Pliant Therapeutics Inc Aktie

Senior biotech analyst here at RBC Capital Markets. Our next presenting company is Pliant Therapeutics, represented by the President and CEO, Bernard Coulie. Bernard, thanks again for being here.

Thank you. Thanks for having us.

So maybe let's kick things off on 095. You guys had updated the dose escalation data recently at the AACR conference. Can you maybe talk a little bit about maybe the program overall and what you guys are seeing with regards to longer follow-up and responses in patients still on treatment that has, I guess, continued to foster enthusiasm around the program.

Yes, absolutely. So 101095 is a small molecule, so twice daily dosing, oral. It's an integrin blocker, av?8, av?1, 2 key integrins in the tumor microenvironment. av?8 is expressed on both tumor cells as well as inflammatory cells and av?1 is expressed on. So the idea behind or the hypothesis behind the program is blocking TGF-? in terms of converting from latent to active or even blocking the interaction between TGF-? and its receptor because TGF-? is thought to be a key driver of immune exclusion in these tumors in response to checkpoint inhibitors.

And so the first kind of hypothesis is like by blocking the conversion of TGF-?, we will resensitize refractory tumors. Tumors -- I mean, refractory to checkpoint inhibitors. So the initial data set in December, which was a very small Phase Ia, 16 patients in total, 5 different dose cohorts, we started to see -- from the mid-dose on, we started to see interesting responders. And so we had 4 out of 13 patients that had a response. One was a complete, 2 -- 3 were partial responders.

At that time, median duration of response was 15 months. Average tumor reduction in terms of size was around 70%, if I remember well. But what was even more interesting was that the design of the study is such that you give 14 days of monotherapy with a small molecule followed by a rechallenge with an ICI, KEYTRUDA in our case.

And so what we saw was that after 14 days with just our drug, in the responders only, we saw this surge of interferon gamma. So it went up anywhere between 3 and 12x versus baseline over a very short period of time. The complete responder, which is a cholangiocarcinoma, which went through 5 lines of therapy and was progressing actually had the 12x surge in terms of interferon gamma.

So at AACR, we presented an update on this study. I mean -- and by the way, the drug is well tolerated. I mean, safe. We didn't see any major side effects except rash in about 40% of patients, which was mild to moderate. So the updated AACR that was given by Tim Yap, Dr. Yap at MD Anderson -- from MD Anderson.

In the meantime, the average duration has increased to 19 months. Actually, the cholangiocarcinoma patient has passed 24 months now. So it's 2 years complete response for a cholangio patient, I think average PFS is less than 3 months, right?

So the second patient is a melanoma patient. That patient has passed, I think, 80 weeks now. The third non-small cell was a -- turned out, and this was also an update at AACR was actually a complete responder in the target lesion, but a confirmed partial responder in a nontarget bone lesion. Now we never did a PET ligand, a PET study to see if that was actually a true met or not, so -- which is unfortunate, but it's what it is. That patient started to progress after week 58. So that's not a responder anymore. And again, safety, same. So very, very promising data. So I think based on that, we decided to start our Phase Ib study.

Yes. So let's talk about the Phase Ib a little bit more, the dose expansion cohort, combo, pembro following the 14-day monotherapy run. And just maybe the rationale for going after ccRCC, TMB-High tumors, non-small cell. Just how you guys sort of thought about the optimization of the dosing and the dose levels and indications?

Yes. Maybe starting with the dose. So the dose we're going to use in our Phase Ib, that's actually ongoing. First patient in was announced a couple of weeks ago. And actually, in the meantime, patients -- we have additional patients that were enrolled.

The dose we're going to move forward, at least in this Phase Ib is 1 gram twice daily. So 1,000 milligrams twice daily. That was the dose at which we started to see the effect in our Phase Ia. So we only had 3 patients at the lower doses, 250 milligram twice daily and 500 milligram twice daily. So it was a rapid dose escalation. So moving forward, the mid-dose from our Phase Ia will be the selected dose for the Phase Ib.

So the rationale behind choosing the different cohorts, non-small cell, out of the 3 patients that were enrolled in the first part of the study where they were non-small cell lung cancer patients, one never got into the combination because it didn't go through DLT period. But the 2 ones that went into a combo, one of which was a complete responder in the target lesion. And the other one was actually at the lowest dose, the primary refractory had stable disease and never responded to ICIs before.

So there is kind of, I would say, hypothesis that these kind of patients may be more susceptible to our approach. So that's the reason to use non-small cell. It's both TMB-High and TMB -- non-TMB-High for the non-small cell ratio of about 60% to 40%.

For the second cohort, that's renal cell carcinoma, this is a prototype tumor for us that has a highly inflamed TME, so tumor microenvironment. So it could be a prototype for HCC, head and neck. And so that's the reason to kind of choose that one because that's where we feel that a TGF-?-based approach makes a lot of sense. And also on top of that, Scholar Rock published actually data with their TGF-? latent TGF-? stabilizing approach, which is an antibody with an ORR of, I think, 25%, if I remember well, in renal cell carcinoma. So there is definitely evidence that TGF-? may be relevant for that type of tumor.

And then the third one is TMB-High, right? We saw 3 out of 4 responders in our Phase I were TMB-high patients. So we're going for a TMB-High cohort as well, which includes melanoma, colorectal, urothelial, endometrial and then of course, biliary tract. So cholangiocarcinoma seems to be a very interesting one that we want to pursue.

And when might we see some initial data from the dose expansion in these indications?

So I mean, starting '27. I mean it's hard to pinpoint a month because let's see how fast it goes and if patients stay on treatment. So again, it's 14 days of run-in in monotherapy and then scans every 9 weeks. So the rechallenge with the ICI happens after at day 14. So first patient is in. So I hope to see data starting in the spring of '27.

