Good afternoon, everyone. Thanks for joining us. I'm Alex Thompson, biotech analyst here at Stifel. It's my pleasure to introduce the, Pliant Therapeutics team, Bernard and Eric here. Maybe I'll turn it over to Bernard. Do you want to do a quick overview, and, then we'll jump into some Q&A? Absolutely. So, thanks for attending. Pleasure to be here, and I want to thank Alex and the Stifel team for the invite. So, Pliant Therapeutics is focused on developing novel treatments for fibrotic diseases. Our platform that we use for that are integrin receptors. It's based on small molecules, small molecule inhibitors that are selective for specific integrin receptors, that have good oral bioavailability, have turned out to be safe, safe drugs so far. Our lead program is bexotegrast- Mm-hmm ... which is currently in phase IIb for idiopathic pulmonary fibrosis or IPF. That's a global trial that's ongoing and recruiting and actually, enrolling as we speak. That same molecule, bexotegrast, is also being evaluated in a very rare liver disease, fibrotic liver disease called primary sclerosing cholangitis. And, we recently, announced dose or released dose data. We also had a late-breaker presentation, and Éric probably will talk about that, at, AASLD, earlier this week. And so the initial results that we had seen before in IPF in phase IIa were confirmed again in, in, in- Mm-hmm ... PSC. This is a Phase IIa trial that looked at a number of biomarkers of fibrosis. Of course, evaluated safety in the first place. The drug appears to be safe in this specific patient population that's quite different from IPF, but also we see significance at the higher dose and, and actually across all the different doses we have tested, we see effects on a number of different biomarkers. So again, that's an additional indication that can be covered by- Right ... by this drug. In terms of next steps, we're probably going to discuss that- Yeah ... during the Q&A. So- Yeah, I know, and that's a great overview, and we'll definitely dig in a little bit more. But I did want to take a little bit of a step back here and talk about the mechanism for bexotegrast, you know, the rationale specifically for targeting alpha V beta six and alpha V beta one, and sort of tying that then into IPF as your lead indication. Right. Maybe if you could start... I don't, I don't know which one of you wants to jump into that, but let's, let's start there. I can take care of the biology. So, exactly right, Alex. So the bexotegrast is a selective inhibitor of two integrins, alpha V beta one and beta six. Integrins are receptors that connect cells with the extracellular matrix. In this case, alpha V beta one and beta six are selectively upregulated in fibrotic tissue. So they're in normal tissue, normal organ systems, their expression levels are low or absent. Why are they important? They are important because they are activators of latent TGF-beta. Mm-hmm. So TGF-beta is being secreted into the extracellular matrix, remains latent, kind of it's tethered in that extracellular matrix and is being activated by these two integrins, which leads then to active TGF-beta binding to its receptor and then activation of the pro-fibrotic cascade because TGF-beta is the key, I would say, modulator, the master regulator of fibrosis, in, in, in fibrotic tissue. So how does that tie to IPF? Both receptors are overexpressed in IPF patients. We and others have shown that. So by blocking those two receptors, we selectively block TGF-beta overactivation in the lung, and so which leads to an anti-fibrotic effect in IPF that we have seen and that we have, you know, seen based on biomarkers, that we have seen based on imaging, and that we also have seen based on measuring actually the pivotal endpoint, which is forced vital capacity. In PSC, the story is exactly the same. Both alpha V beta six and beta one are overexpressed in bile ducts and the liver in patients with PSC. By blocking those, we see a very strong, potent anti-fibrotic effect. Key here is the safety because- Yeah ... these receptors are not expressed in normal organs, so you don't touch TGF-beta signaling in other organ systems. So we haven't seen any toxicity preclinically or safety issues related to TGF-beta in the patient, which are well known- Yeah ... from the oncology space. Yeah, you're anticipating a lot of my questions, but yeah, like, I do want to dig into more of that too. But I, you know, I think starting with IPF, you know, you presented phase 2a data, you know, I guess last year and then early this year, you know, at 12 weeks across, you know, all 4 of your dose cohorts. You know, and I think there's a lot of focus on FVC there, obviously, across those cohorts. You know, I guess, given that the pivotal