Good day, everyone. Thank you for joining the 23rd Annual Needham Healthcare conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next presenting company, Pliant Therapeutics. Joining us today from Pliant is CEO Bernard Coulie and CMO Éric Lefebvre. For those of you joining on the webcast, if you want to ask a question, please do so at any time. You can submit a question using the chat box at the bottom of your screen. With that, we'll get started. Bernard and Éric, thank you so much for joining us today.
Thank you.
Thanks, Joey. Thanks for having us.
Well, let's start right off with the IPF program. You announced last month some updated development plans for your lead asset, bexotegrast, in IPF. You had originally planned separate trials here, and that's now changed to kind of an adaptive design. So first off, can you walk us through some of the changes?
Yeah. So the key change in the strategy here is that we now have an integration of the phase II-B and the phase III protocols under one master protocol. So that's really eliminating the gap between phase II-B and phase III that's applicable for more traditional development.
In terms of your discussion with regulators, what changed in these are always ongoing talks? What changed and what precipitated this change in the design?
Yeah. In our assessment, the seamless phase II-B/III design was really always the preferred scenario for us because it is eliminating the gap between phase II-B and III really expedites drug development. So it was always our preferred option. And we were very happy to announce that really across globally in this study now, we have the seamless protocol approved. So that's going to hopefully expedite the drug development piece and also accelerate time to NDA.
You mentioned timelines. What impact will these changes have on the timelines, and what gives you confidence that upsizing the Phase IIB portion here will allow you to remain on schedule for the data readout?
Yeah. So we expect just eliminating that gap in between phase II-B and III saves you about two years. That's what we expect as a difference for bringing in the time to NDA. So it's substantial. And the upsizing for the phase II-B portion that we've also announced is expected to have a limited impact on timelines to phase II-B readout because it will occur technically at the peak of enrollment. So we estimate that maybe at the longest, this is a quarter delay in terms of the phase II-B standalone scenario that we were discussing prior to this announcement.
I think you touched on it, but just in terms of the potential phase III, how much would this potentially shorten the time to phase III data or phase III start?
Yeah. I mean, it's the same, about two years is what we expect because, I mean, they're applicable for phase III, the time to readout, and also for the NDA, that's accelerated by approximately two years. And what's important also for folks to understand is that our phase II-B study is powered as a pivotal study, designed as a pivotal study. So it could serve as one of the two pivotals. So in fact, the phase III component that's embedded in the protocol could serve as a second confirmatory study. So that really is an exciting aspect of the seamless.
Yeah. That's a great point. Okay. So those are the recent changes. But I want to zoom out a little bit, big picture on IPF. Obviously, a big market here. Can you go over the treatment landscape? There are two marketed drugs, of course, Esbriet and Ofev. They're not particularly great IPF drugs, but still generating combined $4+ billion in sales. Maybe outline your latest thoughts on the addressable patients in IPF and what the unmet need is here given with those two approved drugs.
Yes, absolutely, Joey. So I mean, the addressable patient population in our models is about 150,000 right now. So we see an increase in incidence as the aging population increases. And this is typically a disease of older patients. At the same time, we anticipate that with new entries like ourselves, the number of patients that will be treated, that volume will increase as well based on the fact that there will be a better safety profile. These are drugs, or at least these new entries are mostly oral. Ones are twice daily dosing.
So there's a lot of upside potential, I think, in terms of those potential new entrants, including ourselves. So what is the medical need? So despite, I think, the standard of care that is available, or let's call it the approved anti-fibrotics, they do leave a lot of room for better options.
I think just looking at the discontinuation rates of the existing drugs, which are anywhere between, I would say, high 30%-mid 50% on an annual basis, basically, I think that already explains the potential. If you think about patients seeking treatment but not opting for the current treatment and looking for something new, we think that's about 40% of newly diagnosed patients. That also means that 60% of newly diagnosed patients actually are not seeking treatment or are not being put on the current approved drugs. I think there is a tremendous potential despite approved drugs only a limited number of patients kind of goes for that. Then of those patients that start on these approved drugs, we see a discontinuation between 30%-50%. Then I haven't even spoken about dose reductions.
This is something that starts to kind of pop up. We see it now in clinical studies where patients actually undergo a dose reduction into what we consider as a non-therapeutic dose, let's say 50% of the initial approved dose, just to mitigate or kind of control some of the side effects. So I think there is a tremendous potential there. And the way we look at our own drug is that we could capture potentially if you look at just patients that discontinue, we could capture about 60% of that in our models.
