ABIVAX Société Anonyme ($ABVX)

Good afternoon, and good evening, everyone. We hope you've had a chance to review the press release we issued after market close in the U.S. today, announcing the positive top line results of the Phase III ABTECT maintenance trial. Joining me on today's call are our CEO, Marc de Garidel; our Chief Medical Officer, Fabio Cataldi; and our Head of Global Medical Affairs, Chris Rabbat. In a few moments, Marc will provide opening remarks, and following that, Fabio will present the top line efficacy results. Chris will then present the top line safety summary overview. Following the prepared remarks, we will open the floor for a Q&A session, where in addition to ABIVAX management, we are honored to be joined by Dr. David Rubin. Dr. Rubin serves as the Chief of the Section of Gastroenterology, Hepatology and Nutrition and the Director of Inflammatory Bowel Diseases Center at the University of Chicago. Dr. Rubin also serves as the Chair of the International Organization for the study of inflammatory bowel diseases. Before I hand the call over to Marc, I'd like to remind you that during today's call, we will be making forward-looking statements. A summary of these forward-looking statements are included on Slide 4 of this deck and can be referenced in our 6-K filing. Now I'd like to hand the call over to our CEO, Marc de Garidel. Marc?

Thank you. Pat, and thank you, everyone, for joining us on today's call. Today marks an important day as we announced the landmark ABTECT maintenance clinical trial results. It is not only an exciting day for ABIVAX, but more importantly, for patients with ulcerative colitis, their family members and the health care providers that care for these patients. Today's results firmly establish obefazimod as a potential new standard of care for the treatment of ulcerative colitis. Both the 25- and 50-milligram doses of obefazimod met the primary endpoint, demonstrated market-leading efficacy with placebo-adjusted clinical remission of 39.3% and 40.3% for the 25- and 50-milligram doses, respectively. Additionally, both doses also met all key secondary endpoints, demonstrating robust and clinically meaningful efficacy. Importantly, obefazimod demonstrated a favorable safety profile over the 44-week period with no new safety signals identified. 580 patients were randomized in the Phase III maintenance trial, and the study achieved an incredible 10% placebo rate, the lowest reported in the Phase III UC rerandomized responder maintenance trial. This speaks to the operational excellence of the team and the study investigators. Now I would like to hand the call over to our Chief Medical Officer, Fabio Cataldi, who will walk through the maintenance trial results in detail. Fabio?

Thank you, Marc. As a reminder, here is the overall ABTECT program design. We conducted 2 independent 8-week induction trials where active drug responders continued into a single maintenance trial. Patients that achieved clinical response to 50 milligram during induction were randomized to either remain on 50 milligram, deescalate to 25 milligram or switch to placebo. Patients that achieved clinical response to 25 milligram either stayed on 25 milligram or were switched to placebo. At the end of 44 weeks of the maintenance trial, we read out the primary endpoints of clinical remission. These are the baseline characteristics for patients that participated in the maintenance trial. As you can see in the table, overall, the 3 cohorts are well balanced across age, induction modified-Mayo score and mean duration of disease. Maintenance patients randomized to placebo had lower induction fecal calprotectin levels as well as slightly lower corticosteroid use and maintenance baseline relative to patients randomized to 25 milligrams and 50 milligrams. As a reminder, patients in our Phase III trial could receive oral corticosteroids only up to 50 milligrams per day and were required to begin tapering immediately upon rerandomization into the maintenance trial. The 50-milligram cohort had a higher proportion of patients who failed prior advanced therapies at 46% compared with the 25-milligram cohort at 39% and the placebo cohort at 38%. Finally, at the bottom of the slide, the overall completion rates are shown. The maintenance trial completion rate was approximately 80% in both the 50 milligrams and the 25-milligram scores versus only a 34% completion rate among induction responders rerandomized to placebo. Looking at these differences in completion rates, you can already begin to see the impact of withdrawing obefazimod from patients who responded to treatment during induction. Here, we are showing the primary endpoint of clinical remission in the maintenance trial. More than half of all patients receiving of obefazimod achieved clinical remission with 50.8% of patients in the 25-milligram arm and 40.3% in the 50-milligram arm compared with just 10.4% in the placebo arm. This translates into highly statistically significant treatment differences versus placebo of 39.3% and 40.3% for the 25-milligram and 50-milligram doses, respectively. As Marc noted, the 10.4% placebo remission rate was historically low, reflecting the high quality of the trial design and execution. Here are the key secondary endpoints where, again, both doses achieved highly statistically significant differences versus placebo. This includes endoscopic improvement, endoscopic remission, endoscopic mucosal improvement, HEMI, corticosteroid-free clinical remission, a sustained clinical remission, which reflects the percentage of patients who achieved clinical remission at both week 8 induction and week 44 maintenance. As you can see, these are very impressive results across all endpoints, including the most objective and stringent endpoint, endoscopic remission and HEMI. Now I'll hand it over to Chris to walk you through the safety summary.