trials in IPF are 1-year studies, what was really the main goal of the phase 2a as you think about it? And then maybe with that, what are the key takeaways in IPF from that, at least the 12-week data so far? Yeah, I mean, I can take it from here. I think the, you know, really to remind the audience, this was primarily... The primary endpoint was safety and tolerability- Yeah ... of bexotegrast. That was important, for us to, to really do a thorough dose ranging and, and really support the, the safety profile of the compound. And then as a secondary endpoint, we had PK, and then at exploratory endpoints included FVC, but also additional biomarkers to, to really highlight the anti-fibrotic properties of the drug. And, you know, when, when we think about the, the results, I think we've, we've seen, as Bernard mentioned, really favorable safety profile, in a vulnerable patient population. Let's, you know, remind the audience also that- Mm-hmm ... these are older patients with that have a lot of cardiovascular comorbidities as well. So, the fact that it's been well-tolerated there really supports its continued development. But in addition to that, we saw in using biomarkers that were based on imaging or blood circulating biomarkers, we supported the anti-fibrotic properties in patients as well- Yeah ... in addition to the FVC changes, and this is something that we had seen preclinically as well. Yeah ... so for us, I think that trial really gave us everything we needed to move forward. Yeah ... and going to late stage. ... I think, I think your answer might be the totality of the data. But if you had to pick sort of one key piece of data across the dose range in the 12-week study, like what, what do you think is the most compelling, you know, data point that supports the signal there in IPF? Yeah, there's two I would say. First, the FVC percent predicted- Yeah is a method of assessing FVC, but correcting for body habitus differences. That's especially important in a small trial. And this is where we saw the really clear dose response, with the patients on 320 milligrams- Yeah - seeing no progression at all, from that perspective, so that was pretty impressive. And then combining that with also, the QLF scores- Yeah ... which is a measure of fibrosis in the lung using a high-resolution CT scan, continued to show that there is evidence to support that the halting of the progression of disease- Yeah Certainly over a 12-week period. So for us, I think these were really two compelling data sets from an efficacy perspective. Then you ended up with the 24-week data for the 320 milligram dose. Kind of, what were your key takeaways from looking out to 24 weeks in that dose cohort? Yeah, so the first, keeping in mind that this was a safety study- Yeah - primarily, continuing to see the safety profile, the favorable safety profile being manifested over the long term. Mm-hmm. We really did that at that top dose because we wanted to support late-stage studies- Yeah and we need to have some long-term evidence, and I think that the drug really delivered well on that front. The other assessment we wanted to see is how durable was the treatment effect. And when we look at patients on bexotegrast at that dose level that saw an improvement at 12 weeks, 89% of them remained above baseline, so they still had an- Yeah ... improvement at 24 weeks. And that really goes in line with the hypothesis that we could stabilize disease much more than what you see currently with the approved agents. Yeah. For us, I would say that, you know, these two findings were the key ones to report on. Then I guess, you know, the question on safety, given the history, I guess specifically with the Biogen antibody against alpha V beta six, are we out of the woods from a safety perspective at this point? I think, I think we've done significant de-risking for bexotegrast in terms of its safety evaluation. We, you know, we have over 600 study participants that have been dosed with bexotegrast to date. We have the IPF patients at the top dose that went out to up to 40 weeks, so 40. Yeah. We saw really good safety there. We also have reported on our PSC population- Yeah ... keeping in mind these patients come in with pre-existing liver disease, so notwithstanding of our agent, they're more likely to experience things like drug-induced liver toxicity and things like that. We look for that, obviously, because the regulators want us to look for that. We haven't seen anything preclinically, but there was really no signal whatsoever from that front. So when you think about, you know, having great data in healthy volunteers, but also having clinical data in patient populations that are considered vulnerable, really supports the favorable safety. So, you know, we'll