Good afternoon, everyone. Thank you for joining the 22nd Annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next presenting company, Pliant Therapeutics. Joining us today from Pliant, is CEO Bernard Coulie and CMO Éric Lefebvre. For those of you joining us on the webcast, if you want to ask a question, please do so at any time. You can ask a question using the chat box feature at the bottom of your screen. With that, we'll go ahead and get started. Bernard and Eric, thank you so much for joining us today.
Thanks, Joey. Thank you for having us.
Now that you've disclosed the 12-week data up to the 320 mg dose, what's been the feedback and positions in the end as well as the IPF community?
I think Éric and I can say that.
Yeah.
Sorry, Bernard.
Yeah, go ahead.
No, it's been really overwhelming enthusiasm, I would say, in the sense that, not only have we been able to show really good safety of the compound, bexotegrast, and also see the efficacy signal on FVC, but it's also the mechanistic work we did prior to that, showing, you know, that the drug reduced TGF-β activation in lungs and also reached the deeply fibrotic areas in IPF lung as assessed by PET. The totality of the data makes the physicians quite excited about the, you know, the opportunity for this compound in IPF.
I would say that, you know, we've gotten spontaneous outreach from sites that we haven't worked with that want to participate to our late-stage program. Really, it's been a big part of the conversation within the IPF community, both, the scientific and the patient communities.
Great. Sort of looking ahead to some additional data you're expected to read out in the middle of this year. It'll be the 24-week data from the 320 mg, the high dose bexo cohort. Just curious, you know, investors are looking for what a good outcome would look like, and they're trying to look at the 12-week dataset that you've put out and trying to extrapolate from that to see what to expect for the 24-week data. Number one, just curious, in addition to safety and PK, what type of data do you plan to announce?
Yeah. I mean, we can't underestimate the value of long-term safety in this patient population just because they're such a vulnerable group of patients, and we know that IPF drug development has been impacted by safety issues, right? Across different programs. For us, showing the long-term safety of our compound will be important. This is the first time that we'll have dosed patients for six months or more, so definitely meaningful and, you know, having that good information will certainly put us in a great position to enroll the late-stage program. In addition to that, you know, it will be the first time that we see any results on FVC past week 12, as you mentioned, we'll see it to at least 24 weeks.
That's going to give us an assessment of how durable the effect on the bexotegrast is. You know, what we hope to see there is the, you know, continued separation between the active and placebo group, continued effects on the fibrotic biomarkers like imaging, which is the QLF endpoint, and also, the circulating biomarkers like PRO-C3 and also integrin beta-6 so that we reported on. We'll see the totality of data there. Yeah, I think that this will, you know, provide great confidence in pushing the program forward.
In terms of the focusing on the FVC, 24-week, is it more important to see that placebo-adjusted FVC difference maintained from the week 12 time point to the week 24? I believe it was around 140 ml difference or right around there.
Mm-hmm.
Sort of maintain week 12 to week 24, or would you expect the difference, to further separate at, week 24?
I mean, it could go, it's a small data set, right? It could go different ways, but I would say that even if we maintain what we saw at week 12, that would be a win for us. The true assessment of efficacy will be in the phase II-B program, this is where the study will be powered for the primary endpoint of FVC. In a short and relatively small trial, I think seeing the separation is all we're, you know, we'd be looking for just to see that there's a difference between active and placebo and understanding that 80% of our patients are receiving antifibrotic, not antifibrotic, but a background therapy in addition to our drug.
It's not a true placebo comparison, and even then, we see that difference between active and placebo. It's quite encouraging, and if we continue to see that, I think that would be very exciting.
Yeah, that's a good point about the patients on background standard of care. Kind of focused honing in a little bit more on some of the week 12 data. you know, it's interesting to look at. The expectations, would you expect to see some level of FVC decline and if we're just looking at the bexo arm at 24 weeks? Is it possible you could see sort of a maintained level again in FVC relative to what we'd seen in the lower dose, the 80 mg and the 160 mg cohorts at week 12?