Thank you, Fabio. Turning to the safety profile, starting at the top of the slide. Treatment-emergent adverse events occurred at a higher rate in the 50-milligram group versus placebo and at a similar rate in the 25-milligram group versus placebo. TEAEs leading to study drug discontinuation were highest in the placebo group and serious TEAEs occurred at a similar rate across the 3 groups. No deaths occurred in the trial. And serious, severe and opportunistic infections occurred at a low rate across the 3 groups, consistent with the non-immunosuppressive profile of the mechanism of action. We observed no cases of acute pancreatitis in any group and no reports of cardiac abnormalities suggestive of cardiac fibrosis. With regard to malignancy events, excluding non-melanoma skin cancer, in the 50-milligram group, there was 1 case of prostate cancer in a 53-year-old patient, 1 case of breast cancer in a 65-year-old patient and colonic dysplasia in a 49-year-old patient. These events occurred in different organ systems with no evidence of and all were considered unrelated by study investigators. Looking now at non-melanoma skin cancers. In the 50-milligram group, 4 cases were observed. Two of the 4 cases were assessed by investigators as not related or unlikely to be related to treatment. Of the remaining 2 cases, 1 patient had a prior history of skin cancer. The squamous cell carcinoma case observed in a 25-milligram patient had a history of skin cancer as well as prior exposure to azathioprine, which is known to increase the risk of NMSC even after the drug is discontinued. Of note, the mean age of patients with NMSC on obefazimod was 62 years compared with 42 years in the overall study population, which is consistent with the known age-related increase in NMSC risk. It is important to view these findings in the context of the underlying UC population. Patients with ulcerative colitis have an elevated background risk of NMSC, estimated at approximately 1 event per 100 patient years, which is why annual skin examinations are recommended in treatment guidelines. While there was a numerical difference in NMSC cases in the 50-milligram arm, importantly, the independent data monitoring committee did not consider this a safety signal. Overall, these maintenance data support a favorable safety profile, consistent with obefazimod's mechanism of action, which restores immune balance rather than broadly suppressing the immune system. Now let's transition to discuss the rate of headache during the maintenance trial. As you may recall from our induction trials, we observed a higher rate of headache in the treatment arms versus placebo. These headaches were associated with treatment initiation, were generally short in duration and were mild to moderate in severity. In the maintenance trial, where patients had already received 8 weeks of induction treatment before randomization, we observed similar exposure-adjusted incidence rates of headache across the 3 groups. Headache also did not lead to study discontinuation in either obefazimod arm. The time to onset of headache during maintenance does not suggest an association with ongoing drug exposure. If headaches were a recurring effect of continued treatment, we would expect them to occur in closer temporal relationship to the start of the maintenance trial. Instead, the distribution of onset of first occurrence appears random, supporting the concept that headache is primarily associated with treatment initiation early in induction rather than continued treatment in maintenance. I'll now hand the call over to Marc to place the program results in the context of currently available therapies.

