Good afternoon, everyone, and welcome back to Oppenheimer's Annual Healthcare Conference. I'm Jones, one of the senior analysts here on the biotech team. I'm delighted to welcome the Pliant Therapeutics team to the call with Bernard Coulie, President and CEO, Keith Cummings, CFO, and Éric Lefebvre, Chief Medical Officer. So gentlemen, thank you very much for taking the time to sit down with us this afternoon, slightly after.
Hey, thank you, Jeff.
Why don't we start off on the PSC program, given it's the most recent update. If you could sort of refresh us on what you've shown through 12 weeks, and then obviously, you've had the recent updates on the 320 mg dose and how that impacts how you're thinking about the program.
Okay, I can give it a start. So we, you know, the primary endpoint of the study was safety and tolerability, and we saw across all the doses, including the top dose of 320, very good safety. In fact, the most commonly reported adverse events occurred less frequently in the active arm compared to placebo, which was really nice to see. We also have seen fewer liver-related AEs, such as cholangitis and pruritus, in our trial, and we've seen no drug-related SAEs. So really good safety profile altogether, and that we're very, very proud of, because this is a population that has pre-existing liver disease, so certainly a new population for us to study bexotegrast in.
Another really important piece of the data that came from the study is the antifibrotic effects that we again were able to demonstrate in this new patient population with suspected liver fibrosis. We saw reductions in ELF and PRO-C3, which are, you know, fibrosis biomarkers, and that was relative to placebo over a 12-week period, so very encouraging. Also, we had an optional MRI sub-study that continued to illustrate some treatment effects, including potentially shorter time for the contrast agent we use to reach the common bile duct, which could suggest improved bile flow and also increase hepatocyte function based on whole liver enhancement with the contrast agent.
Additional findings, we saw that ALP remained stable for patients on bexotegrast and the subset of patients that were elevated at baseline, whereas we saw a continued increase on placebo, and we also had statistical significance for itch at the 160 and 320 mg doses, you know, compared to placebo. We use a itch NRS score that has been used in other liver trials. So very happy, really, that we're able to capture treatment effects over this short period in a phase IIa setting.
Great. So I know that was sort of a broad basket question. I think you mentioned something important there, in that these patients were patients with suspected liver fibrosis. Can you sort of speak to how the patient population is representative of in PSC versus, you know, some of the other trials historically that are out there?
Yeah, I mean, that's a great question. We were really the first to introduce some cutoffs for markers of fibrosis for eligibility. Most of the trials that had been conducted in PSC prior to our trial had enriched for patient with high alkaline phosphatase values. And that was probably more derived from the PBC research. But also we understand that if you have very high alkaline phosphatase levels and you have PSC, you're more likely to, you know, to see outcomes over 10-15-year periods, so we know that. But it doesn't, you know, that for what we did, because we wanted to really take a better opportunity to show the antifibrotic potential, what we did is we...
You know, patients need to have a transient elastography or FibroScan value that was higher than 8 kPa, so this enriches for F2s and F3s. We also, you know, had a threshold for ELF as well, to really capture people with active fibrogenesis. And then if patients had historical liver biopsy, we could use that as well as evidence. But that really has resulted in us cutting off really the low end in terms of fibrosis in our population, and it's a bit different than what's been done, and I think this is probably the population that is at a greater risk of progression. So really, you know, I think the results from our study have also had thought leaders start to rethink about how we need to design these PSC trials.
Okay. That's, and that's helpful for us to keep in mind. Now, obviously, with the recently reported 320 mg dose and the 12-week data, it's a little bit of a head scratcher in that it clearly looks to be efficacious. The product has antifibrotic impact across the board, but there doesn't seem or the dose effect isn't particularly clear here. And I know you've put some thought into it, so can you share how you're thinking about how you then consider your next trial?
Yeah, I think, you know, with what we had seen in the prior data release, with the doses at 40 mg-160 mg, we also have the same, let's say, the same type of results, right? We saw that, you know, we even saw activity at the 40 mg dose for the fibrosis biomarkers. So you know, we had not expected to see greater results or greater impact on these biomarkers with 320 mg in light of what we had seen previously. And also had already taken a position that, you know, potentially short duration, like 12 weeks, and also a small number of patients may not, you know, be enough to be able to tease out a dose effect.
