Okay, great. Good afternoon. Welcome. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan. And our next presenting company is Pliant Therapeutics. And presenting on behalf of the company is CEO Bernard Coulie. There's a Q&A after the presentation. Just raise your hand and wait for the mic before asking your question if you have one. And for folks tuning in via the webcast, questions can be submitted via the portal. With that, Bernard, thanks for joining us.
Thanks, Eric. First, I want to thank Eric and the J.P. Morgan team to give us the opportunity to present Pliant to you this afternoon. And thanks for attending. Pliant is breaking new grounds in fibrosis. As you know, we have built an industry-leading fibrosis platform, which is based on small molecules that address integrins as their molecular target. We have built a proprietary library of over 10,000 real compounds that are addressing specific integrins. And out of that library, we have been feeding our pipeline with our lead program being bexotegrast. So bexotegrast will be the main topic of the conversation this afternoon, obviously. It's currently in a phase IIb, phase III registrational program called BEACON-IPF. And we anticipate to have phase IIb data in the second quarter of 2026. And again, this is a potentially registrational trial.
This is a refinement of an earlier guidance in terms of timeline. We have been guiding towards mid-2026. Based on the enrollment going very, very well, we anticipate to beat that timeline, and so it will be the second quarter of next year, so bexotegrast has disease-modifying potential in IPF. We have consistently shown that it improves FVC, so it's not just a slowing of decline, but actually an improvement of FVC, Forced Vital Capacity, which is the pivotal endpoint in any IPF or pulmonary fibrosis trial. It has a favorable safety and tolerability profile. It's potentially disease-modifying because we have observed reversal of actual fibrosis even after 12 weeks of treatment in a recent phase IIa study measuring total collagen using a PET ligand, and I will highlight some of those data because these are relatively new. We kind of disclosed them earlier this year.
Then finally, we have found across two different trials a clinically meaningful effect on cough severity. To our knowledge, this is the only antifibrotic, be it investigational or approved, that actually has an effect on symptoms. cough is like the second most reported symptom in patients with IPF and has a dramatic impact on their quality of life. We will also spend some time this afternoon on the market and the commercial opportunity. Today, the IPF market, or the combined pulmonary fibrosis market, is about $4 billion. We anticipate it will grow to $6-$10 billion, driven by a number of phenomena that we will discuss. The company itself is well-funded into the front end of 2027, which is way beyond phase IIb data. We have $465 million in cash at the end of the third quarter.
This is our pipeline with some of the anticipated milestones as well as timings. Let's focus on BEACON-IPF first. Our phase IIb part of that study will fully enroll in the weeks to come. We still guide towards first quarter 2025. Our phase III will start at the same time. Last patient first visit in the phase IIb is actually the start of first patient in the phase III. We enrolled 360 patients in that phase IIb portion. The 361st patient that will be randomized is actually the first patient in the phase III. The phase IIb data, as I mentioned, will be disclosed second quarter of 2026. What is new here is the fact that we also will expand in another indication called progressive pulmonary fibrosis, or PPF.
We initiate a potentially pivotal phase IIb called BEACON-PPF second half of this year. We will be more precise about the exact timing once we have gone through a number of preparations. And then again, this quarter, we will release interim phase 1 data from our oncology trial where we have three cohorts fully enrolled. So if we look at the compiled data from everything we have done so far from a development perspective as it relates to bexotegrast, we have basically outperformed at every stage. So these are all phase II, phase 1, and preclinical data taken together.
What we have shown so far is an improvement in lung function as measured by FVC, symptomatic improvement on cough, reduction in lung fibrosis measured by two different technologies, imaging technologies, an additive effect on standard of care on both approved drugs where we saw an 80% increase in terms of forced vital capacity. We see a favorable safety and tolerability profile. We have dosed over 850 participants so far. There are patients that have passed the 52-week, albeit blinded, threshold. We have once-daily dosing. And then going back to the earlier studies we've done in the past, type phase 1 and early phase II work, we have shown that the two doses that we are currently testing in phase IIb, phase III actually fully saturate the alpha-v beta-6 receptor using PET imaging. We see a reduction of TGF-β signaling, which is our main pathway that we want to address.
