All right, great. Good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global BioPharma Conference. My name is Tom Smith. I'm one of the senior biotech analysts here at Leerink, and it's my pleasure to welcome our next company to the stage, Pliant Therapeutics. Really happy to be joined by CMO Éric Lefebvre and CFO Keith Cummings. Gentlemen, thanks for joining us.
Thank you.
Thank you.
Keith, why don't you go ahead and kick us off here with maybe a brief overview of the company, some of the key upcoming milestones, and sort of the setup here as we think about the next 12 months?
Sure. Yeah, so Pliant Therapeutics was founded in 2015. We started operations in 2016, based on technology out of UCSF that was based on integrin biology and the targeting of integrins for inhibition. Sure, early on in the course of the company's history, we built a robust medicinal chemistry capability, as well as a high-throughput screening function for integrin biology. And that. We made a few discoveries along the way around how to make small molecules absorbable, bioavailable, and selective for specific integrins. This has been a difficulty for the space for a long, long period of time.
Since then, we've built a library of about 10,000 integrin binding molecules, and out of that library, we've generated three clinical programs to date, soon, hopefully, to be a fourth. The first program is bexotegrast, which, I'm sure a lot of people are aware of. This is an alpha v beta 6, alpha v beta 1 dual inhibitor that we're developing for IPF and PSC. The second one that we developed was an alpha v beta 1 inhibitor that we, that we developed for NASH, that we licensed to Novartis, also subsequently got that one back. And third was our alpha v beta 8, alpha v beta 1 dual inhibitor that, that we're currently in phase I for, oncology. We also have an alpha 7 beta 1 allosteric agonist that we're developing for DMD.
That will be, w e'll be filing a CTA for phase I trials for that molecule in the first quarter of this year, so coming up very shortly. The key updates for the year are gonna be around bexotegrast as well as the oncology asset. So bexotegrast, we read out our 12-week high-dose PSC data earlier this year. Coming up mid-year, this year, we'll have a 24-week readout from the high dose in PSC patients. That will be mainly a safety readout, but we'll also be looking at circulating biomarkers, et cetera.
Additionally, we have, h opefully, we'll be able to announce at some point that we have an active program for the DMD molecule. And then we're currently in our third cohort out of five in a SAD/MAD trial of phase I for the oncology asset. We'll have some data towards the end of this year. It will be safety, PK, and PD data in combination with pembrolizumab.
Okay, great. Yeah, thanks for the overview, and I want to start off talking about bexotegrast. You had an announcement earlier this morning. I want to come to that, but maybe before we touch on that, maybe take a step back and just thinking through your approach in the biology, I guess, what gives you confidence that your approach to dual inhibition at alpha v beta 6, and alpha v beta 1 is likely to avoid some of the setbacks that we've seen in previous approaches to drug in the pathway?
Yeah, so there's been two. There's the Biogen program that was an alpha v beta 6 antibody, and there was the Morphic AbbVie compound more recently that was a small molecule against alpha v beta 6. You know, first of all, you know, we have chronic tox completed for bexotegrast. It's nine months in monkeys, six months in mice, and those trials were completely clean. We saw no, the NOEL was set at the highest dose we tested, so we didn't see any target organs. What we know about the Biogen program is that was an active IgG1 antibody that was immunostimulatory.
They saw signals of lung infiltrates in their preclinical studies, and then they started seeing exacerbations in their phase II-A, and then again, in their phase II-B studies. We haven't seen anything like that in preclinical studies or with bexotegrast. And we've tested our drug in over 700 patients now, and in IPF patients up to 40 weeks, and we haven't seen any signal for exacerbation.
So we feel pretty good about the cause of the, I mean, the Biogen molecule's difficulty. The other one was the Morphic-AbbVie molecule, where they saw bladder cancer in monkeys at 26- and 28-day tox. Again, we have nine month tox in monkeys, and we haven't seen anything like that. We actually went back and reran all of the slides from those animals and have not seen anything like that. So we don't feel that that's a non-target toxicity. And we've, you know, we feel like we've got a, so far, a very safe and tolerable molecule.
Great. Okay, I wanna talk about some of the data that you generated in the phase II-A INTEGRIS-IPF study, and, you know, I guess maybe just sort of high level characterize the data that you generated, how you're looking on safety. I think you already spoke to the or how you, how you're looking on efficacy. You already spoke to the safety, but, the data that came from that study that gave you the confidence to kick off the, the phase II-B study?