Yeah. I mean, if we see maintenance of the week 12 effects, that would be great. I think overall, even if we did see a little bit of a decline, that wouldn't be completely unexpected because we know that, you know, there's no cure for IPF yet. You know, if we're able to further reduce the decline in FVC and bring it more to a pattern of stabilization of the disease, that would be great. I don't know if that answers your question.
Yeah
F or me it's, you know, that continued improvement may or may not manifest itself in longer term studies where we'll have more patients. You know, seeing that on incremental benefit is what we're looking for.
No, that's fair. I suppose I'll ask another one, this time not on the bexo arm, but the FVC sort of rate of decline in the placebo arm. Just looking at the sort of rate of decline, would you sort of expect that week 24 data and, you know, I'm gonna use quantitative numbers, but even qualitative description would be fine. Week 24 data 150-200 mils or how should we think about the trajectory of that decline of the placebo group going from, you know, week 12 to week 24?
Yeah, I mean, that's a great question. I mean, it's difficult to answer just because more recent trials, including ours and the Boehringer Ingelheim trial on their PDE4 inhibitor showed a more rapid rate of decline over 12 weeks in patients that were predominantly or majority on standard of care agents. It's hard for us to put that into the context of the early trials that led to the approvals of the two agents, nintedanib and pirfenidone, because they seem to progress less rapidly in those large trials. It could be that we're in a different era now, right?
It's possible that patients coming into trials are more at risk and by, you know, as assessed by their study investigator, and it's possible also that treatment effects over time on these approved agents maybe is waning. It would be hard to really extrapolate for what we saw at week 12 to say exactly where we'll land at week 24, but I think we would expect to see a continued decline. At what magnitude is hard to predict, especially 'cause it is a relatively small sample size. You know, one patient that progresses more or less can really change, can really skew the results there.
Yeah. Last question on kind of the upcoming 24 week data and going back to the bexo arm in terms of the FVC. How important is it to have the FVC remain above zero at week 24, or are you just looking for separation from placebo? You know, the implication would be that if it were maintained above zero, that could imply, you know, stabilization of disease. That's kind of the rationale behind the question.
Yeah. I mean, I think less, you know, even if we saw that it was below zero, but it was different, we still had that separation between active and placebo, we'd be very happy with that. Ultimately, if you can even, you know, further slow down the decline, when you add a new agent like bexotegrast on top of standard of care agents, it would still lead to a meaningful improvement, right? I mean, if you think about the approved agents, they slowed the decline by about half of what you could see on placebo or pure placebo patients. That's what the registrational data told us.
If we were able, for example, to reduce it by 75% instead of 50% the decline, that would be a big win for patients because more patients would live longer, potentially, you know, breathe better and potentially live longer.
Thank you. That's very helpful. Once you announce the 24 week data from the 320 mg cohort, what are the next steps in the IPF program? Can you outline the design of the phase II-B and maybe walk us through some of the major differences in the design versus the current phase II program?
Yeah, that's. We'll be communicating on the more exquisite details of our phase II-B study as we get closer to its start. We're planning to initiate the study to really start this mid-year. This is on target. We have, you know, we're in the finalization of all the essential documents to be able to proceed with that. You know, what we can say right now is that we have a trial that will use efficacy as its primary endpoint. That will be the, you know, FVC change from baseline in milliliters. That's what we'll have. We'll have a 52-week duration for treatment, and that's the standard also for late-stage studies.
The other part is two doses, the 160 and 320 milligrams go into it. The plan is to really select based on the phase II-B results, the dose that will go into phase III. One of the differences is we'll increase the proportion of patients who are not receiving background therapy to 30% because we want to start generating meaningful data on really assessing the effect size of the treatment benefits that can be expected at in monotherapy because of it. You know, our drug and safety profile and we believe with the efficacy could really play a meaningful role in even monotherapy, so not needing to be combined with background therapy.
Obviously we need to build the evidence on that, and phase II-B would be the start of that. All said, you know, our trial would have at least 80% power to show a difference in between active and placebo. It would meet the criteria that are required for a late-stage study to be considered pivotal. Obviously that would be, you know, that would depend on the results and also how the regulators view the data coming out of phase II-B, but that could put us in a position where we have to, you know, we conduct a single phase III study with the selected phase III dose. That would really expedite also the path to NDA.