Then going back to the early work in explant tissue from patients with IPF and other forms of pulmonary fibrosis, we have seen a reduction of pro-fibrotic gene expression. I will come back to these data because we continue to use this technology to evaluate our program versus some of the competitors and also to evaluate our program in other indications. The four differentiators for bexotegrast as we see them today basically is the combination of the fact that we improve lung function, the compound is safe and well-tolerated, we are potentially disease-modifying by reversing fibrosis, and we see symptomatic improvement on cough, which at least, again, to our knowledge, is unique for an antifibrotic. How do we compare to some of the competitors being investigational products or approved products?
These are 12-week FVC data except for the BMS compound, which are 24-week forced vital capacity data. And we basically outperform versus all of our competitors. But it's not only that. If you look at the adverse events, we have basically no notable adverse events in our phase II studies. nerandomilast is the PDE4 inhibitor from Boehringer Ingelheim. And they have a problem of diarrhea. And this is a class effect. It's inherent to PDE4 inhibitors. Of course, on top of standard of care, notably Ofev, it basically doubles the incidence of diarrhea above 30%. Admilparant, which is the LPAR1 antagonist from BMS, has a modest effect. And this is a 24-week study, has a modest effect in IPF and a slightly better effect in PPF. One of the side effects that has been noted there is hypotension and potential risk for syncope.
And then you see some other products that are currently in development where, again, there are notable side effects. And then at the very right end of this chart, you see the approved agents and how they performed a long time ago. So coming back to the human tissue work. So we use fresh explanted tissue from patients with lung fibrosis that are undergoing lung transplant. And so what you see here are tissues from patients with IPF or IPF and PPF. So in the first experiment, we compared the activity of our drug on pro-fibrotic gene expression in these tissues to nerandomilast. So this is the PDE4 inhibitor from Boehringer Ingelheim. And what we see across the entire pro-fibrotic gene panel is a significantly better effect. I think nerandomilast moves some of the genes a little bit.
If we look at admilparant on the right-hand side in experiment two, we see much less of an effect. And actually, it increases the expression of COL1A1. And COL1A1 is what we consider as one of the most important pro-fibrotic genes because it's driving the production of collagen, which is the main component of the fibrotic scar tissue. Turning now to the market. So the U.S. prevalence of fibrosis ILDs is about 400,000 patients. The separations between the different segments are not absolute. We know there's about 150,000 IPF patients in the U.S. We think there are about 70,000 to 100,000 patients with progressive pulmonary fibrosis. And then we see all the subsegmenting in terms of the different underlying diseases such as RA and scleroderma. So this is a huge market.
If we look at what the market is today with the two combined approved drugs being Ofev and Esbriet, it's about $4.1 billion. This is 2023. The majority of that is driven by Ofev, $3.8 billion. What we anticipate in terms of drivers of future market growth are some external factors such as an aging population and improved diagnosis. Notably, a lot of these patients are undertreated. The market is actually completely underpenetrated. We expect that bexotegrast will increase both treatment rate as well as duration on treatment. Because if you look at these numbers, they're kind of an eye-opener, I would say. This is the prevalence of IPF across the three main geographies. If you look at the total number of patients treated, it's about 60%.
If you look at the number of patients optimally treated with one of the two approved drugs, and optimally treated means they are on the right dose and they stay on drug, it's a fraction. It's less than 25% of patients. Actually, 60% of patients with diagnosed IPF will never see one of the two approved drugs. And the reason for that is that the available therapies have no impact on progression, have no impact on survival, have no impact on the quality of life. And often, there is an efficacy safety trade-off that results in a patient or a physician's refusal to receive or prescribe treatment. And so this intolerability leads to suboptimal dosing.
