Ladies and gentlemen, thank you for standing by. Welcome to the Pliant Therapeutics Webcast to review data from the INTEGRIS-IPF clinical trial of Bexotegrast. At this time, all participants are in a listen only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will hear an automatic message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker host, Christopher Keenan, Vice President of Investor Relations. Please go ahead.
Thank you, Livia. Good morning, everyone. Thank you for joining us for Pliant's presentation of data from the INTEGRIS Phase 2a clinical trial evaluating bexotegrast at 320 milligrams in patients with idiopathic pulmonary fibrosis. The press release referenced during this call was issued yesterday and is available under the Investors and Media section of our corporate website. The slides accompanying this webcast presentation are now available under the Events and Presentation section of our website. During today's call, we will be making forward-looking statements, including those related to the therapeutic potential of bexotegrast and our plans for the future development of bexotegrast. Forward-looking statements relate to the future, they are subject to inherent uncertainties and risks that are difficult to predict and many of which are outside of our control.
Important risks and uncertainties are set forth in our most recent public filings with the SEC, which are available at sec.gov. Pliant undertakes no obligation to update any forward-looking statements, whether as a result of new information, future developments or otherwise. Joining me today with prepared remarks are members of the Pliant management team, including Dr. Bernard Coulie, President and Chief Executive Officer, Dr. Éric Lefebvre, Chief Medical Officer, and Dr. Greg Cosgrove, Pliant's Vice President of Clinical Development and head of our IPF program. We are also joined today by Dr. Toby Maher, Professor of Medicine and Director of Interstitial Lung Disease at Keck School of Medicine, the University of Southern California, Los Angeles. Dr. Maher has spent the last 20 years specializing in the management of all forms of pulmonary fibrosis and orphan interstitial lung diseases. Dr.
Keith Cummings, Pliant's chief financial officer, will join us for the question and answer portion of the call. With that, let me turn the call over to Bernard.
Thanks, Chris. Good morning, everybody, thank you for joining us. It's a great pleasure for me and my colleagues to share with you the extremely compelling data that we announced yesterday from our INTEGRIS-IPF Phase 2a clinical trial of our lead asset, bexotegrast. Bexotegrast is an oral small molecule dual selective inhibitor of αvβ6 and αvβ1, currently in clinical development for IPF and PSC. Today's results from the 320-milligram dose cohort of INTEGRIS-IPF continue to exceed our expectations, building further upon the exceptional data we already presented in July from the three lower doses. Today's data are unprecedented in IPF clinical drug development. Please note that while we are presenting and discussing all doses studied in the trial to date, the discussion slides will highlight the data from the 320-milligram group.
We've always been focused on building the strongest foundation to drive innovative and potentially life-changing treatments for IPF patients. To date, bexatogras has been dosed to over 600 human participants, including healthy volunteers and patients with IPF or PSC, with no safety concerns observed. Turning now to our newest data set. The 320-milligram data complement the findings from our previously reported data from lower- doses and continue to tell a compelling story about this novel drug candidate. With safety the focus of this trial, it is important to see bexatogras continuing to have a favorable safety profile at this highest dose. We are excited to see results on the exploratory efficacy measures, including FVC and FVC % predicted. bexatogras 320 milligrams demonstrated statistically significant increases in FVC across all time points, outperforming lower dose groups.
Additionally, no bexotegrast treated patients experienced disease progression. Eric will begin with an overview of the INTEGRIS-IPF trial and turn it over to Greg to review the safety, pharmacokinetics and results from the exploratory efficacy endpoints. Eric will discuss overall conclusions, including next steps for the program. Following this, we will hear from Dr. Toby Maher on his thoughts on these results before I conclude and open the call to questions. Let me turn the call over to Eric.
Good morning. I'm pleased to share the outstanding results from our Phase 2a INTEGRIS-IPF trial. This summary will focus on the 320-milligram dose group of bexotegrast. This dose was well-tolerated over 12 weeks of treatment, similar to lower doses as we previously reported. All drug-related AEs were mild or moderate. There were few discontinuations due to adverse events and no drug-related serious adverse events. The bexotegrast 320-milligram dose demonstrated statistically significant increase in FVC. This increase was observed at all time points, resulting in a mean difference from placebo of 140 milliliters at week 12. No participants experienced a decline of 10% or greater in FVC percent predicted, a well-established predictor of death and disease progression in IPF.
The bexotegrast treatment effect was observed with and without standard of care agents. The biomarker results further support bexotegrast anti-fibrotic mechanism of action. Dose-dependent anti-fibrotic effects were seen on QLF imaging, with the best results seen in the two top doses in our study, including the 320 mg. Last, bexotegrast re-reduced circulating PRO-C3 levels and also integrin β6 levels, with the greatest effect observed at 320 mg. Let me now turn the call over to Greg.
