ABIVAX Société Anonyme (ABVX) Earnings Call Transcript & Summary

Good morning. And welcome to the ABIVAX KOL webinar on ABX464 for the treatment of ulcerative colitis. [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 would now like to turn the call over to your host, Professor Hartmut Ehrlich, Chief Executive Officer of ABIVAX. Please go ahead, professor.

Thank you, Sarah, and good morning, good afternoon, ladies and gentlemen. My name is Hartmut Eli, I'm the CEO of ABIVAX, and it is my pleasure to welcome you to this KOL meeting on treatment options for ulcerative colitis. In particular, we are very grateful to our distinguished speaker today, Professor Bruce Sands who is the Dr. Burrill, the Colon -- Crohn Professor at the Icahn School of Medicine at the Mount Sinai Hospitals in New York. Today, Bruce will be giving the overview on current treatments in this space. And afterwards, I will provide a quick update on ABX464 before we move into a 15- to 20-minute Q&A session. So without much further ado, Bruce, thank you very much for being with us today, and the floor is yours.

Harmit, thank you very much. It's a pleasure to be here today. And over the next 25 minutes or so, I'm going to review some background and treatment and unmet need in inflammatory bowel disease, really with a focus on ulcerative colitis. And we start by considering what these diseases are. They're both inflammatory bowel disease There are 2 major forms of course, Crohn's disease and ulcerative colitis. Crohn's disease is a pen enteric and full thickness inflammatory condition. It is immune-mediated as is ulcerative colitis. There is a fair bit of genetic overlap between these 2 conditions. But fundamentally, the cardinal symptoms are relatively similar. In Crohn's disease, we see that patients in the majority have abdominal pain or diarrhea and to a lesser extent, will have rectal bleeding as part of their main symptomology. In ulcerative colitis, which is really confined to the large intestine and really to the mucosa of the large intestine. We see that bleeding is the major symptom of the condition as well as diarrhea. Abdominal pain tends to be far less prominent than in Crohn's disease. It really is usually cramping before bowel movement relieve by, it's not a chronic issue as it can be with Crohn's disease. So they are distinct conditions. They have distinct locations in the bowel and distinct pathophysiology, perhaps with some overlapping symptoms and some overlap in genetics. Fundamentally, It is simple enough to investigate ulcerative colitis and to diagnose it endoscopically. And we are able, very objectively to score the severity of the condition This is the modified Baron Score, which was really adopted pretty much into the Mayo Score, which is the current disease activity index that has the most currency with regulatory authorities. And in the upper left-hand side, you can see a fairly normal-looking colonic mucosa. It has a beautiful shiny surface that's like pink. You can see the vascular pattern shining through very clearly. On the upper right-hand side, you see mild inflammation where there's a fair bit of erythema, edema, you see a stippling of the light pattern, which is consistent with the submucosal inflammatory infiltrate. But you do not yet see breakdown of the mucosa as you do in the lower left-hand side where there's moderate disease, some -- beginning of some ulceration and purulent exudate, which are really neutrophils pouring out through the epithelium and ulceration. And finally, in the lower left-hand side, you can see severe disease where you see really break down of the lining of the colon marked edema, exudate marked ulceration in a continuous fashion, usually from anus to some proximal extent that can vary from just the rectum to involve the entirety of the large bowel. Now, these diseases are highly prevalent in the Western world, in Western Europe, in North America, in Australia and New Zealand, we see the highest rates of prevalence whereas we see intermediate rates in certain parts of South America, such as Argentina and other parts of Europe. And we see the lowest rates in the developing world, in Brazil, South Africa, Russia, China and Japan. So these rates are as observed now. But there is still a rising prevalence of IBD in the Western world as well as in parts of Asia and the developing world. Here, you see various countries in the Western world and projection of the rising prevalence in each of these countries between 2010 and what is anticipated for 2030. And you can see increases on the order of 200% or more over this 20-year period of time between 2010 and 2030, as is projected. Ulcerative colitis and Crohn's disease do have a slight effect on mortality. But since they affect a fairly young population, and there's not a huge effect on mortality There is an accretion of more and more patients over time as the instance rates drives. And as you see here, while the rates -- instance rates of ulcerative colitis are fairly low in most of Asia, although rising very quickly in India, for example, with an enormous population. Since China and other parts of the world that have low instance rates but rising is increasing, we can expect the prevalence to grow quite a bit. And Gil Kaplan in Calgary has made projections of how IBD will evolve in the Western world in newly industrialized countries and in developing countries over the next 20, 30 years. And you can see that there is a period of compounding prevalence leading up to prevalence equilibrium in 2050. But what this amounts to is essentially a global epidemic of this immune-mediated set of diseases. So it's a major problem. And what do we have in our armamentarium to treat these patients. For Crohn's disease, historically, 30 years ago, as I was coming out of my training in the mid-90s, we had 5-aminosalicylates, not terribly effective for Crohn's disease, modestly effective for mild to moderate ulcerative colitis. There's some use of antibiotics in Crohn's disease. Steroids are used for both diseases in the short term. but really have many problems in terms of side effects, tolerance and long-term durability of efficacy. Immune modulators, such as mercaptopurine and azathioprine had historically a role in treating these diseases but have many safety issues of their own and a marked degree of intolerance. In Crohn's disease, we were using some methotrexate as a steroid-sparing agent. And for acute severe ulcerative colitis and hospitalized IV steroid refractory patients, historically, we might use cyclosporine in the short term because it's fairly toxic and not effective in the long term. We really think of corticosteroids as a turning point in the treatment of patients with IBD because we know that the prognosis of the patient who's requiring treatment with corticosteroids. They're sick enough to warrant that. Their prognosis is actually not very good. You can see it one month in this population-based study out of Olmsted County, Minnesota, Mayo Clinic. You can see that about half of patients have complete remission at one month, only partial remission, 30% and 60% have no