We have data, actually, if you look at the Galapagos data in the placebo group, 40% of patients in that placebo group were not on the correct dose in terms of standard of care and permanent discontinuation. So what does the market then look like in terms of growth potential? Today, it's about an estimated $4.6 billion. This is 2024. And some contribution from population growth and access, but the majority of the growth lies within treatment rate and persistence. Increasing the number of patients that are being treated and increasing the duration of treatment, making sure that these patients actually receive lifelong treatment. And that basically doubles the market size. Where do we fit in? bexotegrast is expected to address unmet needs in four different key patient segments.
So, active switchers, basically patients who decide to stop because of intolerability often or progression, patients that are treatment naive, never saw any treatment, patients that are untreated but discontinued a long time ago. And then finally, in a combination treatment setting, patients progressing on existing drugs. They still can continue. They can tolerate the drug, but would benefit from something that would help them to improve. So, switching our attention now to progressive pulmonary fibrosis. And what's the market opportunity there? And again, just to remind you, we will start a PPF trial mid-year. This is an additional indication to our program. It's called BEACON-PPF. Of course, our main competitors, Boehringer Ingelheim and BMS, are already testing their drugs in this indication. So, PPF has a high unmet medical need, which is very similar to IPF.
So in terms of the disease course, in terms of symptoms, in terms of mortality, it's very similar to IPF. Also, in terms of approach from a management and therapy perspective, PPF is very similar to IPF. However, the majority of PPF patients remain untreated. There's one drug approved, Ofev. Esbriet was never approved. And the estimations are that there are about 25%-30% of PPF patients actually receiving Ofev. There are a number of reasons. I mean, it's product-specific, but it's also launch-specific because this is a potentially different prescribing population. These are not necessarily pulmonologists. Often rheumatologists actually prescribe or at least are treating these patients. PPF potentially significantly expands the commercial potential of bexotegrast beyond IPF. The reason for that is that PPF, basically in terms of the addressable patient population, increases it with 100,000 just alone in the U.S.
We know from Ofev net sales that they actually grew the moment they were approved for PPF, while Esbriet basically remained flat. And why do we think bexotegrast works in PPF? Again, here we use explanted tissue from patients that are having lung transplant for lung fibrosis due to an underlying, I mean, because of PPF, not IPF. So these are tissues from three patients with hypersensitivity pneumonitis, HP, two patients with RA-ILD, two patients with scleroderma, and NSIP stands for nonspecific interstitial pneumonia. And what we see across the entire panel that we always test, we see a significant reduction in terms of pro-fibrotic gene expression. We see it on COL1A1 notably, and it's even better, slightly better than what we see with IPF. And we see a nice dose response if we look at the COL1A1 gene expression levels on the right-hand side.
Coming back to BEACON-IPF, so we will complete enrollment in the next couple of weeks in terms of our phase IIb study. The phase IIb study is 360 patients in total. The primary endpoint, the key primary endpoint, is change from baseline in absolute FVC. In terms of secondary endpoints, we look at time to progression. We look also at FVC changes in the subgroups, patients on monotherapy as well as in combination therapy. We look at a number of quality of life measures, including cough, because, of course, this will be a key differentiator, I think, versus some of the other existing drugs. And of course, safety and tolerability. And again, once we have the last patient-first visit, we will start enrolling our phase III. We haven't disclosed yet the number of patients there. It's, again, two doses, 160, 320.
We will provide additional updates on the size of the study and anticipated enrollment later. To conclude, a few words on the PET study. We did this collagen PET study in Mass General. This was a single-center study by Sydney Montesi. Looking at the quantification of type 1 collagen after 12 weeks of treatment with 160 milligrams, not 320. This was the mid-dose. And they have a specific, so Mass General, Peter Caravan has developed a very specific type 1 collagen PET ligand. It binds to collagen 1, both mature collagen 1 as well as soluble or freshly synthesized collagen. And it allows you to basically measure how much collagen there is in the lung. And they did a lot of titration and validation experiments before. What you see here on the right-hand side is a study that Dr.