obviously have- Yeah ... more data as we really conduct the phase IIb study in IPF, but I think we're in a really good place now. Yeah, and I think that's a good transition to the BEACON study. I guess, can we talk a little about the design of the BEACON study, how it compares to contemporary studies in the space? You know, as well as some of the questions around powering and geographic site distribution. Yeah, so it is a global study, the BEACON study. It is evaluating two different doses, the 160 and 320 milligram doses, compared to placebo. The primary endpoint of the study in this situation is efficacy. Yeah. We're looking at the approvable endpoint that's used in pivotal trials. The study is powered at for at least 80% to show a difference between active and placebo. We're also including a key secondary endpoint, which is time to disease progression, using the usual criteria that are seen across pivotal studies as well. The other point to mention, we will be increasing the subgroup of patients that are not on background therapies to 30% in our study, at least 30%. We'll start generating some really compelling data from a monotherapy perspective because we believe- Mm-hmm ... this drug, with its favorable safety and efficacy, could really be positioned in that, that line. And then I would say that, you know, it really has the, the attributes of what you would see for a pivotal study. Yeah. And so therefore, we believe that there's a likelihood that after conducting this study, if the data's positive, that it would count as part of the one of the two pivotal studies. Yeah. Obviously, this is an end of phase II discussion- Yes. Yeah, yeah. Yeah, yeah. ... it's depending on the data, but it would put us in a situation where we would have one dose to study in a single phase III study. Have you commented at all publicly about powering assumptions? We have not disclosed what power assumptions we have used, but I can comment on the fact that, you know, looking at the 24-week results- Yeah ... of the 320 milligram cohort, that the effect size that we saw, that is something that we're looking to replicate- Yeah ... at week 52. So we have not made any very aggressive assumptions that, for example, the placebo group would continue to decline at the same trajectory that it did over 24 weeks in the IPF study, the INTEGRIS-IPF study. We've also included, ... in our study, the ability to re-estimate sample size based on a blinded review of the standard deviations for FVC we're seeing. So for example, we've also been very conservative in that approach. Mm-hmm. But if we see that we would need to upsize, for example, the study, to account for more variability, we would do that as well. And so, I mean, I think that we're really in a position to have a positive study with all the attributes we're putting in, in this, the safeguards. Are you sort of, it sounds like, are you powered around the 320 milligram effect size, or are you also powering around to potentially hit on 160 as well? We're powered to any one of these doses would have at least 80% power. Okay. The effect size was primarily considering the 320 milligram dose. Okay. Can you talk a little bit about enrollment and how that's been going? And then maybe, you know, at what point do you think you would be ready to guide top-line timing? Yeah. So we're right now enrolling, well. We are activating more and more sites every day. And you know, we haven't revised our guidance in terms of... We expect that the study will be enrolled in a year or less. Yep. Reminding you that we started enrolling this summer. Yep. Right? So, in as we move forward in the months ahead, we'll have more of a real-time characterization of the true enrollment rate, then we'll be able to, you know, provide guidance. Yep ... there. But currently, all the activities are on track, and I could tell you that it's all hands on deck for enrollment of BEACON-IPF. Yep ... at the company. Great. I, I guess, you know, thinking maybe a little bit more longer term, you know, there is some competition in this space, you know, in, in phase II and phase III. How are you thinking about the IPF landscape over the next five to ten years, and, you know, how is bexotegrast product profile sort of playing out from a competitive perspective? So, if we look at the overall IPF landscape, we and others anticipate the market will grow to a $6 billion-$10 billion market. Mm-hmm. Mainly US, but, you know, the number is global. This expansion is driven by both, you know, organic growth, I would argue, in terms of incidence increasing and, I mean, aging population, but also by volume growth. Because with new agents like ours coming on the market, we anticipate that notably, like, persistence rates will go up