response, even at 1 month, they're steroid refractory. But at 1 year, you see fully more than half of patients who are either steroid-dependent or really a large number of required total colectomy and proctectomy and performance of the j-pouch or permanent ileostomy. And while that surgery is in the sense, curative, the quality of life is okay, it is not what our patients desire. So this is a turning point in the care of patients with ulcerative colitis. Really, major advance in the late 1990s was the approval of TNF inhibitors, first infliximab followed by adalimumab, certolizumab pegol, PEGylated Fab' fragment for the treatment of Crohn's disease and golimumab, a human anti-TNF antibody approved only for ulcerative colitis in United States. These were really a revolution in the treatment of patients with ulcerative colitis and Crohn's disease and it wasn't until a bit later that we had the next class supplier logics, which were the anti-integrin antibodies. We can mention that natalizumab was approved for Crohn's disease, but was abandoned for its use because of the risk of PML. Vedolizumab clearly doesn't have that risk and does have efficacy as we'll see. And finally, more recently, the approval of anti IL-12/23 antibody essentially ustekinumab in anti-T40 antibody. And I'll show you the data behind each of these. It's not all the data, but representative data. Well, here, you see the classic studies that led to the approval of infliximab for the treatment of moderate to severe ulcerative colitis. This was the first biologic approved for ulcerative colitis, and you can see that in 2 independent studies, about 2/3 of patients have clinical response at week 8 and about half of them have clinical remission at week 8. This incorporates both patient-reported outcomes in the Mayo Score as well as endoscopic improvement as part of the Mayo Score, really a score of 0 or 1, no ulceration. The next stage that came along was vedolizumab. I'm not going over all the data for all the anti-TNFs, of course, we could show you data in support of adalimumab, which is the most widely used agent biologic to treat ulcerative colitis or golimumab. But here now, we're turning to the anti-integrin antibody vedolizumab directed at alpha4beta7, which disrupts the interaction of alpha4beta7 integrin on leukocytes in circulation with MAdCAM on the endothelium of the gut and thereby disrupting site trafficking. And here, you see 6-week outcomes of clinical response, clinical remission and mucosal healing. Clinical remission rates, you can see are 16.9% versus 5.4% with placebo. So an effect size of about 11.5% higher rate of patients with clinical response. And it should be noted that about half of these patients actually had prior failure of infliximab. Now the responders from the induction phase of this pivotal trial were rerandomized into maintenance dosing every 8 weeks of vedolizumab or every 4 weeks, every 8 weeks is the approved dose. And you can see that, that performs quite well in regards to clinical response -- durable clinical response, mucosal healing, durable clinical remission and very importantly, corticosteroid free remission, it's a major unmet need to have corticosteroid free remission that is durable. So you can see that these remission rates are as high as 45% with every 4 weeks, but the approved dose of corticosteroid free remission, the approved dose of every 8 weeks is about 31.4%. And remember that we're really looking at data of patients who were responders at week 6 and then re-randomized. So roughly speaking, you could divide all these rates by half and you know roughly in the clinic, how many patients initiated on treatment would be in one of these endpoints at the end of 1 year. What about the comparison of vedolizumab to anti-TNF. We have only 1 direct head-to-head randomized controlled trial of vedolizumab against adalimumab, which once again is widely used in the treatment of ulcerative colitis. And as was demonstrated in VARSITY Study, vedolizumab is superior to an adalimumab by about 8.8%, which is about the superiority of adalimumab over placebo that led to its approval for the treatment of UC. So you can see it's not the majority of patients who are in clinical remission at week 52. It's only about 1/3 of patients. And furthermore, this drug is effective in anti-TNF-exposed patients, but not essentially more so than patients who had prior infliximab exposure, who then went on to get treated with adalimumab in the study. That was about 20% of patients in this particular trial. Most of the benefits seeing in this study was really from anti-TNF naive patients. Now we have another tool for the treatment of anti TNF refractory patients, and that is the oral JAK inhibitor, tofacitinib, it's a pan-JAK inhibitor with some relative specificity for JAK1 and JAK3. And in the induction phase, you can see that the treatment effect over placebo was somewhere in the range of 10% to 13% superior over placebo. This again was a fairly refractory group of patients, about half of whom had prior anti-TNF failure. And once again, if you play this out over a year, about half of the patients in response, which granted was much higher rate than remission that you see here at week 8, about half were in remission. And finally, we have ustekinumab for ulcerative colitis, the latest kid on the block in anti IL-12 and 23 inhibitor already approved for Crohn's disease, And you can see that at the 6-milligram per kilogram IV loading dose, you can see clinical response rates on the order of 61.8%, but clinical remission rates that once again have an effect size over placebo of about 10%. There was also an outcome of histo-endoscopic mucosal healing, what you can see combining both endoscopic improvement and histologic improvement in the same patient, and this was also an endpoint that was achieved first time that this was looked at in a clinical trial. So that's what we have in our armamentarium. I should mention that ustekinumab, is a very safe agent. It's delivered subcutaneously every 8 weeks, but you see these clinical response rates. And once again, at one year, you can see rates that are somewhat lower over the course of 52 weeks of maintenance of remission. And what about things that are in here -- not in the here now, but are on their way to the clinic. There are a number of areas of very active investigation. You already mentioned vedolizumab but etrolizumab is a second leukocyte trafficking antibody, there are anti-IL-23 specific antibodies such as brazikumab, risankizumab mirikizumab and guselkumab. I'll show you some of those data. There are novel Janus kinase inhibitors like filgotinib and upadacitinib, there's Sphingosine 1-phosphate receptor modulators such as ozanimod and etrasimod. And finally, there are microbiome-directed therapies such as FMT, and I'll show you some data on one of these. Let's turn first to etrolizumab in ulcerative colitis. This Phase 2a study, which had a primary endpoint of week 10 with etrolizumab, which is directed at alpha -- sorry, not alpha at all, but at beta 7 integrin and therefore, will inhibit both alpha E beta 7 and