I mean, I think for us, the INTEGRIS-IPF study gave us a lot of good information. I mean, we talked about safety, but it is a vulnerable patient population. As you know, these are older patients with multiple comorbidities. So the fact that it was well-tolerated, not only on its own, but in presence of combination with the approved agents for IPF, was really an important finding. And then in terms of the key findings from an efficacy perspective, so we had the improvements in FVC over placebo in a patient population that was predominantly treated with background therapy, either nintedanib or pirfenidone. But 80% of our patient population received these treatments, but we were still able to capture an effect on FVC in that 12-week period.
We saw the best effects of the 320 mg when we looked at the absolute change in FVC from baseline in milliliters. And then we also saw a very striking dose-dependent reduction in the proportion of patients experiencing an FVC percent predicted decline of 10% or greater. And that's important because it is an indicator of mortality. It's also used as a clinical endpoint in IPF trials, just as a matter of information. And then we also were able to show antifibrotic effects, again, of our agent.
Looking at, for example, the QLF score, we saw minimal to no progression of lung fibrosis using that score, in contrast to continued increase in placebo. And then we also had changes in markers, circulating markers like PRO-C3. So altogether, I think that, put into context of also the translational research we had done prior to going into INTEGRIS, gave us great confidence that this drug is doing what it's supposed to be doing and going to the lungs and addressing fibrosis.
Got it. And can you talk to dose selection for the phase II-B, what went into taking the two dose levels forward?
Yeah. So for us, you know, the 160 and the 320 mg doses are the ones that really had the most consistent effects, so the greatest effects, overall, and they were well-tolerated. So for us, bringing these two doses in phase II-B were, you know, it was an, I would say, an easy decision because of the favorable safety. We had nothing to prevent us from testing them.
The thought is in phase II-B, what we'll be doing in the BEACON study is having 30% of patients not on background therapies and 70% of patients on background therapies. We want to see, for example, if does the 320 mg dose deliver better efficacy in the setting of monotherapy? And if it does, is it as well-tolerated in the presence of combination with nintedanib or pirfenidone? So it will give us good information in that sense, and then we'll be able to select a dose for phase III based on these findings.
Got it. That makes a lot of sense. You announced some important changes to the BEACON-IPF study this morning based on updated regulatory feedback. Maybe you could just walk through the feedback that you received, the changes that you made, sort of the rationale behind all of that, and where that leaves you with the BEACON-IPF study.
You know, I think this was great news, the acceptance of the BEACON study as a seamless phase II-B/III design. This was always our plan, our preferred scenario. And we're very happy that EMA actually accepted that, in addition to pretty much, I mean, all the countries where we submitted it. So we're feeling very proud about that because it is a way to bring in the timelines for phase III readout in a significant fashion. And really excited to have this opportunity for bexotegrast, because we do think it has the potential to be an asset that really merits, you know, more usage. For example, our investigators are super excited about the profile of the drug. I think that is going to put us in a great position, and the time saving is really critical as well.
Okay. And we, I guess, talk about sort of the mechanics of transitioning this to sort of this phase II-B/III seamless design. We talked about adding, I think, 90 patients you disclosed in the press release.
Could you just walk through sort of the mechanics of that, how that alters. I mean, as you said, it potentially pulls forward the pivotal sort of readout here. What does it do to the actual, I guess, phase II-B, top-line data?
Yeah. So just maybe stepping back a little bit, our phase II-B data, the component of the phase II-B component of this study has been really endorsed by the agency, the FDA. They see this as a robust phase II-B evaluation. Also, we had a meeting last year where they were very complimentary of the work we're doing and also giving us some statistical considerations for once we analyze the data, to make sure we put, you know, we leverage this study as much as we can. And reading between the lines, that kind of also suggests the idea of it potentially serving as one of the two pivotal studies for approval.
One thing that we were always wanting to do, and outside of the setting of the seamless, was to do a sample size re-estimation, once a certain proportion of patients reach the one year time point in BEACON to see if our standard deviations for FVC were where we thought they would be, or whether they would be closer to what was seen in the phase III Galapagos study. And now, given the fact that we have the seamless , we felt that in, you know, just basically upsizing the phase II-B would be able to address that without waiting any further. And also would have a very minimal impact on timelines because that those additional 90 patients will come in at the tail end of phase II-B enrollment, when most of the sites are activated. So we're expecting very limited impact on the readout for the timeline for readout for that.
