Ventyx Bio - VTX002 Phase 2 Results Update (10-9-2023)

Ventex Biosciences held a conference call to update participants on the results of their VPX002 Phase 2 trial for ulcerative colitis. The CEO, Dr. Raju Mohan, introduced the team and expressed gratitude to everyone involved in the trial. The Chief Medical Officer, Bill Sanborn, presented the data, highlighting that VTX002 showed promising efficacy and safety results. The drug demonstrated high rates of clinical and endoscopic remission compared to placebo. The team believes VTX002 has the potential to be a leading oral treatment for ulcerative colitis. Good afternoon, ladies and gentlemen, and welcome to the Ventex Biosciences VPX002 Phase 2 Results Update and Conference Call. At this time, all participants have been placed on a listening mode, and the floor will be open for your questions following the presentation. If you would like to ask a question at that time, please press star and one on your telephone keypad. If at any point your question has been answered, you may remove yourself from the queue by pressing star and two. So others can hear your questions clearly, we ask that you pick up your handset for best sound quality. Lastly, if you should require operator assistance, please press star and zero. As a reminder, this conference call is being recorded. I would now like to turn the call over to Dr. Marty Oster, Ventex Chief Financial Officer. You may begin. Thank you, David. I'd like to start by thanking everyone for joining us today on our VPX002 Phase 2 Results call. Before we discuss the Phase 2 ulcerative colitis results in greater detail, we do have some preliminary items to cover. First, I'd like to note the VPX002 results partially, so now available on our website at www.ventexbio.com. The slides that are being presented today will be available on our website following the conclusion of our prepared remarks this afternoon. Next, on the slide two, I'd like to caution everyone that during this call, we will be making forward-looking statements under the Safe Harbor Act. These forward-looking statements are based on current information, assumptions, and expectations that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risk factors can be found in our most recent Forms 10-K and Forms 10-Q file with the SEC, and as such, we advise you to refer to the risks and uncertainties our business outlined in these filings to learn more about an investment in ventix bioscience. Now, with great pleasure, I'd like to turn the call over to our founder and CEO, Dr. Raju Mohan, who will make some opening remarks and overview today's agenda. Raju? Yeah. Thank you, Marty, and good afternoon, everybody, and welcome again to our conference call on VPX002 Phase 2 results. So, before we begin, I'm going to have a brief intro to the ventix team here. So, joining me are Bill Sanborn, who's President and Chief Medical Officer, Marty Oster, Chief Financial Officer, Chris Krueger, our Chief Business Officer. I'm also joined by Sheila Vigranti, who's the Executive Chair of the Board, but in her own right, an expert on trials in ulcerative colitis. We also have our advisor, Bruce Vance, on the line. Bruce is a world expert in IBD, both as a clinician, as a KOL, and Bruce is also the Chair of our Steering Committee for the trials, so thanks, Bruce, for joining this call. Before I hand it over to Bill, I'd like to thank a few folks. First, thank you to the ventix team for all the work that has gone into the successful execution of this trial. To all our internal, external investigators, our CROs, our partners that work with us tirelessly and closely and were integral to the success of this program. And finally, I would like to thank the patients who participated in this trial and who are a constant reminder to us, to us as a team, as to why we believe in what we do. So, with that, let me hand it over to Bill to walk you through the data. Bill? Thank you, Raju, and thank you to all of the people who joined us on short notice. As an executive summary, we believe that the data that we will review this afternoon shows VTX002 as a potential best-in-disease oral agent. Why do I say that? We demonstrated highly differentiated efficacy on stringent and objective outcome measures, including a compelling clinical remission rate and an unprecedented rate of complete endoscopic remission, sometimes called endoscopic normalization. And we note that this achievement of endoscopic remission or normalization has been a high-priority treatment objective for various expert groups, such as the International Organization of Inflammatory Bowel Disease in their Stride I and Stride II consensus documents. We also demonstrated an excellent safety profile. We saw no cases of atrial ventricular block or bradycardia, no serious or opportunistic infections, and no cases of macular edema. And we believe that our data support for the development of VTX002 and ulcerative colitis. Going to slide seven, let's review briefly the trial design. The key eligibility criteria were patients with moderately to severely active ulcerative colitis, as defined by the modified Mayo Clinic score, the three-component score, and insufficient response, loss of response, or intolerance to conventional or advanced therapies. The primary endpoint for the study was clinical remission at week 13, as defined by the modified Mayo score. Key secondary endpoints include endoscopic improvement, symptomatic remission, histologic remission, and endoscopic improvement, histologic remission as a combined definition. We randomized 213 patients in a one-to-one-to-one ratio. Patients received VTX002 60 milligrams or 30 milligrams once daily or placebo. There was a one-week titration period. Patients in the 30-milligram dose reached target dose at day six and in the 60-milligram dose at week eight. And then there was a full 12 weeks of dosing at the target dose with the primary endpoint at week 13. We do have an extension portion of the trial, which we will report out at some date in the future. Going to slide eight. From the subject disposition perspective, at a high level we had a very high trial completion rate. You can see that was 94 percent on placebo and 96 percent on the