alpha4beta7, so has a slightly different profile potentially than vedolizumab in early phase studies. This looked promising at week 10, clearly superior in the primary endpoint of clinical remission at week 10, again, an effect size of roughly 10%, as we've seen with many of these agents that I've shown you. And also what you see is that the majority of this efficacy as is similar in vedolizumab is in the anti-TNF naive patients at week 10. Unfortunately, the story is a bit mixed. We had a press release from August this past year, which showed induction was met in -- for its primary endpoint in 2 out of 3 studies, but maintenance did not meet the primary endpoint in comparison to placebo in Hickory or Laurel studies, which were prior anti-TNF exposure in anti-TNF naive patients. And as these are chronic conditions, It's not sufficient to show an induction in effect, really the regulatory authorities expecting maintenance effect as well. So where this goes from here is uncertain. A bit less uncertain is upadacitinib, a JAK1 specific inhibitor. And in the U-ACHIEVE study, this really appeared to be very promising. You can see a dose effect that is titrating upward, up to a shouldering. It seems to have efficacy in both bio-naive and bio-inadequate responders and both -- and bio naive as well. And importantly, endoscopic outcomes, histologic outcomes, all of these were really met very robustly. However, as we know with tofacitinib. There are a number of concerns about the safety, black box warnings with tofacitinib about the risk of venous thromboembolism, potentially mace and cancer as well. And so therefore, there is a desire to improve upon the safety profile of JAK inhibitors, it's uncertain whether this is a class effect for all the JAK inhibitors, however, we really are trying to constrain this to the bowel to target delivery to the gut and see if that can actually improve the safety profile of this class of agents. And so here, you see the example of TD-1473, which so far we have just Phase 1b data looking fairly promising with regard to rectal bleeding improvement and endoscopic improvement. This is in much larger studies, Phase 2/3. And I think soon we might have some information about this, but we don't know if this will play out. Turning now to the S1P1 receptor agonist. We have ozanimod in UC, this was in Phase 2. And you can see the data here. This is not a highly refractory group of patients. Only 20% of these patients had prior treatment with the anti-TNF. But you see clinical remission rates superior to placebo with the higher dose of 1 milligram that once again appear very similar, roughly 10% or so superiority. You can see mucosal healing really, what we'd call endoscopic improvement at reasonable rates. And you can see a maintenance effect at least out to week 32, particularly with the 1-milligram ozanimod dose compared to placebo. And more recently, we've had the presentation of data from the True North study, the pivotal trial that in theory should lead to the approval of this agent showing as very similar to what I showed you before, superiority in clinical remission during induction of about 12% over placebo. So of course, higher rates of clinical response, somewhat lower rates of endoscopic improvement. And it's not confined only to ozanimod, but also the second agent etrasimod also shows these are exploratory end points but more conventional than the ones that were used for the primary outcomes, and you can see here rates that show this to be a fairly effective agent. Of course, there are effects of lymphopenia expected with this drug and with fingolimod at least, there are cases of progressive multifocal leukoencephalopathy on the order of 3 to 4 per 100,000 patients treated, otherwise, though it does appear to be fairly a safe mechanism of action. And turning now coming to the end. We have the anti-p19 antibodies directed toward IL-23. Here, we have data from mirikizumab in ulcerative colitis, and you can see very reasonable effect sizes, dose response to some degree, although some mixed results with the very highest dose as we have come to expect better results in bio-naive and bio experience, but still very respectable rates of remission during induction and very good rates of clinical response and endoscopic improvement as well, as well as durability over 52 weeks. So this is randomization to every 12-week versus every 4-week regimens. You can see they appear to be fairly comparable over the course of a year. And so a number of these anti-p19 antibodies are moving forward in later phase studies, and I do expect them to be positive. And now turning to the microbiome. Of course, there have been at least 6 trials of fecal microbial therapy. I think many of us believe that that this is too heterogeneous a modality to really move forward in any large-scale commercial sense. But here, you have one of a number of efforts still in very early phase. This is a Phase 1b study of Series 287. Here, the population was mild to moderate ulcerative colitis, but with a very promising result, with pretreatment with vancomycin, including endoscopic improvement. So this is at least a very good proof of principle. This is the mixture of sporulated species of clostridia. And we'll see how this plays out over later phases of study. And finally, to contextualize what Hartmut will present to you, we can show the data for ABX464 in its early phase studies against vedolizumab and tofacitinib efficacy. And you can see that for the induction phases, the delta's treatment effects for clinical remission and the scope of improvement for vedolizumab and tofacitinib in Phase 3 are on the order of somewhere between 11% and 16%, whereas you can see that for the 1-year maintenance, clinical remission for these agents is somewhat higher. But remember, you can conceptualize this as being far lower because these are both studies that employed randomization of responders during induction. And by contrast, you see the Phase 2a data clinical remission with ABX464 with a delta of 24% endoscopic -- for clinical remission, endoscopic improvement for 39%. Really, it looks to be very promising result in my view. So in conclusion, what I've showed you is that there's a rise in prevalence of inflammatory bowel disease across the world. And there are significant unmet needs for durable long-term efficacy with our agents as well as safe agents. We have problems with TNF inhibitors, including black box warnings for severe infections and lymphoma. For tofacitinib, we have the concerns of mace, venous thromboembolism, cancer potentially as well as for pisaster. And we want agents that have an ease of administration, I didn't really say this, but the peak incidence of these conditions is in the second decade of life. So we have many people in the prime of life. They're busy. They're working, taking care of families, to have to do an infusion or an injection is really an inconvenience and the vast majority of patients would prefer to have an oral agent to ease the administration. So with that, I'll conclude and turn it back to Hartmut and take your questions later. Thanks very much.