Thank you, Eric. On slide 4, I'd like to review the participant disposition. We screened 168 individuals and randomized 119, which are allocated into the two groups. Minimal number discontinuations occurred in both the bexotegrast as well as placebo group, and the safety analysis and efficacy intent to treat analysis cohorts are similar. Approximately 80% of individuals were on standard of care agents with a 50/50 split between nintedanib and pirfenidone. On the next slide, the baseline demographics are listed, which you can review. The characteristics are similar for all different cohorts. Further, on the following slide, the baseline disease characteristics on slide 6 are similarly similar between each group. The safety evaluation delineated on slide 7 suggest bexotegrast is well-tolerated, and there are no dose relationship for adverse events.
There are no drug-related SAEs observed. The most frequent treatment adverse event was diarrhea. 14 of 15 participants who received bexotegrast were on standard of care agents, resulting in diarrhea. The safety data are further described on slide 8 in a summary, and I would point out to you that the treatment emergent adverse events related to study drug were similar throughout the cohorts, if not increased in the placebo group. To highlight, the serious treatment emergent adverse events related to study drug were not identified in any of the bexotegrast groups. Most treatment adverse events were mild to moderate, as delineated in the treatment adverse events CTCAE grade three or higher. There was 1 death in the 320 milligram cohort in a patient with severe IPF, pre-existing atrial fibrillation who underwent an elective cardiac ablation and subsequently decompensated following that procedure.
On slide 9, the most frequent treatment emergent adverse events are identified, which is diarrhea as previously discussed. As you can see, there is no dose-responsive relationship in diarrhea. Slide 10 lists the serious adverse events reported in the study. Of note, there were no drug-related serious adverse events identified. The exciting results are described on slide 11. FVC change from baseline at 12 weeks. As described by Éric earlier, we see a statistically significant increase in FVC at the 320 milligram cohort and in the 80 milligram cohort. On slide 12, you see a time point description, and I'd highlight the 320 milligram cohort where we see that statistically significant increase occurring at week four, eight, and 12. Furthermore, you can see the delineation in the 80 milligram cohort where that statistically significant increase is identified at week 12.
To complement these data on slide 13, the proportion of participants with a relative decline of greater or equal to 10% in FVC % predicted is detailed. As you can see, a dose-responsive relationship is suggested with no participants progressing to that threshold in the 320 milligram cohort. On slide 14, we describe the results in individuals on standard of care in which a statistically significant increase is identified in the 320 milligram cohort and a statistically significant difference is noted in the 80 milligram cohort. In those not on standard of care, we suggest a treatment effect, while not statistically significant, believe evident even in the small sample size described. On slide 15, the radiographic biomarker QLF is described.
We see again features of an anti-fibrotic effect with no progression based on QLF at week 12 in the 160 milligram cohort and minimal progression in the 320 milligram cohort. To complement these data, the biomarker analyses in INTEGRIS-IPF again suggests a dose-responsive decrease in PRO-C3 with a statistically significant difference at the 320 milligram cohort at week 4. An additional biomarker that we now are able to describe is integrin β 6, a TGF-β-responsive gene which is reduced both at week 4 and at week 12, and most marked at the 320 milligram cohort. There are two important aspects regarding these data. First, that this suggests that integrin β 6 is a responsive gene to TGF-β signaling inhibition and consistent with our mechanism of action.
This biomarker has been identified to have a prognostic significance at baseline, suggesting increased mortality and progression with elevated levels. Given the decrease in FVC, the limited number of individuals with a decline of greater than 10% and the QLF data, it suggests it may represent a disease-responsive biomarker in individuals with IPF, given its significant decline at week four and week 12. Eric, I'll turn it over to you.
Thanks, Greg. In conclusion, the bexotegrast 320 milligram dose demonstrated favorable safety and tolerability profile and outperformed lower dose groups in overall treatment effects. These treatment effects were observed on or off standard of care and support bexotegrast's potential to advance the treatment of IPF. The 320 milligram group will continue until all participants have been treated for at least 24 weeks, with final data expected in 2Q 2023. Pliant plans to initiate its Phase 2b clinical trial of bexotegrast in mid-year. Let me now turn the call over to Dr. Toby Maher to provide his insights into today's data. Toby?
Thanks, Eric. I think the data are incredibly compelling and as a clinician treating IPF patients, very exciting. You know, we have two existing treatments for IPF with pirfenidone and nintedanib. At best, the drugs slow disease decline, and they create major challenges with side effect management and in clinical practice as many as a third of patients will discontinue treatment within a year.
