Good afternoon, everyone, and welcome to the Pliant Therapeutics Fireside Chat here at the Oppenheimer Healthcare Conference. I'm Jeff Jones. I'm a Senior Analyst here on the Biotechnology team, and I'm thrilled to welcome the CEO, Bernard Coulie, and the Chief Medical Officer, Éric Lefebvre. Welcome, gentlemen. Thank you very much for taking the time to join us this afternoon. Thanks, Jeff. To start off with, for those who aren't familiar with the story, can you give us a quick overview of the company, and in particular, your integrin targeting technology platform? Absolutely. At Pliant, we have been really focused for the past, I would say, six years on developing novel treatments for fibrotic diseases. Integrins are key drivers of initiating and propagating fibrosis as they are expressed on certain cell types and interact with the extracellular matrix. Notably, two specific integrins called αvβ1 and αvβ6 have been shown to be key drivers of fibrosis. In order to drug those specific targets, we developed a platform that both is focused on, you know, testing these compounds in fibrosis-specific assays, as well as developing chemistries, small molecules against these integrins by screening them in a high throughput platform. We have come out with a number of compounds, including our lead compound, coming out of that library that are highly selective for specific integrins driven by, I would say, the biological hypothesis, as well as having proper PK characteristics, which historically has been a challenge with small molecules that are targeting integrins. Notably, we have accomplished high oral bioavailability, low clearance, and as a consequence, we have drugs that are active at low doses, even in the setting of once-daily dosing because of a long half-life. I think it's worthwhile to spend a little bit of time talking about the biology of the integrin family. Mm-hmm. As you note, there are integrins with roles in specific diseases, and you have, you know, really an, a nice chemistry platform for targeting them. You can you highlight a little of the biology of the integrins and how that's relevant to, tissue targeting in fibrotic or other diseases? Absolutely. Let's come back to the two targets that are addressed by our lead program, bexotegrast, which are, as I mentioned before, αvβ1 and αvβ6. Both receptors do exactly the same thing, except they do it on different cell types. Both receptors are upstream activators of TGF-β. TGF-β is the key, I would say, driver, the master regulator of fibrosis. αvβ1 and β6 are selectively upregulated in fibrotic tissue. This is how fibrosis happens. It's like these two integrins activate TGF-β. As a consequence, you get fibrosis, and actually, it's a forward kind of activating mechanism because TGF-β induces more of these receptors. What is unique about these two receptors are that they are uniquely overexpressed in fibrotic tissue and absent in normal tissue. This allows us to address specifically overactivation of TGF-β in fibrotic tissue if we can block those. What happens is, with our drug, we block these two integrins, and as a consequence, TGF-β levels go down, and fibrosis. I mean, that's how anti-fibrotic activity is being generated without touching TGF-β signaling in normal, I would say, unaffected, organ systems, which allows us to make it safe because we know that systemic inhibition of TGF-β leads to unacceptable toxicities, and this is known from the oncology field, unacceptable toxicities in patients with fibrosis. αvβ1 and β 6 are super important in IPF. They have been shown by us and others to be upregulated in fibrotic lung tissue, and the same in PSC tissue. Both in liver as well as in bile ducts, we see that both receptors are upregulated, hence the choice of the two indications for our lead program. In oncology, there's another player, αvβ8, which is expressed on immune cells and tumor cells. Has no real anti-fibrotic activity, but it is important in activating TGF-β as part of, I would say, immune exclusion in response to checkpoint inhibitors. Blocking this will prevent the development of resistance against checkpoint inhibitors. This is kind of the driver of our oncology program. Great, I think you touched on, but maybe expand a little on the, as you noted, you've looked at tissues, and tissues of patients with PSC and IPF and been able to evaluate your molecules in those tissues. I think that's a really unique aspect to some of call it your technology platform, your ability to access those tissues and do studies in relevant diseased tissues versus just animal models. Yeah, exactly. It provides kind of a bridge to, you know, a system to bridge the gap between an animal model and a patient situation. To your point, we do a lot of our research and drug screening on human tissue from patients with IPF or with liver fibrosis, with PSC, but we're talking about fresh tissue. Basically, there's this tissue that comes out of our neighboring academic centers, notably Stanford and UCSF, where we have a collaboration that anytime a patient is being transplanted, let's say for lung fibrosis in the case of IPF, that we get a piece of that explanted lung, which is highly fibrotic, by the way, because these are end-stage disease patients. We kind of rush back to the lab, do these precision-cut tissue slices, and it allows us to study our drugs for a couple of days. We can keep this tissue alive for a couple of days, and allows us to kind of test our drugs, do those response compared to standard of care, compared to other competitor molecules, and really kind of establish the effect of the drug in the real kind of actively fibrosing tissue of patients versus an animal model. It's remarkable how some of, you know, I would argue the dose responses and the IC50s that we kind of generated out of that are almost overlapping or identical with what we see in terms of dose response in the clinical setting of a Phase II-A study. Right. No, I think that's a really