Okay. So the changes here were based on feedback from EMA, European regulators, and it sounds like virtually most ex-U.S. territories, but not explicitly FDA feedback. I mean, is there any potential for a more expedited path in the U.S? And typically, the phase II-B and then a separate phase III study has been the regulatory path, but is there any possibility of that being expedited?
Well, we will certainly, you know, leverage this good relationship that we have with the agency and be transparent with them in terms of all the safety data that's generated from the phase II-B part. We'll have the DSMB reviews. We'll have opportunities to engage with them. And, you know, we understand from the FDA that their position seems to be that phase II-B data is what makes them feel more comfortable about assessing benefit-risk. So it could be that it's in that scenario, when the phase II-B reads out, that the agency becomes open to saying: "Okay, well, now amend your protocol to incorporate the phase III component of the seamless ," and then they come into the study into phase III. But nonetheless, they will be in phase II-B , and we will continue to try to leverage opportunities to bring them into the phase III part.
Okay. I guess I want to clarify a couple of things. So, on the one aspect, you mentioned the sample size re-estimation, that's something that hasn't happened yet?
Well, we've-
Or where that was-
We've. That's it.
Okay.
The 90 patients extra were what we were thinking we would need to accommodate for larger standard deviations, and what we did is just we decided to make that decision because of the seamless also, and the more sites that we have that will participate to this larger effort as well.
Got it. And you mentioned the sort of periodic DSMB reviews. Just remind us, I guess, how often that committee meets, and there hasn't been any, I guess, notification from that committee, like adverse or otherwise, right?
No. And so w e haven't disclosed as such the cadence, but it's pretty much the cookie-cutter standard DSMB, where you have milestones when so many patients reach a certain time point, and also at one point, we expect it to be very much quarterly.
Okay. Got it. And, can you comment on where you are with enrollment? Or I guess, if not able to sort of quantify where you are with enrollment, just qualitatively, how is enrollment going in BEACON-IPF?
Yeah, I mean, we're really tracking. We're doing great. We're activating sites every day. We're going into new countries. So, it's a big part of what we're doing now, and we're tracking to all our projections. So we're where we need to be, and I think the good news will only help us, you know, either meet these timelines or exceed the timelines.
Okay. And going into or enrolling the additional 90 patients, are you activating additional sites to accommodate that, or how does that-- You mentioned it shouldn't have too much of an impact on your timelines.
Yeah.
But how are you accomplishing that?
We will augment the number of sites to accommodate the seamless , first and foremost, right? Because now it's a larger study, because it has the phase II-B part and the phase III part, and that will also help us with those 90 patients. But it's the tail end of enrollment, plus those new sites that will be coming on board that would put us in a position where we're talking about a couple of months, probably, in terms of impact.
Got it. Okay. I want to talk about expectations for BEACON IPF. Obviously, the primary endpoint here is the absolute FVC change at week 52. Maybe just walk us through and help sort of frame what you're looking for with the top-line results.
Yeah. So, you know, seeing this difference between active and placebo overall, w e have a study that's powered at least at 80% to show a difference between active and placebo at, using the FVC absolute change. And, you know, we feel that we've been pretty conservative also in our assessment here. We haven't disclosed the effect size that we used for power calculations, but it's really, you know, thinking about what we saw at 24 weeks in the 320 mg cohort, that we're trying to replicate at a later time point. So we didn't make an assumption that the placebo group would continue to decline as fast as it did in the first 12-24 weeks. We've been conservative that way, and the upsizing is also gonna help us with power, potentially.
Understood. Is there, is there an expectation for sort of deepening efficacy or, like, greater treatment effect with longer duration of dosing?
I mean, that's what we would expect, right? But in terms of the delta, at 52 weeks, it's pretty similar to what we saw already at 24 weeks.
Okay. There's been a lot of development work in IPF. Unfortunately, there's been some disappointing results. I guess, most recently, you know, people think of pamrevlumab.
They think of PRM-151. There was an inhaled galectin-3 study that also failed. I guess, are there learnings from some of these studies and it's sort of more unfortunate readouts that you can incorporate into BEACON?