Thank you, Bruce, for this excellent review of the current state-of-the-art treatments for ulcerative colitis And in the next 10 or 12 slides, I would just like to briefly introduce where we believe ABX464 fits in, but what you just presented. So can we go to Slide #3, please? One more. And I just wanted to use this slide for a little historical vignette on ABIVAX, a company that was founded in December of 2013 with the goal to go to the Euronext stock market in Paris within the next 18 months, which is what we accomplished by raising EUR 57.7 million in June 2015, which was and is the largest IPO in biotech at the Euronext in Paris. While initially, ABIVAX was actually focusing on antivirals including ABX464 for the potential treatment of patients with HIV. While we were working through the mechanism of action, we realized the very potent anti-inflammatory properties that the molecule had, which we then confirmed in the standard animal model for IBD, which is the DSS mouse model. And based on these data, the ACO leadership at the time, in particular, Séverine Vermeire really encouraged us to bring the molecule into the clinic. And when we got the initial top line results from the Phase 2a proof-of-concept study. ABIVAX really shifted its focus to move towards chronic inflammation and really initially inflammatory bowel disease. So next slide, please, which summarizes the attributes of ABX464 as we look at them now. As many of you know, it's coming from our proprietary compound library, which was designed to modulate RNA biogenesis, It is a small molecule in molecular weight around 340, which is administered as an oral capsule daily. It has a first-in-class novel mechanism of action. which is centered around the selective upregulation of an anti-inflammatory microRNA, miR-124, which I will detail in the next slide, but please bear with me on this one. Just to say, looking back at more than 800 patients and volunteers that were receiving ABX464. We can summarize the safety profile at this point as very good. And of course, I will show you the data that makes us claim that there is a strong anti-inflammatory effect that was actually confirmed in our Phase 2a proof-of-concept study. So next slide, please. This is a cartoon basically showing the mechanism of action, which I mentioned is centered around the upregulation of a specific microRNA, miR-124 which is then activating what we call a physiologic break of inflammation. And what we have been able to establish is that ABX464 upon binding to its molecular target, which is the cat binding complex, the CBC. The CBC acquires the ability to actually splice a long noncoding RNA with which has the sequence, the exact sequence of miR-124 embedded, which becomes available in the nucleus in the cytoplasm, and miR-124 then acts an any micro RNA. And as you know, there are more than 1,500 microRNAs at least that are described in the literature. But they all work by down regulating the translation of their respected target genes. And the target genes for miR-124 are listed here. So let me focus on the outcome. which then is a reduction in MCP-1, CCL2, the monocyte chemo tract and protein, the reduction of IL-6, Th17 cells, IL-17 and TNF alpha. And importantly to say these reductions result in approximately 40% to 75% reduction of the activity of these chemo and cytokines So in contrast to some of the monoclonal antibodies, we are not blocking the target genes to 100% But we are blocking several of the target genes to -- within a range of 40% to 75% reduction which might be important, specifically when it gets to the safety of the molecule. On the next slide, we have summarized the important efficacy outcomes from the Phase 2a proof-of-concept study, which was conducted in 32 patients, randomized 2:1, double-blind, placebo-controlled. And importantly, What we included based on Severine in systems from the very beginning, is a central blinding reading of the endoscopies in order to take the buyers out of these assessments. So the central reviewer didn't know whether it was an active patient, whether it was a placebo patient, and he also didn't know whether this was before treatment with ABX464 or after 2-month treatment of ABX464 which was, of course, the primary endpoint in this clinical trial. So importantly, when we looked at the data, it became apparent that all parameters trended in the right direction. Bruce already mentioned, the clinical remission rate after reduction of the placebo rate was around 22% to 25%, which, of course, caused a lot of excitement But in addition, we also saw an endoscopic improvement, as you can see on this slide, we saw that about 70% of the patients were in clinical response. And we saw statistically significant reductions of the total as well as the partial mile score. And to remind you, again, this study was not powered for statistical significance. So this is merely an effect of the difference in the effect size between active and placebo. Also indirectal biopsies, we were able to identify a statistically significant increase of the expression of miR-124. And while these results in the table are very impressive I think I really want to spend a minute to introduce one particular patient on the next slide, and this was the first patient that Severine Vermeire actually entered into this study. What you see on the left is, as you saw it in Bruce's slides already the typical endoscopy of patient with moderate to severe ulcerative colitis. You see the ulcerative lesions, you see the bleeding. This patient actually had been treated with vedolizumab with infliximab and adalimumab and was resistant to all of them, so that is only option at the time actually was, as Bruce mentioned before, colectomy . Now fortunately, that patient was entered into the ABX464 study. It's the longest patient on this study. He is on ABX464 now for around 3.5 years. His treatment started in November of 2017. And you can see on the left slide, which is an endoscopy after one year. You can see that this patient was in a complete remission. He also was in complete remission after 2 years