In terms of the discussion with regulators, can you walk us through the thought process and the interaction there in the rationale for ultimately deciding on a separate phase II-B and a phase III in IPF?
Yeah. I think, I think this division seems to be more conservative than other divisions for sure, in the sense that we don't believe we're the first ones to propose a seamless p hase II-B/III design. You know, the response we got in really doing a dedicated phase II-B study followed by phase III, that was, you know, I think saying a lot. I think they, you know, they wanna see meaningful benefits, and they also, they're also conscious that this is a vulnerable patient population, I think. I think that's why they're more conservative than other divisions.
A last set of questions on IPF. Just taking a step back, big picture, looking at the competitive landscape, wanted to get your thoughts on some competitor programs. There are two phase III IPF competitor programs that are ongoing. What are the differentiating features of bexo, at least to date from these programs? I guess more directly, what do you think will ultimately win in the IPF market or the ideal target product profile?
Yeah. I mean, the key competitors that we see are the PDE4 inhibitor of Boehringer, sorry, as well as the LPA1 antagonist of BMS. Boehringer obviously generated very similar data to ours over 12 weeks, where they saw a not just reduction in decline, but actually a positive deflection of FVC, albeit not as large as ours, and also declining towards the end of the treatment period. I think one of the key issues with the PDE4 inhibitor, and that's a class effect, is diarrhea. Combination with standard of care, notably nintedanib or OFEV, Boehringer's own standard of care drug, will be problematic. It's also reflected in the phase III design, where they're also testing a lower dose, a dose that they have never been reported on in terms of FVC effect.
BMS LPA1 antagonist is a true antifibrotic. I mean, with the PDE4 antagonist, it's unclear how it works mechanistically. I mean, it's hard to link that to fibrosis. LPA1 antagonism definitely has an antifibrotic effect, has been shown in the past. They just. I mean, we will see the data from their phase II study. At ATS, we saw the abstract. They don't mention FVC. They mention a decline in reduction of FVC percent predicted. Very curious to see how that looks like on a curve. These are 26-week data. The effect was based on the table that they published, I would say relatively modest. Again, we need to see the full data set. What is important, though, that the drug seems to be well-tolerated. It's twice daily dosing as well.
I think those are the two competitors. We did a physician type of research, study where we looked at what are the specific characteristics from a TPP perspective that, you know, is appealing. There were basically four key criteria that came out of that. One is oral dosing.
Yeah.
V ersus infusion or even versus inhalation. Once daily dosing, of course, like our drug is, like bexo is great, oral dosing came out as key. The second one is combinable with, you know, standard of care, so a clear effect, efficacy in monotherapy as well as in combination therapy. An antifibrotic effect. This was much to our surprise, but physicians are really kind of do care about is this truly antifibrotic. QLF, one of our measures also in phase II-B, will remain an important variable or parameter to measure 'cause it will kind of build that label. Ultimately, last but not least, tolerability, safety are key.
Yeah.
Of course the existing standard of care drugs have significant tolerability issues. Again, to compare and contrast with the PDE4 inhibitor of Boehringer, where you have again diarrhea, I think that's not, a favorable, I think, attribute in terms of a potential TPP.
Just curious, with the recent phase III failure from Roche, what impact, if any, does that have on, you know, your development program going forward?
I mean, first, it's too bad it happens, right?
Yeah.
We are really looking forward in getting more drugs to these patients. I mean, it's a competitor, but that's not how we look at it. I think anything that can help these patients will be important. Same for FibroGen, by the way. We think it's important that this kind of be successful and moves forward.
Yeah.
Pentraxin-2 failure obviously will impact our own phase II-B, phase III recruitment. There is no doubt about that. I mean, this was a very significant study. Those patients obviously will come out of that study. We saw something very similar when Galapagos.
Galapagos, yeah.
