Everyone, we're back. We have the Pliant Therapeutics team here, Bernard Coulie, CEO, and Keith Cummins, CFO, for a fireside chat. Maybe I'll kick things over to Bernard to give a brief company overview, and then we'll jump into a Q&A. Bernard, over to you. Thanks, Alex. Thanks for having us. So, we are at Pliant Therapeutics. As you know, Pliant is focused on developing novel therapeutics for fibrotic diseases, and I think most of the conversation today will be really around our lead program, which is bexotegrast. Bexotegrast is a small- molecule inhibitor of two integrins, αvβ6 and αvβ1, which are key drivers in fibrosis Currently, in a pivotal trial, actually a phase II-B, phase III trial in idiopathic pulmonary fibrosis, we intend also to expand into other indications of pulmonary fibrosis, so-called progressive pulmonary fibrosis, to start, at a later point in time, and then we can have a discussion around that. Recently, we also obtained data in primary sclerosing cholangitis, which is a rare liver disease, also progressive, for which there are no, therapies available. So the phase II-A data showed, you know, first, the drug was safe, but also that it's, anti-fibrotic in this very specific, disease- Affecting mainly the bile ducts. And so that's kind of our key asset. We have a number of other pipeline assets. One is in phase 1b testing. It's an oncology asset, again, a small molecule integrin inhibitor of αvβ1 in this case. We have a program that's ready to start in phase I. We have an open CTA, and that's a DMD program, so it's muscular diseases, again, against a specific integrin. And we have a number of preclinical programs focusing on other fibrotic diseases, including, for example, cardiac fibrosis. It's kind of a new target for us. The company itself is basically built on two pillars. So we have this fibrosis platform based on a number of assays that we developed in-house, cell-based, animal model-based, but notably human tissue-based. We do a lot of human tissue work, notably from patients receiving a transplant here in UCSF or Stanford, where we get the disease tissue and kind of basically test our drugs, just to evaluate effect, et cetera, and then our integrin chemistry platform, which is now actually kind of led to a library of over 10,000 compounds that are very much focused on specific integrin receptors, which I think is unique in the world, which also allows us to kind of create new programs or potentially also do platform deals around this specific integrin library. Great, great overview. I did definitely wanna dig into bexotegrast and the path there. I did want to start, though, with, you know, TGF-beta. You know, clearly there's a role of TGF-beta as a central regulator of fibrosis, but, you know, why can't we just target that systemically? And how does that targeting αvβ6 and αvβ1 sort of get around some of those issues of systemic targeting? Yeah, so as you mentioned, Alex, so the TGF-beta is what we consider or call a master regulator of fibrosis. I mean, it's a factor that's very important in normal homeostasis. It's anti-inflammatory. It's important in wound healing as well, but if wound healing goes out of control, basically that leads to fibrosis. And so what happens in specific fibrotic tissues is that there is an overactivation of TGF-beta, mainly driven by the two integrins, αvβ1 and αvβ6. And so if you want to target in a systemic way TGF-beta, let's say, using an antibody or a neutralizing ligand, or a ligand-neutralizing antibody, or a small molecule against the receptor, you will end up with what I would consider as unacceptable toxicities that are related to systemic TGF-beta inhibition. They include cardiotoxicity, a pro-inflammatory phenotype, certain rare skin cancers, et cetera. And this is well known from, clinical practice in the sense that anti-TGF-beta antibodies have been developed and continue to be developed, notably for cancer, where some of those, toxicities are acceptable, I would argue- But not in fibrosis, and so using these two integrins, which are selectively upregulated in fibrotic tissue, as our targets of our drug, allow us to basically confine the effect, the anti-TGF-beta effect, to the fibrotic tissue, rather than having a systemic effect, and so what we have shown over and over again in our pre-clinical talks, in our healthy volunteer work, and now in our phase II-A, phase II-B work in different patient populations, that this approach is safe. We haven't seen any of the typical toxicities related to systemic TGF-beta inhibition. Actually, we haven't seen any major safety or tolerability issues whatsoever, so it seems that we have, although it's, I mean, it's an oral drug, it's systemically available, it really works where it needs to work, being in fibrotic tissue. Yeah, and then drawing that line to then IPF as your lead indication, you know, can you talk