of treatment. And as we just learned in January of this year, this patient is still in complete remission after 3 years of treatment So I think we can certainly say the treatment was transformative for this particular patient. The next slide just shows you two factors around the activity of ABX464. On the left, the fast onset where you see that the curves between ABX464 and placebo-treated patients start to go to grow apart from each other, certainly as early as 2 weeks. And on the right slide -- on the right side of the slide, You can see that there is a comparable efficacy between both biologics naive patients and biologics refractory patients. The next slide then goes into what Bruce mentioned, the long-term efficacy of ABX464. And here are the results for a 12-month treatment and 24-month treatment. And to color long story short, clinical remission was 75% at month 12. And that was actually data that Severine Vermeire presented in October of 2019 at the UEG meeting in Barcelona. And this was the first time Bruce and I met after Severine's presentation where this rate of remission after one year of treatment, which was then extended to 2 years where we still saw a 69% remission rate which clearly raised eyebrows at this meeting. The 3-year evaluation is going to be due in August or September of this year. On the next slide, I just want to show you the reduction of the partial male score and Faecal Calprotectin during the maintenance phase for all patients and also patients previously on biologics. And what you see importantly again, is the curves are similar with a very important reduction, especially official protecting during the first 3 months of maintenance treatment. And after the first 3 months, the Faecal Calprotectin. The medians actually were within the normal range for Faecal Calprotectin, meaning less than 50 micrograms per gram. Please keep this in mind when I introduce the design of the Phase 2b that we are focusing on today because this was an important finding that we then translate it into the protocol for the 2b study. which, as you know, just completed induction treatment in all patients. But before we go there, just a quick summary of the safety profile with a cutoff date of November 30 of last year, where you see how well-tolerated, ABX464 is -- sorry, can we move the slide, please? Thank you. And the main adverse events, as you can see here, headache, especially during the first 2 weeks of treatment, mild or moderate and typically treatable with OTC medication And if you look at the numbers in the 30% that we see in treated patients is actually partially ameliorated by the placebo rate of 12%. But this is clearly an AE -- related to ABX464. And we are also seeing when it comes to abdominal pain, a slight imbalance of the number where we have about 2% or 3% more in the active group than the placebo group. Importantly, as I mentioned, the frequent as are transient, mild and we are seeing a similar profile in the non completed study with more than 500 patients currently across various indications. Importantly, we don't see any new AEs in the long-term maintenance study, which I mentioned before. We don't see any clinically meaningful changes in laboratory parameters, whether it's the liver function test, hemoglobin, the number and percentage of lymphocytes, neutrophils, et cetera, and no increased incidence of infection. So with this, we then started the Phase 2b study, which is detailed on the next slide. A few comments on the design, 4 study arms. We were using placebo 25, 50 and 100 milligrams every day. total of 254 patients in 15 European countries, U.S. and Canada. Important, again, central blinded reading of the endoscopy And this is, of course, the study that we will be releasing the top-level data on during the second half of May. The full maintenance data, the first year maintenance data will take until Q1 of next year. But shortly after the presentation of the top line results, which I said will be end of May. Probably in mid-June, we will be able to report on the 1-year maintenance data of the patients that have completed maintenance by then, which is roughly around 30, still more than we had in the Phase 2a. And so how are we going to bring ABX464 to the finish line? The -- this is on the next slide, the end of the Phase 2b meeting with FDA is planned for the third quarter of this year. We are again working with IQVIA in preparing for these studies, which are likely to recruit around 2x 600 patients with the first patient in planned for the end of the fourth quarter of this year. Similarly, based on the feedback of our steering committee, Bruce is part of this. Our plan is to not go for Crohn's disease, the same path as we did for ulcerative colitis. But because the mechanism of disease propagation is very similar between the 2 diseases and also because, as you saw in the beginning, drugs that work in one disease often also work on the other one. We are going to skip the Phase 2a and are going straight into a Phase 2b or maybe even a Phase 2b/3 dependent on the feedback we will be getting from FDA. And here, we are expecting to have the first patient in that study also before the year is over for rheumatoid arthritis. where we are going to provide the top line data more in the later part of June of this year, we are planning to move on into Phase 2b by the first quarter of next year. So the next slide just summarizes the news flow. And as you know, so is very, very important for us. Not only will we provide the top line results of the 2b ulcerative colitis, also the top line results of the Phase 2a in RA. And also with our second product, ABX196, which is a synthetic agonist of INK T cells, so a different field. This is cancer. We are expecting by the end of Q2 to have the enrollment of the dose escalation phase of our Phase 1/2 study complete and be able to release the initial top line results. And next slide, with this, I really would like to thank you for your attention and move on with the Q&A. And Sarah, I think you have some comments on the technicalities on how to submit questions.

