Good afternoon, everyone. Thanks for joining us. I'm Brian Abrahams, Senior Biotech Analyst here at RBC Capital Markets. Our next featured company is Pliant Therapeutics. We have with us, their CEO, Bernard Coulie, and their CMO, Eric Lefebvre. Thanks so much.
Thanks, Brian. Thanks for having us.
Absolutely. Well, it's very timely because we just saw some new bexotegrast data this morning, so would love to dig a little bit more into those results. Maybe just starting with a little bit of context around this study. I know this is an investigator study. It's not—it hasn't been a part of your overall development path necessarily, but it's using the drug at one of the doses that you have studied, and in obviously the IPF indication, which you're moving forward in. So tell us a little bit more about how this study came about, where the focus was with regards to PET versus PET and/or function, and what you saw.
Yeah. Absolutely. I mean, I can kick it off, and obviously Eric can chime in on some of the details. Actually, this is a study that was sponsored by us. It was not an investigator-sponsored study. It was a side study of—I mean, it's not called INTEGRIS as such, but it is a—and it's also in clinicaltrials.gov as 205 , if I remember well. This is a study that came, as part of our collaboration with MGH, and notably Peter Caravan, who's the head of bioimaging there. We had done preclinical work in both bleomycin but also other models of fibrosis using some of his PET probes that are selective for collagen.
They had done their own validation as well in IPF patients and looked at healthy volunteers as well, and showed that there is a close correlation between the amount of PET tracer that is being absorbed in tissue and the amount of collagen present, so both in an animal model as well as in human IPF tissue. So then they did their kind of validation work in patients. And so we kind of started thinking about this as part of our overall development program because this is actually the only way to really measure the true biological effect of the drug. If you think about it, what we have done in the past, and notably human tissue work, was that we showed a significant reduction in the expression levels of profibrotic genes, including COL1A1, the main driver of collagen production.
Yeah.
In our Integris IPF study, as you know, we showed, in an, I would say, indirect manner, a reduction in fibrosis using biomarkers such as PRO-C3 as well as imaging with high-resolution CT and looking at quantitative lung fibrosis. This was a way to really measure how much collagen output is there and how much can we kind of block it. And that was kind of the premise, the hypothesis behind this study. It took a while to get it started. Actually, the study was initiated at the time we didn't have 320 milligram exposure data, so this is the reason it's only 160 milligrams. We decided to do one single dose because it's, to start with, expensive, and second, it's single-centered, so we wanted to keep it something that is manageable and that we could have a readout at some point in time. Then the pandemic hits.
We had to kind of, you know, stop enrolling there. And then by the time, the center opened again, and by the way, MGH was closed for a while, during the pandemic. You know, in Boston, they had their fair share of issues there as well. So once it opened again, the study started enrolling, and, you know, obviously now we have the data. And so it—again, it builds on the story we have been telling, is very much anti-fibrotic activity. In this case, we have correlated multiple measures, not just imaging of collagen, but we see again a separation of FVC, now at 160 milligrams, actually better than what we saw in the INTEGRIS-IPF study.
Yeah.
PRO-C3 reduction, beta-6 reduction, and notably cough. So if you look at the deck, that's on our website, and you look at the baseline patient characteristics, you will see that the FVC at baseline was 2.7 liters for the active group, 2.2 liters for the placebo. Low numbers, so I mean, one outlier can have a major impact there. But clearly, this is a patient population that was more advanced compared to our INTEGRIS-IPF study, probably reflecting it's a single-center and it's Mass Gen, which is a referral center, so probably they see the, you know, the more advanced, worse patients that were included. That's always a risk if you run a study.
Yeah.
In our case.
Especially in the drug arm, I think you had the number of months since diagnosis, I think, was particularly long.
Long. 50 months. Yeah.
Yeah. Versus, in the placebo.
The placebo, but there was again one patient that was recently.
79 and 70.
Yeah. That was recently diagnosed, and it's only three patients.
Yeah.
You will see in the placebo, we also had a patient with 1.7 liters FVC at baseline, which is pretty low. Also from a cough perspective, that's an, I think, interesting because we saw 6 out of 8 patients—sorry, six out of seven patients in the active arm had significant cough, clinically relevant cough at baseline, which is a score of 30 or more on a VAS score, and two out of three placebo patients. So we were able to kind of evaluate true effect on cough. We had seen an effect in the INTEGRIS-IPF study, but baseline cough data were pretty mild. Now we had, you know, more pronounced cough, which again helped us to show an effect.