about the evidence for upregulation of fibrosis, αvβ6, αvβ1 activity in lungs, that led you to kind of select that as your lead? Absolutely. I mean, we and others have done extensive work in terms of not just showing that both receptors are upregulated in fibrotic tissue and like in lung tissue using different approaches. I mean, biopsies or at least, you know, resection specimens from patients that are undergoing, you know, lung transplant show that these receptors are upregulated. We have shown that, and others again have shown, that the activation of TGF-beta in the lung can be blocked by blocking these two receptors. We have used, you know, bronchoscopy-type of approaches to measure some of the biomarkers that are downstream of the TGF-beta receptor, and where we see a reduction of that specific biomarker called pSMAD, which again indicates that these are the two receptors that are driving the activation of TGF-beta and hence lead to fibrosis. A couple of years ago, we did even a PET study using a PET ligand that is very specific for alpha V beta 6, which was developed at Stanford here. And so using that PET ligand, we showed that in patients with fibrotic lungs, no matter what. I mean, we did initially IPF studies, but we also looked now afterwards at scleroderma lungs and RA lungs, and we see an overexpression of that receptor. So I think the evidence is there. There's a lot of evidence that this indeed are key activators of TGF-beta in the lungs of patients with lung fibrosis. Before we talk about your proof of concept work, I did want to kind of lay out the current state of the IPF market and what really is the bar for a new therapy here. Like, where is this unmet need today, and what do we want to see for a new drug? So it's a great question. I think the situation we are in today, and which hasn't changed in the past decade, but things are changing now, are basically two drugs that have been approved, one of which is generic, the other one will become generic soon. Esbriet and Ofev, totally different mechanisms of action, which have shown, I would argue, modest activity, but don't change the course of the disease in IPF, in the sense that overall survival doesn't change, right? So there's no real clinical outcome in terms of-- or clinical benefit, in terms of effect of these drugs, but they have shown improvement in forced vital capacity decline. The issue with these two drugs is tolerability. In both cases, there'll be different tolerability issues, basically leading to only 40% of patients with IPF actually being treated. 60% of patients are not being treated for the simple reason that or the physician or the patient prefers not to be treated because of the tolerability issues. A persistence rate or, discontinuation rate, which is basically the same, of around 50%, meaning that within a year, 50% of patients will not be on drug anymore, and within those that are still on one of the standard of care drugs or approved drugs, about 40% will have a dose reduction in order to just mitigate some of the side effects, and the side effects are not trivial. I mean, there's you know, very significant diarrhea, for example, with nintedanib. There is liver toxicity, et cetera. So there's a, you know, an immense opportunity in terms of improving, both on the efficacy side as on the tolerability side. And I think this is our focus, has been our focus, showing that our approach has been well tolerated- no side effects whatsoever. Our drug is being described as an easy-to-take drug. In our clinical studies, the physicians, not the patients, know whether they are on placebo or active for the simple reason there is nothing to distinguish between the two from a safety perspective. And again, we have shown a dramatic increase or improvement in forced vital capacity, even on top of standard of care. So that's where the space is. And so what can be done? What can be done is being on top of standard of care because we have seen improvements. So patients that are on standard of care and are happy with that, we can add added benefit with our approach. Patients that can no longer tolerate, we could be the preferred switch. And actually, looking at just a patient population of 60% that is not even being treated, we could be first line, and that's kind of where we see the opportunity. Yeah. And we spent a lot of time, and you spent a lot of time talking about INTEGRIS- IPF, the phase II-A. So maybe, you know, let's talk about kind of the high-level takeaways from both the twelve-week and the twenty-four-week data, and maybe distilling it down to, in your view, the most, you know, compelling evidence of activity that you've generated to date in IPF across that study. Yeah. So the INTEGRIS-IPF study was a phase II-A, evaluating basically four different doses: 40, 80, 160, and 320 mgs over 12 weeks. At the highest dose, we went out to 24 weeks. Primary