Pliant Therapeutics, Inc. (PLRX) Earnings Call Transcript & Summary

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. [Operator Instructions] 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, Olivia, and good morning, everyone. Thank you for joining us for Pliant's presentation of data from the INTEGRIS Phase IIa 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 & Media section of our corporate website. The slides accompanying this webcast presentation are now available under the Events & Presentations 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. Because 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 of 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, and 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 IIa clinical trial of our lead asset, bexotegrast. Bexotegrast is an oral, small molecule, dual-selective inhibitor of alpha v beta 6 and alpha v beta 1, currently in clinical development for IPF and PSC. Today's results from the 320-milligram dose cohort of INTEGRIS-IPF continued to exceed our expectations, building further upon the exceptional data we already presented in July from the 3 lower doses. Today's data are unprecedented in IPF clinical drug development. Please note that while we are presenting and discussing all those studies-- studied in the trial today. 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, bexotegrast 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 sets. 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 bexotegrast 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 percent predicted. Bexotegrast 320-milligram demonstrated statistically significant increases in FVC across all time points, outperforming lower dose groups. Additionally, no bexotegrast-treated patients experienced disease progression. Éric will begin with an overview of the INTEGRIS-IPF and turn it over to Greg to review the safety, pharmacokinetics and results from the exploratory efficacy endpoints. Éric will then 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 IIa 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 a few discontinuations due to adverse events and no drug-related serious adverse events. The bexotegrast 320-milligram dose demonstrated a statistically significant increase in FVC, and 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. And the bexotegrast treatment effect was observed with and without standard of care agents. The biomarker results further support bexotegrast's antifibrotic mechanism of action. Dose-dependent antifibrotic effect we're seeing on QLF imaging with the best results seen in the 2 top doses in our study, including the 320 milligram. And last, bexotegrast's reduced circulating PRO-C3 levels and also integrin beta-6 levels with the greatest effect observed at 320 milligrams. Let me now turn the call over to Greg.

Thank you, Eric. On Slide 4, I'd like to review the participant disposition. We've screened 168 individuals and randomized 119, which are allocated into the 2 groups. Minimal number of 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. And 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 suggests bexotegrast is well tolerated, and there are no dose relationship for adverse events. There are no drug-related SAEs observed. And 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's groups. And most treatment adverse events were mild to moderate as delineated in the treatment adverse events CTCAE Grade 3 or higher. There was one death in the 320-milligram cohort in a patient with severe IPF, preexisting 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. And 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 Eric 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 4, 8 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% and FVC percent 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 differences noted in the 80-milligram cohort. In those not on standard-of-care, we suggest a treatment effect while not statistically significant, I believe, evident even in the small sample size described. On Slide 15, the radiographic biomarker QLF is described. We see again features of an antifibrotic effect with no progression based on QLF at week 12 on 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 beta-6, a TGF beta responsive gene, which is reduced both at week 4 and at week 12 and most marked at the 320-milligram cohort. There are 2 important aspects regarding these data, first, that this suggests that integrin beta-6 is a responsive gene to TGF beta signaling inhibition and consistent with our mechanism of action. Furthermore, this biomarker has been identified to have a prognostic significance at baseline suggesting increased mortality and progression with elevated levels. Therefore, 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 the disease responsive biomarker in individuals with IPF, given its significant decline at week 4 and week 12. Eric, I'll turn it over to you.

Thanks, Greg. So 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 the second quarter of 2023. Pliant plans to initiate its Phase IIb clinical trial at bexotegrast in midyear. Let me now turn the call over to Dr. Toby Maher, to provide his insights into today's data. Toby?

Thanks, Eric. And I think that the data are incredibly compelling and, as a clinician treating IPF patients, very exciting. We have 2 existing treatments for IPF with pirfenidone and nintedanib. At best, the drug slowed disease decline, and they create major challenges with side effect management and in clinical practice as many as 1/3 of patients will discontinue treatment within a year. So to see the 320-milligram results where we're seeing stabilization of disease, albeit over 3 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. And I think this data builds incredibly well on the data that was discussed in the middle of last year and, for me, was seen 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. So overall, very, very exciting, and 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 results 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. But 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.

[Operator Instructions] And our first question coming from the line of Brian Abrahams with RBC Capital.