two active treatment arms. I will note that when the trial initially began, the modified Mayo entry criteria were four to nine. Shortly after that, the FDA asked us to revise it to five to nine. So our primary efficacy analysis is in modified Mayo score patients five to nine. Of the 213 patients randomized, four patients had a score of four. So those four patients are included in the safety analyses but not in the primary efficacy analyses. Going to slide nine. Let's look at the baseline demographic characteristics. Patients were well balanced with regard to age, gender, distribution across North America, Europe, and other jurisdictions, duration of disease. You can see that about 45 percent of patients had pancolitis and about 10 percent of patients had proctitis. The baseline Mayo endoscopic scores using essentially red endoscopy were evenly distributed between baseline scores of two or three. About a third of patients were using corticosteroids at baseline and across the three groups, 22.4 percent or 22.5 percent of patients had received prior advanced therapy. Going to slide 10. So now we come to the primary endpoint and one of the key secondary endpoints. On the left, you can see clinical remission, which was achieved by 28 percent of patients on the VTX002 60 milligram dose and 11 percent of patients on placebo, comprising a 17 percent delta. And then for endoscopic improvement, 37 percent of patients achieved endoscopic improvement on the 60 milligram dose, comprising a 21 percent delta. For each of these two endpoints, you can see robust dose response across the two doses, indicating that each of the doses are statistically significant at P value less than 0.05, but the largest effect size is seen with the 60 milligram dose. Moving on to slide 11. Here we come to what we think are the most exciting parts of the study, the really complete endoscopic remission and deep remission endpoints. So on the left, we see endoscopic remission defined as a male endoscopic score of zero, which occurred in 29 percent, almost one in three patients on the 60 milligram dose and only 7 percent of patients on placebo, comprising a 22 percent delta. Once again, you see a P value less than 0.05 for the 30 milligram dose, but dose response between the two doses. And then on the right, an aspirational endpoint that people have not even dared to go for previously, the combination of clinical remission and endoscopic remission with a score of zero in the same patient. Let's call that double remission. So you see that occurred in 22 percent of patients, so just a little more than one in five patients achieved double remission on VTX002 60 milligrams, only 6 percent on placebo. And once again, you see a P value less than 0.05 for the 30 milligram dose, but dose response between the two doses. Let's go on to slide 12. So now how do we put this in perspective to the other things that we think about? Let's begin by looking at the S1P modulator class. Looking at the left, we have placebo-adjusted clinical remission rates. So for a Xanamod in phase three, it was 12 percent. Recall it was 10 percent in phase two. For a tracimod, we have two phase three trials. In one trial, it was 10 percent. The other was 20 percent. If you average those, it's 15 percent, and we had 17 percent. However, what we think is the really more differentiating outcome measure of endoscopic remission, 22 percent with 002 at the 60 milligram dose, 9 and 10 percent, so quite consistent across the two tracimod phase three trials, and just 3 percent with the Xanamod. Moving on to slide 13. Well, let's then think about how these fit into the larger landscape of what I would call not the legacy drugs, but more of the next generation range of advanced therapies. And here you can see, if you look at the absolute clinical remission rate, it occurred in 28 percent of patients treated with VTX002. Only one trial had a numeric number larger than that. It was one of the two JAK inhibitor trials with Renvoke, and you can see that our clinical remission rate in absolute terms is very competitive with this group of advanced therapies. You can also see that there's some variation in the placebo rate, and we would have expected a placebo rate with our patient mixture to perhaps be in the 8 percent range, so we were on the unlucky side of that, which occasionally happens in phase two. But despite that, we still ended up with a 17 percent placebo-adjusted remission rate and, again, that 28 percent absolute difference. Let's go on to slide 14 and look at the more aspirational and very difficult-to-achieve endpoints of endoscopic remission. And here you can see, for placebo-adjusted rates, we have 22 percent with VTX002, 60 milligrams. We've talked already about the 9 and 10 percent rates seen in phase three with the TRAS mod, 3 percent with the Zeposia, Renvoke, 13 and 16 percent, Xeljanz, another JAK inhibitor, 5 percent, Tromphaia, 10 percent, and the recently announced phase three data, the Merck Prometheus TL1A antibody, PRA023, 12 percent endoscopic remission rate, and Entebio, one of the legacy drugs, but widely used, 1 percent endoscopic score of zero. Next slide. And then here on slide 15, let's look at the absolute endoscopic remission rates. So I'll reiterate what I said a few minutes ago, 29 percent with VTX002, 60 milligrams, so almost one in three patients with complete endoscopic remission, and nobody else is really close. The next highest numbers are in the sort of 15 percent range and many below 10 percent. Next slide. How did we achieve this? Well, we have talked about for some time with all of you our hypothesis that a deeper level of absolute lymphocyte count reduction would result in dose-dependent increased and improved clinical efficacy, and I think we showed that today. We also guided that our lower dose, the 30 milligram dose, we intended to be right in the zone for absolute lymphocyte reduction with Zyposia and with Atracibod at their target doses, and you see that. So our 30 milligram dose has an ALC reduction from baseline right in the 54, 55 percent range, and then we see about 10 percent higher, 67, 68 percent reduction from baseline in the ALC with the 60 milligram dose. To remind you, there are