Thank you, Chris. To put the efficacy results in context, let's look at the clinical remission rates for currently available treatments. The far left of the slide shows obefazimod's new Phase III results followed by currently available oral therapies with biologics displayed on the far right. Key points of comparison are the placebo-adjusted clinical remission rates, which appear on top of the bracket for each treatment. As you can see, obefazimod compares favorably with therapies available today. Importantly, the strong competitive profile is evident whether efficacy is assessed by placebo-adjusted treatment effect or by absolute clinical remission rates with obefazimod delivering highly competitive results on both measures. To illustrate the strength of this efficacy in another way, this slide takes a closer look at the placebo-adjusted clinical remission results. Here, obefazimod is shown on the far left with currently available therapies grouped by mechanism of action. As you can tell, both 25-milligram and 50-milligram doses delivered placebo-adjusted clinical remission rates of approximately 40%, placing obefazimod among the highest efficacy results reported in maintenance studies to date. The only comparable results comes from the highest approved dose of a JAK inhibitor, while obefazimod substantially outperformed all S1P, IL-23s, alpha4beta7 and most JAK comparator therapies. Again, keeping in mind that this leading placebo-adjusted treatment effects were achieved alongside clinical remission rates exceeding 50%. Finally, let's turn to endoscopic remission, one of the most clinically meaningful endpoints in ulcerative colitis. As you can see, obefazimod delivered placebo-adjusted endoscopic remission rates of 38% and 31% for the 50-milligram and 25-milligram doses, respectively. These results are clearly differentiated from every other therapy. While most therapies cluster in the 8% to 20% range, obefazimod stands alone at 31% and 38%, demonstrating a level of efficacy that is well beyond the range achieved by other treatment classes. This finding is particularly important because achieving endoscopic remission has been consistently associated with lower relapse rates and better long-term patient outcomes. Taken together with the clinical remission data we reviewed earlier, these results demonstrate that obefazimod is delivering not only strong symptomatic benefit, but also the deep and durable disease control that physicians increasingly seek for their patients. In summary, there are 4 key takeaways from today's Phase III maintenance results. First, this was an exceptionally well-executed study, and we would like to thank the patients, investigators, study coordinators and clinical teams whose commitment made these results possible. Second, obefazimod delivered highly compelling efficacy results. Both the 25- and 50-milligram doses achieved the primary endpoint with clinical remission rates exceeding 50% and placebo-adjusted treatment effects of approximately 40%, placing obefazimod among the top-performing therapies available today. Third, strength of the efficacy profile extended beyond clinical remission. Obefazimod achieved best-in-class placebo-adjusted endoscopic remission rates, substantially exceeding those reported for currently available therapies and demonstrating meaningful differentiation on one of the most clinically relevant endpoints in ulcerative colitis. Fourth, these efficacy results were achieved with a favorable safety profile through 44 weeks and are complemented by the long-term Phase IIa/IIb open-label extension data we announced in May. Notably, in that study, patients who received 50-milligram of obefazimod for 2 to 4 years and then transitioned to 25 milligram for up to an additional 3 years maintained durable clinical remission and a favorable safety profile for up to 7 years of treatment exposure. Taken together, we believe these results validate the transformational potential of obefazimod and position us well as we advance toward our planned NDA submission in late 2026. Before moving to Q&A, I'd like to turn the call over to Dr. David Rubin for his perspective on today's results. David?

Okay. Well, thanks, Marc, and welcome, everybody. Again, my name is David Rubin. I'm a Professor of Medicine at the University of Chicago. I also direct our Tertiary Inflammatory Bowel Disease Center here. And obviously, I work on clinical trials. I'm also the Chair of the International Organization for the study of IBD, and it's really my pleasure to address you all today. I will disclose that I am also an adviser to ABIVAX and have worked with them, although I only saw these data yesterday and, of course, have been appropriately blinded. I want to start by saying and helping you understand, number one, that this is indeed a novel mechanism of action for patients with inflammatory bowel disease and very specific here, ulcerative colitis. And while we are coming to understand it further, the way we're thinking about it is that this is a mechanism that may provide a restoration of homeostatic balance rather than suppression of the overactive immune response. That is, I think, supported by the evidence we're seeing from both Phase II and now these very impressive Phase III results. I have a number of comments, and then, of course, I welcome your thoughtful questions. The first thing I want to say is that this is, in fact, a very positive study, as I'm sure you can understand. But also that this was a very positive study in a group of patients with moderately to severely active UC who -- many of whom were refractory to multiple other lines of therapy. In fact, although it was a small number, this is the largest number of patients who even had been resistant to [ Janus ] kinase inhibitor therapies before they enrolled in this study. And if you look at the demographic table that was presented to you, you may have even noticed that the group that were randomized to the 50-milligram arm in maintenance actually had a more refractory population, setting the bar even higher for that group. The delta we see over placebo is a nice way to look at the overall effect. And so on the one hand, you can emphasize that there's a very low placebo rate, which is the lowest we've seen in these types of studies. That is another way to reflect how sick these patients are and how refractory they've been. But also it sets the floor so that you understand what the ceiling is and how to interpret it. And that delta is really quite impressive. And as you already saw in the comparative lineup of other clinical trials and therapies that it exceeds all of our other therapies. The closest we have would be the Rinvoq data at 30 milligrams in maintenance. And the other way you adjust this, of course, is to go back to say, well, how many patients in those trials were resistant to 1, 2, 3 or even 4 classes of prior therapies and how refractory were they. And arguably, the data for obefazimod show that this works in the most refractory of our patients. The other point I want to make is we didn't even look at endoscopic remission in the past. We accepted what was called endoscopic improvement, where people had Mayo endoscopic scores of 2 or 3 on entry to these studies, and we defined clinical remission as a Mayo endoscopic score of 0 or 1 collected together. When you look at a Mayo endoscopic score of 0, you have to accept that, that is essentially the bowel is completely healed and almost looks normal to us, which is why we call it endoscopic remission. And if you overlap the endoscopic remission data with the clinical remission data here, you can easily see that the majority of patients who were in clinical remission also achieved this very impressive endpoint, which, as you heard, is associated with downstream stability, which is, of course, what we want and supports indirectly that we're the mechanism that may be reinstating or sustaining homeostatic control in these patients. And then, of course, I want to comment on safety. When you combine the safety scene in this Phase III maintenance set of data with what we've seen over the long-term follow-up in Phase II, it continues to support that there is a very nice safety profile here. There are no new signals. I will specifically comment looking for things like infection. And I do want to specifically call out that I do not think those 3 cancers that were described in colonic dysplasia, breast and prostate are related to drug nor do I think that they're related to their -- the patients otherwise. It is, of course, known that people with long-standing colitis have an increased risk for colonic dysplasia, especially people with severe colitis. So I don't find that to be worrisome in any way. So overall, I think this is a very positive study for you all to interpret in your own ways, and I'm very happy to take questions from the group. Thank you very much.