And if you just consider 1/3 of the patients that are seeking treatment but are not on standard of care, I mean, combined, this is like a $1.5 billion-$1.7 billion potential market. We have shown with our drug that we are providing additional benefit, efficacy on top of standard of care.
Also, combination with the existing drugs may be beneficial as well.
Another market question in IPF, and how the loss of exclusivity affect the IPF market? Esbriet was off patent in 2022, and I think Ofev is sometime in 2025. So what does that mean for potential new entrants such as bexotegrast?
Yeah. I think, I mean, definitely there is a drive or there will be a drive in terms of converting from branded to generic with the existing drugs. And we've seen that with pirfenidone. Generic pirfenidone starts to kind of eat into the branded pirfenidone prescription volume. But if you look at the overall picture here, price is not the barrier. Tolerability is the barrier for entry to these drugs. And so we don't anticipate that the entry of generics or loss of exclusivity will dramatically change that. I mean, the best example is that Ofev has continued to grow being branded versus pirfenidone, which is turning into a generic. So I think there is definitely I think that the bigger issue is tolerability versus price in terms of barrier to entry.
Got it. Competitive programs in IPF, there are a couple of them. I want to get your thoughts on kind of assessing the competitive landscape and the potential threats from these programs. I'll just mention a few. BMS has one in phase III, Boehringer. It's got another one in phase III. United has an inhaled drug in phase III, and there's a deuterated pirfenidone in phase II. I know that's a lot there, and you don't have to talk about each one specifically. But what are your high-level thoughts on what you think is going to win the market here and where Bexo can have the advantage?
Yeah. I think the two key competitors of the ones that you mentioned are Boehringer and BMS. I would argue just by the size of the companies themselves and their development and commercial power they have. The BMS LPAR-1 antagonist is definitely, I think, a competitor as we see it, although they had a modest effect in terms of effect on forced vital capacity in their phase IIb study on top of standard of care. At 12 weeks, about 29 mL improvement. What we saw was 140 mL improvement versus placebo with bexotegrast. So we think we may have an edge from an efficacy perspective, but of course, that needs to be kind of further explored in phase III. The LPAR-1 antagonist is also being studied for progressive pulmonary fibrosis. So it's definitely a field that we'd consider going into as well.
It has a side effect, hypotension, that's something we are aware of how much that's going to affect dropout rates in their clinical studies and potential kind of in terms of commercial potential, it's hard to say. The Boehringer PDE4 inhibitor is an interesting one. Unlike the LPAR-1 antagonist, unlike bexotegrast, the anti-fibrotic mode of action is unclear. PDE4 is an anti-inflammatory. It has some bronchodilation effects. I mean, it has been on the market for COPD. So it's unclear whether it has truly an anti-fibrotic effect. Despite that, of course, Boehringer is a very powerful player in the IPF space. So it's, I think, a formidable competitor. Big issue with the PDE4 inhibitor at the high dose, and this is a class effect, is diarrhea.
So combining that with one of the approved standard of care drugs, notably Boehringer's own Ofev, is going to be a problem because we already saw in phase II-A that they saw a doubling of diarrhea as a side effect when both drugs are combined. The inhaled treprostinil from United, interesting entrant. I mean, they saw a clear effect, of course, in PAH. They have some effect on lung fibrosis or ILD combined with PAH. Whether it's going to work in an IPF standalone without pulmonary arterial hypertension remains to be seen.
A sub-analysis that was recently published showed that there was actually no improvement on FVC in those patients that don't have pulmonary arterial hypertension and just standalone IPF. So I think some of the initial effects they saw on FVC could have been driven by vasodilation rather than a true anti-fibrotic effect. Also, it's an inhaled drug.
It's 12 administrations a day, so three times four administrations, which for an IPF patient is not trivial. I mean, patient compliance in terms of administration will be challenged. We saw that already in their reported data. And you need about 10 out of 12 successful inhalations to see a potential effect. So it remains to be seen. Deuterated pirfenidone is something that we don't really consider as a true competitor. I mean, it's a way to try to manage pirfenidone side effects by blunting the Cmax using this deuterated approach.
But whether the use of pirfenidone in IPF is a valuable and, I mean, a valid option in the future, I think, compared to some of the new entrants, probably not. If you think about the ideal product profile as we see it, it's oral, once or twice daily dosing, and a perfect safety profile and tolerability profile.