And what do you think are the most important elements for discerning 095's monotherapy contribution to activity? Is it the dose dependence that you're seeing? Is it the interferon gamma spike that you wouldn't otherwise see? Are there -- is it too early to benchmark the response rates you're seeing versus what you would expect with pembro alone? I guess what drives the most confidence?

Yes. I mean the ORR is to kind of compare that with historical ORR is a little bit tricky because the sample size is so small and it's a little bit all over the place as it relates to indications, right? And so it's -- I mean we have a bar and we can discuss it, what is the efficacy bar that we want to reach? But coming back to the Phase I, I think the one -- maybe 2 components that I think really provided us the conviction that this made it convincing that this is kind of really working on its own in combination -- I mean it's triggering the effect, and it's not just a challenge of the immune checkpoint inhibitor is the interferon gamma, to your point. I mean it's a one-to-one correlation in terms of the surge in interferon gamma and a response.

And the second one is the durability. I mean the fact that you have a cholangiocarcinoma patient who has passed 24 months now that was progressing...

Progressing...

That's not what you would expect. And I think that -- those are 2 components. The overall ORR was 30%. DCR 60%. So those are very good numbers, but a small sample size. What we haven't published and haven't publicly disclosed our ctDNA levels. We have those for the 4 responders and to say the least, they're very interesting. So there may be something there as well, and this is something that we will measure in our Phase Ib.

And then coming back to the Phase Ib, really kind of coming back to your question, how sure will you be about the effect of the drug itself? It will be the monotherapy 14 days that will learn us a lot in terms of all the different biomarkers we're going to measure. And then, of course, we're going to do tumor biopsies as well at start and then a couple of weeks into treatment because that will help us also to understand which patients are responding from a tumor microenvironment perspective.

And then maybe just a question or two more on 095, and I want to leave some time for the platform as well. So could you envision this being used in patients primarily with increased av?8 expression? Or do you think that just the expression of av?8 is sufficiently broad that you wouldn't necessarily be narrowing the eligible population?

It's an excellent question. And I think the answer will be, let's see what the data, the biopsy data are telling us. av?8 is constitutively expressed on T cells, on T lymphocytes, on activated T lymphocytes. So probably most patients have av?8 in their tumor microenvironment. The question is, what is the relative contribution of that compartment to the overall effect of our drug because av?8 is also expressed on tumor cells, and we will learn much more about that. And that is not necessarily correlated, whether it's -- if it's expressed on the inflammatory cells, will it be expressed on tumor cells as well? We don't know.

And then there is av?1, which may be an interesting contributor to the overall effect as well. We know that there are other programs that have been pursued or still being pursued with an antibody against av?8, in some cases, not a lot of results in one case of which we know probably a very severe toxicity related to rash. And then we are aware, and it's not in the public domain that Genentech is moving forward with their av?8 antibody program as well. And that's earlier stage compared to ours.

And then you guys have been really on the forefront of the integrin pathway for multiple indications. And obviously, things have had -- didn't work out in IPF necessarily, but there's been a lot of now advances that you guys are on the cutting edge on in cancer. But I know there's also ways you can leverage the platform for elements of drug delivery, delivery of siRNA. So can you talk a little bit about where you guys stand with regards to some of the preclinical studies you're doing to that effect and where you see this being differentiated versus kind of the other targeting delivery systems out there for siRNA?

So over the 10 years of our existence, we have built, I think, an unmatched small molecule library of integrin targets -- I mean targeting small molecules. And basically, we -- that library is about 15,000 compounds, I think, is completely annotated. So we know exactly the receptor profile of each of those small molecules.

And of course, seeing what was happening in the space of delivery, drug delivery, whether it's siRNA or like ADCs or what have you, integrins are a target that people are pursuing and are looking at. So we decided to kind of see if we could do the same with a small molecule approach because all the other approaches are antibody-based or peptide-based. The advantages of a small molecule, I think, are pretty obvious, but we can go through that.

In any case, what we did was we started basically labeling a whole bunch of small molecules with siRNA that knocks down a host gene and then just injected in mice. And then just harvest all the tissues and then looked where do we have knockdown. And so that's how we started to see the differences between the different profiles and the selectivity of certain compounds and maybe not so selective of other compounds.

And so what we are doing today is moving forward with some of those individual molecules with specific target genes that are relevant for certain indications. So our initial work was done in muscle. It's an easy target. We know what kind of target genes you're going after, and we have comparators. We have benchmarks like Sarepta, for example, or the transferrin receptor antibody approach. We did it in adipocytes. It works as well. Whether that's an indication we want to pursue, I'm not sure. We see it in kidney. And now we start seeing it -- and we have done it in lung as well because av?6 is a typical epithelial lung target. av?1 is a fibroblast target. So that could be a potential target cell as well. And now we start to also evaluate what is considered as intractable targets or intractable -- sorry, tissues that with standard siRNA delivery technologies, you cannot reach. And so we start to explore whether that would make sense for us as well.

And so what's the status of the preclinical data package now at this point? And what are your latest thoughts about when we might see an update there? Is that something we could see this year? And what would be the initial scope when you do report out some of these findings?

Yes. So the muscle program is the furthest advanced. So that's currently in nonhuman primate testing stage. So looking at PK/PD, local delivery, target gene knockdown, circulating biomarkers, what have you, we haven't disclosed the target in terms of the integrin that we are using or integrins. We haven't disclosed the target gene as it relates to the muscle itself. So that will follow.

Most aggressive time line could be an IND by the end of '27, early '28, if that's the one we want to pursue. But of course, again, it's crowded. And then the other platform development, tissue-specific platform developments are, I would say, most of them are mouse stage right now. And we anticipate we'll go to nonhuman primates later this year or early next year.