endpoint was safety, so it was not efficacy. It was not powered to show efficacy. Efficacy was a exploratory secondary endpoint. What we showed first was the drug was well tolerated and safe, so we hit that, which was important. It up to 40 weeks, actually, but you know, within that 24-week window, there were no concerns whatsoever in terms of safety or tolerability. What we also showed was a consistent increase in forced vital capacity at the highest dose and a separation of forced vital capacity in terms of active versus placebo at both eighty and one hundred and sixty milligrams, so across at least three different doses, we see an effect on forced vital capacity, but we did measure a number of other exploratory efficacy endpoints, including the amount of fibrosis in the lung, using a high-resolution CT approach, where we saw a dose-dependent reduction in fibrosis. We saw a reduction in a number of what we call pro-fibrogenesis type of biomarkers, again, consistent across the different doses in a dose-responsive manner, and then ultimately, we also saw a reduction in the number of patients that had progression of their disease by a decline of FVC of more than 10%. And again, that was, you know, in a dose-dependent fashion. So multiple endpoints, all pointing in the same direction of efficacy in a dose-dependent manner. And at 24 weeks, we saw a continuation of the separation between active and placebo, and notably, those patients that were above baseline, meaning had an improved FVC, not just a reduced decline, remained above that baseline. And so it seems that over 24 weeks, and hopefully over a longer period of time as well, that we have an improvement in the majority of patients that remains over time. So there is no kind of continuous d ecline. And I think that, to me, that was the key reason to kind of move to our next study, BEACON-IPF, which is- Yeah, and- Of course, our long-term study. Then a couple follow-ups here. I guess on the 24-week follow-up data, you did have some patients go out to far beyond 24 weeks, right? And I guess my question here is are we completely out of the woods as it relates to theoretical talks with αvβ6 targeting, just given the history of that former Biogen antibody there, in your view? I think we are very much so. We have now up to 40 weeks in our phase II-A. We have now patients getting to 52 weeks in our large BEACON-IPF trial. Because the study has been going on for a year now. And we haven't seen any concerning signals coming out of this. I mean, obviously, we are blinded, but we do have regular DSMB reviews of the safety data. There's no evidence at this point in time, or at least the DSMB has indicated, you know, safe to continue. So, meaning that there is no-- I mean, the key concern would be acute exacerbations. That has been seen in the past with antibodies targeting the same target, αvβ6. Those exacerbations started to appear in those older phase II-B trials. A round week six, with a max or median around four months. We are now up to 52 weeks, and we haven't seen any of that, and so we're testing the highest dose, 320 mgs. So I think from a safety perspective, of course, we want to see the unblinded data and get everybody through 52 weeks, but so far, we don't see any of those concerning events that happened in the past with other drugs. And then on the patient population, the II-A, you know, how important is it to include patients that are on background therapy as it relates to sort of de-risking, you know, the path forward here in your pivotal study? The importance for us is that standard of care is there to stay for a while, right? So by the time we anticipate to be able to go to market, to launch, and or at least to file, which is not too far away, there is still a significant portion of patients that will be on standard of care. That's, you know, give or take 40%. That's a significant portion of the market. So for us, it's important to kind of include those patients in our studies as well, to show that benefit on top of standard of care. At the same time, you cannot take patients off standard of care in your clinical trials. Once your patient is being treated for his or her disease, we cannot stop that. In order to kind of have, you know, from a clinical operations perspective, just making sure that you get your studies enrolled, it is important to have those patients in your population as well. And it also shows the safety of our drug on top of those standard of care drugs. We don't have any DDI issues with our drug vis-à-vis standard of care, so, you know, we are pretty comfortable doing that. And our aim in BEACON IPF is very much to kind of have the two populations covered, those patients that are only on our treatment, and then the patients that are on standard of care, in a I would say 70%-30% ratio, where 70% of patients will be on standard of care. The study