three marketed products for multiple sclerosis, Ponvori, Maisont, and Gelenia, who have ALC reductions from baseline in the sort of 68 to 72 percent range, and there's a tremendous safety experience with that level of lymphocyte reduction, more than a million years of patient exposure with Gelenia and no black box warnings around infection or malignancy. Next slide. So what about other safety issues? Here you can see we had some patients with adverse events, really all mild, that didn't lead to drug discontinuation and not related to steady drug. For adverse events leading to discontinuation, we saw that in one percent of the 30 milligram group and four percent of the 60 milligram group, so that's one in two patients respectively. You can see in the footnote what those are, and they're really not related to the drug. We had just five SAEs in total, two in the 30 milligram group, three in the 60 milligram group, not much to say about these. They were judged as unrelated to the drug. Next slide. Let's focus in on adverse events of interest for the S1P class. We'll begin with cardiovascular events. We saw three patients, or four percent, who developed hypertension on placebo and one patient, or one percent, on the 60 milligram VTX002 drug arm. No cases of first or second degree AV block and no cases of asymptomatic or symptomatic bradycardia. This is exactly what you expect to see with an optimized dose titration regimen, and we think our dose titration regimen worked perfectly, and it's differentiated from what you see with drugs where titration is not employed, where you will see some steady background rate of both AV block and bradycardia, which in some cases is symptomatic. The other thing I would say is that we used the same titration regimen up through the 30 milligram dose in both of the arms. So really, from a sample size perspective, we have 143 patients, 73 on 30 and 70 on 60, who employed that titration up through the 30 milligram dose, so we think we actually have quite a large sample size to take some confidence in the robustness of these results. We saw no severe infections, no opportunistic infections. There was a single mild case of propezoster in the 30 milligram dose. One dermatome judged as mild. Treatment was not discontinued, and it resolved after about five days of acyclovir therapy on continued 002. No cases of macular edema. Move on to slide 19. So I'm going to stop here, let Raju draw some conclusions, and we look forward to taking your questions. Thank you so much for your attention. Yeah. Thank you, Bill. And so just summary conclusions from the slides presented, the data presented, and just to reiterate some key points. So PTX002, as Bill has shown here, and the data point to it, is potentially a best in disease oral drug, based both on its efficacy and safety profile. It's highly differentiated in its efficacy. The data that Bill showed in terms of what he calls a double remission, I would go as far as calling it a deep double remission, both in terms of the clinical remission and endoscopic remission, and an unprecedented rate of complete endoscopic remission, score of zero. And again, as Bill knows and as Bruce will speak to it, achievement of endoscopic remission normalization to the degree achieved by 002 is not only aspirational, it's a high-priority treatment objective for clinicians across the world. The other piece of data that adds to the differentiated profile of this compound is the excellent safety profile, both by design of the molecule itself. PTX002 has a very attractive in vitro profile. It is a peripherally-restricted compound. It has no meaningful penetration into the CNS. And also, from our trial regimen, the employment of our titration regimen leads to this safety profile shown here, in particular on cardio or lack of, I would say, class-mediated cardiovascular effects. As Bill said, no incidence of AV block or bradycardia, no serious opportunistic infections, and no macular edema with this compound. And again, we just reiterate here that collectively the data that is shown here support PTX002 not only is, again, best in class, best in disease, but also support for the development of this molecule for patients with ulcerative colitis. So with that, thanks again to the team for presenting the data, for the team in putting together the slide deck. We'll now open the floor to Q&A. At this time, if you'd like to ask a question, please press the star and one keys on your telephone keypad. Keep in mind, you may remove yourself from the question queue by pressing star and two. We also ask that in the interest of time, the questioners limit themselves to one question each. We'll take our first question from Chris Schubitani with Goldman Sachs. Please go ahead. Your line is open. This is Steven on for Chris. Thank you for taking our question. Maybe one on the data from us for the placebo response rate. As Bill mentioned, they were slightly higher than maybe you had been anticipating. Can you maybe comment on what drove that and how that changes the interpretation of the results you saw? Yeah, thanks, Steve. Here, Bill, why don't you address it? Yeah, this is always a big question. We know that oral therapies can have more variability, I think, in terms of how you might see higher placebo rates at some time in some occasions. We were about 50-50 for a male endoscopic score, two versus three. So if you have a preponderance of three scores, that can sometimes drive down the placebo rate. And advanced therapy, we're about 23%. Prior advanced therapy, you know, trials can be 40% or 50%, and sometimes that leads to a lower placebo rate. So I think all those things may have contributed. I'm going to ask Bruce Sands actually to chip in. He and Brian Fagan and Bip Gareth and others published a meta-analysis recently on looking at the treatment effect size that you see in Phase II and ulcerative colitis trials versus Phase III. And my read of their data, but Bruce can speak to it, is that the effect size generally goes up in Phase III because the trials are larger and somewhat less susceptible to the variations in placebo rate. So what I would say is we have a really strong and stellar clinical remission rate despite an 11% placebo