From a data disclosure perspective, we will -- we anticipate to disclose data this year. What the scope of that data set will be needs to be determined because the question will be, is this just a data set without any further context? Or are we going to be a little bit more specific about indications that we want to pursue, et cetera, right?

Right. And then you sort of alluded to some of the potential advantages that a small molecule approach might have over a peptide-based approach. So I guess are there any read-throughs that you see from some of the av?6 targeting siRNA data from in FSHD and DM1 that Sarepta and Arrowhead reported? And maybe can you talk about where you see any potential advantages for a small molecule muscle targeting approach?

Yes. So I mean, the Sarepta data, I think, show that in their case, an av?6 targeting peptide actually works, right? It does deliver siRNA to the tissue. I mean, although they didn't do a head-to-head, they did show from a tissue concentration perspective that with their approach, even at, if I remember well, the mid-dose, they see kind of a fourfold higher concentration of their siRNA. This is in the DUX4 patient population compared to transferrin receptor antibody approaches that were published by Avidity before. So it was a comparison based on historical data, not a head-to-head comparison. But I think it makes sense.

So they're using a peptide that is targeting av?6. It's an RGD peptide. So it has a -- the head of the peptide is an RGD sequence, which binds to RGD-binding integrins like av?6, but also av?1, ?5, ?3 and ?8. so selectivity could be a challenge. And the way to address that is adding more amino acids to the peptide and trying to kind of make it more selective.

The other -- it's a bulky protein or a bulky molecule because they add -- and this comes from the Arrowhead technology, they add lipids to it in order to increase its plasma exposure, its half-life. These PK enhancers, as they are called, are meant to increase plasma protein binding in order to prevent renal clearance because peptides and siRNA are renally cleared. Our small molecules are metabolized in the liver. They're not renally cleared and have a high plasma protein binding and long half-life, notably once we go to higher species.

We will show the mouse data at some point. Those are non-modified small molecules plus an siRNA with a linker in between. We know that the half-life of our small molecules in mice is anywhere between 1 hour and 2 hours, still 3 administrations, and we see months of knockdown. So it seems that exposure may not be the issue. And so our molecules can be much less bulky than the Sarepta approach, maybe leading to higher efficiency from an uptake perspective or endocytosis perspective.

I think it also potentially provides an advantage in terms of endosomal escape. But notably, subcu administration seems to be very feasible. I mean these are highly soluble molecules. So I think that's -- I mean it's an administration, whether that's a key advantage, I don't know.

I want to go back to the platform. I mean it's not just about the muscle versus Sarepta. It's actually about any other tissue that we can deliver to -- with our technology. So whether it's Sarepta or the transferrin approach, which are very nonselective, what we have seen in mice is uptake in skeletal muscle and nothing in cardiac muscle, nothing in lung, nothing in liver, nothing in fat.

So those -- we want to confirm that in monkeys as well, but it seems that working with these different integrins, you are able to kind of dial in selectivity as you wish, which allows you to go after other target genes, right? Because the way the transferrin approach is being made selective is by going for selective genes, myostatin, DUX4 that are specific. We don't know what all...

Selectivity you shouldn't need.

You can go after more you can go after specific targets that are expressed somewhere else, but you're not going to touch because you're not going to get into that cell. And ultimately, we don't really know what all this accumulation of siRNA in cells. I mean from -- I mean, there's not a lot of tox evidence, except for transferrin receptor antibody approaches definitely have their safety issues, for sure.

Maybe just in the last few minutes, you guys have undergone such a transformation in the past few years. I guess what would be your key takeaways for folks today looking at Pliant now for the next 6, 12, 24 months as to what are going to be some of the key de-risking catalysts and the key aspects of maturity of some of these new initiatives that seem to be gaining a lot of steam.

Yes. I mean, first and foremost, 2 biggest assets we have is cash and people. I mean, obviously, we restructured the company to a very significant degree. I mean we're very open about that. We were 170-plus when we were in a pivotal IPF trial, and we are about 40-plus now. So there is a significant reduction, but we kept the core development capability, which is something we have been always very, very good at. We were able to enroll an IPF trial in record time. It was 200 -- sorry, 360 patients and get to unfortunate data quickly, which allowed us to preserve cash, right? And so we have a core development team that will -- is already excelling as it relates to the oncology trial.

And then we have that integrin platform. And so I think that's where we see our strength is really kind of we have enough cash. We have people. We can kind of make that pivot successfully. And so what is for the next 12 months? Obviously, the oncology data will tell us a lot. I think it's extremely promising. If we could confirm what we have seen in Phase Ia, I think this could be a very interesting asset.

And I know investors are a bit like IO-IO again, and a lot of people have been burned. I can tell you, strategics do look at this differently. And notably, the interferon gamma is a signal that everybody is focused on. And then the platform, right? I mean this could be a game changer for the company. But first, we need to confirm and it's still 2 years from the clinic. So that's still a lot of work to be done.

It's a minimal investment right now because its existing chemistry and then a linker and siRNA is literally off the shelf these days. You have excellent CDMOs that can make it for you. Running these monkey studies, I mean, it's a bit capital-intensive. It's not the same as running a clinical trial. So let's see where we get and then start to kind of identify what we consider as programs that will make us very competitive.

I mean going after Sarepta with another DUX4, I mean, we need to have a clear upside there if we want to do that. But there may be other things that we can go after. So I mean catalyst in 2026, very much essentially these data, the siRNA data and then '27 will be catalyst-rich because all those cohorts will be almost fully enrolled, and we will start to see a lot of data. I mean the total number of patients is ultimately up to 106, if I remember well. It's 36 per cohort. 108 -- sorry, 108 patients in total.