To see the 320 milligram results where we're seeing stabilization of disease, albeit over three months, and a very clean safety and tolerability profile with a number of drop-offs that's actually smaller than we've seen in other comparable trials is for me very exciting because we might be in a position where we have a drug that is both efficacious, hopefully truly stopping disease progression, and which is genuinely tolerated. I think this data builds incredibly well on the data that was discussed in the middle of last year.
You know, for me would seem to provide a much clearer dosing rationale moving forward, for later-phase studies, than we perhaps had earlier, where there was a little bit of inconsistency between the 80 and 160 milligram results. Overall, very, very exciting. I think many congratulations are due to you guys at Pliant.
Thank you, Toby. We greatly appreciate your insightful comments. The team and I are extremely pleased to share these exceptional data with you as they mark another milestone in the development of bexotegrast as an innovative approach to addressing the unmet needs of IPF patients. Before we go into Q&A, I would like to thank our investigators and their teams, as well as the members of the Pliant team for their dedication and support to the successful execution of this trial. More than that, special thanks to the INTEGRIS-IPF clinical trial participants, their families and support networks for helping us advance this promising program. With that, let's open the call to questions, Chris.
Okay, Olivia, you can open it up.
Certainly. Ladies and gentlemen, as a reminder to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. First question coming from the line of Brian Abrahams with RBC Capital. Your line is open.
Hey, good morning, guys. congratulations on the data. A couple of quick questions from me. First off, you know, we usually think about NFR products as slowing rates of decline and the flattening you're seeing on QLF in the high dose arms versus the worsening of placebo aligns with that. In a prior arm and now in the 320 milligram , it looks like you're actually seeing lung function improvement. I'm wondering if you think these represent a true treatment effect and what your latest views are on a potential mechanistic explanation for this. Then I had a follow-up. Thanks.
Thanks. Maybe, Greg, you can address the question.
Sure. Thanks, Brian. Given the mechanism of action of bexotegrast with a decrease in collagen deposition within the lung, these data are consistent with that intervention, such that with decreased collagen deposition, we would anticipate a change in the compliance of the lung leading to a change in FVC. I do believe that first and foremost, this is anticipated, given the focus of our investigations and exciting, to say the least.
Got it. That's really helpful. It looks like for the 320 milligram arm, you see a really strong increase in FVC, and then, maybe a little bit of what appears to be a waning in the effect size. I was wondering if you could maybe talk about the potential explanations there. I know you had a couple of patients who dropped out.
Just sort of wondering if you could talk about, timing and reason for discontinuations, how it might relate to the shape of those curves on FVC, and whether or not overall you're seeing any correlations between or among drug exposure, GI side effect and efficacy, in the dropout, the patients who dropped out or any other patients in the study that might affect how you think about therapeutic window and go forward dosing. Thanks.
Certainly. In that 320 milligram cohort, three individuals withdrew from the study. One we previously discussed, the participant who actually was a high responder, but unfortunately had that progression following the procedure. Two additional individuals withdrew, both with diarrhea, one who was on nintedanib and one participant who had underlying ulcerative colitis with pre-existing diarrhea. All three were high responders and therefore the presence of their results certainly are indicated at week four. I believe the decline to week eight is a result of their data not being available and subsequently imputed in that they were at depicted as the average of the cohort rather than their true response rate. That's perhaps the inflection point at week four that's not represented following.
Brian, I'll address, this is Eric. I'll address the exposure response. We have not conducted an exposure response at this stage because of course it's a relatively small data set, but it's clear that we do have a very evident dose response. As we get more patients in later stage studies, obviously, and longer durations, we'll be able to tease out the effect of exposures in a more meaningful way. We didn't have any, in terms of, you know, in terms of events or side effects with exposure. We really didn't see anything meaningful to report on here, you know, with the exception that these, you know, two discontinuations due to diarrhea were at the top dose.
You know, both of these events, these patients had mild diarrhea, so it's unfortunate that they chose to discontinue the study.
Super helpful. Thanks so much for the for the clarity and congrats again on the results.
Thank you. One moment please for our next question. Our next question coming from the line of Yasmeen Rahimi with Piper Sandler. Your line is open.
Good morning, team, and really congrats on stellar data. Very thrilled for you. Given that Dr. Toby is on the line, I would like to maybe ask him a few questions. Dr. Toby, is there an opportunity you could comment on what the shape of the curve is likely to look at at week 24? A lot of clients, you know, are hoping to look at the curve and try to come up with a realistic expectation around that. What would forced vital capacity placebo arm look like at 24 weeks? What range based on historical data? And that could also be helpful.
Lastly, maybe you could help us understand sort of, Given this data will become available to investigators who will be part of the Phase 2b study, how encouraged they would be and how this would expedite getting patients into a future Phase 2b study. Thank you again for allowing me to ask my questions.
