Cantor Global Healthcare Conference. I'm Pete Stavropoulos, biotech analyst at Cantor. You know, with us, we have, Pliant Therapeutics, a company I do cover. Pleased to have with us, Bernard Coulie, the CEO, Keith Cummings, the CFO, and, Éric Lefebvre, the CMO. So, let's start off, if you can just, give us a brief overview, of the company and an introduction of yourselves.
Okay. So hello, I'm Bernard, CEO of the company, and I can give a brief overview of the company as such. So of course, we're a public company, focused on developing novel therapeutics for fibrotic diseases. Our lead program is a molecule called bexotograst, currently in phase 2b, phase 3 for idiopathic pulmonary fibrosis. We will discuss this probably during this conference. Also, expanding into progressive pulmonary fibrosis, which is another form of interstitial lung disease. The same molecule has also been evaluated in phase 2a in primary sclerosing cholangitis with positive data.
And then we have a pipeline of other products, a phase Ib program in oncology, and then one program in, muscular dystrophy and other related diseases, and then a wide pipeline of, all of them integrin-based small molecules that are kind of aimed at different forms of fibrosis. And I forgot to mention, our platform is basically, a small molecule, focused platform targeting integrins, which are key drivers of fibrosis.
Eric Lefebvre, Chief Medical Officer, and I've been with Pliant now for over six years. A little bit of myself. I've been over twenty years in pharma and biotech and working on fibrosis now for the last ten years.
I'm Keith Cummings, CFO. Been at Pliant for about going on six years now. I was an MD by training, but spent ten years in investment banking before this, so.
Excellent. Thank you. So, you know, let's start off with what the future holds for bexo beyond IPF and PSC programs. You know, then we can touch on some of the non-bexo programs. Can you just briefly talk about interstitial lung disease as a group, which I believe IPF falls under? And you know, do these fibrosing ILD indications overlap in disease pathophysiology? And sort of what I'm driving at is if an alpha V beta 6 alpha V beta 1 dual inhibitor like bexo could actually have you know clinical activity in these indications.
Yeah, absolutely. So let's start with the ILD space, right? So interstitial lung diseases are comprised of a number of different diseases that are not necessarily related, but that have... What they have in common is the fact that pulmonary fibrosis happens, often progressive. I mean, that's kind of where you want to focus because these are the patients that have the worst outcome. IPF constitutes about, it depends on the region, about 60% of that overall ILD population. So it is a very sizable group still of in terms of number of patients. ILDs outside of IPF are often related to connective tissue diseases or inflammatory conditions such as rheumatoid arthritis, scleroderma, rare forms of connective tissue disease, hypersensitivity pneumonitis, et cetera.
Although it's a very diverse group of diseases and the etiology is different, it looks like that the common pathway in terms of driving fibrosis is addressed by bexotograst. We know from our own internal data, and we have published on this as well, is that alpha V beta 1 and alpha V beta 6, so the two integrins that are targeted by bexo, are upregulated, notably alpha V beta 6, are upregulated in the lungs of patients with non-IPF interstitial lung disease, which just reflects the fact that this is a main driver of fibrosis. We use a lot of human tissue in terms of testing our drugs, tissue coming from patients with a specific lung fibrosis undergoing a lung transplant, and so which is, I think, pretty unique to Pliant in terms of kind of testing our drugs.
And so again, we have shown that our drug is equally potent in different forms of fibrosis. Again, we tested scleroderma, RA, and some other forms compared to IPF. And so obviously, this is a direction we want to go just based on mechanism of action and the fact that our main competitors are doing exactly the same. I mean, the addressable market is, if you look at the combined ILD space by 2034, according to our kind of estimates, and I would say confirmed by others, is about $10-11 billion. Right now, the market is about $4 billion, so that's kind of the anticipated increase in, you know, market growth over the next ten years.
If you look at incidence rates, I mean, right now, the number of patients in the US with IPF is around 140-150, and the estimates in terms of non-IPF ILD is about 100, so 250,000 patients in total in the US. You can add another 180,000 in Europe and about 60,000-70,000 in Japan. So in terms of seven major markets, I would argue 500,000 patients that have ILD, and we anticipate the incidence will just increase, so.