Certainly, we don't know how accurate the circulating biomarkers can be at distinguishing, you know, what's the best dose. So what we had communicated to, to the street as well is that, you know, for late stage, we're thinking we'll have to do further dose ranging for longer duration and greater sample sizes. And we haven't given guidance on that, what the doses will be, but certainly, these results are what we need now to, you know, to write up and put a briefing book together, and have that conversation with the agency in terms of what late stage could look like, and also what doses we might be evaluating there. But certainly there would be a high and a low dose.
This is our base assumption, because we'll need more time and more patients to really tease that out.
Okay. And you mentioned some of your expectations around higher doses based on prior studies. Could you just, you know, flag or remind us, what that was coming from? And I believe it was some of your preclinical data.
Yeah, I mean, we've seen across the preclinical evaluation, whether that's in animal models or precision-cut tissue slices coming from explanted tissue, you know, whether that's from lung or liver, we continue to see this dose response in our preclinical evaluation. And certainly, I think that if we think about the IPF program, the PET study that we did in IPF patients showed it's really dose-dependent and exposure-dependent target engagement in the IPF lung. So we have really great tools in the lung to evaluate target engagement. We don't have the same tools in PSC, and we also know that the drug has... bexotegrast has more affinity to the liver than the lung.
In preclinical evaluation, it's about 3x more concentrated in the liver than the lung, so that could also explain why we're, you know, seeing even activity at the lower doses.
Okay. That, that's helpful. Thank you. And then you were speaking to sort of the next steps here, and proceeding to the agency with the briefing package, and you've also got a 24-week endpoint reading out for the 320 mg. So I guess, what's, what's the anticipated timing there? Do you wait for the, the 24-week data, or do you go ahead to the agency, with the materials you have in hand at this point?
Yeah, that's the latter. So, you know, we have the complete dose - I mean, the dose comparison at 12 weeks. That's, you know, the 320 mg group is the only one that went beyond 12 weeks, so it's gonna be primarily for safety reasons that we wanna confirm that the good tolerability over 12 weeks is also seen for longer treatment. But in terms of being able to show, you know, apples to apples across doses, this is what we have. So we're gonna be writing the briefing book with these data, and we're gonna be putting in a meeting request. We expect that, you know, the meeting with the FDA would occur sometime mid-year this year.
Okay. And then I think it's worth reminding the investor community that with the study design, and this is something that was seen with the IPF trial, when you get out to the 320 mg, 24-week, you have a smaller placebo group that makes it out that far. So there's greater variability in that placebo arm, so it, you know, any efficacy should be taken with some caution there.
Yeah, I fully agree. I mean, for us, as I mentioned, safety was really the key criteria for extending the treatment duration at that top dose because we wanted to provide long-term data at the top dose we plan to study. And that would also give us coverage for the lower doses as well as we go into late stage. But, definitely a great point. I mean, having a reduced sample size for your placebo group beyond 12 weeks, you really, you know, limits you in terms of the comparisons you can make from an efficacy perspective.
And then in terms of the discussion with the agency, I think you're obviously dose ranging, what that looks like, but another key issue for the PSC space in general is endpoints. I guess, where does the universe of PSC developers stand today in terms of thinking around endpoints and histology, liver biopsy, things like that, versus biomarkers?
Yeah, I mean, it's a great question, and, we certainly want to tease that out in our interaction as well. We want to understand, is there a place for a non-invasive endpoint for a pivotal study in terms of the surrogate endpoint? Thinking about something like ELF, for example. We certainly haven't seen anything in writing from the agency that suggests that this could be the case, but we've also, you know, heard that potentially other sponsors are thinking about that, so we want to understand that. And if, you know, the agency still sees the need for histology, we know how the sampling, you know, sampling variability is with PSC is even greater than for NASH.
So we will want to know how much data do they need to see for histology is more supportive or is it, are they expecting to, for us to use the playbook that was used by Gilead in phase III, for example, for their, cilofexor drug or, the other phase III trial that's ongoing. Their primary endpoint is histology. So we really want to understand that better because obviously, you know, in the setting of not having to, or rely on histology for success of your trial, could open up a really big range of possibilities, and accelerate, the treatment as well as to, you know, the path to registration.
In those historical PSC trials, they used essentially a two-year pivotal endpoint, if I recall. And do you think that remains the case, or is there an opportunity to look at a half quarter time frame for your, for the pivotal endpoint?