Montesi did and published on in terms of the difference between patients with IPF versus healthy volunteers in terms of their level of collagen. And obviously, in IPF patients, it's more because they have fibrosis. Our study actually is the first interventional study. Now, if you look at the PET standardized uptake values at week 12, what we see is a reduction in post-treatment SUVs, indicating actually a reduction in total lung collagen. So we not only block it, we don't slow it. We actually reduce it. So this reduced post-treatment total lung collagen suggests that there is reversal of fibrosis happening. This is just an image, but it tells you a lot. On the two upper panels is a patient that's on bexotegrast, 160 milligrams. So more red means less collagen. More yellow or white means more collagen. And so these pictures were analyzed and picked blindly.
So we asked for two pictures that are kind of where we see a delta, but the analysis was done without knowing the therapy. And so participant A was on bexotegrast. We see a reduction in SUVs and a corresponding increase in forced vital capacity, 130 milliliters. And we see just the opposite in the placebo group. If we look at the overall FVC evolution over 12 weeks, we see a consistent improvement of FVC in the active group. So it's above baseline. It remains above baseline. And it remains separated from the placebo group. Interestingly enough, there is a correlation between the change in SUVs, so the amount of total lung collagen, and the change in FVC. But what was also noteworthy was the fact that these patients were more advanced. They had more cough at baseline. So it allowed us to really measure an effect on cough severity.
What we see in the placebo group is that the cough remains the same, actually starts increasing towards the end. In the treated group, we see a reduction of cough. What is not shown here is that when we stopped treating, the cough came back. Patients actually made a point about that, noting that something happened in terms of their cough, and it came back when the drug was stopped. We also noted that there's a correlation between change in cough severity and that it's predicted by change in FVC. Just one last minute. In terms of PLN-101095, this is our oncology program. It's a dual selective inhibitor of alpha-v beta-8 and alpha-v beta-1. It basically is aiming to reprogram the tumor microenvironment in terms of immune suppression. We know that tumor or immune exclusion in a tumor is driven by TGF-beta.
And so we try to block that. This is a small molecule. Twice-daily dosing has shown activity in multiple PD-1 resistant tumor models. And this is our clinical study design. We have completed the first three cohorts and started enrollment in the fourth cohort. We're looking at safety, looking at PK. We have some PD markers. The study is not really designed to look at anti-tumoral activity, but if it would be present, we will disclose that as well. Thank you for your attention, and happy to take any questions.
Well, great. Thanks, Bernard. And yes, we have some time for questions. I'll start. So I guess you kind of raised, at least non-clinically, some of the biomarker profiles, the effect on collagen expression between bexotegrast and probably one of your kind of chief development competitors here, nerandomilast. It's a mouthful. I guess from a clinical design or pivotal design perspective, how should we think about sort of any points of differentiation in the design of your BEACON phase IIb or phase III program relative to the FIBRONEER-IPF study?
It's basically identical, I would argue, so we basically use the same inclusion-exclusion criteria. Of course, we don't know all the details about all the biomarkers they use, but in terms of FVC, in terms of how we do the quality control in our studies, the powering, et cetera, is very, very similar to the two main competitors. Actually, it's a bit of copy-paste in terms of the different studies. Both Bristol and Boehringer are using very similar protocols, and so do we, and this is not only the case for IPF. It will also be the case for PPF. In PPF, we use progression criteria that were initially evaluated and used in the INBUILD trial. This is the one that led to the approval of Ofev in PPF, and so again, we use the same in terms of inclusion in our PPF trial.
And maybe what's worth noting, sorry, Eric, because I was just thinking about it. nerandomilast, in their phase 2a, they had about an 80-ml delta. And then recently, they announced, without giving much detail, that in the FIBRONEER study , they hit their primary endpoint. There's no mentioning of subgroups, dose, safety, tolerability, what have you, secondary, but at least they hit their primary endpoint, which I think bodes well for us as well because we had a very similar phase IIa design in terms of the type of patients, even the size, although they only tested one dose. We tested multiple doses. So I think where we had 140-ml delta versus placebo, the fact that they hit their primary in phase III, I think is very encouraging.