Yeah. I guess the shape of the curve in the untreated group of patients, one would expect by 24 weeks untreated patients on placebo to be losing approximately 120- 150 mils of forced vital capacity. I think clearly the, the shape of the treated curve remains to be seen, I think as I see it, true success would be
Stabilization of FVC, so a flat treatment response curve. It's worth remembering that as we age or certainly once we're all over the age of 35, we naturally lose about 25- 30 mils of FVC a year. One would expect with natural aging some gradual loss, and one might perhaps expect that to come out in the results over time. One would hope that we might see stabilization in disease if the drug is truly interacting with disease relevant pathways and preventing further fibrosis accumulation. The second part of the question, you may need to remind me again.
Thank you. how excited you would be to enroll? Yeah. A lot of investors trying to map out time of enrollment for a Phase 2b study. We know Galapagos took about a year to enroll 750 patients, but on weaker data. With this data set, like, you know, how motivated are investigators going to be to get their patients into this future Phase 2b study?
Yeah. I think this is going to be a very attractive late phase trial program for investigators and patients. It's an orally dosed drug. As we've touched on, the safety profile looks very good. I think there's compelling evidence of efficacy from this early phase program. I, you know, I think recruitment should be good. Probably the timelines that we saw with the Galapagos ISABELA trial are probably as good as one might hope for because that was conducted without any phase three competition. You know, recruitment was pretty good. I would hope for that level and speed of recruitment with Pliant's late phase program.
Great. Thank you. I'll jump back in the queue.
Thank you. One moment please for our next question. Our next question coming from the line of Eric Joseph with JP Morgan. Your line is open.
Hi. Hi, good morning. Congrats on the data. Thanks for taking the questions. A couple questions. First, on the incremental performance of the placebo arm, it seems that the additional patients here weren't poorer than those in the dataset presented in July. Just trying to get a sense of why that might have been the case and what that portends for expected performance of untreated patients in a Phase 2b study, and whether that might result in any changes to the screening criteria? And then, secondly, obviously these data entertain a lot of questions around disease or bexotegrast being a disease-modifying therapy for IPF. I guess for Dr. Maher, is there sort of a consensus view of what a consensus definition of what disease modifying would mean?
What endpoints would be appropriate to look at? Whether the population kind of presented here in the INTEGRIS-IPF trial would be aggressive enough or the appropriate population to sort of assess a disease-modifying intervention. Thanks for taking the questions.
Thanks, thanks, Eric. Just summarizing the questions. The first question really kind of covers the placebo response rate that we have seen with the 320 milligram, and how that kind of compares to the previously reported placebo response in July, which I mean, obviously turns out to be worse now. The second question, and Greg will address that question, and then Eric will address the question in terms of what criteria to look for in terms of patients to pick up a potential disease-modifying effect of the drug. Greg.
Certainly. The difference between July and the current data are exemplified by the fact that we have additional placebos enrolled and therefore, that curve is informed by their rate of progression. This, as we discussed in July, appears to be a more progressive rate than historical data would suggest from the 2 or 4 registrational trials for nintedanib and pirfenidone. Certainly there are a lot of hypotheses as to why we're seeing a rate of progression that is greater than historical data. I believe it reflects the current status of progression in IPF as of 2023 in contrast to 2020 or 2015.
Eric, I think that, this is Eric, the additional information is that once we have the complete dataset, we performed an outlier analysis statistically, and we identified 1 participant in the placebo group that was a statistical outlier across all the treatment groups, and that participant was excluded from the MITT analysis. That also is what explained the different results from the prior study. In terms of the inclusion and exclusion criteria, it's fair to say that we're still working on these. You know, it is, at least at this point, we don't expect to make any major changes to our inclusion and exclusion criteria for Phase 2b, but we will be taking a look closely at these.
Just pointing out that we do expect patients to progress and some patients to die on these studies because obviously IPF is a life-threatening disease. You know, just to give you a little bit of context, in the Boehringer Ingelheim trial on their PDE4 inhibitor, they saw 2 deaths on treatment, on active treatment, over 12 weeks. That's really good to keep as context.
Okay, thanks. Maybe just picking up on adjusting the question around disease modifying, what sort of the appropriate criteria and patient population would be to.
Yeah
Arrive at that potential benefit with bexotegrast.
Yeah, I think there, you know, Eric, I think that if you're, you know, in our prior to reading out on the lower dose groups last summer and this new dose information, we weren't really sure if we would be able to detect an add-on benefit of the combination over a 12-week period, especially in a small sample size. The data from these studies suggest that you can capture that. You know, with let's say a greater sample size, longer duration, you would also expect that this difference here would be captured and would be statistically significant. That would be, you know, what we would need to show that this is a disease-modifying therapy.