I mean, that's, that's the beauty of, you know, non-invasives, right? If you're able to show an effect, and if you think that it has the reasonable expectation that it may affect how patients feel, function, or survive, then you do have a case to make for a shorter duration. Histology takes a while because of the, the sheer nature of the, the disease that's quite slow progressing compared to other fibrotic diseases. But, you know, taking out of the-- taking the histology out of the equation, like I mentioned, could really also have you revisit the, the treatment period for pivotal studies.
As we think about those potential non-invasive endpoints, I think you already mentioned ELF and some of the others that you measured within the phase II trial, PRO-C3, and the MRI scan, the Itch NRS, and things like that. To our understanding, ELF score is probably the most well-validated in terms of PSC. I guess could you comment in terms of what you think the most relevant endpoints are for a clinical trial and really that are most clinically relevant here?
I mean, ELF for us remains, one of the non-invasives that we're particularly, interested in, because we know that it represents active fibrosis product or collagen production, so that's important. We also know that it is a well-established prognostic biomarker in PSC. In fact, EASL now recommends yearly testing for ELF in addition to, FibroScan, as a way to monitor the risk for their patients. So that's important. And we also have evidence from, trials such as the, you know, phase III simtuzumab, phase IIb simtuzumab program. And we also have... you know, we know that certain registries are starting to collect ELF data. So there's, I think, more work that potentially needs to be done, but it certainly seems to have a higher shot on goal in terms of a non-invasive, I would say.
FibroScan is interesting, but it also is, you know, has a lot of operator or inter-operator or intra-operator variability. It's not the most accurate test. It's great for ruling out cirrhosis, but in terms of distinguishing stages of fibrosis or regression of fibrosis, it's a little bit less capable of doing that. And then you have MRE, but MRE is a, you know, an interesting, certainly interesting technology, very accurate, but it's very hard to scale in a global study just because very few centers have access to magnetic resonance elastography, and those that have are limited. So you could potentially see this as a subset, but certainly as a primary endpoint would be difficult.
But certainly, you know, we wanna, we know there's probably an approach where you could see where a phase III trial, for example, a late-stage trial, could have multiple non-invasives. And given the fact that there's no drugs approved, you know, would directionally, you know, hitting your primary endpoint and directionally hitting the other non-invasive give you a higher shot to get the product approved. That's possible, especially in the light of, you know, the patient community that's growing impatient as well. So these are all aspects that we're considering at this time.
Okay. I guess just to wrap up on the PSC story, you know, maybe more strategically or financially, how you're thinking about the program and next steps in the context of the broader business?
Yeah, I think, Jeff, this is—I mean, IPF is key, right? I mean, we have clear data from our phase IIa. The drug is safe. It's a tremendous market opportunity if you think about it. If you look at research that we did and others did amongst physicians and payers, I think a small molecule, once daily drug that is safe, well-tolerated, and works in IPF is, you know, that's the future, and that's also where our competitors are thinking. And so, you know, having successfully entered a phase IIb, phase III program, a clear path towards approval and knowing what the regulatory precedent is, obviously IPF is a focus.
So PSC is, I would argue, a second priority, in the sense that we need to have more clarity in terms of what is the path to registration here. To your point, all the questions you raised are the relevant ones that we see as well: endpoints, duration, what could be a near-term catalyst in a larger trial. PBC will depend on feedback from the FDA, as well as the availability of additional cash. Right now, all the cash that we have, and we have a lot of it, will be deployed towards BEACON-IPF and making sure we get to our phase IIb readout, which I think will be, of course, a major catalyst and drive the continuation of the program.
Any, you know, development in PSC will depend on additional cash, which will be non-dilutive probably in nature. We are working on a number of potential partnerships on our earliest stage programs, including oncology, DMD, as well as a potential platform deal. Who knows? The other point I want to make is it's not only IPF. There is the broader basket of pulmonary fibrosis or progressive pulmonary fibrosis as it's been defined, so all the non-IPF ILD disease that, you know, offer a potential expansion of that market, and significant one. I think Boehringer has set the precedent right there.
Once we get phase IIb data, again, our focus will be also in terms of expanding the indications beyond IPF and going into pulmonary fibrosis as a broader basket kind of set of diseases, as part of our phase III program.
Okay. So, you know, clearly, IPF, I don't think anyone would argue IPF is the larger market opportunity, as we've sort of just hammered out, a much clearer regulatory path there. And I think you've demonstrated some nice data in terms of, you know, how this fits in with standard of care, the challenges with the GI tolerability, with, with not only standard of care, but some of the competitive molecules. So, I guess, remind us where you are today with the Phase IIb study, timelines there, and what we should be thinking about.