[Operator Instructions] I'll turn it over to Chris Maggos of LifeSci Advisors to moderate the Q&A session.

Thanks, Sarah. We already have quite a few questions, so I'll get going. Dr. Sands, the first one's for you. It's a little bit long, so bear with me, and I can repeat the three parts or four parts to it, if you need any reminding. So it's from Damien Choplain at Kepler Cheuvreux, one of the analysts. How would you use ABX464 in your clinical practice, where in the treatment -- where in the treatment algorithm, if we assume that the clinical profile seen in Phase 2a is confirmed in late-stage trials, what level of clinical remission versus placebo would you consider as a game changer? Do you see the innovative MOA of ABX464 as a break to its adoption by physicians or patients? Or on the contrary as something positive?

Okay. I think there were at least 3 parts to that. So the first question relates to if the profile that we saw in the early phase held up in the pivotal trials, where would it fit into the treatment algorithm. And I think a number of factors come into play. One is the convenience. It's an oral medication. So it has convenience that's superior to any of the injectable or IP biologics that we have. The second would be the safety profile. So far, the safety profile looks really excellent. I think the minor things that we're seeing seem to be quite manageable and not prohibited what patients really get concerned about are risks of infection, risks of cancer. They're not so worried about headache that could be treated with acetaminophen, for example. And I think the third thing is the efficacy. So If the efficacy that we saw in the early phases really holds up in later phases, there would be no reason that you could not use this agent anywhere in the treatment paradigm. That would include as first-line treatment for mild, moderate or potentially even moderate to severe disease. It could be for patients who are newly diagnosed. Of course, this all depends on access to the agent in real life. But assuming the pricing is well-priced and there is good market access. We could see this drug very widely adopted anywhere in the treatment algorithm. I wouldn't see this being reserved for biologic inadequate responders, even though it does seem to work in that population as well. So I think it's very broad. The second part of the question was what would I consider to be transformational efficacy in terms of clinical remission, superiority over placebo. Well I showed you in almost all of the agents that we've reported rates that are essentially 10% superiority over placebo. If we're lucky, we see 13%. If we see 18%, 20%, 25% superiority with regard to clinical remission, that will be astounding. And more importantly, if we see that sustained over a year, a maintenance effect, that would be also quite astounding as a breakthrough. And then the third would be, are there barriers to adoption due to the novel mechanism? And I don't think so. I think our patients in gastroenterologists as well have become very open to novel mechanisms of action. We became used to novel the novelty of biologic therapies This has far less rigmarole in its adoption than a biologic therapy. If the safety profile holds up, it doesn't require a lot of monitoring. I think just because its novel does not mean that it will not be used. And I think the notion that it's restoring immune homeostasis is a very appealing idea certainly to patients rather than broadly suppressing the immune system as we've come to see with a lot of our agents. So I hope that answers all the parts of the questions.

Yes. Thank you, I don't know Harmit or Jean-Marc, if you'd like to add anything, but I think that was very complete. Maybe -- I'll move on. So Eric Le Berrigaud -- sorry.

Well, Chris, let me -- sorry, I had some issues around the mute-unmute button. I think Bruce's answer was so all encompassing that there is absolutely no need for us to add to that.

Okay. Thank you. Sorry, there was a question from Eric Le Berrigaud from Bryan Garnier, but I think you covered it Dr. Sands in your comments just now. And then Chris Redhead from goetzpartners. Which of the next-generation therapies aside from ABX464 has the most promise?

That's a really good question. They're sort of each promising in their own different way, but all of them have sort of wrinkles to them. I think the next one that we're going to see really on the market is clearly the S1P1 receptor modulators. And those are oral. I think that means they're convenient. They do have the issue of cardiac effects and bradycardia that quickly can tack a flack. So I think we'll work around that. I think we need to see how the PML story plays out with that, whether that is a deterrent for patients with IBD, it's not a deterrent for the use of these agents in MS. But neurologists and certainly MS patients are probably less threatened by the idea of PML since it is already a neurologic condition. I think the JAK inhibitors while they have seemingly really wonderful efficacy, really have a number of safety profile issues, whether we should tar the entire class with the same brush is not clear to me whether JAK1 specificity really will confer improved safety is -- doesn't seem very likely to me when you look at the profile of upadacitinib, but I guess we'll see. The anti P19s are going to be safe, I think, but clearly, will be an expensive and inconvenient biologic agent. So that's sort of how I see it. It's hard for me to handicap microbiome directed therapies because they're in such early phase. Obviously, they have an appeal, but it's too early to really comment.

Great. Thank you. So David Sanef of Degroof Petercam, forgive me if I'm pronouncing your name is wrong. Can you please -- I think you've covered the first part of this, but this -- I'm asking because the second part would be interesting, Dr. Sands. Can you comment on the positioning of ABX464 in the treatment cascade of moderate to severe UC. And then taking into account the strong safety profile, what efficacy data would you need to be ideally shown in the Phase 2b, Phase 3 study to consider ABX464 before any biologic?

Well, I'll answer the second part of the question first. I think if it holds up the way it looked in the early phase data, There's no question that this could be used first line. But I think if you're looking for a bare minimum, I think if we see remission rates that equal what we're seeing for the biologics in moderate to severe disease, there's no reason you wouldn't use this first line because of the convenience of it and the safety of it. And so we're generally talking of a minimum of a 10% effect size for clinical remission during the induction. Of course, there's a lot of promise that the maintenance effect is going to be superior. But one of the things about oral therapies, of course, that are not biologics is There's no concern about loss of response because of immunogenicity, which is mainly a concern with anti-TNFs to a far lesser degree with devaluate or with anti-P19s. And the first part of the question was really more about the sequencing. And again, I think patients will always choose a drug for if efficacy is equal, assuming there's no issue with access in the market, they will choose convenience and safety, almost over efficacy. So if there's equal efficacy, I have no doubt that a drug that's orally delivered and looks safe in the long term, is going to be chosen even as a first line before biologic therapies. There's no reason to want to go to a biologic first.

Great. As a follow-up question from Chris Redhead at goetzpartners related to this. So efficacy, I think he meets the observed efficacy so far is better sustained compared to other drugs, evidence that this also applies to other drugs in development. Any ideas as to why efficacy is maintained for ABX464 compared to others?

I think that would be a question better directed to Hartmut.

Yes. Can you hear me?

Yes.

Okay. As I have shown you in the slide on the mechanism of action, The activity of ABX464 is strongly related to the upregulation of the microRNA miR-124. And we have actually been able to show in the 2A induction and then in the maintenance study that the upregulation of miR-124 is sustained for this particular time. So we believe that if we are seeing this long-term effect It is really related to the mechanism of action and the molecules involved.

Next question is from Julien Mara at Ingress. Can you share color on the powering of the study, including the assumptions used? I think that's for the ABIVAX team.

Yes. I have to pump this question forward to our Head of Clinical Operations, Paul Gineste.

Yes. Good afternoon, good morning, everyone. Yes, the -- as mentioned by Hartmut, the sample size of our current Phase 2b is 254 patients. And we do expect, according to the attention, a side effect of 12% between the placebo and the active groups.