Yeah. Yes, it is an encouraging point, right, in terms of sort of operationally de-risking going from a phase IIa to a phase IIb or 3 trial. But it also sort of does beg the question about sort of competition in this space, assuming both products are ultimately successful and approved. I guess, how do you think about the competitive dynamic and just generally the incorporation of these different modalities? Is it more kind of a direct competition, or do you see potential or kind of need at some point for bexotegrast and nerandomilast to be used in combination?
Yeah, they didn't make it easy. I agree.
Practice.
At all parameters, even tougher. Anyway, no, I think, I mean, from a timing perspective, yes, you're right. Boehringer will be ahead of us. BMS, from a timing perspective, is very close to us if we think about projected NDA timelines, or at least when we get phase III data and their public disclosure of when they anticipate phase III data. It could be a couple of months. That could be a new entry into the market together with us. As it relates to Boehringer, let's wait for the data before I give you an answer to this question because they will probably present their IPF data and potentially PPF data as well.
We heard that they may have those data at the end of this quarter, early next quarter, and they probably wait till the American Thoracic Society meeting, ATS, here in San Francisco in May to kind of disclose that whole data set. It all depends, right? I mean, if they are hitting primaries and secondaries and their dose is clear, there are no safety or tolerability issues, and it's in combination or in monotherapy setting, obviously, this will be a very strong competitor, and we will have to think about how to deal with them. But I'm not sure that will be the case because they already have a very high incidence of diarrhea in monotherapy, and in combination therapy, it just basically doubles. So that could be already a first differentiator versus us if we can maintain the safety tolerability profile that we have seen so far.
But if it comes down to combination therapy, because it is possible, and I anticipate this field will evolve at some point to combination therapy, not with standard of care, but with all these novel agents coming into the market, our DDI potential is very low or not there. So we can be combined with a compound like nerandomilast. And from a mechanistic perspective, although it's very hard to imagine how a PDE4 can work as an antifibrotic, I mean, it's not overlapping. It is complementary. We're not addressing the same pathways. Again, let's wait for the data, and then we have to start kind of building our competitive profile versus notably the Boehringer drug. As for BMS, we need to see how it plays out in phase III.
The effect that they saw in phase IIb was very moderate, but actually, they doubled the dose for phase III, which then led to an increase probably of the hypotension. But again, those are data that we will see at a later point in time.
Just from a statistical analysis perspective or statistical assumptions going into the BEACON-IPF trial, can you just talk about some of the considerations there? I guess, what performance is the trial adequately sized to detect? And just sort of what are your expectations on placebo and performance?
So the phase IIb trial is powered at 80%. We haven't publicly disclosed the specific assumptions from a power perspective. But it's safe to say that we looked at historical trials in terms of variability, notably at the placebo groups, and there are quite a lot that you can use, as well as the effect size that we observed at 24 weeks and basically used that as assumed to be the effect size at 52 weeks. So extremely conservative estimations as it relates to the effect size, and we have powered towards that. As you know, we started the trial with 270 patients and changed that to 360 when we did the amendment for the seamless design because at that point in time, Galapagos had published their ISABELLA trial data, their big phase III, which failed.
But at least it taught us what the variability was in their placebo group, which was clearly higher than other historical data. And so we adjusted our power. So right now, from a variability perspective, our power for the phase IIb is towards, I would say, the worst-case scenario from a variability perspective, which is the Galapagos trial. We cannot change the size of the phase IIb. The 360 is what it is. And so that will be completed. We can change the size of the phase III as it goes along based on, and we don't disclose the current estimation. At some point, we will. But for example, a number of data sets will appear, including, I think, the most important one, the Boehringer data in May. We will have a close look at that and see how variability looks.
That will tell us if we are right in terms of power or if we have to add more patients. Overall, if we combine the two studies in terms of number of patients, we are basically in the same ballpark as the big phase IIIs that are currently being conducted. As you know, FIBRONEER is 1,200 patients, at least the IPF trial. And so the combination of our two studies is very close to that.
You're set on terms of, with respect to sizing BEACON-IPF. Nevertheless, is there still a futility analysis incorporated into the necessary?
No.
Okay.
No. Just we run it, finish it, and then it will be all top-line data.