Congratulations on the data. A couple of quick questions from me. First off, we usually think about antifibrotics,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. But in a prior arm and now in the 320-mg arm, it looks like you're actually seeing lung function improvement. So I'm wondering if these -- if you think these represent a true treatment effect and what your latest views are on a potential mechanistic explanation for this? And then I have a follow-up.

I think 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. So 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. And then 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. So 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 effects and efficacy in the dropout -- in 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.

Certainly. In that 320-milligram cohort, 3 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 preexisting diarrhea. So all 3 were high responders. And therefore, the presence of their results certainly are indicated at week 4. But I believe the decline to week 8 is a result of their data not being available and subsequently imputed in that they were depicted as the average of the cohort rather than their true response rate. And so that's perhaps the inflection point at week 4 that's not represented following.

Yes. And Brian, I'll address -- this is Éric. I'll address the exposure response. So 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. And as we get more patients in later stage studies, obviously, and longer durations, we'll be able to tease out the effective exposures in a more meaningful way. We didn't have any -- in terms of events or side effects with exposure, we really didn't see anything meaningful to report on here with the exception that these 2 discontinuations due to diarrhea were at the top dose. However, both of these events -- these patients had mild diarrhea. So it's unfortunate that they chose to discontinue their study.

Super helpful. Thanks so much for the clarity and congrats again on the results.

[Operator Instructions] And our next question coming from the line of Yasmeen Rahimi with Piper Sandler.

Congrats on stellar data, I am very thrilled for you. Given that Dr. Toby is on the line, I would like to maybe ask him 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 are hoping to look at the curve and try to come up with a realistic expectation around that. So what would in forced vital capacity placebo arm look like at 24 weeks, what range based on historical data? And that could also be helpful. And then lastly, maybe you could help us understand sort of how do you -- given this data will become available to investigators who will be part of the Phase IIb study, how encouraged they would be and how this would expedite getting patients into a future Phase IIb study?

Yes. So 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 to 150 ml of forced vital capacity. I think clearly, the shape of the treated curve remains to be seen. But I think as I see it, true success would be stabilization of FVC, so a flat treatment response curve. And it's worth remembering that as we age or certainly, once we're all over the age of 35, we naturally lose about 30 -- 25 to 30 ml of FVC a year. So one would expect with natural aging some gradual loss, and one might perhaps expect that to come out in the results over time. But 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. And then the second part of the question, you may need to remind me.

How excited you would be to enroll, yes, because a lot of investors trying to map out a time of enrollment for a Phase IIb study. And we know, Galapagos took about a year to enroll 750 patients, but on weaker data. So with this data set like how motivated are investigators going to be to get their patients into this future Phase IIb study?

Yes. So 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. And I think there's compelling evidence of efficacy from this early phase program. So I think recruitment should be good. And 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 III competition. And so recruitment was pretty good. So I would hope for that level and speed of recruitment with clients' late-phase program.

[Operator Instructions] And our next question coming from the line of Eric Joseph with JPMorgan.

So a couple of questions. First on the incremental performance of the placebo arm. It seems that additionally patients here weren't poorer than those in the data set 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 IIb 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. So I guess for Dr. Maher, is there sort of a consensus view of what consensus definition of what disease modifying would mean, what endpoints would be appropriate to look at? And 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, Eric. So just summarizing the question. So the first question really kind of covers the placebo response rate that we have seen with a 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. And then 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. So 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, it appears to be a more progressive rate than historical data would suggest from the 2 or 4 registrational trials for nintedanib and pirfenidone. And certainly, there are a lot of hypotheses as to why we're seeing a rate of progression that is greater than historical data, but I believe it reflects the current status of progression in IPF as of 2023 in contrast to 2020 -- 2015.

And Eric, I think that the -- this is Éric. The additional information is that once we have the complete data set, 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. So that also is what explained the different results from the prior study. And in terms of an inclusion/exclusion criteria, it's fair to say that we're still working on these. It is, at least at this point, we don't expect to make any major changes to -- in an exclusion criteria for Phase IIb, 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. And 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. So that's really good to keep as context.

Okay. And maybe just picking up on addressing the question around disease modifying, what sort of the appropriate criteria in patient population would be to, yes, arrive at that potential benefit with bexotegrast?

I think Eric, I think that if you're -- 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. But the data from these studies suggests that you can capture that. And 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. So -- and that would be -- what we would need to show that this is a disease-modifying therapy. But I think these data are very encouraging on that front because if you can capture something in a small data sets, 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.

