Pliant Therapeutics, Inc. ($PLRX)

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.