rate, and you can take some comfort in that when you see all the objective secondary outcome measures. Bruce, do you want to talk about the research that you did and then also as the PI on the trial what your thoughts are about the placebo rate here? Yeah, I think what you said is correct, Bill. When I look at the baseline demographic and these characteristics, I don't see anything terribly unusual about the patient population. One thing I always do look at is corticosteroid use of baseline. Here it was about 30% across the board. That's not at all unusual. That will sometimes drive a higher placebo response rate, but I don't think that was the case here. I don't think there's anything terribly different about the balance of, you know, endoscopic subscores or prior advanced therapies. So I think it's just variability that you see in the smaller sample size, and as you alluded to, the work that we did to compile all the results from Phase II UC studies and Phase III UC studies suggests exactly that, that you see some kind of regression to the mean, if you want to put it that way, with larger sample sizes and you see most of the time you see a better control of the placebo response rate in the next phase of study. So I think the absolute rate of efficacy is quite good, and my take on the data that we've just seen is that I think it substantiates Ventex's hypothesis that better lymphocyte suppression might indeed translate to better efficacy, and I think this compound really seems to do that in a way that is not achieved with the other agents approved or about to be approved in this class for ulcerative colitis. It seems like the lymphocyte suppression is much more similar to what is seen with the MS agents, I think Olimod and Ponomod, and, of course, we do have a lot of safety data with those agents in MS. So, altogether, I would say I was very pleasantly surprised to some degree how good these data were. I think, really, the male endoscopic score of zero is something aspirational, and if we look at, and Bill went through all the data, but essentially, even something like the Selcomab or Rupatacitinib, we're not seeing much better data, in fact, not better data than we're seeing with this agent here for male endoscopic subscore of zero, which is truly aspirational, and also the Hemi scores, also aspirational. And I think many of us didn't think that we would see this level of efficacy with this class of drug because we hadn't seen it before. Great. Thank you very much. I appreciate it. The other one, one other thing I could add is, you know, we look forward to presenting the data in due course at scientific conferences and showing details and everything, but just looking at the primary outcome measure of clinical remission, we probably saw the largest treatment effect in subgroup analysis in patients treated with North America and then Western Europe, and we saw a stronger effect in patients with a history of biologic or advanced therapy, and all those things, you know, really argue that the underlying treatment effect is robust and with a larger sample size will, you know, drive the placebo rate back towards its historic mean. I agree with that. We'll take our next question from Michael Yee with Jefferies. Please go ahead. Your line is open. Thank you, guys. Good afternoon, and congrats on the data. We had a question and then a clarification. Maybe for Bill or the team, it seems like the market is reacting to the data a little bit differently in the aftermarket, and I wanted to understand or for you to emphasize your view is the takeaway is that you had a somewhat higher placebo rate on the Mayo, but everything else, particularly the endoscopic remission, is keenly very high, and that's the emphasis here, not the placebo number that seems to be just a little bit high. Is that the takeaway? Related to that, is there any way to use that to your advantage as either a primary endpoint in another study or what are the ways you can leverage this, which you seem to believe is based on your lymphocyte drops in the mechanism? Thank you. Well, without commenting on the market, which will find its way as it really fully appreciates our data, I would say that the 17% delta for clinical remission is actually very robust. Few trials have beat that. You have the black box restricted JAK inhibitor, Renvoke, that has a higher number. You have the Phase II data with the Merck Prometheus drug, but recall that they had a 1% placebo rate, and coming back to Bruce's meta-analysis, those 1% placebo rates are rarely replicated in Phase III. Renvoke, for instance, had a 0% placebo in Phase II and about a 5% placebo rate in Phase III. So I think we really nailed it from my perspective with a 17% delta, despite the fact that we have an 11% placebo rate. And the reason you should really take comfort in that is that you've seen the endoscopic zero rates across all the drugs. It never occurs. And, Michael, I thought your team did a beautiful job last week creating the table for all the endoscopic improvement rates. We actually have all the data to send you if you want it for endoscopic zero rates. You can update that table. But endoscopic zero rates, they rarely occur, and 29% absolute number is amazing. Yep. Okay, I think that point was made, and I do see you plotted some of them there on the 15 show. The endoscopic remission, I think, is something that we are, or perhaps people actually are not so familiar with. So that was the takeaway here on that part. And then is there any way to leverage this, or we will find a way, or the regulatory, or it's a commercial marketing thing? Make a comment about that. Of course. You know, we've seen the data only for a few days, so we need to fully absorb it. But we are, of course, starting to make plans for end-of-Phase 2 meeting. I will point out that this is a really robust and rigorously conducted Phase 2 trial. So you see sometimes a Phase 2 trial where they just do a single dose, and then they get caught in Phase 3 needing to dose find. Or you do dose finding in Phase 2, and you don't get a definitive answer, and you end up getting caught doing dose finding in Phase 3. That's not the situation for us here. We achieved at the top dose right