I mean, you did present a little bit of data, and you did mention it, earlier, you know, at ERS. Anything to really highlight about that before we move on to the next question?
Yeah, again, it kind of confirms what we just said, was like the effect of the drug is across different forms of lung fibrosis. And I think that to me is kind of the key driver to kind of step into this space. And our initial plan was to kind of wait for phase 2b data in IPF. I think a number of market changes have driven, you know, a decision to kind of, or at least we are evaluating, kind of accelerating that program. A little bit at risk without having the phase 2b data at, in IPF, but actually starting at the time that we will start our phase 3 in IPF, so somewhere next year. Again, competitors are moving forward, and I think we need to be there, right?
And the two main competitors being BI and BMS, and the other reality is, of course, IRA. So the faster we can have an approval in PPF that is as close as possible to IPF, the less the impact of IRA, you know, in the future.
Okay, you know, and in terms of a strategy, sort of a go-forward strategy, you know, would you actually do some type of umbrella study, you know, encompassing all of it, ILDs, or would you develop them as individual programs?
Yeah, I think for the moment being, and Eric, Eric can comment on this as well, if we look at what BMS is doing and Boehringer is doing, it's these are umbrella studies, right? I mean, if you look at the individual number of patients with a specific disease, like scleroderma-related lung fibrosis, I think the numbers are relatively low. So preferably an umbrella study in order to kind of get as many patients in as possible. We know Boehringer is running. I mean, the data have been disclosed, a 1,700 patient study in non-IPF ILD. I mean, just that has to be an umbrella study, otherwise, you can't get to those numbers. So ultimately, that's the plan.
Yeah, I think just maybe adding, the key is really finding the subsets of these different ILDs that have the patients that have more risk of progression. And that's usually easily defined by a CT scan, where you look at the extent of fibrosis in these individuals, and it's something that's been done before, so something that we would replicate, obviously.
How much, you know, heterogeneities are actually within a small group?
Yeah. I mean, for example, the cutoff that is used most often is a 10% extent of at least 10% of extent on fibrosis on CT scan, and that seems to identify the patients that are at greater risk of progression.
Okay, so you know, we can move on to, I guess your next asset that's in the clinic. Just briefly touch on it. It's the small molecule alpha V beta 8, alpha V beta 1 inhibitor for solid tumors, so you know, just give us a little bit of background on this molecule, sort of where it came from, and the rationale for going into oncology.
Yeah. So the molecule is homemade. So we are, you know, it comes out of our own chemistry efforts and screening. And again, an example of, you know, our integrin platform that is amenable to kind of identifying small molecules that are highly selective, potent, and safe, and addressing specific mechanisms that are relevant to different diseases. Now, oncology with originally, it was a plan B in case of, you know, Bexo wouldn't work, that at least we had a fallback position. Now, of course, with all the focus on Bexo, I think this program is less of a priority, and ultimately, we plan to partner it. So this is a phase 1b that's ongoing in all comers, solid tumors, patients that are resistant to Pembro, primary or secondary.
I mean, the protocol I don't think we need to go through that in detail. It's in our corporate deck. The mechanism of action is basically dual, so it blocks alpha V beta 8 and alpha V beta 1. Alpha V beta 1 we know is a strong antifibrotic mechanism, and so we anticipate that having antifibrotic activity in a tumor setting has impact on the tumor microenvironment, notably, for example, in highly fibrotic tumors like pancreatic tumors. Alpha V beta 8 is a known activator of TGF-beta within the context of resistance to anti-PD-1, so it kind of works in collaboration, I would say, with GARP, which is another target that FV is pursuing in that kind of similar indications.
Alpha V beta 8 activates TGF-beta in the tumor microenvironment, which leads to resistance by downregulating the immune response. Basically, it induces immune exclusion of the tumor and turns a cold, warm or hot tumor into a cold tumor. What we have shown is by switching off this mechanism, by blocking alpha V beta 8, we see kind of a change in the, you know, immune response in the sense that cytotoxic CD8+ T cells get activated and invade the tumor again, while the regulatory T cells are being downregulated. And so. That's the overall mechanism behind this. This is not just us who have found this. This was biology that was actually elucidated by, notably. Genentech has worked a lot on this specific mechanism.