Very good. And another question from Damien Choplain at Kepler. Does the clinical success in UC or Crohn's disease imply a higher probability of success in RA rheumatoid arthritis?

I'm not an RAA expert, so I probably won't answer that.

I'm not an RAA expert either, but considering the fact that miR-124 has very typical expression parameters with respect to the specific cells, with respect to the organs, et cetera, certainly where I'm sitting, I can only follow the answer that Bruce has given I don't think we can take this as a given. The only comment that I want to make on this is that we saw in one of the key models for one of the key animals -- in one of the key animal models for rheumatoid arthritis, that we did see an effect in rheumatoid arthritis, and this is what we hope to be able to translate into clinical efficacy, but that still remains to be seen.

Another question from Choplain at Kepler. How many patients continue in the maintenance phase of the study out of the 254 patients treated with ABX464 induction phase?

Well, that question actually is 2 questions. Because What we are seeing, and we have not yet locked the database, so we cannot be absolutely sure about the data. But what we are seeing is about a 10% dropout rate during the induction phase which is comparable to what we have been seeing in the 2a study. And similarly, I can confirm, I cannot provide exact numbers or percentages. But I can confirm that what we have been seeing in the 2A from the point of view of patients' willingness to move from the induction onto the maintenance. You may recall that we had 22 out of 23 that were eligible that could be moving on. And we are seeing a very similar trend in the current study. So that despite the fact that the number is substantially higher, the overall numbers seem to -- from the point of view of dropouts and patients not willing to move on, which in the current study is probably limited to 1 or 2 handful of patients are, again, very, very similar.

Next question is from Julie Wizbiker at Pharmaceutic Trade Press. Hello, why did you use placebo for the control arm instead of an authorized drug?

I think that's a question for Bruce.

This is a standard design in IBD clinical trials. We really don't have -- I'm trying to wreck my brains now if we have any example of a pivotal trial in IBD to date where we've incorporated a direct comparison to active drug. I know it's done quite a bit in RA. But that hasn't been the way that development has occurred in IBD.

Any insight into why, Dr. Sands?

Well, I think by comparison to RA, IBD is not as common to disease. And it is certainly easier to demonstrate an effect over placebo than it is over active comparator. I think that is one reason why the -- it should be stated though that in most of our trials It's not a direct comparison to solely placebo. It's usually add on placebo to platform therapy, whatever they're not adequately responding to continuing or drug added on.

Another question from Eric Le Berrigaud at Bryan Garnier. Professor Sands, are you fully backing the decision to move to a Phase 2b/3 in Crohn's? Based on what has been seen in UC is replication of effect highly likely, would you consider the bar anyhow different in Crohn's disease versus ulcerative colitis?

I am fully supportive of this move because we want to -- if this is indeed effective, we want to speed it to the full population of IBD patients. There is a huge unmet need for safe, effective convenient therapies to treat Crohn's disease. And as you saw, it is entirely true that the vast majority of agents that work for UC also work for Crohn's disease. So I think the likelihood of success if it proves to be effective and you see the likelihood of success in Crohn's disease is very high. There are some other wrinkles to the outcomes and the design of the studies, but it's entirely doable and quite important that we try to do it.

Thank you. David Sanef at Degroof. Do you envision the ABX464 dosing regimens in the Phase 3 study to be the same as in Phase 2 studies? I guess that's for ABIVAX.

Yes. Thank you for the question, David. We have been publicly saying that if we are able to reproduce the Phase 2a data, which was done exclusively with a dosing regimen of 50 milligrams a day. We would have, as you just heard, a very competitive drug in our portfolio. Now The Phase IIb on purpose is also looking at 25-milligram for induction and is also looking at 100 milligrams for induction. So you can imagine that they are will, at the end, be a very close look at the efficacy and safety data that we are accomplishing with the 3 dosage regimen, at least for the induction part. And clearly, if we are seeing a similar efficacy with 25 milligrams There would be no reason to use 50. And at the same time, if there would be a substantial increase in the rate of patients with remission as clinical outcome after 8 weeks and if the tolerability and safety would be comparable, then that could mean going up with the dose. But our current sort of standard answer is, the 50 milligrams has given us a very interesting drug.

Another question from Tong Leo, SMBC Nikko. Did you allow any type of rescue therapy in Phase 2a/2b studies? And if yes, how does it balance between placebo and active arms.

No, I don't actually think that rescue therapies are typically part of a treatment regimen at least in clinical studies. But I think, again, Bruce is much better suited to address this.

I can't say I know the specifics of what was done. But generally, I can tell you that rescue therapies may be given in the course of maintenance therapy generally. But universally, those would be considered as a failure of the primary outcome. So there's no question about that. I certainly can't answer how often patients needed rescue therapies.

Thank you. Another question from Salvatore Scafidi at Ecosse Capitale. What do you think about the use of FC IL-22 in ulcerative colitis ( Genentech)? I guess that's for you, Dr. Sands.

Yes, I didn't mention that. It's an interesting concept that could be very important in frustration of homeostasis of the gut, which is sort of a novel mode of action, but insufficient evidence at this point in time to know how safe, how effective.

Another question from an anonymous source investor. In the induction phase, ABX464 is being evaluated at 8 and 16 weeks. How will the 16-week data impact your insight and the use of ABX464?

Typically the primary endpoint, especially if you look at clinical remission, is taken at 8 weeks or at 10 weeks. However, based on the very interesting data, as I mentioned, from our Phase 2a study, And the rapid decline of the Faecal Calprotectin and also the partial male score during the first 3 months of maintenance made it interesting enough for us to -- for all patients that do not achieve a clinical remission have a second assessment after 16 weeks. Given the fact that it is, of course, important what kind of long-term results, 1 year, 2 years, et cetera, you are achieving with your product. But also here, we wanted to see for patients that are not brought into clinical remission after 8 weeks. What percentage do we are accomplishing a clinical remission than within 16 weeks, which would be 4 months. So this is really an attempt to better understand the timing of the efficacy of ABX464 and put this into considerations around overall usage of the product.