where you want to be from a lymphocyte reduction standpoint and where it lands us in a wealth of drug safety in this class. The lower dose was also effective but less effective. So we think we identified the top dose. We've identified a less effective dose. The safety profile of the top dose is excellent and very similar to placebo in the lower dose. So you can't have a better outcome than that in a Phase 2 trial. We see this as having the potential to be one of the adequate and well-controlled trials. And, you know, that's something else that people want to appreciate, is we can really race forward with this. We anticipate that you would need a single Phase 3 trial with co-primary endpoints at Week 13 and Week 52. Exactly what the outcome measures will be, I'm not going to commit to it today, but elevating endoscopic remission to a key secondary endpoint certainly seems like a strong consideration. We look forward to discussing that with the various regulatory authorities at the end of Phase 2 meetings. Hi, Mike, this is Sheila. If I can just add to that and have Bill and Bruce comment, I think the question you may be asking also is, you know, what is the importance of endoscopic remission and why it is absolutely something that we'll be looking to leverage in the future development program and from a regulatory perspective as well because it really does matter. There is a strong data correlating endoscopic remission, I mean scores of zero, with increased durability of remission and responses as well as a higher percentage of patients being able to come off steroids, so steroid-free remission. So it's a very important clinical outcome measure that, again, we just haven't been able to achieve with the legacy drugs and even the newer generation agents. So to see this, it's very clinically meaningful, and maybe Bill and Bruce can comment on that. Yeah, I'll start and then Bruce can chime in. Bruce's colleague, John Fred Columbell, and I, and Bruce, as I recall, published a paper with another treat-straight-through trial with Remicade back in the day, and what we saw was that if you got all the way to endoscopic zero at the induction time point, that you had a 20% greater steroid-free clinical remission at six months and a year relative to patients who got to an endoscopy score of one. So it made a huge difference in the long-term outcome. So, Bruce, that's my take on it. How do you see it from clinical trial data, from the STRIDE consensus document perspective, and all the other things that you're involved with? Yeah, I see it in exactly the same way. The reason that this made it into STRIDE is because we know that the outcomes are better, corticosteroid-free remission rates are better in the long-term, and I think if you really reflect on what it means to have a zero, it's really normalization of mucosa. When we have a one, a male one, there still can be obscuring of the vascular pattern. You don't see it. It means there's still, in a high likelihood, an inflammatory infiltrate, and that alone, you know, histologically, is a predictor of a higher rate of relapse and lower rates of corticosteroid-free remission and higher rates of surgery if you don't achieve that zero and the histologic part of it. And you've also substantiated the histologic part of it as well. So I think there's a good reason the field is moving toward that. The reason it hasn't moved toward that faster is because it's been so difficult to achieve. Makes sense. Thank you. We'll take our next question from Derek Arquilla with Wells Fargo. Please go ahead. Your line is open. Hey, guys. Congrats on the data, and thanks for taking the questions. Just two from us. I guess first off, how would you expect OO2's effect size to change when you move into larger trials? I know you're hoping that maybe the placebo rate comes down a little bit, but maybe more color there. And then just given the results today, and obviously, you know, some very compelling stuff on endoscopics for zero, I guess do you plan to move this program forward internally, or is this something you look to partner? I guess when will we kind of get an update on those decisions? Thanks. You know, let me address the latter, and then I have Bill add in. So, again, as you know, we own all our programs outright. We have complete control on the commercial and IP rights of the compounds. So we have a number of options, whether we move this ourselves or with a partner. I think we will have guidance in the future. I think what's important is the data are compelling. They are attractive not just to clinicians, as we've seen Bruce speak to it. I think it will be meaningful for patients, attract the attention of investors, and certainly attract the attention of potential pharma partners as well. And as you guided, we are in the planning stages for Phase 3, and we'll have an update on our plans to initiate the Phase 2 trial in 2024. I'll have Bill give a little more color as well. Yeah. So just to reiterate again, typically what happens is going from a Phase 2 clinical trial with a sample size of, you know, 50 to 70 per arm in Phase 2 to Phase 3, the clinical effect size for the various outcome measures decreases, not increases. And that's typically because the placebo rate is better controlled. So I think, you know, the odds are in our favor as we come back to a replicating larger Phase 3 trial for the placebo rate to be closer to the mean. The other thing that you will see is I think we would anticipate to intentionally recruit a larger proportion of patients that have prior biologic failure, and that's likely to bring the rate down. And with that, you probably end up with a higher proportion of patients who have a myoendoscopic subscore of 3 at baseline, and that all comes together and should nicely control the placebo rate. One other point that I'd like to make is for biologic drugs, without exception, between the end of induction and the one-year maintenance time point, they all lose efficacy. 