I think that probably will constitute about probably the majority of the future market.
Yeah. No, well said. Given those competitive programs, what impact do you think that will have on the Beacon enrollment? Do you see any headwinds there?
Well, I would say that we always plan for competition. We know that there are new entrants, and that's certainly something to always keep in mind. So we're set up for that. And I would say that in our multiple readouts for the INTEGRIS-IPF study, that's been given us a lot of opportunity to engage with the scientific community, KOLs, PIs. There's a great degree of enthusiasm on bexotegrast that really we can leverage for the purposes of enrollments. We've been active in terms of publishing these results. We've also had quite a few advisory boards around the data.
And I think what's come out of all that is that these KOLs and PIs understand the rationale for targeting TGF-β activation as a way to reduce fibrosis. So that's really important. They also are compelled by the efficacy signals we saw from that phase IIa study.
What's really been a big differentiator for them, and when you keep in mind what Bernard just said, is really the safety profile. Having a drug that they characterize themselves right before, even before any readout, was the, "Your drug is easy. Patients don't know what they're on. We don't know what they're on. It's very well tolerated." That's a big step up from existing therapies today. If the safety profiles continue to be what it is today and we continue to see efficacy results, I think we'll really be in a good shape. We're feeling confident that we can tackle the competition.
Got it. And moving to your phase II trial here, the Beacon, simple question, but quite challenging to maybe get arms around here for some investors. What are your expectations on the placebo response rates and perhaps the trajectory of that decline over time? How should we think about that?
Yeah. So we haven't disclosed the effect size that we expect to see at 52 weeks, but we've been talking in general terms about not having done any further extrapolation for the difference between active and placebo based on the 24-week results of the 320-mg cohorts. And in fact, if we're able to replicate that difference at 52 weeks, similar to what we saw at 24 weeks in INTEGRIS-IPF, that would be the success. And so therefore, we're not expecting that what we saw in 12 weeks in terms or 24 weeks in terms of the decrease on placebo would necessarily maintain, but the difference would maintain as compared to the 24-week results.
In terms of potential additional indications beyond IPF, what are your thoughts on development in interstitial lung disease, ILD, just given that Ofev is indicated for that, BMS is running trial in ILD? Do you have any plans to expand into that potentially?
Absolutely. I mean, we're very excited about this possibility. We're in the planning stages for that. Progressive pulmonary fibrosis is one of the indications that is sought out by our competitors right now. This is something that we also would be examining in our assessment. Positive phase II-B data from our IPF study, so the BEACON-IPF study, would also pave the way for a potential straight-to-phase III approach with a single dose of bexotegrast and to get a broader indication really from the get-go, or short after the initial IPF indication. For us, that would be a big plus. We know that the hurdle that this removes for physicians is that if you have a drug that's approved for the treatment of IPF, IPF is an exclusionary diagnosis, right?
So you have to eliminate all other causes of interstitial lung diseases before you can conclude that it's IPF, and then you can treat. So if you have a drug that's approved for the treatment of pulmonary fibrosis, for example, then you remove those hurdles, and you can treat patients with fibrosis when you are made aware that they're or you find that they have fibrosis, and the diagnosis piece can still take place, but at least the treatment isn't held up because of the diagnosis.
Got it. That makes sense. I want to switch now to from IPF to PSC, other program you have up and running. What's your latest take on the potential registrational endpoints for PSC? Right now, it looks like that it's still just strictly histological, so liver biopsy, fibrosis improvement. Is it still your sense that FDA still would want to see histology, even though there's lots of variability? And maybe as a follow-up, what endpoints do you think that the agency would be open to, and what could these be?
Yeah. It's a great question because currently, I mean, if you look at the two phase III programs that have taken place in PSC, they've both used the histology as a primary endpoint, and they define the endpoint as no progression of fibrosis. We're aware that the Gilead study was terminated, didn't meet the endpoint. I'm not sure if it's the endpoint or the drug. It's hard to tell. But the limitations for us in terms of histology is, first, it's not performed routinely as part of standard of care in PSC patients. There's a lot of the heterogeneity of liver fibrosis. It's referred to as a patchy disease in PSC. So it can really impact the histology endpoint that way. So we're very keen on exploring the potential for non-invasives as part of a pivotal endpoint.
We will be having a discussion with the FDA around mid-year this year to discuss clinical endpoints and the path to registration to really better understand what's the current thinking they have in terms of what it needs to get a drug approved in PSC. That's really something we'll be able to communicate once we have that guidance from the agency. We think that could really expedite our program, but also really enable other programs to move forward because I think the histology endpoint is a really big barrier, I think, to wanting to develop drugs in this indication.