Excellent.

Thank you.

Thanks so much. Congrats on all the progress. Appreciate it. Thanks. Thanks, everyone.

Thanks so much, Brian.

Good afternoon, everyone, and welcome back to Oppenheimer's 36th Annual Healthcare Conference. I'm Jeff Jones, one of the biotech analysts on the team here. I'm delighted to welcome from Pliant Therapeutics, Bernard Coulie and Keith Cummings, CEO and CFO, respectively. So gentlemen, welcome. And of course, since you're on the East Coast, hope -- or on the West Coast, I hope you've got better weather than we do out here.

So well, 2025 was really a major year of transition for you guys at Pliant. Bernard, why don't you give us just a little bit of a feel for how you're positioning the story today, obviously, transitioning to oncology. But why don't you just give an introduction.

Absolutely, and thanks for having us, Jeff. Very much appreciate it. As you know, of course, we are an integrin small molecule platform company. Over the past 10 years, we have developed a library of small molecules and a biology platform that helped us to kind of really elucidate all of these different receptors in different disease systems and indications. And our initial focus was, of course, on fibrosis. With stopping the program last year, we obviously had to kind of rethink how to kind of continue the company. And I think there was no better way than to focus again on that integrin platform.

So while doing that, we have and are in the process of developing a pipeline of products that are based on that unique integrin-targeting small molecule platform. Our most advanced program is PLN-101095, which is a dual av?8 and av?1 integrin small molecule blocker. Not for fibrosis, but as you mentioned, in oncology, we had a readout of our initial Phase I, which was a safety PK type of study in all-comers, patients refractory to immune checkpoint inhibitors, solid tumors, that showed very encouraging data, although the study wasn't designed to kind of really look for clinical responses.

We saw a number of very interesting data, both related to clinical response as well as to a number of biomarker readouts, and we will, of course, dig into this in more detail. Furthermore, we have earlier-stage programs, again, based on our integrin platform, and I would like to mention specifically a targeted drug delivery platform that we are started to build. And this is based on siRNA molecules that are linked to our small molecule integrin or integrin-binding small molecules, basically serving as warheads to deliver a payload to cells. And this is in a very specific and very selective manner.

And the reason we can do this is because of course, we master that chemistry as it relates to designing small molecules that are very selective to certain integrin receptors. We do know from a biology perspective, the expression patterns of specific cell types, as it relates to specific integrins. And for example, we can deliver siRNA in a highly select manner to, let's say, muscle cells or adipocytes without touching any other tissue.

And we have built this platform. We have products that are moving forward, all the initial work was done in murine models. Right now, we are kind of confirming what we have seen in terms of targeted delivery of these siRNAs with concomitant knockdown of a target gene -- therapeutic gene in nonhuman primates. And we anticipate to have data later this year, probably towards the end of the second quarter as we are dosing the nonhuman primates as we speak.

So I think those are kind of the key kind of new areas of focus, but all based on that same platform that we have been building for the past 10 years.

Okay. And so would it be fair to say that you're spending less time or you shifted away from exploring business development and licensing, which was the -- maybe the message shortly after the IPF transition.

Yes. This was, of course -- I mean we haven't shifted away from that entirely. Let me make that very clear. We continue to evaluate external opportunities, external assets for potential in-licensing or acquisition. Clinical stage assets, mostly small molecules or antibodies in a relatively broad spectrum of indications and that hasn't changed. So I would argue, cardio-metabolic, pulmonary, I&I in general, but also, of course, oncology as long as there is a complementarity to our existing oncology program. But the oncology program right now, based on the data we have generated made last year is kind of moving forward. If there is anything else, we can add to that to strengthen that pipeline and to increase shareholder value, we will definitely do that. So we haven't moved away from that entirely.

All right. So why don't we dig into 1095 and talk about this as a program in the data you've put out relatively recently. The target av?8, av?1, can you talk about the role of those integrins and checkpoint reexistence and maybe set the stage with the TGF-beta pathway there.

Absolutely. So PLN-101095, just to make that clear, is a small molecule, so it's orally administered twice daily. So in response to immune activity, sustained immune activity, tumors will express both av?8 and av?1. They will utilize this basically to mediate activation of TGF-beta. So TGF-beta is being activated by these 2 integrins in the tumor microenvironment. Av?1 are -- receptors are expressed on CAFs, on cancer-associated fibroblast, well, av?8 is expressed on tumor cells as well as on regulatory T cells. So what happens is TGF-beta gets activated and basically through that activation, it will reduce the -- or will induce immune suppression leading to a reduced immune response of the tumor, whether it's by the patient's own immune system or a checkpoint inhibitor. And so by blocking that conversion, by blocking these integrins, we will block the conversion of latent to active TGF-beta, thereby reducing the TGF-beta tone in the tumor micro environment and basically taking away that immune suppression that -- basically escaping from the immune response and reestablishing immune-sensitive environment as such.

So what will happen is TGF-beta gets reduced, interferon-gamma will increase again and hence, checkpoint inhibitors or the patient's own immune system may attack the tumor. That's basically the whole principle behind this. And this is, I mean, well-established biology, this is not something that we all figured out ourselves. This has been around, and of course, the role of TGF-beta in cancer therapy has been studied extensively, I think one of the key issues with TGF-beta inhibition systemically is tolerability and safety even in patients with cancer. And so our approach, again, is very tumor specific. It doesn't suppress TGF-beta systemically. It only suppresses there where the receptors are expressed notably in the tumor microenvironment.

All right. And so given you're effectively reestablishing the immune sensitivity of these tumors. We should be thinking about this as not single agent activity, but essentially reestablishing activity of checkpoint inhibitors. Would that be right?