There are a couple of other programs in the clinic, but all of them are antibodies and are Alpha V beta 8 specific, so currently phase 1b, we are in the third cohort. We anticipate to kind of continue dosing, and anticipate to have, by the end of the year, early 2025, a data set, that is covering safety, PK, as well as a number of biomarkers, and some clinical markers as well. But again, we plan to partner this program.
All right. I'm gonna ask Keith, you know, at what point would you partner this program? How much value do you actually want to
Yeah, well, I can't comment on what potential terms are, but, you know, what we think we need is what Bernard said. We need the package of safety PK data with some, you know, PD markers to, you know, see that we're having an effect on the tumor microenvironment. Once we have that, I think that's the time that we partner with them.
I mean, it's a known mechanism.
Yeah.
It's not that you have to educate potential buyers. There are people that know exactly what this, you know, what the impact could be, and I think the threshold issue is safety. Because other programs have hit some safety issues that were related to resensitizing towards Pembro, and then having Pembro side effects really breaking through. And so the question is, what's the optimal dose to kind of resensitize without having the typical side effects of Pembro, like the, you know, the rash, for example, and some other stuff.
Excellent. All right, so let's switch gears to your main program, bexotograst IPF. Before we get into that program, just want your take on the top-line data that was released yesterday from the FIBRONEER trial.
Yeah, top-line data.
I mean, I haven't seen many data. There was, like, no data, right? The top line, no data, but, I mean, all joking aside, I think this is, this is a very important milestone in this space. I mean, to... I mean, Boehringer mentioned it specifically in this their press release. This is the first phase III trial that succeeds in hitting their primary in the past, in over, like, 10 years. I mean, so I think that, that is key. It's key for the patient community to have success, and it's key for companies like ourselves to have success. Because I think the key message for me is their phase IIa kind of, you know, showed a clear effect, and that now is confirmed in the phase III.
There was a lot of skepticism in the, you know, community, patients community, investor community, even strategics: Are phase II data translatable into a phase III success? And I think Boehringer now has shown that that's the case. If we look at our own phase II data versus their phase II data, we had very similar effect in terms of active versus placebo, actually a little bit more. They had about a delta of 85 milliliters; we had 140 milliliters. Of course, these are relatively small studies, but the sample size was comparable between the two studies. The placebo response was comparable between the two studies. I think the only difference was the fact that they had a higher dropout rate and had diarrhea, which is a known side effect of PDE4 inhibition. We don't have that.
So I think this bodes well in terms of success from our phase 2b read out because, you know, in terms of power, et cetera, it's very similar to you know, the way Boehringer has approached this. So I think this is great news for everybody involved, but I would love to see the data.
Yes.
And so that's, you know, that's the advantage of, you know, a private company. They don't have to show it, but we anticipate to see it at ATS, probably next year, so.
All right, now, if we can talk a little bit about the IPF, the INTEGRIS study, you know, some of the key data highlights, and then roll right into the safety profile and compare it to BI's program, which I believe, you know, you've mentioned it had diarrhea at somewhere between the range of 17%-31% in phase 2. You know, and just how your profile compares to the other drugs out there.
Yeah, I mean, from a... You know, our study, the INTEGRIS-IPF study, was a study whose primary endpoint was safety and tolerability, and certainly, I think that coming out of the INTEGRIS program, we really have shown that this drug is well-tolerated, no dose relationship for adverse events, low rates of diarrhea. In fact, when we saw diarrhea, it was mostly when combined with nintedanib.
And it also, even in that setting, was less than what Boehringer saw with their PDE4 in their phase 2a, because we, you know, I think when you had standard of care was around 15% or 16% for our drug, there was around 36%, if I recall. So really different, different profile there. And, in terms of, you know, all the, efficacy endpoints, we looked at understanding that our our trial wasn't powered for efficacy. We looked at FVC. We saw, improvements in FVC that were statistically significant, especially at the 320 mg dose. We saw improvements there. We saw fewer, patients experiencing FVC percent predicted decline of 10% or greater. And then, and then that was really a striking dose relationship there.