I can add just a little bit more to that, which is that this sort of evaluation has become fairly common in randomized controlled trials in ulcerative colitis. You saw this in the Optiv program that led to the approval of tofacitinib. You saw this in the unified program that led to the approval of STELARA. And in both of those programs, there were a number of patients who were not in clinical response at the induction time, 8 weeks, who then went on to continue treatment. And at the end of an additional 8 weeks of treatment came into response. As I said, sure, we want rapid induction. But at the end of the day, If that isn't maintained over the longer haul, if you never get to a response in the first place, you haven't really done what you need to do. So it does give a more complete picture of what a drug can do by extending the observation period.

Dr. Jean-Paul Hermit from Lonza asks when does ABIVAX intend to file for commercial approval if Phase 3 unfolds as planned.

If Phase 3 unfolds as planned, we are considering the possibility of filing by the end of 2024.

And he added a follow-up question. Considering the worldwide prevalence of UC are the causes linked to genetic factors or lifestyle, food stress, et cetera?

It's an excellent question. The genetics are not the same across the world. If you look at Asian populations, the genetic architecture is somewhat different from what you see in Western populations. and yet they seem to have the same clinical syndromes of inflammatory bowel disease. So we surmise that there are environmental factors, and we could spend a whole other hour speculating what all the important factors would be.

Well, it's actually interesting. Sorry, Chris, to interrupt you. It's actually interesting that this question came up. Because it's similar to a question, and I need to preface this by saying, we are, of course, also interested in including other geographies, specifically Japan, as I mentioned during -- or in the Phase 3 program. And one of the questions we received from the Japanese authorities was not around the genetics of inflammatory bowel disease, but around the genetics of miR-124 and the long noncoding RNA that's actually being clipped from the point of view. Are we seeing similar heterogeneity between the Western world and Japan? And clearly, with respect to that, there is no concern from our side that ABX464 will be able to upregulate miR-124 also in geographies that sometimes have different genetic prevalence.

Right. Okay. I lost my spot here. We're getting close to the end of the questions. I think I have one or 2 more. Will you report the 8-week and 16-week Faecal Calprotectin data from Vincent G, an investor?

Yes, that's clearly the plan and that's clearly the plan that this is going to be part of the reporting of the top line results at the end of May.

Great. Maybe just one or 2 more here. I think you may have covered most of these. How -- this is one that's not covered. How important is the route of administration versus the pure efficacy data from each agent. I'm not sure I understand the question, but can you talk...

Just asking how do patients prioritize convenience in comparison to efficacy? And I don't know, I think you really would have to do essentially a conjoint analysis in a group of patients and find what they value the most. I think in general, the way that I see patients view things, they look almost at safety first than efficacy than convenience. So convenience is a factor, but all things being equal, they would, of course, rather take something more convenient than not, meaning a fill.

And does that impact -- what about compliance? Is it a big difference in terms of compliance?

You might assume that patients are more compliant with infusions simply because we know they're getting it. But there's actually a documented high rate of missing or delaying infusions. injections are another story altogether because they're doing it in their home generally. So they can be just as noncompliant with that as they are with the pill. So I generally don't find huge differences in compliance among the different modalities.

And do you see an increase -- I'm not sure what's meant here, pervasion of the use of biologics versus new mechanisms of action earlier in the course of the disease.

Well, one of the factors, of course, is the cost of treatment. And as biosimilars for anti-TNFs and in a few years for things like ustekinumab, and vedolizumab become more prevalent I think you can see the treatment base for biologics increasing. I think the reason why that may not occur so quickly with anti-TNFs is still reluctance in relation to its safety profile. That is less of a concern with vedolizumab and with ustekinumab, but still you see the barriers or really the plateauing of efficacy of these approaches. So I think my best answer is we'll see the base broaden, but there will be some limitations to it.

A couple of more questions have come in. Are you confident that the ongoing Phase 2b study has enough U.S. patients to warrant a U.S. pivotal trial as per FDA requirement.

I guess that's a question for me. The total number of patients in the U.S. is certainly lower than the number of patients that we have been recruiting, for example, in France or in other countries. But we believe that based on the data that we will be receiving our Phase 3 program will more than make up for that.

And last question from David, a shareholder. Do you plan to license ABX464 to a pharma to finance the Phase 3 study?

I think for this question, I am handing over to my colleague, Didier Blondel, who is really used to be addressing those kind of financial questions.

Good afternoon, good morning, everyone. So the answer is yes. We plan to have a partner in place, especially before Phase 3 are starting. This is naturally with the not only to fund the late-stage development of the ABX464 but to have a strong partner in place in order to anticipate the future market access and compensation of ABX464. So that's naturally in our plans after naturally, we have the Phase 2b data in hand late May.

Great. Thank you very much. I think that's -- we've covered all the questions here. If I missed anything out, I apologize. But we have, I think, done a very good job of covering the essential questions. So Hartmut, I'll pass it back to you.

Yes. Thank you, Chris. for moderating this very interesting discussion section. Of course, thank you, Bruce, for your terrific presentation. And your stellar answers to the questions that were asked. I also want to thank the other people that were involved like Sarah in making sure that this webcast is going successfully. And I want to thank the participants in the webcast for their time and for their interest and for their questions. I hope this solved many of the questions that you were having and really look forward to have a similar webcast after the data in the second part of May. Thanks to all. Thank you very much.