I think this data are very encouraging on that front because if you can capture something in a small data set, you usually are pretty confident that you can replicate that in larger studies, especially with the effect size being this strong.
Great. Thanks again, and congrats on the data.
Thank you. One moment before our next question. Our next question coming from the lineup, Pete Stavropoulos with Cantor. Your line is open.
Thank you. Good morning, team, and congratulations on this positive data. It was great to see these outcomes. My first question is for Dr. Maher. Seeing this data that was presented and taking into account your clinical experience with the two approved agents for IPF, you know, how do you see Bexso fitting into the current landscape or treatment paradigm? The reason I ask is because I've conducted diligence with a number of KOLs and physicians, and many of them highlight the tolerability issues with the two approved agents, you know, which leaves the high discontinuation rates of treatment of patients.
you know, when you think about Bexso, where it sits, mechanistically, above TGF-β activation and taking into consideration tolerability profile, how do you see it being implementing in newly diagnosed patients?
Yeah. I think that's an interesting question. You know, you've highlighted some of the unmet need there that up to a third of patients will be discontinuing existing treatment, because of side effect profile. Furthermore, there will be a proportion of patients who continue to take the current drugs, but who are plagued by side effects, whilst they continue to take them. There's definitely a need for better tolerated therapy. At the same time, you know, my patients are continuing to die of respiratory failure despite the fact that they are on anti-fibrotic therapy. There's a greater need for efficacy. I think there's a few potential ways that new treatment will be used.
My suspicion is that there will be a low threshold to begin combination therapy in patients who are already established on current anti-fibrotic drugs, but for whom there is a concern about ongoing disease progression. For the group of patients who are, you know, who have tried and failed existing anti-fibrotic drugs, clearly, that is a population of patients in whom we urgently need treatment for and who would undoubtedly be started on therapy. The perhaps more interesting question is what will happen to newly diagnosed patients once, you know, assuming all this plays out, we have this available as a therapeutic option.
I think, you know, notwithstanding issues of reimbursement, if we had a clean drug that has an apparently better efficacy profile than existing therapy, then arguably, there would be a very low threshold to initiate patients on this in advance of using existing anti-fibrotics as add-on, combination, therapy sort of later down the line if there was subsequent disease progression.
Okay. Thank you. Very helpful. I have two questions for management. You know, as we look forward towards the Phase 2b, you know, in a registrational study, how are you thinking about the secondary endpoints that could help differentiate the product from current standard of care and other agents in development? The second question I have is, you know, can you go into a little bit more detail about the biomarker integrin β6? You know, how should we view correlations with clinical outcomes and how this biomarker ties back to bexotegrast's mechanism of action?
Thanks for the question. This is Derek. For the key secondary endpoints of our Phase 2b study, we'll be coming out with more details as we get closer to trial start. The typical endpoint, key secondary endpoint is clinical outcomes. This clinical outcomes is usually a composite endpoint that includes death of any cause, respiratory-related hospitalizations, which are predominantly acute exacerbations. Then there's this responder analysis, the 10% or greater change in FVC % predicted. This is something that, you know, we would expect in our Phase 2b study also to be a key secondary endpoint, and this is also something that we would test in a Phase 3 program.
We believe that there is a possibility that we might see also a change in these endpoints given the trajectory of FVC that we've seen on the 220 milligram group, and also this dose-responsive change in the responder analysis. I think this puts us in a great position to evaluate this key secondary endpoint in late-stage studies. Now I'll pass it over to Greg to give a little bit more detail on the integrin β 6 levels.
Sure. The referenced article on the slide by Bowman et al. was published last year, and it detailed that integrin β6, amongst many other biomarkers evaluated, was correlated its level. Highest levels were correlated with disease progression as well as increased risk for mortality at baseline. In our study, it is the first in which an interventional study detailed the changes in integrin β6. Obviously, we're interested given that αvβ6 is a target, and therefore this represents a very interesting biomarker being that it's TGF-β responsive, as I mentioned. We think it demonstrates in our study target engagement since it suggests the decrease is related to decreased TGF-β signaling.
Its change over time and its association with change in important endpoints such as FVC as well as QLF is very interesting and supports our mechanism of action and a further supportive evidence perhaps of a biomarker that is disease responsive.
All right. Thank you very much, and congratulations once again.
Thank you.
Thank you. One moment please for our next question. Our next question coming from the line of Tom Schroeder with BTIG. Your line is open.
Good morning. Let me add my congratulations. If we go back to the target engagement studies, my memory is at the time you were aiming for 50% target engagement, and most of the doses seemed to get you there. Now your efficacy looks so good at high doses. Do you have an updated estimate of what you're really aiming for, or is more just better? If more is better, what does your preclinical data say about what the maximum dose is likely to be?
