Pliant Therapeutics, Inc. (PLRX) Earnings Call Transcript & Summary

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.