will be powered. Ultimately, the phase III will be powered to show effect in both subpopulations separately. That's a good transition. I wanted to talk about BEACON-IPF. Can you talk about the design of the trial and the evolution from the II-B to the sort of II-B/III design and the initial FDA feedback, and then why you decided to change? So the initial design was a phase II-B standalone trial, 52 weeks, 80% power, followed by a phase III. Based on our findings in phase II-A, and based on our strong belief in the safety of the drug, we felt a nd the future efficacy of the drug, we felt, we could justify starting at-risk phase III while phase II-B is still ongoing. The rest of the world, so ex-U.S. regulators, Europe, Asia, were fine with that design, based on the data we submitted, clinical data, tox data, et cetera. The U.S., at this point in time, so FDA is reluctant, doesn't want to do it yet, because there is an overlapping phase, where patients in the phase III will be treated at the time that the phase II-B patients are still being treated. Without having the full view on the phase 2b data. And so from a, what I would say, benefit-risk ratio, the FDA was reluctant to kind of allowing to do that. Not based on our safety, but based on some of the historical concerns with, you know, drugs that are addressing potentially the same target, be it antibodies or other programs in the past that had a pretty aggressive, I would say, moving forward from, let's say, II-A straight into phase III- Where after a year, it turned out to be a major, you know, issue, because actually the mortality increased in the active group, and there was no real view on that. And that's where the FDA felt, you know, a more conservative approach needs to be taken. And this is not unique to us, by the way. If we look at some of our competitors, they go through these larger phase IIs settings, phase II-B, let's say BMS, followed by a large phase III. So in our case, we were at least able to kind of have that overlap in the rest of the world, which is important, because it brings in the NDA timeline with about 24 months, right? I mean, this is like a major time saving, so allowing us to be on the market at a much earlier time point, and being competitive with what we consider as the two major competitors, both Boehringer as well as, Bristol Myers Squibb. So the overall design, coming back to your question, is a phase II-B, which is powered to be pivotal, and the FDA accepted that. And at the time that the last patient first visit, so the study is fully enrolled, at that time, the phase III enrollment will start. It's a separate study, so it's not. It's under one master protocol, but these are two separate studies, independent studies, which is important, because you need two independent studies for approval. And that phase III will be, you know, significantly larger compared to the 360 patients we have in the phase II-B. Power can be adjusted based on 2b data once we see, you know, effect size as well as variability. Yep, and then just functionally, in terms of the phase III initiation, will that initially be all ex-US sites until you read out top-line data for the II-B? Is that correct? That's how it stands today. We continue to have conversations with the FDA to see if there is a possibility to change that, as we are accumulating more safety data. You know, through our DSMB reviews, we get more and more data available. So we continue to have the conversation, but today, as it stands, you know, the situation today is very much phase II-B completed, end of phase II meeting. FDA will look at it, and then patients can be enrolled in the ongoing phase III. Overall, it doesn't have much of an impact on timeline, and definitely doesn't much have. And I think there is a concern about this that we feel is not really warranted in the sense that this is a global trial with a significant portion of U.S. patients. The global trial itself reflects the U.S. population as we are running it in Europe, Asia, the Pacific, and Latin America, which is very much a U.S. population, if you think from a diversity perspective, which is important to the FDA. It's a global endpoint. Change in FVC, you know, from baseline. FVC is being measured in the same way everywhere in the world where we do the study. And so there is no, I mean, there's nothing deviating from a U.S. only study, and in that sense, we feel that this global data package coming out of two studies, a phase II-B and a well-powered phase III, will be sufficient for an NDA, of course, on the condition that we see a significant effect. Yeah. Yeah. And so in terms of timelines here, you've got into II-B full enrollment first quarter of next year, and then top line mid 2026, correct? That's correct. That's the II-B portion in itself, correct? Yeah, and the phase 3 is then on-enrolling in mid 2026. It's enrolling for