useful tool if you can get it, and most people can't, so great to have in your case. Let's talk about the lead program, bexotegrast. That's obviously been a key driver behind the movement in your stock since the data came out last summer in more recent updates. As we've talked about, you're pursuing two indications with IPF being the most advanced. Can you give us a little bit of background on IPF, the patients, and current therapeutic options, and why this indication is your first indication? Yeah. Yeah. In terms of unmet need, I think, you know, these two therapies, Ofev and Esbriet, were a real advancement in IPF, back when they were approved about 10 years ago now. It's, you know, they've been approved by the fact that they were able to slow the decline in forced vital capacity or lung function in these IPF patients by about half compared to what no drug would provide. That was a really big advancement, and, you know, at the time was really explaining also the uptake of these drugs. I think that since time has passed, people have seen also that unfortunately, a substantial proportion of the patients are either concerned about initiating treatment because of the tolerability profile of these agents, and some will initiate treatment and unfortunately cannot continue treatment because they're suffering from too many side effects. I think that coincides also with the fact that if you're not improving a disease, but you're only slowing down the disease, then, you know, you're probably less likely to be willing to get to go through the side effects there. We think there is an unmet need in both in terms of efficacy, but also in terms of safety. From an efficacy perspective, having a drug that would stabilize or potentially even improve lung function in IPF patients would be a huge advancement for the field, or having, you know, drugs that are better tolerated over the long term and that most patients can continue treatment for an extended period would be really beneficial. We think this is where bexotegrast has the potential to provide a really new therapeutic agent in the setting of IPF therapies and advance, you know, the number of agents that can be considered that indication. Certainly happy to have seen these great results from our INTEGRIS-IPF study. Speaking of those results, one of the key factors in IPF and the way you've looked at your phase IIs is the use in phase II of FVC, and the relevance to that as, you know, a regulatory endpoint, essentially. Can you touch on the data you've seen to date in your phase II? You know, it's also worth pointing out that, you know, slowing the decline of FVC and where these patients end up, this is really a lethal outcome for them, or they end up in lung transplant. This is when you say an unmet medical need, the outcome, if you're not able to treat these patients is, you know, very substantial. No, that's absolutely right. Just going back to the highlights of our INTEGRIS-IPF data, we saw some really strong evidence in the disclosure we had in July of 2022 that bexotegrast was able to provide an add-on benefit on top of standard of care. We had a population of patients that were predominantly on these agents. I mean, 80% of them, approximately. In a 12-week period, we're able to see either a reduction of the decline or even stabilization of disease across the doses we studied. We had also reported on a responder analysis. Not just simply looking at a change in forced vital capacity in terms of milliliters, but also in terms of FVC percent predicted. That was really striking in terms of the dose response, and again, this was true for the more recent set of data that, you know, where we showed the 320 mg data. We saw no progression based on that FVC percent of predicted change of 10% or greater in that dose group. You know, this is maybe a less understood endpoint, but it's certainly meaningful clinically because it does correlate with progression of disease. But it's also part of the information you find in the label of approved agents because it is studied as part of the clinical outcome measures. Where this, where this endpoint is interesting is also that it adjusts for the body habitus differences across patient populations. In a small study, if you correct for age, height, race, and gender, you have the ability to normalize the results and better interpret them. That's really where I think the most striking results were in that endpoint here. In terms of FVC change from baseline, the 320 mg outperformed the lower dose groups because we had an increase at week four, and that increase continued to manifest over the 12 weeks of treatment. It was statistically significantly different than placebo across all these three time points. That was pretty impressive. We reported on the biomarker data looking at lung fibrosis. We had a very little progression or no progression at 160 mg and 320 mg doses. Strong effects on fibrosis biomarkers, PRO-C3, that were dose-dependent, and also evidence of target engagement by measuring integrin β6 levels. The two top doses overall performed the best in the INTEGRIS-IPF study. Happy to report that there were no dose relationships for adverse events, the drug was really well-tolerated across all doses as well. Really everything we need to advance the program into late stage. I think you've been touching on a couple of times, this issue of tolerability and the challenge that patients have today with current standard of care and tolerability and the potential for your compound and some of these newer therapies to be combined with standard of care and how that's a challenge. Would you mind just highlighting the challenge with current standard of care in the AE profile there? As you know, the very clean AE profile you've observed to date, really the diarrhea signal being critical in these patients given current standard of care, and how that, you know, positions you competitively versus what some other things or some other