100% of them lose efficacy. And it's due to all kinds of things, changes in drug clearance, anti-drug antibodies, but they all lose efficacy. For the small molecule JAK inhibitors, even if you continue the 10-milligram dose with Cell Jans, you lost efficacy. But if you drop down to the preferred dose of 5 milligrams for safety, you lose even more efficacy. And then with Renvoke, the 45-milligram induction dose cannot be continued beyond week 8, and so you're definitely dropping down to 15 or 30. And with that, you have some degradation in efficacy. It's better than placebo for sure, but you're still losing efficacy. By contrast, the only class of drugs where you see a rise in the placebo-adjusted clinical remission rates and other outcome measures between the end of induction and maintenance is with the S1P modulators. Back in the day, Sheila and I collaborated on a Phase II 30-week trial with Ozanamod, and we saw exactly that. There was a 5% absolute increase in the clinical remission delta between week 8 and week 30, and with Atrasamod, there was a 5% absolute increase in the delta between week 12 and week 52. We fully expect that we would see that in our trial as well. So in addition to controlling the placebo rate during induction, we expect to see that sort of class-replicated rise in efficacy over time for clinical remission during the long-term Phase III trial. Got it. Thanks so much. We'll take our next question from Yasmeen Rahimi with Piper Sandler. Please go ahead. Your line is open. Hi. This is Jungu speaking for Yas at Piper. Congratulations on the data, and thanks for taking our questions. First question is, could you provide some color on potential Phase III trial design? And the second is, what would warrant capital efficiency to partner BTX002? Sorry, what was the second question there? What would warrant capital efficiency to partner BTX002? Yeah, why don't you address the first one? From a clinical trial design perspective, we believe that the optimal Phase III trial would be a so-called treat-straight-through trial where you randomize patients to drug or placebo. You have co-prime endpoints for induction and maintenance. So in our case, it would be at week 13 and week 52. And if patients have no clinical response at the end of induction, then they can move over into an open-label extension. If they have at least clinical response, they keep on their blinded treatment assignment out through the end of the year. This is the trial design that was used successfully for the two pivotal studies of Remicade for ulcerative colitis. It was used successfully in Phase II with Ozeanamod, and it was used successfully in one of the two Phase III trials of Atrasamod. And we think that given what I described a few minutes ago, where you see actually a rising clinical remission rate over time with long-term therapy, that there's no need to re-randomize responding patients. The treat-straight-through design best mimics what happens in clinical practice. It's the most robust measure of efficacy, and that's the design we would do. And from a speed and efficiency standpoint, it's also really fast. And then in terms of capital efficiency, we're planning a single trial. We've proven our ability to strongly execute, as we've shown in the Phase II study here. And as Bill guided from the Phase II data, we have a true dose-finding trial. So we have one dose of I don't think any more capital efficient than a trial that we are proposing in our Phase III, and we'll have more guidance in the future. Other than that, I'll bring back to the point I made earlier, which is we have multiple options for the company itself in terms of how we raise capital, whether it's through equity financing or other financial means and or partnerships. We'll have more guidance for that in the future. All right. Thank you so much. That was very helpful. Just to reiterate what I sort of said earlier, we think that the totality of the strength of the Phase II trial allows us to select a single dose for Phase III. That's been the predicate from the other S1P modulators that, you know, if you show dose response and comparable safety across the doses, you're able to take just a single dose into Phase III for both induction and maintenance. And, you know, we have a well-formed development team here, and we think we can efficiently recruit and execute a single Phase III trial. Thank you. We'll take our next question from Vikram Purohit with Morgan Stanley. Please go ahead. Your line is open. Hi. Good afternoon. Thanks for taking our questions. Two from our side. But first, and sorry if you mentioned this and we missed it, but are you able to provide any perspective on how the components of clinical remission, so the stool frequency sub-score, rectal bleeding sub-score, endoscopic sub-score, how those trended versus your expectations before you receive the data? And then secondly, on safety, if this kind of safety profile were to be replicated in a Phase III study, do you think there's a possibility here for a differentiated safety level versus a random mod and a CRAS mod? And if so, how impactful do you think that could be for real-world uptake? Thanks. You know, again, we'll look forward to showing more of the details at a future medical meeting, but I think it's fair to say you've seen our endoscopic data and it has a really low placebo rate. So we did the reasoning backwards. We saw some symptom placebo effect, which we think we'll be able to deal with in Phase III through all the mechanisms that we've talked about. And on the safety perspective, you know, labeling is always a negotiation, but, you know, you can't get better than zero. So we really are pleased with the just complete absence across two doses in Phase II of bradycardia and AV block, and we think that sets us up as we, you know, replicate that in Phase III for, you know, we look forward to negotiating an appropriate label for that when the time comes. I think the answer to your question is yes, there is potential for differentiation on safety from the data that we have in hand compared to data from other programs, and I think that's key. You know, regardless of labeling. We'll take our next question from Alex Thompson with Stiefel. Please go ahead. Your line is open. Hey, great. Thanks for taking my question, and congrats on the data as well. I guess, Bill, correct me if I'm wrong, but I believe your proportion of, you know, advanced therapy in high-risk patients is