[Operator Instructions] And our next question coming from the line of Pete Stavropoulos with Cantor.

And congratulations on this positive data. It was great to see these outcomes. So my first question is for Dr. Maher. Seeing this data that was presented and taking into account your clinical experience with the 2 approved agents for IPF, how do you see Bexo fitting into the current landscape or treatment paradigm? And the reason I ask is because I've conducted diligence with a number of KOLs and physicians and many of them highlight the other tolerability issues with the 2 approved agents, which leaves the high discontinuation rates of treatment of patients. So when you think about bexo, where it sits mechanistically, above TGF-beta activation and taken into consideration tolerability profile, how do you see being implementing in newly diagnosed patients?

Yes. And I think that's an interesting question. You've highlighted some of the unmet need there that's up to 1/3 of patients will be discontinuing existing treatment because of side effect profile. And 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. So there's definitely a need for better-tolerated therapy. At the same time, my patients are continuing to die of respiratory failure despite the fact that they are on antifibrotic therapy. So there's a greater need for efficacy. So 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 of therapy in patients who are already established on current antifibrotic drugs, but for whom there is a concern about ongoing disease progression. For the group of patients who are -- who have tried and failed existing antifibrotic drugs, and clearly, that is a population of patients in whom we would -- who 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 assuming all this plays out, we have this available as a therapeutic option. And I think 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 antifibrotics as add-on combination therapy sort of later down the line if there was subsequent disease progression.

Okay. Very helpful. And I have 2 questions for management. So as we look forward towards the Phase IIb in a registrational study, how are you thinking about the secondary end points that could help differentiate the product from current standard-of-care and other agents in development? And then the second question I have is, can you go into a little bit more detail about the biomarker IT B6? How should we view correlations with clinical outcomes and how this biomarker ties back to Bexo's mechanism of action?

Thanks for the question. This is Éric. So for the key secondary endpoints of our Phase IIb study, we'll be coming out with more details as we get closer to trial start. But the typical endpoint -- key secondary endpoint is clinical outcomes. And this clinical outcome is usually a composite endpoint that includes death of any cause; respiratory-related hospitalizations which are predominantly acute exacerbations; and then there's this responder analysis, the 10% or greater change in FVC percent predicted. So this is something that we would expect in our Phase IIb study also to be a key secondary endpoint. And this is also something that we would test in a Phase III 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 320-milligram group and also this dose responsive change in the responder analysis. So I think this puts us in a great position to evaluate this key secondary endpoint in late-stage studies. And then I'll pass it over to Greg to give a little bit more detail on the integrin beta-6 levels.

The referenced article on the slide by Bowman et al was published last year. And it detailed that integrin beta-6 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. So in our study, it is the first in which an interventional study detailed the changes in integrin beta-6. And obviously, we're interested given that alpha v beta 6 is a target, and therefore, this represents a very interesting biomarker being that it's TGF beta responses, as I mentioned. And so we think it demonstrates in our study target engagement since it suggests the decreases related to decreased TGF beta signaling, but it's changed 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.

And congratulations once again.

Thank you.

[Operator Instructions] And our next question coming from the line of Tom Shrader with BTIG.

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 seem to get you there. Now your efficacy looks so good at high doses. Do you have an estimate of what you're really aiming for? Or is more just better? And if more is better, what does your preclinical data say about what the maximum dose is likely to be?

Yes. So certainly, from our target engagement data, we conducted in IPF patients. We saw that the top doses -- studies specifically 240 and 320-milligram used as single doses were providing near saturation of alpha v beta 6 in the IPF lung. Remember, the study was conducted also in IPF patients. 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 BAL study we conducted as well that we have more suppression prior to the next dose or at trough levels when we get to higher doses. So we would anticipate not only having more patients or all patients above the IC50, let's say, at the 320-milligram dose, but also more patients achieving close to IC80 concentrations once they reach peak concentrations. And certainly, in our experience preclinically, that was also important in providing antifibrotic effects. So 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 IIa study, but also -- provides also a 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 and is it dose dependent?

So there -- I mean it's really the reciprocal data that 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% progressions. And we've seen fewer patients at the 320 milligram, and this was in contrast with the lower dose group. So 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.