programs are showing today. Yeah. Some of these Adverse Events seen with the approved agents, I mean, GI side effects are pretty common, especially with Ofev. It is, it is this 62% incidence if you go to the label of that drug, so it's meaningful. To the point that physicians are talking about these side effects when they put patients on drug. There's also some risk for flare-up in terms of liver biochemistry results and even rash, photosensitivity or some of the Adverse Events that you see. I think overall, it's this, we are aware that there's approximately 30% of patients or higher that cannot continue treatment for the long term, so that limits the ability for these treatments to be effective. In our experience, that is significant, substantial for bexotegrast. We've treated over 600 study participants to date. That includes healthy volunteers and also phase II patients coming from our IPF study and also the PSC study. We continue to see really a favorable safety profile with really mild headache and mild constipation being the top two AEs that we see overall and very few discontinuations over time. This has been a particularly interesting profile when you think about, you know, the existing therapies and along with the efficacy signal we saw in this study really suggesting that this drug will have a good benefit risk profile, right? That's really what you want in these vulnerable patients. You know, sort of next up for you guys coming later next quarter, but next quarter starting in two weeks, is the 24-week data, longer term at the higher 320 or at the highest dose tested to date, the 320 mg. Clearly really important given the given these patients are definitely treated for a long term. You know, can you speak to why that's important as we look to the plan towards the phase II-B and the phase III? You're hitting the nail on the head. The reason why we did this long-term extension or long-term treatment at the 320 mg dose because we wanted to have long-term safety data to advance that dose and the lower doses into late stage, right? For us, it was really important to look at that long-term tolerability. Happy to report that, you know, there's really no new information, at least from the blinded review of the data, that changes anything to the favorable benefit risk profile that we're seeing with bexotegrast. We'll have now a much more robust assessment of the safety for long term, because at the previous disclosure in January, we were censored to the adverse event data up to week 12. We reported all the SAE information, but now we'll have, you know, everything that happened in terms of adverse event in the trial. Really good information there. Right, you know, knock on wood, but certainly for us, the 320 and the 160 make it to late stages because of, you know, the profile to date. In terms of the particularity of this next analysis that we'll report on, each of the dose levels in the INTEGRIS-IPF study had their own placebo cohort inside of them in a 3-to-1 randomization from active to placebo. There's a total of eight participants that were randomized to placebo in the 320 mg dose group. What we'll see in this final analysis in Q2 are these eight patients on placebo, how they evolve over time in terms of their change in forced vital capacity, change in QLF biomarkers, and then comparing that to the 21 patients who were treated with bexotegrast 320 mg. It will really be the first time where we see this subset separated from the rest of the placebo cohort and looking at how both different treatment groups evolve over the long term. Right. This then feeds into the Phase II-A study. Can you just sort of highlight how you're thinking about that study, number of doses, how long you're following these endpoints? Yeah. Really we're putting this trial in the best potential setting to potentially count as a part of the registrational package, potentially as one of the two confirmatory studies, by giving it the same primary endpoint as you know, the approvable endpoint. The change in FVC in terms of milliliters. We'll have key secondary outcomes of the clinical outcomes that you see also in registrational studies. We'll have at least 80% power to show a difference. We're bringing in two doses, the 160 mg and the 320 mg doses, to treat for 52 weeks, which is also the standard in IPF therapies. We'll have about 30% of patients not on standard of care, and 70% of patients on standard of care. This is how we're building this study. We'll also have include biomarkers similar to what we had in our phase II-A study, and also QLF as a secondary endpoint. Got it. That's looking to start, mid-year effectively? That's right. That's right. Right around the corner as well. Now for the second indication, again, for bexotegrast, PSC, primary sclerosing cholangitis, you announced some updated information today, started dosing patients at that higher dose. You haven't talked a lot about the study, so it's probably worth refreshing on PSC generally. Again, a little of the biology and why this is an important indication, and then we can talk about the phase II. Yeah. In terms of the biology, it's very similar to what Bernard Coulie was mentioning before. Fibroblasts in the liver express, and these are mainly derived from activated hepatic stellate cells, they express αvβ1 to activate TGF-β. The cholangiocytes that line the inside of the bile ducts will express αvβ 6 upon injury, you know, that's coming from the cholestasis in a way to activate TGF-β. That indication was selected by design. There are no approved therapies at all for the treatment of PSC, there's a very high unmet need, and a higher recurrence also when some of these patients, when they progress to cirrhosis, you see with following a transplant, you have about 20% recurrence. It is, therapies are really urgently needed. For our program, our IPF, or sorry, INTEGRIS-PSC program, we're evaluating very the same doses as we have in our, the IPF study, so the 40, 