They failed. We saw this influx of patients and sites, by the way, into our phase II study. It will be beneficial to recruitment. It's unfortunate for patients, obviously. Yeah. It's hard to kind of judge right now because we haven't started dosing yet or, you know, phase II-B, but that will start soon.
Last question, IPF. Wanted to get this in there in terms of the phase II-B trial. I know you haven't started it yet, but what are some reasonable expectations on enrollment timelines, and when do you think we could see the initial data from that trial?
I mean, it's hard to predict, yet in terms of when you'll see the readout, but I can tell you that we're putting all our efforts into having the most speedy enrollment. Just to give you one of our benchmark is the rapidity of the Galapagos phase III, how it enrolled, right? It enrolled in within a year. This is what we're trying to replicate as well, to be as fast as possible. We don't wanna lose phase, you know, anytime. Yeah.
You know, people have made their assumptions, but, in essence, you know, if we can have a less or a one year or less enrollment, that will put us in a really great position to read out phase II-B and then to be able to initiate phase III shortly after.
Great. Now we'll switch to PSC. Bexo is in a phase II trial there. Can you review the design of that PSC trial? In addition to safety PK, what other data do you plan to disclose in the top line announcement in the third quarter of this year?
The trial design for the INTEGRIS-PSC study is really similar to that of the IPF equivalent, in the sense that we have the 40, the 80, and 160 milligram doses that are administered for 12 weeks. This is compared to a placebo group that's basically the pool placebo group for all these different dose cohorts. At, you know, in the third quarter data release, you'll see the safety and tolerability, the PK, but also, you know, in terms of exploratory efficacy and exploratory endpoints, we have biomarkers that are very relevant in PSC and chronic liver diseases that have fibrosis. This is the PRO-C3 biomarker that you may have heard about in other liver studies. Also, you know, we've seen dose-dependent changes in our IPF program.
We have also a biomarker called the Enhanced Liver Fibrosis score, and this is another biomarker that's been well-established, well-studied in liver disease. Both of these biomarkers have relevance in PSC in the sense that they can predict transplant-free survival in the natural history setting, but they can also move or change with treatment as biomarkers. That was seen in the NGN program, which evaluated PSC, in which they saw really rapid changes. This is something that we'll be looking out for because showing anti-fibrotic properties in liver will be important because the next step in phase III is expected to be biopsy studies, right? Where you need to see changes in terms of histology. Having that non-invasive assessment of fibrosis biomarkers will be important.
Maybe the last point to mention on the PSC trial is that we also have recently initiated the enrollment of the 320 milligram cohort, similar to what we've done for INTEGRIS-IPF. That cohort will also go to 24 weeks or later, so similar to what you've seen for the IPF study.
For some of those key exploratory endpoints, you mentioned the PRO-C3, ELF, ALP as well. Can you sort of force rank those in terms of importance or relevance in terms of what would be considered positive outcome? Also for each of those endpoints, would you be looking for more absolute changes or relative changes for each of those? Or is it more just a in an ALP case, it'd be normalization. Just wanna get your thoughts on that.
That's a great question. I mean, what we do know from the failed simtuzumab study that was going back in time for if you follow that program, they had a PSC evaluation. They couldn't see changes in ELF with their compound simtuzumab, but they saw that the ELF score was something that correlated with outcomes, right? This has been seen in trials. It's hard to say at this point what amount of change in a biomarker equates to a reduction in outcomes, and let alone what change in the biomarker correlates to an improvement in histology, let's say by one stage. These things are quite, let's say, you need to have quite a, you know, basically the exploration cohorts, validation cohorts to generate that data.
We do know is that there is significant amount of data that shows that ELF PRO-C3 can actually, levels in a natural history settings can influence the outcomes as well. What we plan to do is really start generating this data from our program, but also look at what's existing and think about, you know, potentially having these biomarkers that will play a role in late stage evaluation as well, potentially as biomarkers. It's hard to say right now 'cause there's still emerging data that needs to be generated. To your point on normalization, you know, PSC patients in general tend, if we think about PRO-C3, they tend to have higher levels in normal or healthy individuals. So you can look at the absolute change, the percent change.