Got it. Well, actually, no, let me just come back to the sort of market sizing. You did a number of slides here, which are great, kind of marking out the market opportunity, one of which is the fact that really just a lot of opportunity just in expanding the proportion of treated patients, right, and also them being adequately treated. I guess when looking at the proportion of treated patients right now, does that factor in sort of clinical benefit? What I mean to say is through not only better compliance, through tolerability, do you see a potential to sort of grow the market strictly through patients deriving benefit, staying on therapy longer?
Yeah, absolutely. And I think, I mean, it's longer duration because of better tolerability, but also the fact that, I mean, I think I had it on another slide I mentioned. So the efficacy-safety trade-off. So if you have a drug that does change outcome, it will pull those patients. I mean, it definitely will lower the barrier for patients to accept treatment. And again, 60% of IPF patients never see any of the standard of care drugs or approved drugs because of the perceived risk-benefit ratio being a lot of risk and no benefit. And so it's not only about lowering the risk and improving tolerability. It's also about being truly disease-modifying and changing the course of the disease, which I think is hard to capture in numbers because it's unclear how that will play out.
But definitely, I think that will be a key driver for our own success, notably when we consider some of the competitors that may come into the market, but where we have much less evidence that they are truly antifibrotic. Of course, we have done that collagen PET study that helps us to make that argument. I anticipate, and we already heard, that some other sponsors may use the same technology to start evaluating that as well. But I think this is the cough could be another key driver in terms of expansion, but it's hard to kind of quantify.
Just delving into the PPF opportunity, I guess, how does, I guess, relative to what we've observed in IPF translation from earlier stage development to later stage development, obviously, several instances of some amount of variability there, how do we think about sort of the predictiveness of earlier stage trials in PPF to later stage development? Is it a similar framework, or?
Yeah, I mean, we haven't done earlier stage PPF work. And actually, if we think about it, also BMS. I mean, BMS did a phase IIb in PPF. BI never did anything in PPF and then went straight from their smaller phase IIa IPF study into a large PPF trial. Of course, they have experience because of Ofev, right? It is a different patient population if we think about background therapy. But I think it could be more to our benefit than to our disadvantage. I mean, there's only 25%-30% of patients with PPF that are on Ofev. That means 75% of patients never saw standard of care or an approved drug. So you are truly. It's a very pure population in that sense.
What we have seen in IPF patients is, for example, in our and other trials, because of the long-term duration of, I mean, the standard of care has been approved for a decade or more. So a lot of patients have seen those drugs. And what we have seen in our trials is that notably patients that are on standard of care and are progressing or getting into the trial, these are the worst-off patients. They are on standard of care and continue to progress. Remember, we had all our placebo response rates on standard of care where we see the placebo FVC going down as if they were not taking even a drug, which was questioned initially, but everybody was seeing the same thing.
We don't have that issue with PPF where you still have a relatively new population in terms of experience with standard of care or with an approved drug like Ofev. So also, if you look at our human tissue data, we see a very profound response. So I anticipate that if anything, we should definitely be as good as what we see in IPF and in PPF as well from an effect size perspective. Those are the reasons we test two doses, right? So as you know, we do 160 and 320 milligrams in IPF. We anticipate 320 will outperform 160, but it's possible that with PPF, you end up with a lower dose potentially to see the same effect.
And maybe just from a trial execution standpoint, I guess, how does the ability and the efficiency of recruiting patients in a PPF trial compare with an IPF study?
It's very similar. We looked at that, and we are kind of already preparing for that. A lot of the existing centers will participate, and we will expand. The opportunity, of course, is in leveraging two studies. A key reason for screen failure in any IPF trial, including in ours, is the non-definitive diagnosis of IPF. So by definition, that's a PPF patient if he or she is progressing. And so you can basically run in and losing that patient in a screen failure, add that patient into your PPF trial.
Okay. Okay. Good point. All right. Well, I think we'll leave it there for time. So thanks everybody for joining the session. Thank you for the presentation, Bernard.
Thanks, Eric. Thank you.