That's the basis, right? I think that I would consider that as the basis, and that's what we have shown so far. However, interestingly enough, I mean, the design of the Phase I study was basically 14 days of a lead-in period with a monotherapy setting with PLN-101095, after which in our case, pembro as the checkpoint inhibitor, was introduced. And what we see in those 14 days, although it's too short to see a clinical response, obviously, in terms of tumor size reduction. What we do see are significant changes -- very significant changes in a number of biomarkers, notably interferon gamma in those patients that would respond to reintroduction of pembro.

And so what we see from a biomarker perspective in patients that are responders, meaning that there is a resetting of their immune sensitivity is 3- to 12-fold increase of interferon gamma over 14 days between baseline and 14 days later, which lasts for about 28 days after which it starts to decline. So with that in mind, so we do see an interesting signal in a monotherapy setting, not just in combination, and we did see clear evidence for monotherapy efficacy in a number of different animal models.

So taken together, we definitely plan to kind of evaluate our drug also in the monotherapy setting, albeit not right now. So in terms of next phase of development, we are initiating a Phase Ib dose expansion study. That will be first patient in probably second quarter, definitely second quarter of this year. And so that will be in combination with pembro. Based on those initial response results, we will identify an indication where we feel like we can kind of try to evaluate monotherapy as well.

Okay. And in the Phase I, I guess, the -- you saw some responses across non-small cell melanoma, cholangiocarcinoma, for that -- for your next trial, are you going to limit the enrollment to those tumor groups? Or how are you thinking about selecting patients for those tumors or for the trial.

So we will -- I mean more detail will follow during our fourth quarter financial update. But high level, what I can give you is basically we will limit the number of indications, but actually still wanting to make sure that we don't miss anything. So we will have a cohort with small -- non-small cell lung cancer because obviously, we saw the effect there. We do see, amongst the responders, we have evaluated in our Phase I -- initial Phase I, we see that all responders had a tumor mutation burden that was high at inclusion. So we will include that also as a separate cohort. And that will be a number of different tumor types that will be studied and more detail will follow.

Now we have a third cohort, which will be renal cell carcinoma. And that's, again, based on av?8 expression profiles as well as previous data with other anti-TGF-beta approaches showing a clear effect in that tumor type. So anyway, that's kind of the overall design. And as I mentioned -- I mean all the preparations have started, and we anticipate to have our Phase Ib first patient in second quarter this year.

And is -- I mean, we've talked a bit about the mechanism of action here. And as you noted, the renal data, which has some validation based on what AbbVie is doing. It's probably worth highlighting some of the other validation that's been generated, not necessarily this av?8 and av?1, but the TGF-beta pathway in some of these tumors? And what are the findings we're seeing? Where does that give you confidence? And how does that help you in thinking about the design of the next steps?

So what we have seen, in general, I mean from a competitor perspective, there are av?8 specific programs. That's 1 set of data. We know that there are earlier-stage programs from Genentech, there is a program in Phase Ib or II from Pfizer and some others. And those are all antibodies. By the way, I think one has to be very careful in terms of extrapolating data from those potentials -- I mean, from those studies to what we are doing because I think the fact that we have a small molecule and that it covers av?1 as well makes it quite differentiated from those programs.

And so I think one has to be again careful about extrapolating the anti-GARP program from AbbVie kind of closely relates to our program in terms of GARP being the chaperone protein that provides TGF-beta or that offers -- kind of basically presents TGF-beta to av?8 and obviously, there are in later-stage development in a pretty kind of wide range of different indications. So that helps us kind of select indications as well. And then there is a whole group of programs that are directly TGF-beta target. So most of them are TGF-beta traps combined -- often bispecifics, combined with, let's say, a PD-1 or a PD-L1.

There's a whole bunch of Phase I programs there and I think Incyte and Hengrui have like later-stage programs there, Phase II, Phase III and then again, you have other bispecifics outside of the PD-1 combined with TGF-beta, such as EGFR, Bicara, VEGF, et cetera, et cetera. And all of those programs basically provide, I would say, a certain rationale to kind of target specific tumor types where we think that TGF-beta is relevant because the key driver of the TGF-beta activation in all cases, will -- are these 2 integrins notably av?8 and av?1.

So selecting indications is based on other programs as well as our internal data in terms of av?8 expression in certain tumor types that we have.

So we kind of skipped over it, but would you highlight what you actually showed in your Phase I, what's gotten you excited for moving forward? And then I'd like to talk a little bit about the interferon gamma as a biomarker.

Absolutely. So we treated in total 16 patients in our Phase I over 5 different dose levels, so 5 cohorts ranging from 250 milligrams twice daily to all the way up to 2,000 milligrams or 2 grams twice daily. And so from 1,000 milligram BID, we started to see responses. We had -- in total, we had 4 clinical responders, 3 partial and 1 complete responder. That was the cholangiocarcinoma, and you mentioned before, melanoma, non-small cell and head and neck cancer.

Those were the 4 different tumor types that -- where we saw the clear response. The average duration at the time of analysis towards the end of November, early December, was 15 months. And those patients -- at least 3 out of 4 patients continue to be responders. More data, by the way, I want to make sure that that's understood. The full data set will be presented in the very near term at a scientific conference.

So you will see all the data up to a later time point. Of course, in terms of average tumor size reduction, it was 71% in those 4 responders. So the ORR was 40% in secondary non-refractory -- sorry, secondary refractory at that dose of 1,000 milligrams BID or higher.