dramatically. Yep. The issues with the existing standard of care drugs right now is, you know, you know, persistence rate is somewhere between 50%-70%. Yep. Right? And then there is a switch, and then you have another issue. I mean, the tolerability is terrible. And so with newer agents, we anticipate patients will just be on drug longer and will probably go on drug faster because... Still, because of the tolerability issues with standard of care, there's always some hesitance whether or not or a delay in putting a newly diagnosed IPF patient on treatment. So how do we fit into that? We anticipate to be first line- Mm ... as mono or add-on. And in case of second line, in terms of switch to or add on to another existing drug. And so the add-on or the combo could be both the existing standard of care drugs, Ofev and Esbriet, but also with potential new entrants like the Boehringer Ingelheim PDE4 inhibitor, or the BMS LPAR1 blocker. Our mechanisms are perfectly, you know, complementary, so that could work. We have no or very low DDI potential, so we anticipate combination is not an issue. Obviously, we are doing it in our BEACON-IPF trial with a standard of care. We anticipate that in terms of the generics appearing now, I mean, Esbriet is generic. Yep. Ofev will become generic. If we look at what is happening, we don't see an increase in utilization. Yep. Price was never really a barrier anyway. Yeah. It's more tolerability, that's the barrier. So we will see conversion from branded to generic, but we not anticipate the generics to expand. And we, based on our market research, the future, the drive of that $6 billion-$10 billion market will be novel oral therapeutics. Yep. So that's us, BI. BMS. BMS. Inhaled IV, I mean, IV probably not anymore- Yeah ... because FibroGen has stopped, but inhaled like Tyvaso and maybe other, efforts that are ongoing in the clinical development space, will be just single-digit numbers in that, you know- Yeah ... in that overall percentage of, you know, utilization, which will be driven by novel oral ones. I guess, you know, we don't need to get into the nuanced differences in mechanism, but between, you know, BMS, Boehringer, and bexotegrast, like, what would you highlight as sort of the key, you know, key differences, at least in terms of the data sets that we've seen so far? I mean, first, ease of use. It's a once a day, once-daily pill. Yep. Both BMS and Boehringer is twice daily. I'm not sure if that's a big player, but, you know, at least it's different. Safety. Safety and tolerability, this is so critical. We know that from the existing, you know, prescription kind of dynamic in terms of standard of care today, we have nothing so far. Yep. Both Boehringer and BMS have a little bit of an issue. Boehringer's PDE4 inhibitor causes diarrhea. Yep. That's on top of Ofev, which causes diarrhea as well. So we've seen that in their Phase 2a, where we saw pretty high dropout rate because of diarrhea. Yep. So how are they going to manage that in their 52-week trial? We don't know, but it's something that is different compared to us. BMS, although they downplay it a little bit, but they have hypotension. Yep. And that was something that we were aware of, but didn't really appreciate what the impact was. But, talking to investigators, study sites that are, you know, have participated in their phase IIb trial, we, we saw that that is an issue. And also, don't forget, if you look at the phase IIb data from Bristol, so the LPAR1 antagonist, on top of standard of care in IPF, the effect is very modest. Yep. Very modest. Yep. It was a well-powered Phase IIb. We don't anticipate that that will be much different in their Phase III. Okay. Well, I wanna spend the rest of the time here talking about PSC. Maybe if we could talk just briefly about the mechanistic rationale there, and then I wanna get into kind of the feedback that you heard at AASLD. So mechanistically, it's very similar to what happens in IPF in the sense that PSC is a disease driven by bile duct fibrosis, right? So what happens in the disease is that, fibrosis starts around the bile ducts, both extrahepatic and intrahepatic. What happens is the bile ducts will be literally squeezed. As a consequence, there is a blockade of bile flow, so bile will reflux into the liver, will ultimately destroy the liver, which leads to cirrhosis. And that, that's as simple as it is. It's a 10-15-year course. The only option, the only option patients have, there's nothing approved, is a liver transplant. Mm. But the disease tends to come back because it's actually an autoimmune disease. 