Yes. Certainly from our target engagement data we conducted in IPF patients, we saw that the top doses studied, specifically 240 and 320 milligram used as single doses, were providing near saturation of alpha V beta six in the IPF lung. Remember this study was conducted also in IPF patients.
Yep.
Important to keep in mind that this study evaluated the receptor occupancy at maximum concentrations or peak concentrations or Cmax. We do believe that having higher doses would, and this is based on the bowel study we've conducted as well, that we have more suppression prior to the next dose or at trough levels when we get to higher doses. We would anticipate not only having more patients or all patients above the IC-50, let's say at the 320 milligram dose, but also more patients achieving close to IC-8 0 concentrations once they reach peak concentrations. Certainly in our experience preclinically, that was also important in providing anti-fibrotic effects. This is why we're extremely excited about the results from this 320 milligram dose.
It is the top dose that we're planning to evaluate in our late-stage program. We do think that this provides a really nice risk benefit with really strong efficacy signal from this Phase 2a study, but also provides also a, you know, really favorable safety profile that is really important in these vulnerable patients.
Okay. If I can squeeze in one follow-up. The data on slide 14 for patients with a 10% decline is so incredibly clean. Have you plotted something like patients with no decline? Does it look as good? What fraction of patients have no decline? Is it dose dependent?
I mean, it's really the reciprocal data you would see for no decline, but I would tell you that we have not disclosed these data, but we also looked at the 5% progression, and we've seen fewer patients at the 320 milligram, and this was in contrast with the lower dose group. We do see consistency at that dose and this suggests that we should expect fewer patients to progress in a meaningful way at the top dose.
Okay, great. Congrats again.
Thank you.
Thank you. One moment please for our next question. Our next question coming from the line of Alex Thompson with Stifel. Your line is open.
Hey, thanks. Again, congrats on the data. Had 1 quick follow-up on MITT, and 1 on the phase 2b trial. On your MITT analysis excluding that placebo patient, I was also wondering how that impacts sort of the dose groups as well. It looks like from your prior data release, there's some minor differences between sort of FVCs recorded in the 40, 80, and 160 milligrams. Just curious what's going on there. On the phase 2b initiation, just curious what else is gating to starting that study? Do you need additional go ahead from FDA, et cetera? Thanks.
Great. The first question, the MMRM analysis that we conducted includes data on all patients, and it's informed by the data from all patients. Once you remove a patient, it will have a minimal impact on the other dose groups just because you removed the, you know, the data from this patient as well in the model. You know, that results in slight site changes also in the previous dose group. In terms of the next steps, we really have conducted our interaction with the FDA last year, we've gotten guidance on the fact that, you know, their recommendation was to conduct a dedicated phase 2b program to start.
That means that we don't have to conduct an end of phase 2 meeting prior to starting this study, which brings in the timelines by approximately two quarters for the start of the study. Midyear is what we're planning, and there's no further interactions that we're planning to do before, you know, to start up for this study.
Great. Thanks.
Thank you. One moment for our next question, please. Our next question coming from the line of Michael Yee with SVB Securities. Your line is open.
Good morning, thanks for taking our questions, and congrats on the data. Could you help characterize the one patient death with respect to their experience on therapy prior to the death and discuss how you think about their underlying mortality risk for this patient, given them being GAP stage three?
Sure. As I mentioned, in looking at the time point curve, that participant actually was a high responder, so their course was relatively unremarkable with evidence of significant response to bexotegrast. Unfortunately, they progressed following that intervention. I think that that characterizes their response.
Got it. Thanks. Separately, can you just discuss the difference between FVC at week 12 across the different subgroups? Dr. Maher, if that's consistent with what you'd expect to see with this treatment?
Well, I think certainly we see the statistically significant difference both at 320 and 80 milligrams, which has resulted in a lot of excitement. It really is demonstrating what we believe is that unique mechanism of action of bexotegrast moving forward. In terms of, is it expected, I would argue that we're in uncharted waters here that since prior studies have been focused on decreasing the rate of decline and these would suggest stabilization and perhaps improvement in FVC.
I think did you ask for Toby Maher's take on that as well?
Yes.
Okay.
Yep, always happy to give my insights. I think importantly, if you look at the placebo arm in the trial, the placebo arm overall has behaved as we would expect for a group of IPF patients, so that the overall rate of decline over 12 weeks is consistent with other studies and is actually very similar to that was seen in the BI PDE4 trial that was published last year. If anything, the subgroup of patients who weren't on standard of care actually had a more indolent rate of disease decline than one might expect, but the overall population behaves as expected. I think that's always important when you then interpret the change in FVC in the treatment groups.