You can also look at, patients that are above a certain threshold, which is, you know, let's say 20 nanograms per ml is what they've seen in other studies. If you're above that, you have a more, you know, like how many of those patients tend to reduce. There's different ways to look at the data. Seeing, you know, I think from an, in a big picture, what we'd like to see are changes that tend to have a dose trend. If we see, for example, the 160 milligram performing better than the 40 milligram in terms of PRO-C3 change similar to what we've seen in IPF, that would be really encouraging. The building the evidence on these biomarkers, and certainly they're not approvable endpoints yet.
Certainly, yeah, I think they can play a role with careful consideration in late stage program.
Got it. That's very helpful. Staying with PSC, bexo, you know, you've shown good tissue penetration into fibrotic lung tissue in of course IPF patients. Just curious, what are the read-throughs to tissue penetration in the liver for the PSC trial? What was the relative tissue distribution of the drug, lung and liver in some of your preclinical studies or modeling?
Yeah. We've done that in vivo in our preclinical tox package, right? We've looked at that, and what we see is the distribution in the lung in terms of drug concentration seem to be very similar. That was done in cynomolgus monkeys, and we saw that lung concentration are pretty much roughly what plasma concentrations are. The liver gets threefold higher exposure of drugs. You know, you would expect more drug and more, potentially more activity in the liver compared to the lung.
You touched on it, or Bernard touched on it a little bit earlier in terms of the registrational endpoints for PSC. What's your latest take on what the potential registrational endpoints would be? Right now, it appears that it's still just a strictly histological endpoint, liver biopsy. Is it your sense that FDA could or would be open to others, and what would those be, perhaps a composite endpoint? Just speculation.
The FDA had issued a paper about clinical endpoints in PSC, several years ago now. The EMA was the one that came out with a reflection paper that was a lot more, I would say, detailed in what they expect to see. Both of these agencies have participated to public forums where they articulated similar thoughts. They seem to be aligned generally. What we know is that histology, whether it's improvement in fibrosis or even no worsening of fibrosis, that could be contemplated as a surrogate endpoint. Histology, if you're going to use a surrogate endpoint to get to accelerated approval, that would be the path that's currently available. The other way is to go for clinical outcomes, which can take more time as we know, right?
Because this is, if you look at that reflection paper, for example, that the EMA published in 2018, you have two years of treatment. That's the earliest time point they recommend to sponsors to look for the improvement in histology, and then they go up to five years for outcomes. The surrogate endpoint still seems to be the quickest route. I think the concerns that people have is that because of the patchiness of the fibrosis in PSC, because the disease really emerges around the injured bile ducts.
Yeah.
Then you would have potentially more sampling variability, that could make the, you know, could you lose, not capture the progression or regression of fibrosis. EMA has proposed also to consider a biomarker that may be relevant to your mechanisms of action that could be combined with histology potentially as a composite or co-primary. Those are all, I would say, you know, possibilities. Certainly we haven't, you know, right now we're thinking about late stage development, but we have not engaged with the agency in terms of what they would like to see. That, you know, I think we're gonna be using our INTEGRIS-PSC data to start these conversations because of course the agency will show me what you got.
First let's show them the data from the trial, and then we can engage in more meaningful conversations. Yeah, we're actively thinking about it right now.
Great. Very, very interesting. Last couple questions. Wanna touch on some of the earlier stage programs. PLN-101095, your dual inhibitor αvβ8, αvβ1. Can you outline the rationale for the plan development in solid tumors, and what would a phase I trial look like?
Maybe I can address the first part, and then Éric can spend some time on the phase I design. What has been shown in the literature is that TGF-β or activation of TGF-β within the solid tumor microenvironment drives immune exclusion, so resistance to checkpoint inhibitors. I mean, it's the hypothesis on which, for example, an anti-GARP or approach is based on. As you know, AbbVie has one in development that they licensed from argenx, if I remember well. GARP actually presents TGF-β to the αvβ8 receptor. αvβ8 drives that inappropriate activation of TGF-β that leads to immune.