We also saw that, if you look at the extent of fibrosis on CT scan, this is using a technology called QLF, or that stands for Quantitative Lung Fibrosis. Again, the two top doses provided the greatest effect, and then we saw an effect on cough at the 300-milligram dose and that 300-milligram dose also went to longer than 12 weeks. So it went to at least 24 weeks, and we saw good long-term safety there. The biomarkers as well, integrin beta 6, proC3, that are relevant to our mechanism of action. So it's really strong data coming from that program.
But then you also presented additional data here at ERS earlier this month, I believe, you know? And so just walk us through that data and how it sort of fits into the totality of what you've seen with the INTEGRIS.
Yeah. So it was a good, good conference. It was just, actually last week or ten days ago, that we had two late-breaker presentations at the conference, and one was on the collagen PET data. So this was a 12-week trial where we looked at the ability of bexotograst to reduce type one collagen content in the lung, so an in vivo imaging trial. We compared that to placebo. So it was a small trial, but a big result, if you wish, because we had 10 patients enrolled. We saw that bexotograst dosed at 160 milligrams, 'cause that... We didn't have coverage for the 320 when we launched into that study.... was able to reduce collagen deposition in the lung, in contrast to an increase seen over 12 weeks for placebo.
Most of these patients were treated with background therapy as well, so I think it's even more meaningful, and we saw an improvement in FVC at the 160 milligram dose, consistent with the INTEGRIS trial. We also saw a reduction in cough severity, and these patients in this study specifically had more severe cough at baseline, so more of an opportunity to show a change. And again, we saw integrin beta-6 levels, ProC3 levels going in the right direction, decreasing, and I would say that from the IPF community, this was really interesting work because it's the first interventional study that was able to measure that, and we don't have such data for other programs, right, at this point.
So that, that's a big, I think a big finding from a translational perspective. And then we had also another presentation. You mentioned the ILD work that we did using precision-cut tissue slices, where we saw that bexotograst also provided anti-fibrotic effects based on gene expression, and really opens the door to a potential PPF program. And then we looked at biomarkers as well. So quite an interesting conference for us.
So you did have also biomarkers from the INTEGRIS study, but you affected, if I read it correctly, biomarkers that change in ILD as well, in general?
That's right. I mean, and we, you know, integrin beta-6 level, that's what is If you look at the conclusion of our poster, for the biomarker evaluation, that's the most exciting one because there's been recent papers, one in ILD and one in IPF, that have shown that integrin beta-6 circulating levels are one of the highest predictive, factors for disease progression. And we affected, obviously, this, these integrin beta-6 levels in our trials, including that, you know, the other markers that are relevant, such as, PLAUR or UPAR, Spondin-1, and MMP-10.
So these are, you know, we really know from all the biomarker work that's been done in IPF, that some are more predictive, and we affect, I would say, you know, the more meaningful ones in IPF with our treatment, which is consistent with all the efficacy results we've seen as well.
Excellent. You know, I guess in the last six or so minutes, BEACON, the BEACON study. Let's touch on that, overall design and, sort of, you know, how the INTEGRIS data helped guide the design to increase the probability of success.
Yeah. Thank you. So, BEACON-IPF is our late-stage evaluation. It's being conducted as a seamless phase 2b/3 study, so there is actually two different independent studies in one master protocol. So it's very efficient from a development perspective because basically, the. You know, we have 360 patients participating to the phase IIb part. There will be two different doses, 160 and 320, compared to placebo. As soon as we enroll the 360th patient, then we start enrolling the phase III cohort. So it shaves about two years off the development timelines, which is meaningful, and that's something we're really excited about. The trial design, 52-week endpoint for both duration for both the phase 2b and phase 3 part, same eligibility criteria.
And then we will target to have at least 30% of patients that are not on background therapies to really start generating compelling data from a monotherapy perspective because we think that bexotograst truly has an opportunity to be used in first line as well. So we expect to finish enrollment of the phase IIb part in the first quarter of next year, and then to read out on the phase 2b evaluation in mid-2026.
Okay, just to make sure, so when phase IIb is completely enrolled, that triggers enrollment into the phase 3.
That's right.
There's no other gating factor.
That's right.
Okay, and also, did I hear 30% is the minimum?
Yes.
As a monotherapy?
Yes.
Okay, and then I guess, you know, the study, you know, was originally to enroll about, I think, 89 patients into each arm. You know, two active, one placebo, and then it was increased to about 120. So what drove that decision?