Operator, we can now move to the question-and-answer session.

[Operator Instructions] And our first question will come from the line of Yatin Suneja from Guggenheim.

Congratulations to the transformational results. Just 2 quick ones for me. So first one for the company. Could you talk about the consistency of effect across naive and experienced patient population? What -- how would you characterize that? And then with regard to the malignancies that you're seeing at the higher doses, could you provide a little bit more like what is the underlying or the background rate? Why are we only seeing that with the 50 because I think that's where some of the questions that we are getting from investors.

Chris, why don't you take that one?

Yes. So with regards to the ATIR, advanced treatment inactive responder yes and no data, we've held that back. We haven't released that, obviously, on the call here, and we'll be looking to present that at a future meeting. So I can't comment specifically on the maintenance results. We know that in induction, we did see a difference in those refractory patients with the higher dose versus the lower dose, and we've seen that in other treatments in this space. So I think we'll have to wait and see for the data when it comes up at a future conference.

And then your second question, Yatin.

Yes. So maybe just before we get there, I think one important, I think, element to put under context, which was, I think, already explained by David, is when you look at the malignancy and MSC rates, when you account for exposure adjustment and prior skin cancer history, obefazimod is generally in line with what we would expect to see in this ulcerative colitis patient population.

Chris, do you want to speak about specific?

Yes. So it's important to evaluate this with the totality of the evidence, right? So the observed malignancies were single events, not organ-specific and therefore, lack clustering. They occurred largely in patients with recognized risk factors, too, and were reviewed throughout the program by independent monitoring committees. At the same time, we observed a favorable safety profile through 44 weeks in Phase III, and it's also supported by more than 440 patient years of long-term Phase II experience as well. So when we view that in the context of the total safety database, the findings observed are well within the range of what could be expected for a moderate to severely active UC population, and we remain highly confident in the overall benefit risk of obefazimod.

I'll echo that. I said it a little bit in my comments as well. This doesn't stand out to me. Patients with severe ulcerative colitis can develop dysplasia over time. That's not a surprise in any way. There's no signal. And you look back at their Phase II results, which had long-term follow-up at the 50-milligram dose even, and you don't see any signals there. So I think that this is not worrisome.

Great. Thank you, Dr. Rubin.

Our next question will come from the line of Judah Frommer from Morgan Stanley.

Congrats on the update here. Just curious about the role that you and maybe Dr. Rubin feel the 25-milligram dose could play here given the update. I would say, given the efficacy being fairly similar to where the 50-milligram is and arguably the safety being better and then also kind of rounding out with the Study 108 data and patients seeing a benefit there as well. So any initial thoughts on 25 milligram versus 50 milligram in the commercial setting?

Yes. So maybe I'll let, obviously, David respond on the side. I think when we look at the evidence, both doses demonstrated exceptional efficacy and a favorable safety profile. So we're continuing to analyze obviously the data to understand whether the meaningful difference that could exist in specific patient population. And by the way, we will report obviously more at the next congress, very likely at UET if we get accepted about more detail about that. You will also recall that 50 milligram in the endoscopic remission was indeed better than the 25 milligram. So as of today, at least from a company standpoint, subject to see further analysis, we just got the data literally 2 days ago. Our thinking is that both doses will be very helpful for patients, and we plan to file at year-end with those 2 doses for maintenance.

So my comments on this, it's a very important question, obviously. Of course, traditionally, the agency in the U.S. has approved the lowest effective dose. But in recent years, with our IL-23 therapies and with our JAK inhibitors, they've recognized that in the ulcerative colitis space and also Crohn's that we need some dose flexibility. And in fact, there are patient populations who need the higher dose. And the mistake we made in our earlier era of therapies was when we didn't have that flexibility and we learned quickly that we were underdosing many people. So until we have the subset analyses to give clarity on who might do best with the higher dose, we're left with understanding that the safety looks similar in both arms, which is reassuring. And our general experience overall that some people clearly need higher doses. And I do agree that there's a numerical benefit of the 50-milligram dose looking at that hard endpoint of endoscopic remission. That probably won't turn the FDA's eyes since that's not their primary endpoint there. But it's certainly of interest. And I would encourage the agency if I were advising that they approve both doses, so we have that flexibility.

