easier to prescribe for people. Forget if you had a second question.

Yes. Just on the maintenance data, obviously, it's open label, but just given the magnitude of effects seen as well as the duration of responses, what's the likelihood of this not being completely treatment related or some type of influence from it being kind of open-label single arm?

Well, I would say that I agree with you in general that there can be an overestimate of effect when you're looking at open label. But I would add that following it out to 96 weeks suggests that any imaginary effect would be gone. And I'll tell you, taking care of patients with ulcerative colitis that the most optimistic approach to diet or other things may give someone a short-term benefit. But if it's not really disease-modifying, they all relapse by the end of 6 weeks. So you're following patients out now for almost 2 years, and you can appreciate why this looks like it's a sustained effect regardless of being open label.

So I just wanted to do a quick time check. We have about 4 minutes left. So we have time for a couple more questions here.

Great. Thanks, Pat. So our next question comes from Jason Butler at JMP Securities.

I'll just throw on one. Dr. Rubin, you mentioned that the company included several design elements in the Phase III to optimize placebo response. Did these elements make sense to you? And relative to what we saw in the Phase IIb trial, what are your expectations for the placebo rate in the Phase III studies?

I wasn't involved in designing their Phase III. I came on the steering committee after, but I'll tell you that this is exactly what I would have told them to do. I am a big fan of getting prednisone out of the picture so we can demonstrate the real effect of the medicine. And I'm delighted that they have the lower threshold dose of pred and the forced taper built in. That will absolutely reduce your placebo rates as you look at the primary and secondary endpoints in the Phase III, and that will give you a very nice signal of what's going on. I also want to add my bias, which is that prednisone modifies biology. And I think when it's out of the picture, we get a much clearer and more effective signal with effective therapies. We've seen drugs fail because of prednisone and a loss of delta between placebo and drug. That's not what I expect here at all, and I'm very enthusiastic about that. I also am enthusiastic about their efforts to be geographically diverse so we can understand it better and to control some of the site recruitments. And then the last thing I'll say is I I'm delighted that they're brave enough but also smart enough to include refractory patients in up to 60% that are enrolled. That's what we want to see, and that's what's going to get them the early uptake by the market and by my colleagues. And then when we show that it works even better in the naive or the less severe patients with the safety profile of this therapy, which I want to emphasize looks excellent, is going to make this a very easy one for people to use.

Our next question comes from Vikram Purohit at Morgan Stanley.

Can you hear me?

Yes.

Okay. Great. Just 2 from our side for the doctor. So Dr. Rubin, apologies if this has been discussed and if we missed it, but do you have any initial thoughts on using obefazimod as a combination agent? And if you do think it could be a good combination agent, which agents do you think could be good to combine obefazimod with? And then secondly, you mentioned that you expect broad uptake assuming commercial approval here, but based on your experience with other novel agents that have come to market, what do you expect the uptake curve to look like, excuse me? Would you expect broad-based uptake from the onset? Or do you think it will start more refractory and then kind of build its way to earlier lines of treatment over time?

Thank you. I appreciate the questions. First question I want to say is there's been great interest in our space and whether we can combine therapies in novel ways to gain even more efficacy. And I think that there is value in considering that. I also talk frequently about combination approaches, which are phased where you use 2 drugs for induction and then you continue on with 1 drug and maintenance. So I could imagine that in sicker patients, we might want to add another therapy to try to tamp down the high burden of inflammation. But I also want to point out that this drug works so broadly that it remains to be seen whether we'll need to do that. Having said that, whenever we consider combo therapy, we always think about 2 things. Number one is what's the safety of combining. And second is what's a different mechanistic approach that would add to what we're doing and not be redundant. So to give an anti-TNF or an IL-23 with this drug, at this point, my opinion, my expert opinion would be that it would be unnecessary and redundant and not necessarily add things. But on the other hand, maybe adding something like ENTYVIO as a lymphocyte trafficking inhibitor for a cellular strategy would be of interest. But I want to emphasize again that this is a paradigm shift in the way we think about managing IBD. We're not trying to treat the active inflammation. We're trying to turn it off at the beginning and reset the bowel, which is what I always explain to people is how the bowel heals and how we get to where we need to go. And the fact that it's not an onerous delivery system, it's oral is a reason that this is likely to do what we need it to do. So the combo therapy is completely hypothetical, but I will say to you that I don't think it's needed with this yet, and I'm very enthusiastic about seeing how we do with Phase III as a monotherapy. The second point about uptake, I just want to emphasize again that this is a lot easier for people to know. It's oral. It's going to be delivered daily, once daily and then it's non-injectable in IV. You don't have to go through other drugs. We don't have to spend a long time describing adverse events like venous thromboembolic complications, cardiac events or worrying about your eyes. That's a big deal in our field, even though I've tried to minimize it to get people on effective therapies. This won't have that. That is not a small thing. And I want you to keep that in mind because I do think that they're going to have success. Meanwhile, this drug has been talked about in multiple congresses and scientific meetings. Our colleagues are being socialized to it already and are expecting good things and are excited about it, and they've won awards at our meetings for the study results and the design of their Phase II stuff. So I think they're on the right track here.

Tara, I'd like to just maybe close here. And first, I'd like to apologize to those of you who we couldn't get to your questions, but I also want to thank Dr. Rubin for an outstanding presentation and for the thoughtful responses to all the questions. So we ran a bit over, but I think that's indicative of the interest in obefazimod, but also your point of view on the market. So thank you very much again. And as a reminder to everybody, we will have a replay of the webcast on the website later today. Thanks very much, everybody. Have a good day.