almost a year. And so depending on the number of patients we decide to finally include in that protocol, could be fully enrolled or will take a little bit longer, but I think the two data points will be pretty close to each other, right? That allows us for, you know, an NDA that is basically kind of 24 months earlier than in the initial plan, where you do a phase II-B, end of phase II meeting, phase III. It allows us to keep our centers open. I think that's the key. I mean, one of the key delaying factors in a sequential study design is basically you close centers, open them up again, and so we have actually our centers still open, treating patients in phase II-B, now kind of starting to enroll patients in phase III, and by the way, there's no preference for one out of the two, because the doses are the same, the duration is the same, and both have a open label extension component to it, so for a patient, it's equally interesting to be part of a phase II-B or a phase III. Totally makes sense, and there's a lot more I want to get to here, but, there's been some recent news in this space that I wanted to get your take on, too, with the positive top-line data from BI's PDE4 program. Curious what your take is on that. I guess some positive news following some high-profile failures. Just curious your view. Absolutely. I think the fact that and BI alluded to it, Boehringer alluded to it in their press release, this is the first positive phase III in a decade. They're right. I think one of the concerns, you know, affecting us, and I think affecting other players in the space, is the predictability or transferability of a phase II-A data set into a phase III success or phase II-B success. Boehringer Ingelheim's data, phase II-A data that were published in the New England Journal of Medicine a couple of months before we disclosed our initial data, showed basically in the same set of patients with the same level of placebo, FVC decline, a slightly less you know, effect on FVC, but still a positive effect on FVC. Their delta at 12 weeks was around 88 milliliters, in our case, 140 milliliters at the highest dose. They had some, I would say, significant tolerability issues from a diarrhea perspective, which is quite specific to PDE4 inhibitors, because that's the mechanism of the Boehringer drug, but overall, I would argue, clear effect in a phase II-A, well-controlled, placebo-controlled, randomized, study, very similar in design to ours, 12 weeks, so that data set clearly reads true into kind of phase III success. But we haven't seen the data, right? I mean, it's just a press release saying that they hit their primary. There's no mentioning of safety and tolerability. There's no mentioning of dose response. There is no mentioning of effect in subpopulations, patients, patients on standard of care, patients, in monotherapy. So to be awaited so we can really kind of start comparing, contrasting and comparing, where we could be and where they are, and I think it, it is important for the patient population. First and foremost, finally, there's something new. Hopefully, it will be better tolerated than what's out there, and we know from a phase II-A that it does have an effect, clear effect on FVC. Yeah, and, you know, obviously we're running out of time here. You know, we didn't get to touch on PSC, path forward there or the pipeline, but I did wanna touch with Keith too, before we let you go, around sort of with mid-2026 top line data with IPF, where you currently stand on cash runway, and how things set up between now and then. You're mute, Keith. Sorry about that. Yeah, thanks, thanks for that question. We finished the quarter with about close to $440 million. In addition to that, we have access to a credit facility for another $120 million. All in, we're funded into 2026 at this point. I mean, 2027 That gets us, you know, three quarters, probably at least past phase II-B data. The assumption there is that we'll start a PPF trial shortly after phase II-B. We are looking at ways to, like, accelerate that, as Bernard mentioned. And we have some BD opportunities along the way over the next couple of years that could generate some non-dilutive capital to further extend the runway, whether that's around the oncology program, the DMD program, or some type of platform collaboration or regional deal. You know, there's a lot of things on the table that we're looking at. So we feel really good about the cash position at this point. We certainly have the runway to get well past data, and we think we can actually improve it. Great, appreciate that. And, Keith and Bernard, I know we're out of time, but, you know, obviously we could spend a lot more time talking about the pipeline and everything else, so always happy to chat with you both. Thank you for joining us. All right. Thank you. you. Thanks, Alex. Thanks, Alex. Take care. Appreciate it. Bye.