70% of patients have IBD as well, inflammatory bowel disease, so a lot of other medication that they're taking. Notably, the IBD medication doesn't change the course of the disease whatsoever. Mm ... which is interesting. And the mechanistic rationale from our perspective, alpha V beta six is expressed on injured cholangiocytes and initiates that periductal fibrosis, and then alpha V beta one is expressed on activated hepatic stellate cells, which are driving the liver fibrosis. So by blocking both, we block both the origin of the disease as well as the consequence of the disease. Yep. So you've recently, you know, presented some of your 12-week data across the first 3 dose cohorts. Had some of that presentation last week as well, I guess. Can you talk about kind of the key takeaways from the initial data, you know, any feedback that you heard at the meeting, too? Yeah, I think it was a really proud moment for Pliant, but also the indication—the whole field to see such a presentation at the late-breaker sessions. Mm-hmm. It was also talked about at the wrap-up sessions as well, for the meeting. I think what really resonated with PSC experts and hepatologists was really that we saw good safety, again- Yep ... confirming the safety profile that we had seen in other populations. But we also have really been able to showcase a true difference between active and control in each of the assessments that was done. So that's looking at safety. We're looking at basically the biomarker fibrosis biomarkers such as ELF and PRO-C3. We've seen differences in itch, which is a symptom of P- that's associated with PSC as well. And importantly, we had a substudy in INTEGRIS-PSC that looked at MR imaging, and we were able to see basically more... We used a contrast agent that was called gadoxetate, and we saw more enhancement of the liver with bexotegrast, suggesting that the hepatocytes seemed to be healthier, and also more excretion of the contrast agent and a shorter time to reach the common bile duct of that com- Mm ... that contrast agent, suggesting improved bile flow. So altogether, I think that the, you know, the KOLs were really impressed by the comprehensive assessment that we did in our study, and also that treatment difference between active and control- active and placebo, that was, really manifested throughout. And so similarly to IPF, you're now gonna have twelve-week data for the 320 milligram cohort in the first quarter of next year. You know, what, what do you wanna see out of that readout to further, you know, you know, you know, push forward this hypothesis additionally? I think with the great results we've seen to date- Mm ... at the lower doses, having something similar potentially to the 160 milligram would be a win. Is there a reason to believe that there wouldn't be a dose response in this case? I think that was a question with the IPF 320 cohort, too. I mean, the one question we have is how discriminate circulating biomarkers are- Yeah ... to discriminate for dose response or... That's something that's unknown, right? Yep. I think we need to keep that in mind. But in our minds, if we see that, you know, in terms of ELF, PRO-C3, continue to see the difference in imaging, adverse events and what have you, I mean, this would really make a really good case for it to be considered also as a dose to evaluate in late-stage studies. Yep. We're planning to, once we get the results in the first quarter next year, we will put together a package to- Yep ... engage with regulators and talk about late-stage planning. Yeah, I think that's one of the questions with PSC. So there's nothing approved, right? And so the flip side of that is that the regulatory path is a little bit less clear as well. So what is your current understanding of what actually a pivotal path could look like in PSC? The best place to look is really at what's been done in phase III to date. Yeah. So there are two trials. Gilead had a trial of their FXR agonist, cilofexor, that was terminated for futility, but had a histology-based endpoint, which was defined as no progression of fibrosis stage. And, Dr. Falk has a derivative of Urso or UDCA that they're testing in Europe- Yeah ... and has the same type of endpoint. So we're assuming that the base plan would include histology Yep ... pre- and post-treatment. The way it's been done to date is two years of treatment, pre and- Yeah ... and you look at differences pre and post. But we also would augment our trial design by including non-invasive, such as ELF- Yeah ... potentially PROC3, potentially imaging as well. Obviously, FibroScan measures that would, you know, further support the treatment effects. And in the setting of, let's say, a favorable effect on, on all these biomarkers and, and histology, and with a good safety profile, you would see how I think that could be a really compelling case to regulators to get your drug approved