From a safety perspective, the drug was well tolerated. I mentioned before, anti-TGF-beta has its kind of potential significant safety and tolerability issues. We never saw anything of that, most common reported side effect was mild to moderate rash in about half of the patients, which is probably a combined effect or driven by both the combination of pembro and PLN-101095. But then to your point, we saw a very significant increase in interferon gamma during the monotherapy phase of the study.

So the first 14 days where we had only monotherapy with our drug, and we saw this 3 to 12x increase in interferon gamma during the baseline and 14 days of treatment in all the responders. So the question is, of course, is this potentially an early predictor of treatment response.

In our Phase Ib study, we're going to continue to evaluate that, although it will be a very unbiased approach. So we're not going to select patients based on their initial response as it relates to interferon gamma increase. So we want to make sure that we expand the number of patients, measure interferon gamma over 2 weeks and see if we can confirm an increase being related to a response and no increase related to probably no response.

So that's kind of the idea behind that. So this could be a predictive biomarker, which ultimately thinking Phase II or Phase III controlled studies where you would use this to kind of basically select patients that are potential responders and kind of try to increase your response rate to its maximum using this biomarker.

Was there any correlation with rash and the interferon gamma response?

No, we didn't.

Okay. And then as we think about the rest of the year for you guys, 2026, what are the key updates we should be keeping an eye on?

So the key updates, I mean, first, as it relates to our lead program will be just clinical execution, right? I mean, getting those centers up. So the plan is to have first patient in the second quarter of this year. We would like to have most of the clinical sites opened by the end of the year and having a significant portion of patients across three different cohorts enrolled. So we will provide continuous updates on that, of course.

Secondly, we will provide -- first, I would say, look at the nonhuman primate and other data that we have generated with our targeted drug delivery platform that is still preclinical, but of course, nonhuman primates will be a key data set that will decide or will kind of be determining whether or not this is a viable program. And if so, then we obviously will go full steam ahead and try to get this to the clinic as soon as possible.

And then the other update potentially could relate to acquisition or in-licensing of potential assets. As I mentioned before, we continue to do so. In terms of evaluating assets, if something comes our way that makes a lot of sense and we can afford it, we would definitely provide an update on that as well.

Okay. In terms of the drug delivery platform with siRNA, is this something you would need to partner with some -- with an external source for the siRNAs for the payload, if you will, or are you thinking about this as an engine for internal R&D? Or is it more of a partnering -- external partnering type approach.

I do see it as an internal effort to continue and to kind of build our pipeline further. siRNA as such -- access to siRNA is -- these days, it's not too difficult, right? It's more or less a commodity. Delivery is key, the siRNA itself basically, we use contract manufacturing to get siRNAs against specific targets. So what is key is choosing the right target and making sure you have selective delivery to the cell types that are of interest from an indication perspective.

Right now, we have shown that at least in murine models for muscle and adipocytes. So those will be the first ones that we will focus on, but potentially expanding to other cell types, other tissue types as such. So I don't see this immediately as a partnering -- how would I say asset or partnerable asset. Of course, it's always partnerable, but I would like to kind of continue development if we can confirm what is -- what we have seen before in mice, now in monkeys as well.

And I'm pretty sure that once we start looking for those -- showing those data that there will be interest. I wouldn't be surprised if that's not the case.

Okay. And can you remind us, although you report out in a few weeks, cash runway and then what's in those runway assumptions?

Yes, Jeff, we finished third quarter with about -- if you -- pro forma for the payout of our loan facility, we had about $211 million cash, we'll be reporting in a couple of weeks, new cash level. Burn was dramatically decreased in the fourth quarter. We have cash into the second half of 2028 at least at this point. So that includes the full aggressive development of the oncology asset as well as full speed ahead on the platform. So we're doing everything, moving everything forward aggressively with that runway.

All right. Okay. anything else that I'm missing or that you guys would like to flag, of course, this being ahead of your full year-end update?

No. I think -- I mean we covered everything, and thanks for providing us the opportunity to do so, Jeff. I think maybe one thing and Keith clearly alluded to a significant reduction in burn. Obviously, we restructured the company to a much smaller footprint, but what was key -- what is key is that we kept our development capabilities. I mean our DevOps team has shown to be extremely capable and efficient, I would say, that in terms of running large multinational, multicenter studies in IPF notably global studies, this will be key to kind of deliver also in our oncology program from an enrollment and timeline perspective.

The executive team is here to lead the company and to lead the programs towards these very important value drivers and catalysts. And then last but not least, we also kept core med-chem and core integrin biology capabilities to kind of drive that earlier stage program or programs and notably the one that I mentioned before, the targeted siRNA delivery. So we have those capabilities in-house to a large extent, smaller footprint, but the core folks to really kind of move forward our pipeline are still here.

It's a good point. Let me just add one more thing on the runway. That development capability is going to come into play crucially for us. We expect we'll have data from the oncology program at some point next year. So even with our aggressive development, we have probably a year of cash post our initial data reading from Phase Ib.

Yes. All right. Well, guys, we really appreciate the update, and it's been a tough story sort of over the last 1.5 years. But you've always had this oncology asset that's been interesting and what is really a validated pathway and seeing the Phase I data certainly helps give folks comfort that there's a path forward here in oncology, and it's a matter of time and execution and obviously, looking forward to the deeper data set when you guys release that. So I think I am up on questions. So I'll say thank you very much. And I hope that you have some great meetings through the day. And operator, with that, you can take us.

Good afternoon, everyone. Welcome to our 37th Annual Piper Sandler Healthcare Conference. It's day 3 of our conference. My name is Yas Rahimi. I'm a senior biotech analyst at Piper Sandler and a covering analyst of Pliant Therapeutics. Bernard, Chris and Keith, thank you so much for traveling from the Bay Area to be with us. And also congrats to the data this morning. So wonderful to get the news, but maybe a great place to start off would be if you could provide an update of the data introduced this morning for investors who may have missed it as they have been in meetings all day.