Yeah. We thought some of the strongest data that you had in the 12-week PSC were MRI-related, in particular, the relative enhancement. Granted, it was a sub-study, so a smaller number of patients. But is this something you think could be part of a registrational endpoint? You're thinking you'd have a strong case for that?
Yeah. That one might be a little bit tougher, the gadoxetate contrast MR imaging. We're certainly planning to include it as a sub-study for late-stage development. But there's not a lot of data in PSC with this technology at the moment, even though the gadoxetate is used actually to detect cholangiocarcinoma. So it's an approved drug. But we use it in the sense to look at enhancement and also time to elimination to the common bile duct. So that's interesting. But I would say that if an MR technology would have a greater likelihood to make it as an endpoint, it would be MR elastography or liver stiffness. It is very accurate. However, the problem with MRE is that it's not very scalable. A lot of sites don't have access to it.
So when you're performing global studies, that makes it challenging to use it as a primary endpoint. But circulating biomarkers like ELF, for example, have a lot of data supporting, I mean, that endpoint. And so that's one that we'd be keen to explore with the agency and what it would take, for example, for it to be suitable as a primary endpoint in phase III.
You're set to announce 24-week data from the high dose, the 320-mg dose of bexotegrast in PSC, and believe it's middle of this year. What are expectations on the readout? Do you expect to see meaningful change or improvement across efficacy measures relative to what you saw in the 12-week data?
Yeah. So for us, the 24-week analysis was always to support the safety at the top dose for our program. So that's really going to be the key driver of any decisions made. And in fact, looking at the exploratory efficacy markers will be limited by the number of placebo participants that went beyond 12 weeks. So it's going to be the same situation, if you wish, as our IPF program. So we have limited ability to achieve any statistical significance on these endpoints, but we will report on them for completeness. But for us, the true dose ranging and the apples-to-apples comparison was the 12-week interim analysis. And this is what we'll be writing up for our FDA interaction as well.
Once you had the full dataset in PSC, including the 24-week data, would you move forward with the Bexo monotherapy in this indication, or are you still considering looking at some type of combo therapy? I guess what would be the next steps?
Yeah. I mean, I guess.
Oh, go ahead, Bernard. Go ahead.
Yeah. I think we are looking at both, basically. In terms of next steps, I mean, there are two key, I would say, conditions that need to be fulfilled. On one hand, we need to have feedback from the FDA that kind of resembles a developable product. I mean, in terms of development path, it needs to be feasible. Obviously, a 24-month biopsy-only type of trial in hundreds of patients is a challenge for a company like ours, and then have a negative at the end. That's not something that I think because of the endpoint, it's not something that we would consider doing, to be quite honest. So first, we need a feasible development path. And then second, additional cash.
So with the current cash, although we have plenty of it, the focus is truly on BEACON-IPF and then progressive pulmonary fibrosis as well once we have phase II-B data. PSC will, excuse me, require additional funding. That funding could be non-dilutive. I mean, obviously, we are looking at what is possible. In terms of combination therapy, I think it's an interesting venue to explore, and we're definitely looking at it. I mean, we have the in-house assays that you're familiar with, Joey, which is based on human tissue from patients with, for example, PSC. We have been looking at a combination of Bexo with some other potential drugs that could work in PSC based on mode of action, for example, anticholestatics. So I think there is definitely a rationale to combine.
But I think, again, that's an additional complexity in terms of development. So we know the drug works as monotherapy based on our phase II-A data. Combination therapy could potentially add some benefit there, but obviously also allows to kind of redefine the product as a new product. And that opens additional avenues, I mean, additional ways to kind of look at the product, thinking about partnership, thinking about a different type of development. So we are looking at both. So I think that's kind of where we are today.
Got it. Well, you have a couple of earlier stage programs I want to touch on in the few minutes we have left: oncology and muscular dystrophies. I want to start with 1095, the dual inhibitor alpha-v beta 8, alpha-v beta 1. Can you outline the rationale for the development in solid tumors here and why the combo with a PD-1 inhibitor?