Great. Thank you, Dr. Rubin.

And our next question will come from the line of Tom Smith from Leerink Partners.

Congrats on the truly amazing data here. Maybe for Dr. Rubin, just given the maintenance results here, wondering if you could elaborate a bit on how you're thinking about using obe in your clinical practice. Specifically, if you could comment on whether you're viewing this as a better agent for advanced therapy-naive patients or perhaps more refractory patients? and then a quick question for the ABIVAX team. Just wondering if you could comment on whether this changes your outlook at all for the Crohn's data that we're expecting in the middle of next year. Obviously, very strong results here, but just wondering if this has shifted your expectations at all.

All right, Thomas, I'll start. Thank you for your question to me. And I'll say that the decision about which therapy to use for induction and maintenance requires a number of options and considerations, one of which is the presence or absence of extraintestinal manifestations, and we don't really have all that sorted yet. But then, of course, safety and efficacy and speed of onset. And here, we're certainly seeing that this therapy offers all of that and would be a reasonable drug to consider as a first-line advanced therapy if it were affordable and covered properly. And I think that, that's absolutely reasonable. On the flip side, when you see a drug that's working in patients who have multiple lines of prior therapies with different mechanisms that didn't work and it work, it becomes the salvage therapy of interest as well. So you all know this, that the gastroenterologists who are prescribing the therapies, they fall into a bell-shaped curve of early adopters and the laggards who are waiting for more data and more experience. And I think we're going to hit it on both sides, and there'll be enthusiasm. The narrative of the proposed mechanism is a very understandable consideration, and it has -- as an investigator and somebody who's participated in discussing this with patients, it's an easy thing to describe. So I think that, that's great. But if I had a patient, for example, with a history of plaque psoriasis as well as colitis, I'm going to lean towards an IL-23. So I think that's reasonable. And if you don't mind, I'll also comment that I fully expect this mechanism to work in Crohn's disease, and I'm enthusiastic about that study. Thank you.

Great. Maybe, Chris, do you want to add on to that?

Yes. So I think that this gives us even more confidence that the drug is going to work in Crohn's. So we're already very confident. And now when we see these results, particularly with the endoscopic remission data helps us be even stronger so.

Our next question will come from the line of Allison Bratzel from Piper Sandler.

Big congratulations from me as well. Could you just talk to how the 44-week completion rate compared to your expectations? And putting that together with the long-term Phase II data you've generated, what kind of adherence and treatment duration would you expect to see in the real world?

So we think that 82% is a very good completion rate for a trial of this design. So we're excited about that. Where we really see differentiation between the therapies that are available is in the second year of treatment. So we expect this sort of high retention or persistency rate to continue into the second year of treatment into our LTE. And that's where we will see some differentiation between our drug and some of the other drugs that have been approved.

Our next question will come from the line of Sam Slutsky from LifeSci Capital.

Congrats on the efficacy update. Two quick ones. In terms of Crohn's disease, just what have been the gating factors there in terms of enrollment and just confidence that we'll definitely get the data mid next year? And then with the cancer cases that have occurred, do you know offhand the timing that this has occurred at? And then just remind me, I don't believe there was a signal in Phase IIb. Is that correct?

Maybe we'll have Fabio take the first part of that and hand over to Chris for the second part.

Sure. So the timing update primarily reflects the increased competitive landscape in the clinical trials in Crohn's disease. At the moment, we have about 6 trials running in Phase II, 5 running in Phase III and the other in Phase IIIb. So there is really a huge competition ongoing. It's a very difficult disease to recruit historically, and I think it's just increasing the difficulty of basically recruiting patients. We are taking many measures to stay on time, maybe to even bring it in sooner than what we have announced. We are adding new geographical locations or new countries and new sites are really trying to leverage our experience with ABTECT in ulcerative colitis using some of our top recruiting sites and countries to really increase. And I think the message with the ABTECT data and the fibrosis paired with the fibrosis, I think, is going to be really a good real incentive for sites to believe even more in the drug.