on the lower end. Do you think you can comment on whether some of the endoscopic remission may have been driven by those patients? And then a brief follow-up. Maybe you could also contextualize the Phase II atrazumab study, where there was quite a high rate of clinical remission there as well, and how these data compare. Thanks. Yeah, the former, again, we saw generally a larger treatment effect in the advanced therapy experienced patients, and, you know, we'll show all of that with some more color in the future. So I don't think that our clinical remission and the embedded endoscopic improvement and remission within that was driven by the therapy-naive patients, and there was, you know, at least as good and really trending better effect in the advanced therapy failure patients. So I'm not too worried about that. I would characterize the atrazumab Phase II trial as an outlier. You can find outliers in both directions. As I mentioned earlier, the Renvoke Phase II to Phase III, the effect size went up, and with atrazumab it went down. So I just don't find that exceptions make the rule, and Bruce, I'll let you comment on this, but if you look at the totality of conversions from Phase II to Phase III, the effect size goes up, not down, and so that's how I interpret the atrazumab Phase II trial is that the effect size was an outlier. Bruce, do you have thoughts on that? Yeah, I think that you just have convergence on a more stable number when you have larger numbers of patients, and the placebo is what is most changeable here because it really is subjective, in part, when you're looking at clinical admission. Obviously the endoscopic component is very objective, and in Phase II I tend to focus much more on the objective outcomes than on the symptomatic outcomes anyhow. So from that regard, I have every expectation that this is not only going to hold up, but the effect size itself probably will improve, as you said, Bill, in Phase III. Great. Thanks a lot. We'll take our next question from Emily Bogner with HC White and Wright. Please go ahead. Your line is open. Hi. Thanks for taking the question, and I'll give my congrats on the data as well. Based on some of your comments earlier, can you sum up what you're looking to see in the 39-week long-term extension period and how you think about the endoscopic and clinical admission rates changing over that time period? And then maybe a question for Dr. Sands, if you can just talk about how you think about what you would use to take a drug to describe to patients, and based on some of the recent outcomes we've seen from other studies, kind of how you put this in line with that. Thank you. So starting with the extension data, we have sort of intentionally not really been tracking it, other than for safety monitoring, to avoid bias in this readout. But now we'll be able to begin to examine it more carefully. Of the 213 randomized patients, and I'm going to caveat that this is approximate, approximately 60 or so patients went into what we call protocol version 1, meaning that after the 13 weeks of blinded therapy, the patients all went on to 60 milligrams of open-label drug. After that, the subsequent approximately 153 patients who comprised the balance of the study were enrolled under protocol modification, where at week 13, if they had a clinical response to their blinded treatment assignment, they stayed on that blinded treatment assignment for as much as 52, out to week 52. And then if they were responding at week 13 and lost response, then they could cross over to the open-label extension. So we will have approximately 50 patients per arm, and again I'm caveating this, this is approximate, approximately 50 patients per arm of treat straight through placebo-controlled data out to week 52. So it will take some time for that treat straight through placebo-controlled data to mature, but eventually that will come. So we'll be looking at all those things in the weeks and months to come when the time is right, but that's what the long-term data will eventually come out of the Phase II trial. We expect to be able to have a preliminary assessment of the maintenance benefit eventually. And I guess, this is Bruce Sands, I guess you asked me, Part II was really to paraphrase what you said, what are we looking for in a new agent? You know, that's more or less what you asked me. And obviously in relation to the other thing that we already have on hand, you know, I still think that the majority of my patients are really looking for a safe oral therapy, that the majority of them do not want to be on injectables in any form or IV therapies. They really prefer the convenience of oral dosing, but they want safe oral medications. So, you know, the JAK inhibitors really have a shadow on them as a class and really are not going to be used and can't in this country be used as first-line therapy. So I think a highly effective first-line therapy that's oral and that has better safety profiles than a JAK inhibitor is going to be a very useful agent. I think the gastroenterologists as a group are acclimating to this class of agents. I think a lot of the pre-work in acclimation will have been done by the availability of those Anamod and presumably eventually the Tracelod. And then it will be a matter of which agent is the most effective and which one is the best and which has the best characteristics. So I certainly see a place for this agent in first-line therapy. And I think we may find that for those who have failed in advanced therapy, particularly if it's one or maybe two advanced therapies, there really is a strong place for them as well. So I really think obviously we're seeing an expansion of different agent classes in this field. So there will be jostling for position, but I always think that a safe oral therapy is going to be a winner. Great thinking. We'll take our next question from Jeff Jones with Oppenheimer. Please go ahead. Your line is open. Thanks for taking the question, guys, and congrats on the data. Any thoughts mechanistically why you see this difference or magnitude of effect on endoscopic remission versus clinical remission versus what's seen in other programs? Well, I suppose that's the billion-dollar question. Not