Yeah, so we're, in terms of, enrollment, we're on track, according to our projections, so that's going very well. It's still, I would say, premature to provide exact guidance on when the trial will be fully enrolled, just because we haven't, you know, reached that hockey stick part yet. But, in terms of, all the site activities, start-up activities, this is really... and, and screening activity, we're seeing this pick up more and more, so that's really great.
You know, for those who aren't as familiar with the story, how many patients are you looking at here, and sort of what is the, the timeline and, or endpoint in terms of, you know, 12-week, 24-week, 52-week, et cetera?
Yeah, so we, yeah, we have approximately 270 patients that will participate to this BEACON-IPF study. It is a two-dose, two doses for bexotegrast, 160 and 320 mgs are the doses we're comparing to placebo. Treatment period is a year. We have also, we will be having 30% of our patient population that is not currently receiving the background therapies in IPF, and 70% that are that will be taking them, and then we'll stratify for that. We also will stratify for the GAP index, which is more of a prognostic marker, if you wish, in terms of it, it is highly associated.
The greater your GAP stage, the higher risk of mortality, so we want to make sure that's balanced across the different groups, 'cause we'll be looking at also, you know, outcomes, clinical outcomes as a key secondary endpoint. Then, our primary endpoint will be the absolute change in forced vital capacity over a year period. The trial will be powered to at least 80%, and we do believe that if it's successful, it has also the potential to be used as one of two pivotal studies for NDA purposes.
Okay. In terms of trial sites, where are you looking to enroll the study?
Yeah, we're in the major regions, so, North and South America. We have, also Europe, Asia Pacific, and also we're considering additional countries to bring on board, but, really having a, a broad, a broad region, and, and that really helped us, 'cause we had also a multinational program in the INTEGRIS-IPF program, so we built on that. I did added new sites in the same regions, but also added, different countries in the regions we're, in. So over 150 sites, will be participating, so a really, you know, great, footprint for the study, and, really being able to generalize data to generate data that's generalizable as well in terms of patient populations.
Okay. In terms of sort of interim updates or cadence of news around that program, given it's a long-term endpoint, you know, how should we think about, you know, updates coming on that trial?
Yeah. Bernard, do you wanna take it?
Yeah. Yeah, I mean, we'll, as we gain clarity on, you know, when we expect enrollment to be complete, we'll certainly be communicating that in regular updates.
As Eric mentioned, right now we're just staying quiet on that because we need to get to a certain inflection point on the enrollment just to be sure we're guiding correctly.
Given you're planning to use the study for, as one of your pivotals, I'm anticipating we wouldn't anticipate interim data updates, except maybe safety or something like that along the road?
Yeah, that's, that's, that's for sure. I mean, interim analyses would take out the possibility of using this for registrational purposes. So, you know, we haven't disclosed whether we would communicate DSMB meetings and what have you, but we also have also these same mechanisms in place, similar to what we had in the phase IIa program.
Okay. And Keith, obviously we've got the quarterly coming up, so just remind us what was 3Q cash and runway for you guys, and I know you've got plenty of cash.
Yeah. No, so we at the end of the third quarter, we had over $500 million of cash and cash equivalents. That funds the company until into the second half of 2026. And as we've said before, that certainly gets us past our phase IIb readout, we believe, and gives us some amount of cushion, you know, post that data release. So feel really good about the cash runway right now. We are being vigilant, as Bernard mentioned, we're focusing our resources on IPF, and to the extent we can do some things to generate some non-dilutive capital, we'll reevaluate on the PSC front, etc .
But right now, it's all hands on deck for IPF, and that's where that cash is going.
Great. And I guess one last question, Bernard. You mentioned, you know, the various earlier stage programs and the opportunity for licensing and also around the platform. You didn't mention the NASH asset that came back from Novartis that's phase II ready. Is that something that you're still considering for out-licensing, or where does that one sit?
Yeah, actually, yes. Sorry, I forgot to mention that, but that's indeed an asset that's available for out-licensing as well.
Okay. I think we have covered everything in the question queue, and I'm more or less out of questions at this point. Gentlemen, I'm going to clear us from the call, and hope you have a great rest of your day and productive meetings through the rest of the conference.
Thank you so much, Jeff.
Thanks, Jeff.
Thank you.