I'll answer as well because I'm a clinical trial [indiscernible]. I want to explain to you that currently, for example, if you looked at the TL1As, they're trying to -- a couple of the companies are trying to recruit into Crohn's and UC simultaneously. And we don't have the Phase III results to get our arms around. So I would not underestimate the power of seeing these results in ulcerative colitis to generate enthusiasm in the investigators and potential study participants, our patients, because they're going to be excited by what they see here, and they're going to start learning more about what we think the mechanism is and what it's doing. And it's going to generate, I think, a burst of recruitment activity. So actually, I think that's a very good question given the landscape. But because of the novel mechanism, the narrative that seems to make good sense in my mind and experience and now these results, it's like -- it's going to be a burst of energy for the Crohn's recruitment. I think it's going to go well.

Chris, do you want to take the next part?

In terms of the timing of when the cases occurred, it was sort of a spattering in terms of length of exposure. There's no real consistent pattern. It seems random, which fits in with these sort of being unrelated to treatment. So that answer your question, Sam, that's what you're looking for. We're looking at like the date of when they happen.

Well, he wants to know about duration of exposure before the development of the cancer.

Yes. So there's -- I'm just looking at it here. There's no consistent pattern. It's anywhere from 49 days through 311. There's no -- and all in between.

And of course, the Phase II to answer that other part, did not show these signals at all over the long-term follow-up, there were 0.

Yes, there was 0.

Our next question will come from the line of Jason Butler from Citizens.

Congrats as well. Just one for me. Part of the trial protocol was a rerandomization of patients that were 50-milligram responders down to 25 milligram in maintenance. Anything you can say about those patients yet in terms of their maintenance of clinical remission?

Yes. We haven't released the data yet. We do have a sub-analysis of that group, which, again, we'll be looking forward to presenting at a future congress. But yes, that is an area of focus, and we're excited to show that in due time.

Our next question will come from the line of Julian Harrison from BTIG.

Let me add my congratulations on the data. First, Dr. Rubin, now that you have a comprehensive understanding of obefazimod's profile from the ABTECT trials, I'm wondering what percentage of your first, second and late-line UC patients that you envision ultimately being prescribed obefazimod? And then I understand you believe the malignancy observations are not necessarily cause for concern. Can you maybe put those observations in context relative to other approved therapies or other approved therapies in ulcerative colitis, such as TNF and JAK inhibitors? And then for management, on the updated guidance to Crohn's disease data, can you talk about some of the driving factors there for the update?

Okay, Julian. So for me -- and remember, I'm in a referral-based academic practice, but I do see patients almost half my time. I would consider this therapy initially to be probably 15% of my first lines, maybe 10% of my first lines, depending on the factors I mentioned earlier. I would definitely consider this to be a preferred [ third ] line in more than half of my patients based on what we're seeing here. And as we get more experience with it and as I see the subsets that you're all asking for as well, it will guide me in understanding that further. Remember, though, I'm not in community practice, although now at this level of my career, I do have a fair number of patients sent to me earlier in their course so that I do have people who are early line choices, but that's how I would break it down. And if you're asking me to think about the community and how they're going to do it, I think it gets back to what I said. If the drug is available and covered properly, it's oral, it offers this novel mechanism and a stable result over time with that healing of the bowel, it's a very positive message, and I think that's going to have some enthusiasm. They also have a little bit of time between them and the S1Ps and the JAKs. There was some overlap of those other drugs when they got approved and confusion among my colleagues regarding different mechanisms. So there's an opportunity here to really educate people and get things cleared up for management decisions. I'll defer to the Crohn's question perhaps to some of the folks who are from ABTECT.

Yes. Thanks, David. It's Marc. Yes, I think Fabio alluded to it, the delay linked to the Crohn's program is primarily linked to the competitive environment, which is taking place. And the reason why we are increasingly confident in our time line is due to, indeed, one, what we published in February at the ECO about the potential antifibrotic effect of obefazimod, which actually resulted in an acceleration already of recruitment. We saw that in a number of countries. But certainly now with this new very compelling efficacy in hard to treat -- including hard-to-treat patients, that would definitely accelerate the recruitment. But you have to bear in mind that, again, a year ago, this company had basically nearly no cash, and the study was basically on hold for nearly, I would say, 9 months. So we paid the price of not having cash last year, but we are picking up, and we are very confident we'll get to those time lines.

In terms of how the malignancies compare with other treatments in the space. So the overall pattern of findings we observed is well within the range of what's been reported for other advanced therapies in IBD. So that goes for STELARA, OVO, TREMFYA, Zeposia, et cetera, including the JAK inhibitors. And that just further reinforces that we think that this is sort of normal pattern that you would see in ulcerative colitis patients when you study as many patients as we did over the course of the year.

Our next question will come from the line of Sebastiaan van der Schoot from Kempen.

Congratulations on this outstanding data set. For the team, I think that prior to the maintenance results, you have a view that you would best position obefazimod in later lines. Given the results of today, how are you thinking about positioning of obefazimod in the future ulcerative colitis market? And then for Dr. Rubin, I will be interested in your view of the use of an oral versus an injectable and whether this is a point of differentiation that truly matters in your practice.