[Operator Instructions] And our next question coming from the line of Alex Thompson with Stifel.

Congrats on the data. I had one quick follow-up on mITT and one on the Phase IIb trial. So on your mITT analysis, excluding that placebo patients, I was also wondering how that impacts sort of the dose groups as well? It looks like from your prior data release, there are some minor differences between sort of FVCs recorded in the 40, 60 -- 40, 80 and 160 milligrams. Just curious what's going on there? And then on the Phase IIb initiation, just curious what else is getting to starting that study? Do you need additional go ahead from FDA, et cetera?

Great. So the first question, so the MMRM analysis that we conducted includes data on all patients. And it's informed by the data from all patients. And once you remove a patient, it will have a minimal impact on the other dose groups just because you removed the data from this patient as well in the model, so you can -- that results in slight changes also in the previous dose group. In terms of the next steps, we really have conducted our interaction with the FDA last year. So we've gotten guidance on the fact that their recommendation was to conduct a dedicated Phase IIb program to start. And so that means that we don't have to conduct an end of Phase II meeting prior to starting this study, which brings in the timelines by approximately 2 quarters for the start of the study. So midyear is what we're planning, and there's no further interactions that we're planning to do before starting to -- to start up for this study.

[Operator Instructions] And our next question coming from the line of Michael Kratky with SVB Securities.

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 that being [indiscernible]?

Sure. As I mentioned and 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. And so I think that, that characterizes their response.

Got it. And then separately, can you just discuss the difference between FVC at week 12 across the different subgroups? And 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. And so 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.

And I think did you ask for Toby Maher to take on that as well?

Yes.

Always happy to give my insights. So 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, that was seen in the BI PDE4 trial that was published last year. If anything that 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. And 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, 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, but I think that, that's very consistent effect on the reduction in number of patients experiencing a greater than 10% decline, provides a sense check of the data we're looking at in the model reflects therapeutic reality. And 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.

[Operator Instructions] And our next question coming from the line of David Lebowitz with Citi.

And congrats on the update. A few questions specifically on Slide 15, if you will. First, when looking at the 320-mg data, both the standard-of-care and nonstandard-of-care subgroups come out around 19. And I noticed in, I believe it was Slide 12 that the, this dose stay -- the mean is 29.5%. Can you just connect what's different about those 2 data points that the Slide 15 numbers fall below the mean?

Certainly. So they are subgroup analyses. And so you can see perhaps best differentiated if you look at the sample sizes between the SoC subgroup, then not on SoC subgroup. And then if you can flip back to Slide 11, you see that the sample sizes are the totality of those 2 groups together. So given that the responses are different between those on standard-of-care and not on standard-of-care and I believe that, that explains the differences.

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 IIb evaluation to be able to accurately assess -- more accurately assess the treatment effect in that population.

Got it. Got it. And also when looking at the placebo, there's quite a bit of variation between the 2 subgroups. Why would the standard of care subgroup actually do so much worse? Has it just been an issue of the numbers and the particular patients in the standard-of-care group?

I think certainly, the sample size has an influence on that. And as you can see, there are 7 in the SoC subgroup. So the inherent variability in that measurement may lead to the differences that we're seeing.

Got it. And lastly, on that chart, as far as the variability across the patients, it seems, for example, the nonstandard of care patients consistent with the 80-mg are having a different response, except for 320 than in the standard of care group. And I guess, again, is this another function of small numbers? Or is there something about this drug that's different when used as a stand-alone agent versus standard of -- being on top of standard-of-care?

I think that 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 the standard-of-care agents. But to Éric's point, it's obviously something that we want to power in our late-stage studies to really delineate that effect on and off of standard-of-care.

Yes. And there's -- just to add to that, there's really no biological rationale for why this drug would perform less well in patients that are not on standard-of-care. So for us, we're really -- as Greg mentioned, getting this on small numbers that really are hard to interpret the data correctly.

[Operator Instructions] And our next question coming from the line of Joseph Stringer with Needham.

This -- our question is for Dr. Maher. Just curious, what is your ideal target product profile for an IPF drug? And how does the bexo data and profile to date check some of those boxes? And then secondly, how would you compare this or how does this compare to some of the late-stage Phase III IPF programs that are ongoing that are evaluating oral and injectable drugs?