As to what might be expected in the treatment groups, you know, I think that dichotomized 10% rate of progression is an important sense check when it comes to interpreting the rate of FVC change because occasionally you'll see the rate is influenced by outliers. I think that very consistent effect on the reduction in number of patients experiencing a greater than 10% decline provides a sense check that the data we're looking at in the model reflects therapeutic reality. You know, as noted, the fact that
The FVC has been stabilized overall in the population at 12 weeks is for me one of the things that's very exciting with the data.
Understood. Appreciate the color and congrats again.
Thank you.
Thank you. One moment for our next question. Our next question coming from the line of David Lebowitz with Citi. Your line is open.
Thank you very much for taking my question. Congrats on the update. A few questions specifically on slide 15, if you will. First, when looking at the 320 MIG data, both the standard of care and non-standard of care subgroups come out around 19. I noticed in, I believe it was slide 12, that this dose the mean is 29.5. Can you just connect what's different about those two data points that the slide 15 numbers fall below the mean?
Certainly. They are subgroup analyses, you can see perhaps best differentiated if you look at the sample sizes between the sOC subgroup, the not on sOC subgroup. If you can flip back to slide 11, you see that the sample sizes are the totality of those two groups together. Given that the responses are different between those on standard of care and not on standard of care, I believe that explains the differences.
Yeah. The one thing I'd like to add is that, and we haven't talked about it today, but we do plan to include at least 30% of patients not on standard of care in our phase 2b evaluation to be able to more accurately assess the treatment effect in that population.
Got it. Got it. Thank you. Also when looking at the placebo, there's quite a bit of variation between the two subgroups. Why would the standard of care subgroup actually do so much worse? Is it just an issue of the numbers and the particular patients in this standard of care group?
I think certainly the sample size has an influence on that. As you can see, there's seven in the not sOC subgroup. The inherent variability in that measurement may lead to the differences that we're seeing.
Got it. Lastly on that chart, as far as the variability across the patients, it seems, for example, the non-standard of care patients consistent with the AD MIG are having a different response, except for 320 than in the standard of care group. I guess, again, is this another function of small numbers, or is there something about this drug that's different when used as a standalone agent, versus standard of care, being on top of standard of care?
I think it's challenging to interpret the data, with the limited sample size beyond there's a suggestion of a treatment effect in the absence of those standard of care agents. To Eric's point, it's obviously something that we wanna power in our late stage studies to really delineate that effect on and off of standard of care.
Yeah. Just to add to that, there's really no biological rationale for why, you know, this drug would perform less well in patients that are not on standard of care. You know, for us, we're really, as Greg mentioned, pinning this on small numbers that really are hard to interpret the data correctly.
Excellent. Thank you so much for taking my question and congrats.
Thank you.
Thank you.
Thank you. One moment please for our next question. Our next question coming from the line of Joseph Stringer with Needham & Company. Your line is open.
Hi. Thanks for taking our questions. Our question is for Dr. Maher. Just curious, what is your ideal target product profile for an IPF drug, and how does the bexotegrast data and profile to date check some of those boxes? Secondly, how would you compare this or how does this compare to some of the late stage phase 3 IPF programs that are ongoing that are evaluating oral and injectable drugs?
Yeah, so I think my ideal target product profile. I think a simple dosing regimen, so an easy to take oral drug for me trumps an intravenous therapy. Clearly one wants good efficacy, and I think by good efficacy, you know, the goal as I see it, particularly for patients with late stage disease, is to halt further disease decline. If we can get some form of improvement, then that's a bonus. If we could genuinely prevent disease decline across the patient cohort, then for me that would be success. I think that the tolerability component is very important. You know, we're asking these patients to be on therapy for many years, and so.
The fact that they can tolerate it is important in enabling them to continue to take long-term treatment. You know, this is 12-week data, so one doesn't want to jump too far ahead of oneself in interpreting it. If this played out in a 52-week study, then, you know, bexo comes very close to achieving, as, everything I would want from a therapy for my patients. I think just to compare it to other drugs out there, well, we've got FibroGen's intravenous drug, so that's less convenient for dosing. Certainly their phase 2 data, to my reading, was less robust than we've seen with Pliant's data.
We've got BI's PDE4 inhibitor, which perhaps was showing similar efficacy, but actually, had a more challenging tolerability profile with adverse GI events. I think everyone knows by this point that the Pentraxin trial program has been closed due to lack of efficacy. We've also seen Galecto's inhaled Galectin-3 inhibitor, which, their program has been, encountered problems with the DSMB changing study design. It's, it's difficult to know where that will take us, when we see the data later on this year. I think at the moment, Bexo is very well-positioned to move ahead as sort of the leading candidate for the sort of drug that we would hope for in clinical practice.