Thanks, Sebastiaan. So in terms of the positioning, again, I'd like to remind you that more data is going to come at upcoming congresses. So you're going to get a better picture of, again, the drug's performance 25 versus 50 in different type of population. So you have to be patient on this. We will, obviously, conduct extensive market research, both with payers, but also with doctors just as we did when we had the induction results. So we'll be able to get also a better sense of with now the real data where we could be positioned. But in general, what we said is indeed probably the first few years of launch will be more in the hard-to-treat population and then expanding into first line, but pricing and access will be key. And I have next to me here, Michael Nesrallah, who is our new Chief Commercial Officer. So maybe Michael, you may want to say just one word.

Absolutely. So I'll tell you from my experience before joining the company, I was absolutely excited by the opportunity to help patients in ulcerative colitis with a transformational therapy just based on what I saw from the induction data. And based on what we're seeing now from the maintenance data, it really strengthens our results. I see an opportunity here to broaden and as Dr. Rubin said, huge opportunity to help patients in first line as well as those that are refractory, and we'll conduct some market research to sharpen our positioning over time and get a sense for where we can best position obefazimod.

Let me comment on the question regarding small molecule oral therapy compared to a monoclonal antibody protein-based therapy that's delivered as an injection or an infusion. So this is not just about convenience. The important and unique consideration in ulcerative colitis and also in Crohn's, but for sure, ulcerative colitis, is that a moderate to severely inflamed colon leaks protein. And so, at least, in a subset of patients who don't respond to monoclonal antibodies, it's not a mechanism issue, it's an exposure issue because you leak the protein. So you basically inject or infuse and then you poop it into the toilet. Small molecules have been, in my description, a revolution for our IBD patients because of their absorption in the small bowel. They avoid that problem and you have a much more predictable PK. So aside from the fact that patients would like oral when possible and the convenience factor of that, you need to also appreciate the pharmacodynamic benefit of small molecule therapies. And because of that and as we describe this and continue to educate our colleagues, that's a specific advantage here that rheumatologists and dermatologists don't have to think about or talk about. So this is a reason why our small molecules, in general, in colitis have been so important to bring to the market, and this is no exception, obviously.

Great. Thanks, Dr. Rubin.

And next caller will be from Gregory Renza from Truist Securities.

Congratulations on the data, guys. Maybe for both the ABIVAX team and Dr. Rubin, now that we have this data set in hand, I'm curious how this helps to inform your views on the combination potential of obefazimod. What perhaps Dr. Rubin could be a rational combination partner for obe? And maybe for the company, if you could just share the latest plans on working on combinations.

Great. Thanks, Greg. Maybe we'll start with Chris, and then we'll have Dr. Rubin weigh in.

Yes. So we shared our combination strategy in the past, and I'll just reiterate here is that we think that our mechanism is so differentiated that it probably could be combined with any other MOA. For our purposes, we're most interested in combining with oral drugs to pursue a fixed-dose combination and preferably with MOAs that do not carry any sort of safety risk or labeling that we wouldn't want to inherit. And when you put things through that filter, we end up with a few of the candidates that we're running preclinical animal models on now. So namely alpha 4 beta 7, the oral, as well as the IL-23 receptor antagonist. We're also interested in PDE4. We just saw some new data at DDW on one of the PDE4 molecules, which looks impressive. And then, of course, there's also AHR, which, again, we feel is orthogonal to our mechanism and would be additive.

My comment is to say that an inflamed colon when you're inducing is different than a healed colon when you're preventing relapse. And so combo is not all or nothing. It's not combo forever. The way to think about this is in phases, perhaps more intense combination strategies for successful induction and then you leave on the safe, effective therapy and maintenance that is specific to that mechanism. Now it remains to be proven further whether combination with obefazimod is going to do even better than we saw with the drug alone, but it's certainly reasonable to consider what Chris said. I would just say that in general, I think about a hot inflamed colon as needing general cytokine strategies to get things under control when we need them. And so the combination of something like an IL-23 that you just said, Chris, or even other options with appropriate control, anti-TNF even, but then leaving this as the maintenance or the foundational therapy that would continue in the maintenance phase. So I'm pushing for that in the other parts of what we do in our world. And I appreciate the question because that is something we'd like to understand better.

Great. Thank you, Dr. Rubin. And operator, let's move to the next question. I think we have time for 1 or 2 more.

Our next question comes from Etzer Darout from Barclays.

Congrats on the data. This is for Dr. Rubin. So beyond the clinical remission data, physicians have noted to us the importance of the magnitude of the endoscopic improvement as an endpoint, and they sort of view the 50% or better threshold as being compelling. Just wondered if you could speak to the importance of the endoscopic improvements and maybe put that into context with your ulcerative colitis patients in their experience.