80, and 160 mg to be precise, and these dose groups will be treated for 12 weeks and compared to placebo. This is the analysis that we'll report in Q3 this year, we'll be looking at safety and tolerability as the primary endpoint, then pharmacokinetics as secondary. For exploratory endpoints, we're using fibrosis biomarkers such as PRO-C3 that you've already seen reported in the IPF study, and also the Enhanced Liver Fibrosis score that is another well-established biomarker in liver disease. Interestingly, both these biomarkers correlate with or are predictive of transplant-free survival in PSC, so clinically meaningful. We'll be reporting on all that in the third quarter. Part of the information that we've shared today about, you know, the DSMB review is that it also enabled us to start enrolling in a new cohort, new dose level of 320 mg for bexotegrast. It will be done in a very similar way to what we did for the IPF study, is that these patients will go out to at least 24 weeks on treatment and up to 48 weeks. We'll be looking at, you know, supporting the long-term safety of bexotegrast in these vulnerable patients as well. Just to clarify, the 320 mg will go up to 24 weeks or 48? At least for 24 weeks, and then when the last patient reaches 24 weeks, all patients will be brought in to complete dosing and do their end of study visits. Very similar way to how we did the IPF program. Okay. We've got about six minutes left. It's worth, I think, touching on the rest of your pipeline. As Bernard Coulie, as you outlined, the integrins also have a role in Oncology. Again, also, you know, extending the role in NASH, your PLN-1474 program and recent news there. I'll let you guys pick the order you wanna talk about those two. Yeah, let me start with the oncology program because that's, you know, a very active program within our pipeline. We anticipate start dosing patients second quarter. That's again around the corner. The mechanism is, as we discussed, integrin-based. It's a unique combination of an αvβ8 inhibitor and an αvβ1 inhibitor. A number of αvβ8 inhibitors are in the clinic in, you know, in cancer trials. All of them are, you know, antibodies, we are a small molecule, which allows us to kind of actually address two integrins. αvβ8 has been shown to be anti-tumoral. If you block that, we saw anti-tumor activity actually also in mono therapy or in standalone therapy. Obviously, in combination therapy with a checkpoint inhibitor in all our models, we have shown that we are able to overcome that resistance and show a clear reduction in tumor size, tumor growth, as well as infiltration of cytotoxic T-cells invading the tumor again, so turning a cold tumor into a hot tumor, which I think is kind of the goal in these kind of tumors. With αvβ1, we also have anti-fibrotic activity, which is probably, you know, an important driver in what we have seen in certain very difficult tumors like pancreatic cancer tumor, at least in a model, right? Currently we, I mean, the phase I is just around the corner. We will look at solid tumor patients. It will be a MAD mono and combination therapy, safety PK. That's really kind of the initial focus. We will do some biomarker work and then later expand and look at biopsies. Ultimately, this is a program that is potentially partnerable because it's a little bit out of focus as it relates to the indication. It's very much in focus as it relates to integrins, chemistry against those, as well as, you know, the whole concept of TGF-β inhibition, which is, we have all those assays in-house. The compound has been shown to be safe, at least in a GLP toxicology study, so that's another one on our list of, you know, safe compounds moving forward. And again, we're looking forward to those data coming, you know, probably next year and then see, you know. We see this as a potential partnerable program. 1474 came back to us from Novartis. The reason they brought it back is a internal dis- strategy reason, right? I mean, Novartis decided to step out of NASH a while ago, actually. Part of that was a returning of the compound to us. They completed PK studies in the target patient population, so patients with impaired liver function. This is a phase II ready asset. We are waiting for all the information to come back to us. The IND should be transferred back to us, so that's something that will happen in the coming weeks. Then we have to evaluate that package and see what we do with it. I mean, safe to say that with the current cash, that's all focused on bexo, IPF, and potentially PSC moving forward. I would argue the NASH asset is, again, a potential, you know, a program available for partnering. We know there is quite some interest in this space from certain players. There has been some recent successes, but we feel that we are not really a NASH player at this point in time. We're more focused on IPF and PSC. Okay. You bring up cash. Obviously, you guys are well-positioned, but can you just highlight where you guys stand today and what, where this puts you as far as runway? Yeah. I mean, at the end of the quarter, last quarter, we had $330 million, you know, in pro forma cash. As you know, we did another raise in January, that added another net $270+. We are around $600+ million in terms of pro forma cash, which brings us well into second half of 2026 if we continue to execute on all the different programs that we mentioned. We even didn't mention the DMD program. That's another one. We have a multiple levers that we can play, assuming no deals, no partnering, no nothing, we are well into 2026, second half 2026, which is well beyond a potential phase II-B readout in the IPF trial. Great. With that, gentlemen, we are up on time. Thank you very much. It has been great to catch up and refresh on the story. I hope you have many productive, one-on-ones this afternoon. Thank you again, and good luck. Thanks, Jeff. Thanks for giving us the opportunity. Thanks, Jeff. Take care, guys. Take care.