Yeah, I mean, I can start with pamrevlumab. I think that was an unfortunate failure. We hoped that would—that drug would work. You know, there was an interesting statistical analysis done in their phase II-B that was not allowed in the phase III. So they used a—they used an imputation method that we didn't use. What we've done in our phase II-A and what we will do in our phase II-B and phase III are use the mixed model of repeated measures—we'll see as the approvable method. So we don't impute values. It—you can look at it as sort of a conservative way of doing your statistics.
But more importantly, you know, it was not well understood a lot of the PK and so forth around pamrevlumab. They were given two grams of drug every two or three weeks, and it still wasn't clear if that was hitting the target well, 'cause CTGF is a very ubiquitous molecule in the body. So, contrast that to what we've done. We've run numerous preclinical studies looking at the amount of drug needed to saturate the target. We ran a PET study in patients with IPF to show that at the clinical doses we're testing, we're getting close to saturating the target.
So we know that we're hitting the target, and it wasn't clear if pamrevlumab was actually hitting it. So I think, you know, when you look at sort of the total data package that we've got around bexotegrast, it's robust relative to a lot of these others. I don't know if you have thoughts on any of these others, colleague, on here?
Yeah. I mean, I think it's fair to say that the amount of de-risking that was done prior to the clinic is maybe not as much as people would have hoped for, right? And I think that's one key differentiator when we have our advisory boards. I mean, they're very complementary on all the preclinical evaluation, including the precision-cut lung slices that we used from explanted tissue, but also all the translational work that Keith just mentioned now, really in advance of doing our INTEGRIS-IPF study, right? So, altogether, with the results from the INTEGRIS-IPF study, I think people get the confidence from there.
Got it. That makes sense. I wanna shift gears and talk about the data that you now have in PSC, primary sclerosing cholangitis. Maybe if you could just summarize at a high level, the data that you generated in the phase II-A, and then what we can expect. You alluded to the upcoming readout in the middle of the year. Just help sort of frame expectations around that readout.
Yep. So, I mean, the key findings from the INTEGRIS-PSC study were that in this patient population with preexisting liver disease, we had also good tolerability. In that sense, I think, it also provided more confidence around the safety of bexotegrast in IPF patients because we, you know, we were also in another vulnerable patient population and showing good tolerability and safety. And then we were able also to show antifibrotic effects, looking at biomarkers, circulating biomarkers of fibrosis, such as ELF, PRO-C3. We also, looking at the safety, or adverse events, we saw that there were fewer patients on bexotegrast that experienced AEs of ascending cholangitis, so that those are infections that occur in the bile ducts, which are strictured.
This is important clinically because these patients have to be taking antibiotics, also tend to be hospitalized, so it's meaningful for clinicians. And then we also had imaging in our study to show that we showed that there seemed to be more uptake. We used a contrast agent. We saw that the liver seems to be absorbing the contrast agent more, which is reflecting of the hepatocyte health, but also the time to eliminate the contrast agent to the common bile duct was shortened with bexotegrast compared to placebo, and that was also leading to the assumption, potentially, that we're relieving the stricture in the bile ducts with the mechanism.
One of the other findings that was interesting is we saw the effect on itch, either as an AE for pruritus, or we saw using the itch numerical rating scale, and we even had stat sig for the two top doses, the 160 and 320 mg doses there. So really, a myriad of assessments continuing to highlight the treatment differences between active and placebo.
Got it. So you recently announced the sort of interim 12-week results from the 320 mg dose cohort. I think a lot of questions around some of the biomarker data, and I guess comparing the 320 mg dose versus the newly enrolled placebo patients, and maybe some questions around dose response and whether you're, you know, you're seeing a significant separation on those biomarkers as you've gone to the higher dose. I guess how do you, y ou know, these are small patient numbers. It's pretty short treatment duration overall, but how do you rationalize, I guess, what was new from the 320 mg interim data?
Yeah, I think it's, you know, it's a fair comment also. We, you know, we would have all liked to see more dose-dependent changes in the fibrosis biomarkers, but we weren't sure if we were gonna see them anyway because we don't know how accurate they are at determining or selecting doses or what have you. But nonetheless, we saw activity across all the different doses for ELF and PRO-C3, where, you know, I forgot to mention is our trial was enriched for patients with suspected liver fibrosis. So there were more, in fact, selecting for patients that are at greater risk for progression. And what we saw from across the doses is that bexotegrast seemed to blunt the increase in fibrosis over that 12-week period, in contrast to the placebo group.