Thank you. Well, endoscopic improvement refers to patients who had a Mayo endoscopic score of 3 on entry, and achieve a Mayo endoscopic score of 0 or 1. That's what endoscopic improvement means. And in the first study to actually explore this in the modern era, which included when infliximab, received its approval as REMICADE in 2005 for ulcerative colitis. A subsequent study looked at whether there was a clinical outcome of difference in colectomy based on a Mayo score of 0 or 1. And at the time, there wasn't one, but it was a short-term follow-up with a very small number of colectomy events. So the point here, if you saw the data and you have it in front of you, was that endoscopic improvement here with the 50 milligrams was 64.1% as the secondary endpoint here and in 25 milligrams was 54.9%. That is higher than 50%, as you mentioned, and significant and would be a very satisfactory result. And currently, it's the standard. Knowing though that endoscopic remission is achieved in 41% and 47.7% is a remarkable addition to this that we haven't seen before. And that means that those are the people who are 0. So it's really -- you can do the math. You subtract the endoscopic improvement from the remission with a couple of exceptions, and you end up seeing that a lot of these patients got that full healing, and it's not rocket science to understand that when you're completely healed in the long term, you're less likely to have relapse loss of response and arguably, potentially downstream, even less risks of dysplasia or cancer, which we've been studying. So you can think of all the reasons this is a good thing. It also takes one of the factors out of interpretation here because we generally accept centrally read endoscopy is superior to some of the symptoms that are based on patient recall. And so this is a very solid result, and that's how you distinguish the different ones here.

Great. Thanks, Dr. Rubin.

Our next question will come from the line of Andy Chen from Wolfe Research.

And just another question for Dr. Rubin. I think I hear you that on the physician side, there is no concern regarding the malignancies. But just curious on your speculation for how the FDA -- or how cautious the FDA would be. Do you think -- how do you think they would act? And do you think an [indiscernible] will be possible? Or is that a remote possibility here?

Thanks, Andy, for the question. Of course, the FDA is, first and foremost, looking at safety for the people and they will look at this carefully. And it remains to be seen how they choose to interpret it for subsequent labeling and ongoing evaluation. But remember that they also consider the totality of the evidence, and that includes a large Phase II trial that had similar dosing and exposure, longer exposure without signals. And so they can interpret it as they like. I don't really think a single prostate cancer or a breast cancer is going to be reflected on the drug poorly even if it happened to be at the 50-milligram dose, but I'm sure they're going to look at it. The skin cancers, as you already heard, we see in IBD. And you do need to look at prior drug exposures, including, of course, thiopurines in those patients to know more about what else they had and what they're carrying with them and even such things these days as skin tone and risk otherwise. So there's lots of things that you can look at here, and I'm sure the FDA will do their due diligence. But I still am comfortable that they're going to be reasonable about all this. Maybe an AdCom because it's a new mechanism would be of interest. I don't know.

Great. Thanks, Dr. Rubin. And operator, it looks like we have time for about one more caller.

All right. And our last question will come from the line of Faisal Khurshid from Jefferies.

This is Anand on for Faizal. You noted 2 cases related to drug for the non-melanoma skin cancer, one of them had a medical history. Just wondering if any additional info about the second patient. And then noticed in the Crohn's trial enrollment criteria, history of non-melanoma skin cancer is an exclusion criteria, whereas it was not necessarily for ABTECT. I was just wondering if how you think about the non-melanoma skin cancer risk in Crohn's given the long-term immunosuppression there?

Chris, why don't you take that?

Yes. So for the other one, there were other confounders present in the patient other than history of skin cancer, sun exposure, age, et cetera. So even there, we think that there's reason to believe that it's due to the underlying disease and the patient's history as opposed to the treatment.

And then Fabio, maybe you could speak to the difference in the ABTECT study and the Crohn's study. Yes, relative to exclusion criteria.

Yes, of course. The differences between the APE and the Crohn's program is that the Crohn's program started after. So we were already looking for that. And in abundance of precaution, we basically excluded these patients. So that's the only reason why is that. And in reality, just to be clear, this is a history or active malignancy. So patients that have a 5-year disease-free survival are eligible. And that's pretty standard language.

Great. Thanks, Fabio. And operator, I think we'll just close with a few words. First, I want to thank everybody for jumping on to the call today. And most importantly, thank Dr. Rubin for his time and his thoughtful input. And of course, I want to thank the patients, the investigators and the support staff for their efforts in executing the study. With that, I wish everybody a good evening, and we'll talk to you soon.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone, have a great day...