So it is a well-known pathway, if you think about it. And we're not the only one developing an αvβ8 because that's what it is. It's targeting αvβ8 integrin as well as αvβ1. In that sense, it's unique. There are some other programs in the clinic targeting the same integrin, but those are antibody-based and focusing solely on αvβ8. So what does αvβ8 do? αvβ8 is expressed on immune cells in the tumor microenvironment as well as on tumor cells themselves. And so αvβ8 leads to activation of TGF-β in the tumor or in the tumor microenvironment. And activation of TGF-β, and this has been extensively published on, leads to resistance to checkpoint inhibitors. So TGF-β is the main driver of resistance to checkpoint inhibitors.
And so the idea blocking αvβ8 is to kind of change that balance and kind of make a tumor responsive again against a checkpoint inhibitor. So that's also the rationale to combine it with a checkpoint inhibitor as such. αvβ8 blockade on its own doesn't have a lot of single-agent activity. I mean, we see some in our models. But actually, the indication as we see it is really in combination with a checkpoint inhibitor in those patients that are not responding anymore to a checkpoint inhibitor. And that's also how the phase I study is designed.
Yeah. You mentioned the phase I dose escalation trial. You have it up and running in combo with Keytruda in solid tumors. Can you give a brief outline of that trial design, and when should we expect to see initial data from that?
Yeah. I can give you the design, and Bernard can talk about the data disclosure. But we are doing a multiple ascending dose study that goes straight into patients. So we're taking all comers in terms of tumors. They need to be refractory to a checkpoint inhibitor. And then they enter our study. We do a two-week monotherapy treatment with 101095, and then we add Pembro for the remainder. And then we take PK and safety assessments. There's a trial evaluation for response that occurs once the patients reach 14 weeks of treatment.
So they have a scan to look whether there's any improvement or stability in the tumor size, what have you. So now we're really moving forward in terms of the dose escalation, and we're at our third cohort. We've reported on the study design also as part of SITC last year.
We can be happy to provide more information from that perspective. I'll pass it over to Bernard for the readout.
Yeah. We anticipate to have data, and this is an open-label study, of course, to have data this year. The type of data that we plan to disclose right now, for sure, pharmacokinetic data, safety data, whether or not we will have, I mean, not true efficacy data, but potential biomarker data, that hint towards the intended biological effect is something that remains to be seen, could be this year, could be next year. But as we progress through the different cohorts, we plan to start releasing data from that study.
Great. The other program we want to touch on is your 1325 and development for muscular dystrophies. Quickly, what's the mechanistic rationale for this program and this particular indication? When could we see this potentially enter the clinic?
Yeah. I mean, the mechanism is a pretty unique one, but well-validated, at least in animal models as well as in human studies in terms of mutations in this specific target. The target is alpha-7 beta-1. It's a muscular integrin. It's upregulated in muscular dystrophies and acts as a compensation mechanism, as a compensatory mechanism when there is an abnormality in the dystrophin or dystroglycan pathway. We know that upregulation of alpha-7 beta-1 in muscular dystrophy models leads to an improvement of muscle function as well as an increased survival. The idea here is to use, in this case, an antibody, which is an allosteric activator of the receptor, thereby kind of pushing the compensatory mechanism to a higher level.
What we have seen in our mouse models and also human DMD muscle cells is that we see improved function, and we see improved survival of these muscle cells in muscular dystrophy. The advantage of kind of targeting this specific target is that it's independent of the underlying disease. So it doesn't really matter what the genetic defect is. So it could work in any form of muscular dystrophy, including Duchenne, including Becker. And also, it can be combined with any other kind of therapy, right, whether it's a gene therapy, a CRISPR-Cas approach, or even prednisolone.
It can be combined with any of the existing or at least treatments that are in development. So in terms of when we anticipate to see this entering the clinic, we anticipate somewhere this could be as early as this year. So we are kind of moving forward with this program.
It could be as early as this year.
No, that's great. Well, last one from us, Bernard and Éric, is cash. What's your current cash position and current runway expectations and any restrictions on loan facility that you have?
We don't have any restrictions on the loan facility. The current cash is around $495 million, which brings us comfortably into the second half of 2026. We have plenty of runway in view of our Phase IIB readout. Obviously, the focus will be in terms of deployment of funding towards BEACON-IPF and some of the earlier- stage programs. And then, as I mentioned before, PSC will require additional cash if we plan to kind of continue development.
Great. Well, thank you so much, Bernard and Éric, for participating. It was a very informative discussion.
Thank you for having us.
Thanks, Joey. Thanks for your time.
Yeah. Thanks, everyone, for joining us on the webcast. Have a good day and a good rest of the conference.
Thank you.