I mean, it was really the Galapagos phase III program, the ISABELLA program, which saw this largest standard deviations in FVC across all trials conducted to date. Given the fact that, you know, our phase 2b is powered as a pivotal, as I mentioned. So we wanted to make sure that we had the right power in phase 2b as well, and upsize the study to account for those. The more recent trials and the higher variability.
Great. Great, and, you know, what are some of the key secondary endpoints that you're going to assess? Perhaps, you know, how bexo impacts quality of life, sort of help differentiate the label
Yeah
should you get approved?
So the primary endpoint, obviously, is the absolute change in FVC, so that's what everybody uses for approval. And then also one of the key secondary endpoints is the time to disease progression. That's also a very common way. So it includes mortality, the change in FVC percent predicted of 10% or greater, and also the respiratory-related hospitalizations, so that's a composite endpoint. And then we will also measure QLF. So that's something we did in our INTEGRIS study, so we're going to be looking at that as well. And then we'll have a slew of biomarkers, including the ones that we've shown at ERS, that will be evaluated. And we'll look at,
In terms of quality of life, we have patient-reported outcomes, Living with Pulmonary Fibrosis and K-BILD, so those are the two most commonly used. They also have, you know, they capture activities of daily living, which is important for patients with IPF, but also the impact of cough.
Okay. And, can I just ask you how enrollment's proceeding? You know, any operational challenges because of, competitor programs?
Yeah, I mean, we've had competition from the start, but we're doing extremely well in terms of enrollment right now, with most of the regions and countries becoming online now. So I would say that we've reached the hockey stick of enrollment and really feel confident for the first quarter enrollment by next year.
Okay. And, I guess, you know, just briefly touch on the PSC program. You know, Keith, you know, possible strategies for moving that program forward?
Yeah, I mean, you know, it seems clear to us that the drug works in PSC. I mean, it's the second organ system that we've seen a broad anti-fibrotic effect from bexa, so we think it reads through well to IPF. Problem there is the path forward with regulatory. For us, based on what we know today, it doesn't make sense to put resources there when we can focus on progressive pulmonary fibrosis as a you know a big value driver for the company. So we will look to partner PSC in one way or another. And we're you know we'll have those discussions as we go forward.
Great. And, last question. You know, if we're sitting here a year from now, and I ask you, what have you, In the last twelve months, you know, what have been the key value-creating accomplishments for Pliant? You know, what would you like to say?
Yeah. Yeah, well, it's, you know, probably not the answer to your question, but executing efficiently and aggressively on BEACON has been the key value driver for the company. Getting the approvals and converting the trial into a seamless phase 2/3, phase 2b/3, is gonna take at least two years off of our time to phase III data. So, you know, that data is coming much, much faster than originally expected. And the translational work that we've done, whether it's the PET study that we've actually shown, maybe for the first time, an actual reversal of collagen production in the lung, you know, the other organ systems that we've tested, I think all those things have served to de-risk bexo as a program and I think build value there.
We will have data from our oncology program, potentially some BD around that program, that'll, you know, bring non-dilutive capital into the company. Could be a similar story with the DMD program. We're doing work around that we'll talk about at a later date, where we think we can broaden that, the DMD program, outside of muscle, outside of muscular dystrophy, and into other organ systems as well. So that could be a much more sizable program than what we initially thought. So that could also be a big value creator for us. But ultimately, over the next year, we're executing on BEACON.
Anything to add, Bernard, or?
No, I think another value driver remains the platform, right? I mean, we have a unique integrin, I mean, focused small molecule library that is very kind of diverse and can address multiple indications, multiple, you know, applications. So, we continue to kind of, you know, get interest in looking at, you know, what else can we do with those molecules that we cannot kind of cover? So, you know, maybe that could be another, you know, BD opportunity coming in the next 12 months. And we are the only player left in the integrin space right now with the acquisition of Morphic by Eli Lilly, so.
I think you have more. You have the fibrotic toolbox, you know, the atlas, you know? And so, you know, you have a whole set of tools, to move forward into different indications. So, thank you very much, for your time. I appreciate having you here. Look forward to, you know, keeping in touch throughout the year and watching the progress, and having you here in one year.
Thanks, Pete.[crosstalk]