Great. Thank you for taking our questions.
Thank you. One moment, please, for our next question. Our next question coming from the line of Ritu Barua with Cowen. Your line is open.
Good morning, guys. Thanks for taking the question and congrats on this data. Just following up on some client conversations I had this morning, particularly around the AFib event, the death following the AFib patient post-ablation. The footnote mentioned that it was respiratory failure. I guess, do you have any more detail on the day eight respiratory failure, features around that respiratory failure that would set it apart from, say, an IPF-driven exacerbation and respiratory failure? I've got a follow-up about the phase 2b.
Well, I guess what we can say is that there was a temporal association with that intervention and procedure with an antecedent course that was, at least based on unblinding, suggesting a treatment response and a super responder. It appeared that there wasn't an event that or progression of the disease prior to that intervention. Temporally and also supported based on some reports, the intervention was may have been linked to the decompensation.
The DSMB
Yeah. Maybe Ritu just to add to that, I think the just some details on the investigator. The investigator deemed this event not related to study treatment, but due to the underlying disease. Greg mentioned how, you know, this was a severe patient. It's unfortunate because that patient did so well in the first four weeks of treatment. It's, you know, also this information helps us understand that it's unlikely to be associated with treatment just because that patient was improving on therapy rather than going, you know, worsening on therapy. Something certainly to look out for, obviously in all IPF studies, but nothing here that suggests a drug effect.
Got it. If I understood you correctly, you said the DSMB did have access to the antecedent reports, sort of like how the patient was doing from the ablation to day eight, sort of that time period.
Yes.
Okay.
In addition to monthly evaluation, there is also a formal evaluation that occurred, and they recommended to proceed without modification, suggesting.
Got it. Okay.
No, safety concern.
Got it. Just moving to the Phase 2b. Eric, what are your thoughts on the patient numbers that you want for this study, understanding that, you know, a Phase 2 is powered differently than a conservatively powered pivotal, which I believe that you hope this could be. Further, last question. I understand this study has remained blinded. We're gonna get the next data in Q2. How should we set our expectations for the 24-week data? Do you think that we could see continuing improvement separation from placebo at 24 weeks? Do you think that the mechanism suggests there's a plateau between week 12 and 24?
The first question really on the late-stage development, we were waiting for the results for the 320-milligram dose group to reassess the anticipated effect size of bexo. This data really gives us quite a lot of rich data to inform that question. It's premature to give you the number of patients that will be in the phase 2b study. One thing to mention is that we want to power this phase 2b study in a meaningful way. At least 80% power. We wanna have a 1-year duration.
We wanna have this strong, robust phase 2b evaluation because we do believe that if we do it well, there is a possibility that it could count as of one of two confirmatory studies that you would need for the FDA to, you know, to approve an NDA or to submit an NDA. This is certainly a review-dependent question. We wanna put the trial in the best possible position to do that because that could mean, if we're successful, that we would only have to conduct one phase 3 study for the NDA. We'll be communicating on more details 'cause now we'll be, you know, focusing on numbers to come back to you with that specific question as we get closer to trial start.
The last question was what would we anticipate? I would say that the focus will really be on the slope of the decline of the 320 milligram group or the stabilization. That's what we're gonna be really interested in looking at. Keeping in mind that none of the placebo patients in the prior dose groups will have, you know, continued treatment beyond 12 weeks. The ability to compare with placebo will be somewhat diminished because we'll only have 8 placebo patients at most going through that time point as well. Certainly looking at the slope of the curve for the 320 milligram group will be important.
Can you comment at all about the safety that you've seen to date, through 24 weeks? How many patients have made it through 24 weeks right now?
Really, I mean, that's a great question. Thank you for asking it. We've passed, you know, most of the patients have passed that 24 week time point now, and some have gone out to much longer. You know, this provides really great confidence in the safety profile that we reported on today that it continues to manifest in that longer duration. Obviously, we'll, you know, we have to wait to see the unblinded data for the longer duration, but I'm feeling very confident, especially with the results we have in patients, but also the extensive safety data we have in over 500 study participants to date that continue to illustrate the favorable safety profile of this compound.
Thanks for taking all the questions.
Thank you.
Thank you. Ladies and gentlemen, as we pass the hour, I would now like to turn the call back over to Chris Keenan for closing statement.
Thank you. On behalf of my executive team and all of my fellow clients here, thank you for joining us this morning. This is certainly a great day for clients and potentially for patients with IPF. My team and I look forward to sharing updates from across the client portfolio in the near future. Have a great week, everybody.
Ladies and gentlemen, that does end our conference call today. Thank you for your participation. You may now disconnect.