Yes. So I think my ideal target product profile. So 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, 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, but if we could genuinely prevent disease decline across the patient cohort, then for me, that would be success. And then I think that the tolerability component is very important. 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. And this is 12-week data, so one doesn't want to jump too far ahead of oneself in interpreting it. But if this played out in a 52-week study, then Bexo comes very close to achieving what I would see as everything I would want from a therapy for my patients. I think just to compare it to other drugs out there, where we've got FibroGen's intravenous drug. So that's less convenient for dosing. And certainly, their Phase II data to my reading was less robust than we've seen with client data. We've got BI PDE4 inhibitor which perhaps were 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 galactose -- inhaled galectin-3 inhibitor, which -- that program has been encountered problems with the DSMB changing study design. So it's difficult to know where that will take us when we see the data later on this year. So 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.

[Operator Instructions] And our next question coming from the line of Ritu Baral with Cowen.

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 8 respiratory failure features around that respiratory failure that would set it apart from, say, an IPF-driven exacerbation and respiratory failure? And then I've got a follow-up about the Phase IIb.

Well, I guess what we can say is that there was a temporal association with that intervention and procedure with an anteceding course that was at least based on unblinding suggesting a treatment response and a super responder. So it appeared that there wasn't an event that -- or progression of the disease prior to that intervention. So temporarily and also supported based on some reports, the intervention that was -- may have been linked to the decompensation.

So the DSMB was...

Yes. Maybe, Ritu, just to add to that, I think the -- just some details on the investigators. So the investigator deemed this event not related to study treatment, but due to the underlying disease. And Greg mentioned how this was a severe patient. It's unfortunate because that patient did so well in the first 4 weeks of treatment, but 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 worsening on therapy. So something certainly to look out for, obviously, in all IPF studies, but nothing here that suggests a drug effect.

Got it. And if I understood you correctly, you said the DSMB did have access to the antecedent report sort of like how the patient was doing from the ablation to day 8 sort of that time period?

Yes. So in addition to monthly evaluation, there is also a formal valuation that occurred, and they recommended to proceed without modification suggesting safety concern.

Got it. And then just moving to the Phase IIb. Éric, what are your thoughts on the patient numbers that you want for this study, understanding that a Phase II is powered differently than a conservatively powered pivotal, which I believe that you hope this could be? And for the last question, I understand the study has remained blinded. We're going to 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? Or do you think that the mechanism suggests there's a plateau between week 12 and 24?

So the first question really on late-stage development. We were waiting for the results for the 320-milligram dose group to reassess the anticipated effect size of bexo. And so this data really gives us quite a lot of rich data to inform that question. So it's, I would say, premature to give you the number of patients that will be in the Phase IIb study. But one thing to mention is that we want to power this Phase IIb study in a meaningful way. So at least 80% power, we want to have a 1-year duration. And we want to have this strong, robust Phase IIb evaluation because we do believe that if we do it well, there is a possibility that it could count as of 1 of 2 confirmatory studies that you would need for the FDA to approve an NDA, to submit an NDA. And so this is certainly a review dependent question. But we want to 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 III study for the NDA. So we'll be communicating on more details because now we'll be focusing on numbers to come back to you with that specific question as we get closer to trial start. And then 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. So that's what we're going to be really interested in looking at. keeping in mind that none of the placebo patients in the prior dose groups will have continued treatment beyond 12 weeks. So the ability to compare with placebo will be somewhat diminished because we'll only have a placebo patients at most going through that time point as well. But certainly, looking at the slope of -- the slope of the curve for the 320-milligram group will be important.

And can you comment at all about the safety that you've seen to date through 24 weeks? And how many patients have made for 24 weeks right now?

Yes. So really, I mean, that's a great question. Thank you for asking it. But we've passed -- most of the patients have passed that 24-week time point now and some have gone out to much longer. So 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 -- 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 today that continue to illustrate the favorable safety profile of this compound.

Ladies and gentlemen, as we pass the hour, I would now like to turn the call back over to Chris Keenan for closing statements.

Thank you. On behalf of my executive team and all of my fellow Pliant peers, thank you for joining us this morning. This is certainly a great day for Pliants' and potentially for patients with IPF. My team and I look forward to sharing updates from across the Pliant portfolio in the near future. Have a great week, everybody.

Ladies and gentlemen, that does conclude the conference for today. Thank you for your participation. You may now disconnect. Goodbye.