Absolutely. Maybe I can kick it off, and Eric can provide additional data or detail. And for those here in the audience and listening in, the deck is on the website, and I will refer a couple of times maybe to some slides. So I think for me, the key highlight from what we have generated out of this Phase I study, albeit it's a very early study. It was meant as a safety study, a limited number of patients is the fact that we see a durable response, right? So 15 months -- median of 15 months on the treatment so far to date with 4 responders, responses are deep. We have one complete responder.

And this is in patients that have been heavily pretreated. This is basically kind of end of the line for them. So they failed not just Pembro or other ICIs, but they actually also failed chemotherapy or other targeted therapies before. For example, the cholangiocarcinoma patient, which is actually as part of a Lynch syndrome. This patient has a complete response, has been on treatment for, I think, now about 1.5 years. The patient itself, this is his fifth line of therapy, went through 4 different lines before, continue to progress, had colon cancer before as well, even underwent radiotherapy and seems to be a complete responder and kind of stays like that. So I think that, to me, is the key highlight of the data. Of course, there's much more in that dataset, the fact that we can -- it seems predict response based on the interferon gamma response after 14 days of monotherapy, but maybe, Eric, you can provide additional details on some of the data that we have seen.

I think Bernard alluded to it, the interferon gamma signal was really interesting because we saw it really as a distinguished between responders and nonresponders in our study, and it was rapidly seen in the setting of initial 14-day monotherapy with PLN-101095, and it was also statistically significant compared to basic baseline. And what's interesting about that is that we had also seen this preclinically in our animal models that -- and that's what you would expect by really having an immune -- really an immune response in the tumor microenvironment. So that was really exciting.

Another really good point is that the drug was really well tolerated. And we saw that the most frequent adverse event was rash, but that it was mild to moderate, and we only had one discontinuation due to rash. It was managed topically. So really great feedback from the investigators from that perspective that they really see a therapy that can not only improve response, but is well tolerated in combination with the drug that they use very often, right? Pembro.

And team, I know you had -- you also had provided an interim data readout. So help us sort of put into context the data from this morning versus the interim look. I think Bernard, you alluded to sort of the longer time point. But if you could just maybe shed some more light on sort of comparing contrast the 2 readouts?

Yes, we have one additional responder. So last time we disclosed data were 3 partial responders. Now we had one additional partial responder. And then one of the partial responders of last time turned into a complete responder. This was the cholangiocarcinoma patient. And then to your point, it's just the duration of time on treatment and the duration of the ongoing response without any progression.

And then to Eric's point, safety, right? The safety dataset, of course, is now expanded because of the time we had. The interferon gamma data are new as well as additional biomarker data that we have been analyzing. We only kind of disclosed the interferon gamma, but there's more to come, I would argue. And the plan is once we have the full dataset to present at one of the upcoming conferences.

And team, you've also announced this morning that you're going to move the program forward. So maybe help investors understand what in the dataset warrants advancing the program? And then what would the next steps look like for the program?

Yes. For the next steps, in terms of the program, we have -- we'll move on to Part 2 of the study. So it will still be a Phase Ib study where we will evaluate PLN-101095 in specific tumor types. So that's what we want to do. We'll start with non-small cell lung carcinoma and then also explore other tumor types and then we'll give more information as we select these different tumor types. And we also believe that the 1,000-milligram bid dose makes good sense to evaluate in this study. As really in terms of whether we will still keep the monotherapy, we will still keep that because we want to continue to explore this interferon gamma signal and also the effect on other biomarkers.

And yes, I mean, that's really what we'll be doing. And then yes, the question is whether we have include another dose in that Part 2 or whether we want to, I would say, defer that to later stage of development, right? To fulfill our requirements for Project Optimus. So we want to be really mindful of all these considerations.

And how large of a cohort do you envision in the Ib portion of that sort of.

Yes. I mean probably we have -- it's too early to disclose that, but it's not a large, large footprint we're talking about. So it's something that we would easily execute.

And would you be in a position now that you've made the decision to move forward to next steps and you have the dose and obviously, contingent you wanted to go higher, could you get potential data in 2026? What would the timeline look like post start?

Yes. We don't really have, I mean, formal guidance in terms of timing of data, but I anticipate -- I mean, for sure, its '27, right? If we start in '26, depending on the size of the cohort, I think that will be the determining factor, but '27, we should have both data. Whether '26, I don't know, hard to say. Depends also on the design. Of course, all of this is still open label. So of course, data are coming in as they come in.

And I assume the type of cancers will be very much aligned with the current patient, like the split of the various types are going to be the same as you just reported out, right? There's not a reason to enrich.

I mean we will do a Phase Ib study in non-small cell. So that will be a given kind of set of patients and then look at another mix of potential tumors depending on, I mean, more data to be analyzed coming out of this specific trial to see why are we having certain responders and why are patients still progressing under treatment, and that will define kind of the patient population or the indications that we will study in kind of a more of a mix type of cohort.

And then team, big picture, like does this now represent sort of a shift in the company's strategy as you're thinking about?

I mean not really. I mean we have always been an integrin platform company, right? So what is our strength? Our strength is, on one hand, is understanding the biology and having the chemistry to address integrin receptors within different disease settings. Of course, we spend a lot of time in fibrosis. We went into primary sclerosing -- PSC, primary sclerosing cholangitis, oncology. With these data, obviously, we're going to spend resources to moving forward to advancing this specific program.

But at the same time, we have a number of additional earlier-stage programs that we will be more public about in '26, including, and there was a reference to that in the press release, specific targeted drug delivery, very specific cell types, for example, delivery of siRNA to muscle cells, to adipocytes. We have now in vivo data that support that and need to be confirmed in larger animal species, but we anticipate to kind of start disclosing those data in '26 as well.