on, accelerated approval. So it's something that- Yeah. We're, you know, obviously, there's a lot of assumptions here built in, but we do believe there's a good plan moving forward to put together. And then I guess, you know, obviously, there's been a lot of parallels between PSC, you know, the development and then the IPF development. Would you be in a position to start a phase III trial around middle of next year, too, like you did with IPF, following the 33/20 milligram data? Oh. Yeah. I mean, this phase III can be done. Yeah. I think the way we look at it from a business plan perspective- Yeah is very much doubling down on BEACON-IPF Yeah and making sure we commit our resources to that Yeah -in order to get it fully enrolled and have sufficient, buffer after- Yes, yeah -data come in. So we can start the PSC trial, but we couldn't finish a 24-month phase III trial, obviously, within that cash window. So, what we will do basically is we will look at the 320 data. We will have the conversation with the FDA, and if the development plan or the regulatory path is clear- Yeah and feasible, then we can only start to study when we have additional cash. Yeah. Okay. Additional cash will come from non-dilutive sources. I mean, obviously, in this market, it's, it's not advised- Yeah -to raise capital. Yeah. Okay. So, we have a number of earlier stage programs that- Yeah were always there as kind of a plan B in case of bexotegrast not making it. I think to a large extent, we have de-risked that asset. Yeah. We have some earlier stage assets that definitely could provide that non-dilutive cash to partnerships. Yeah, that's a really interesting point. I think, you know, I guess to the point of a clear regulatory path, is that really a green light from FDA for potential accelerated approval, in your opinion? Well, the path is already there for accelerated- Okay -approval, but I think the real question is also, can we think about combining non-invasives with histology as a primary endpoint? Yeah. That's something that the EMA, the European Medicines Agency, has opened the door to. We know the FDA is also thinking along those lines, so we want that confirmation. Okay. You could imagine, for example, that it could be a certain amount of improvement in ELF with no worsening of fibrosis, right? That could be a composite endpoint. Yeah. Really, it's about exploring that because we believe it would also help us to discriminate the treatment effect a lot more than just relying on histology alone. Yeah. Okay, and then you mentioned sort of, you know, non-dilutive financing, and I think that's a good pivot towards your earlier stage pipeline. You know, can you give us a brief update on where you're at with your oncology and your DMD programs at this point? Yeah, absolutely. So the oncology program is enrolling well, so this, these are all comers, patients with tumors that are resistant to anti-PD-1. We look both at mono and combo, not from an efficacy perspective. We are focusing on safety first. Yeah -because it's a phase I, PK, as well as a number of circulating, you know, biomarkers that are evidence of biological activity. So we're going through all the different cohorts right now. We anticipate to provide updates in terms of data in 2024. Mm-hmm. And so this is a program that is definitely, you know, up for partnering. Yeah. Interestingly enough, there is one program ahead of us, which is an alpha V beta eight antibody- Yeah -by Pfizer, and we saw that they moved from phase I to phase II in a recent pipeline- Mm-hmm update, which means that they have seen an effect, right? Yeah. That's interesting. Awaiting those data to be, you know, presented at some point, but that supports our hypothesis. The DMD program is towards regulatory filing in first- Yeah -quarter, but again, is a program that that's potentially, you know, available for partner. Okay, great. I think finally, you alluded to cash runway a little bit. What's your current guidance and what's embedded in those expectations? So the guidance hasn't changed. At the end of the quarter, we had about $523 million, so well funded, which brings us into second half of 2026. Yeah. Assumptions embedded in that is basically all the different programs moving forward. Yeah. No non-dilutive cash coming in, so we have a lot of potential levers to pull in order to extend that cash runway if need be. Yeah, and you're still expecting 12+ months of buffer between the BEACON top line and, and second half 2026? Yes. If the enrollment... You know, if we get it fully enrolled in a year, that means that we could have data in, let's say, around second half 2025, then that would be a year of cash, yeah. Okay, great. Well, thank you both for joining us. Appreciate it. Thank you. Thank you.