yet. Somehow I think the one thing that's important to remember is that lymphocyte reduction that you get with an S1P modulator is not the same as what you get from HIV or chemotherapy or something. It predominantly affects B cells and CD4 cells, at least CD8 cells, substantially untouched, and NK and NKT cells. I think it's that preservation of NK and NKT that gives you the safety profile that this class has become associated with. The deeper is better. We see that across the dose response and the clinical outcome measures. There's been limited investigation so far into exactly the translational medicine explanation of that. We did collect samples for cell subsets and things in the trial across the whole trial, not just in a subset of patients. And so we're just beginning the process of getting those samples analyzed and things. I'm hopeful we'll have some mechanistic windows in the future to answer your question. I think our data strongly suggests that it's true, that this deep but selective lymphocyte reduction makes a difference in efficacy, and we look forward to exploring the mechanistic stuff in due course. Yeah, and I would add to what Bill is saying, having worked on this class for many years, and this wasn't the intention to always get to these levels of lymphocyte count reduction, but we just haven't been able to achieve that with the prior therapies, including oxanamone, and I would argue atrazumab as well, for different reasons, safety or other concerns. So, you know, we always did see a dose response in IBD in particular, and so I think we just hadn't tested the higher doses and the higher levels of lymphocyte count reduction. That was always the thesis here, to see would this actually translate into different efficacy, and I think we're really seeing that in terms of this deep remission that we're observing, which these are objective endpoints and very clearly measurable in phase two settings, even with that smaller sample size. I think we just have tested the hypothesis, and we're seeing a nice, robust dose response, even higher in terms of dose levels and the lymphocyte count reductions that we've achieved before in the clinic, so more to come, but I think that's what we're seeing at a top line. Okay. Appreciate that. Thanks, Chris. We'll take our next question from Sam Flutsky with Lifesci. Please go ahead. Your line is open. Hey, good afternoon. Thanks for the questions. For Dr. Sanborn and Dr. Stans, so it was mentioned that there was a strong effect with 002 in the treatment experience group. I guess, do you see this as a key differentiator for where the aspect could be used in clinical practice versus other S1Ps? Given that both ozonimod and atrazumab don't really work that well in the biologic and check experience patients, and I'm pretty sure it's as well in everybody's conditions as well. I'm going to start, and then Bruce can weigh in. I don't want to overstate that. You know, people were really asking, you know, what confidence do you have that you'll be able to control the placebo rate in phase three and stuff, and my previous answer was really in that context. So the study is not powered to evaluate the treatment, i.e., even treatment experience subsets. But that said, we saw a nice trend towards a response in the treatment experience group. We will be looking to replicate that in phase three and to adequately power it. I feel uncomfortable about just drawing a line in the sand that we've absolutely nailed that, but I will make the point that that piece of data in subgroup analysis I think makes our phase two data set more robust. Bruce, I don't know if you want to add to that. Yes, I agree with you. I think that is potentially a differentiator. I think it's important to point out that, you know, there was a limitation to the number of biologic classes, which someone could have failed in this study. I think it might have been two classes. Is that right, Bill? Yes, you could fail unlimited number of drugs within a class. So you could have failed two or three TNF blockers and one more class or any two classes and more than one drug within a class. So it's not that restrictive, but it's not completely unrestricted either. That's right. And here's where I would add my clinical experience, really with Ozanamide, which is the only thing that I've had in my hands on the market, which is, you know, mainly I treat patients who have failed advanced therapies. And I have found that with patients with this class, I have achieved success with a fair number of patients, surprising considering what the data seem to show with Ozanamide. With Ozanamide, if you look at it, failure of one class of advanced therapy looks as good as about as good as the naive patients. And I think here there's a potential that failing two classes might also be as good. And so that is a differentiator. Got it. Okay. And then last one for me, just as we think about data across the S1QM space, you showed some of the cross-trial comparisons, but how should we be thinking about the fact that the low dose group had a PD effect on lymphocyte that was similar to Atrazumab and Ozanamide? I guess should we be looking at that lower dose level as a Atrazumab-like control versus the higher dose in the study? Well, it's at least a Ozanamide-like control, and Atrazumab is probably somewhere in the middle. And I'm just going to encourage you and everyone to, the really interesting comparison is across all of the second-generation products. It's not just S1P. As we went through in some detail during my presentation, we think we have a very competitive profile, full stop. It doesn't need to, you know, we're very pleased to directly compare to, for instance, the anti-IL-23 antibodies, which people have been quite excited about in ulcerative colitis. I think in cross-trial comparisons, we're incredibly competitive with that class of drugs. And there are no further questions on the line at this time. I'll return the call to our speakers for any closing comments. Again, thanks to the team for presenting the data. Thank you all for your attention, and I look forward to future discussions. This does conclude today's program. Thank you for your participation, and you may now disconnect.