So there is a platform, and we will start to rebuild the pipeline that is minus the fibrosis asset, but with the oncology asset as the lead asset. We have enough cash, and then Keith can talk about that. We will remain opportunistic as it relates to potential additional assets from outside that would fit our pipeline. But right now, the focus is on the oncology program.

And team, who are some of the competitors in the space on the oncology side as we think about?

It's crowded and it's not. I mean, of course, the whole space of ICI refractory patients. So second line in non-small cell, for example, is crowded. If we look at any kind of the options today, if you look at PFS, it's anywhere between 3 and 5 months. So we may have something that will do much better than that based on what we see today, but of course, needs to be confirmed. True competitors around the same mechanism. There are a couple of companies or a number of companies focusing on bispecifics where TGF-beta is being blocked together with something else like a PD-1 or PD-L, VEGF, EGFR. So that's one specific space.

And then the other one for me, actually, the true competitor from a mechanistic perspective as well as indication perspective is AbbVie. This is the original argenx compound and anti-GARP. GARP and alpha v beta 8, one of our 2 targets that we address with the small molecule are very close to each other. They basically work hand-in-hand in terms of activating TGF-beta, which then leads to immune exclusion of the tumor. GARP kind of serves as a chaperone protein that offers latent TGF-beta to the receptor. So their antibody basically blocks the conversion of TGF-beta by alpha v beta 8. So very, very similar. They are currently in later-stage development in non-small cell, in HCC as well as urothelial cancer. So I think definitely something to keep an eye on, see how that goes and how we will compare to that. That's an antibody. We are a small molecule.

I think I want to kind of reiterate the small molecule part of this, twice daily dosing, small molecule. I think this is one of the reasons we see the efficacy that we see, but also stay away from the typical TGF-beta related toxicity. We have rash, but it's mild to moderate. We are aware of other programs addressing same target with an antibody that had much more rash. So I think we can kind of find a position where we have efficacy without running into some of the target-related toxicities because it's a small molecule, and it gets much better penetration into the tumor.

Bernard, you talked about the platform capability, right? In the emerging research that you just alluded to in terms of specific tissue delivery of large molecules such as siRNAs. So what else -- just maybe talk to us the capabilities of the platform as you're going to be sort of generating a rich pipeline from that?

So what do we have? I mean we have still a number of small molecules preclinical that we -- that are kind of DC ready or already development candidates in, let's say, a year from the clinic that we, for good reasons, decided to put on hold as we were moving forward with our IPF program, fibrosis program. to save resources. Those are available and basically can move into the clinic in different indications. I'm not going to disclose which ones, but these are molecules, small molecules against specific integrins that was based on certain biology related to what I would consider relevant diseases, not necessarily fibrosis, could also be oncology or other chronic indications.

And then we have the siRNA delivery platform that we are moving forward where we're looking at muscle cell and adipocytes, so you can kind of guess what potential indications that could be. We don't disclose the target genes of those siRNAs, but as we move forward, we will be more public about that.

And how soon could some of these programs enter the clinic or at least if we had ready...

Yes, I think '27 is a reasonable time to kind of move these things forward into the clinic, yes. And from a cash perspective, and Keith can talk to that.

Yes, we're fortunate to be in a very strong position. So we -- with our current plan, we have cash through 2028. So that gives us an ample runway past any Phase Ib data that we expect to get. So we have a lot of flexibility with how we direct resources in that time period.

And in terms of enrichment of the pipeline or even being concurrently open if there is a potential opportunity.

Absolutely.

As you think about -- if you think about adding on to the pipeline, maybe investors or programs listening, what are therapeutic areas that you would be interested? Or are you basically agnostic to that?

We are relatively agnostic to that, right. I think from a therapeutic -- I mean, therapy specific perspective, I mean we don't have in-house cell therapy capability or CAR-T or anything like that. So we are very much a small molecule play, but now with the siRNAs, we are venturing into something that is quite different, but using a small molecule as a warhead to kind of deliver. So we are, again, relatively agnostic to indication, relatively agnostic into kind of therapeutic modality as long as it's not kind of too far away from where we are today.

And I think I think also a lot of recognized sort of investors recognize the capability of Pliant in terms of a team of execution from a clinical perspective. So maybe like help us, obviously, it was pretty unfortunate for Bexo to have safety signal. But when it comes to the team that you guys had built and to maybe sort of help us understand sort of how much of that group is maintained.

We have maintained -- yes, we have maintained our development capabilities as much as possible. Of course, a Phase Ib is a different thing than a global Phase IIb and IPF. So we rightsized the company. I have gone through that. It's a smaller company than what it used to be. But the core capabilities are there from a clin ops and clinical perspective. We're actually going to add more capabilities in terms of -- on the clinical oncology side as well as on the regulatory side as it relates to oncology because that's very specific.

So we're going to bring those additional expertise in to support this program. But otherwise, I think we still have a team that's very much first, very motivated to move this forward. It's a program that we know, which has the advantage of something that you buy. You never know what's -- I'm not saying skeletons, but due diligence will never be -- due diligence will never be 100%. This one we know. And so that gives comfort and people are extremely motivated to stay and to kind of really work on this. So all of that is improving. Of course, we also looked at our cash burn and making sure that we have sufficient runway, so we had to kind of rightsize the company.

Wonderful. Well, team, this is an exciting announcement. And obviously, we are very much looking forward into next year, a new year, a new beginning, a new program, lots happening at Pliant. And thank you again for being here with us. I must give a big applause to the Pliant team.

Thanks for having me.

Thanks for having us.