So, you know, we are taking the position that in late stage, we would have to do additional dose finding to really tease that out. And people have pointed to the fact that maybe the placebo patients from the 320 mg cohort seem to progress not as fast as the others. We haven't seen these data ourselves, but just we also can come to that same conclusion looking at, you know, the pre-specified analyses. What we think is it's really important to pool the placebo groups because there's no reason why we would think that these nine patients in the 320 mg cohort that were randomized to placebo are more reflective of the general PSC population, and then the 21 patients that were enrolled previously.
But, you know, I think that the fact that beyond 12 weeks, it's only those nine placebo patients that will go out to 24 weeks, it will limit our ability to, you know, to see stat sig on some of the efficacy comparisons. But nonetheless, we'll be reporting on those. But safety will be the critical finding for us because if we see good safety at six months or more, at the top dose, it really supports the inclusion of that dose, but also the lower doses in the late-stage program.
Right. And also potentially incrementally de-risks on the IPF side-
Exactly.
-through the safety exposure. Now, that makes a lot of sense. Can we talk about next steps in PSC? I mean, one of the overarching questions has been on regulatory path, and I guess whether you would need biopsy data or if this is something where the agency could be more amenable to biomarker changes in ELF. Feels like all of this is somewhat TBD, and they're waiting for a sponsor to come with data and, and propose it. But what do you guys see as, reasonable next steps for bexo and PSC?
Yeah, so we'll be meeting with the agency likely mid-year this year. We're preparing for this interaction now, and we do like. We have also heard through channels that the agency may be more willing to contemplate creative approaches in PSC, and so we're, you know, we're wanting to push that a little bit and just see if there would be an avenue for having a pivotal study that would include non-invasive as a pivotal endpoint, potentially in combination with some AEs that are relevant to the disease. We mentioned cholangitis, but this is something we want to explore.
And that route could also open up the door for shorter duration studies because the phase III-A studies that have gone through right now have been two years in duration with histology. So we, we wanna also get a sense for how much histology is the agency wanting to see. But is there a place where that's if they need to see something, can that be generated in phase II-B, for example, and then having your pivotal as a, as a non-invasive?
Okay, I think that makes a lot of sense. On just one last question, maybe on Bex, like, how do you guys think about potential for indication expansion? And is there a strong appetite? You have the other pipeline programs obviously going as well and a lot on the plate, but how do you think about that?
Yeah, absolutely. I mean, our, you know, our top priority of the company right now is IPF for bexo, but certainly when we have phase II-B data, assuming it's supportive, we would like to branch out into the broader progressive pulmonary fibrosis indication. We probably wouldn't do that before phase II-B data. Just I think that's the critical de-risking point there.
As far as some of the other earlier stage programs go, we are moving those programs forward, but we do see the oncology and DMD programs as long-term BD opportunities for us. So, we're running the phase I in oncology right now. Once we have that data, the safety PK, and PD in combination with checkpoints, I think there's potential there to do something on that. And I think the possibility for DMD is probably earlier than that. There's interest in both of those programs.
Understood.
So we realize that, you know, DMD, we're a fibrosis company, orphan fibrosis, and, you know, we'll look to monetize those over time.
Understood. And just with the oncology first, the human experience readout. There's a Q4 readout, just I guess, help frame expectations. What, what, what should we be looking for with the initial data set?
Well, I think safety in monotherapy as well as combination with checkpoints is key. I mean, this is a well-understood mechanism by pharma companies, so I don't think we have to prove the efficacy at this point. But having some PD markers that are supportive of the drug actually having an effect will be important. But mainly, it's PK and safety.
Got it.
That's what the sponsors are telling us.
Understood. And just with the last couple of seconds we have remaining, just remind us on your current cash position, operational runway, and what readouts are funded from here?
Yeah. So as we announced today, with the seamless design, we've upsized and extended our Oxford Finance debt facility. So that's a $150 million facility that'll we'll have access to a couple of years from now, actually, so it's pretty flexible financing. That, coupled with the $496 million we had at the end of the year, funds the company through 2026. So we feel very comfortable of having, you know, several quarters of cushion past the phase II-B data for IPF, and that's the crucial bogey for us to get to.
Got it. That makes sense. All right. Well, unfortunately, we're up against time, but really appreciate you guys joining us. Thanks for the updates and insights, and we'll stay tuned to the Pliant story.
Great.
Thank you.
Thank you.
Appreciate it.