There was an interesting narrative that came back from these patients, like a number of patients mentioned specifically to the investigator, so Sydney Montesi, who runs the ILD clinic at Mass Gen, that the cough disappeared and came back. And we have week 14 data. It's not in the deck, but we have week 14 data where in the active arm you see the cough score going up again because they stop at 12 weeks. So over two weeks, the number of patients went up again in terms of their cough severity, which is, I mean.
What do you make of that given the mechanism? Because it doesn't seem that consistent with how we might expect people to put it.
The data were pretty tight. So, I mean, definitely as collagen is being produced, you have an impact on matrix stiffness.
Right.
And I think—I think that's part of the story here. I mean, what triggers cough in patients with IPF? I mean, there are a couple of theories around that, but one of which is vagal nerves, you know, sensory nerves that are triggered by-by stiffness that have stretch receptors, right? And the more stiff a matrix becomes, you know, there is more firing of those nerves, and hence you have more cough. We-we know that where we are today, we have seen that with the standard standard of care drugs, you know, nintedanib or pirfenidone, there's no effect on cough. So although with nintedanib, there's probably some reduction of fibrosis, there's no real effect on cough. So again, we don't know. All of this will be measured in our ongoing BEACON-IPF trial, and hopefully we will have more answers there.
But it's very, you know, every data point goes the right direction.
Yeah.
We did not show in this deck, but we did do the obvious correlations, which is, of course, with such a low number of patients, always a bit tricky to do, but both FVC and beta-6 levels are correlated with the SUVs, so the standardized uptake values in terms of imaging. So it does all align, I would think.
Interesting. Okay. That was going to be one of my questions. Then maybe just digging into some of the nuances of the data. So I guess first off, maybe on this on the safety side, it doesn't seem like you're seeing anything notable, but maybe elaborate on some of the safety that was alluded to in the press release, because I know that's still a question for a lot of folks on the mechanism longer term.
Yeah. I think the safety, there were no, there was no nothing noticeable. There were no SAEs.
No.
and.
Most of the events were mild, and, I mean, it's really consistent with the safety evaluation to date. And, you know, we're going to ATS next week, and presenting there our safety, integrated safety summary for bexotegrast. So that's going to be an interesting paper, but it really all supports the good tolerability of the drug.
Okay. We have treated over 200 patients now today, up to 40 weeks in the INTEGRIS-IPF study. I think the average exposure was 27 weeks, and we haven't seen anything. So there is no imbalance in terms of IPF-related or pulmonary fibrosis-related adverse events. There is no imbalance in acute exacerbations. I mean, this—the drug so far has shown a clear—a clean safety—safety profile.
That's including the blinded data from the ongoing study, or is that too early at this point to?
The BEACON-IPF, no, that's not included.
Okay. But from all the additional follow-up, you have additional safety indicators.
So this is INTEGRIS-IPF. There's all these smaller studies we did, as well as PSCs. All of those safety data are included in that.
Okay. And then when you look at the rate of change of FVC in this study reported today, how does that compare to your expectations for what natural history would be like for these patients? I know many of them were on standard of care. And I guess I'm particularly curious because there were some imbalances in terms of the degree of severity or the longevity of disease, and we were all kind of wondering, you know, might that have made it easier or maybe even tougher for Bexo to have shown the effects that it did because that arm had so much more severe, what seemed to be more severe patients with longer disease in it? Or how do we think about those imbalances?
Yeah. I mean, the severity, the severity can be, if we think about more advanced patients, FVC that Bernard mentioned, they had lower FVCs than INTEGRIS. We had, perhaps a bit more representation of the GAP2, GAP3 stages, but that affects, that actually predicts mortality, not progression.
Right.
For me, I mean, what I like about the findings in our IPF 205 study, the collagen PET study, is that the difference between active and placebo is pretty much on par with what we saw at 12 weeks in the INTEGRIS-IPF study. So it's consistent that way. And it's the first time we see an improvement over 12 weeks with the 160 milligram dose, so that was also very nice to see. Yeah. And I mean, to your question, how much do we expect them to progress? I think our data was really that we generated is very similar to the recent programs, where we know that a substantial proportion of patients today are probably not receiving the approved dose but are under dose reduction.
That was seen in the Galapagos phase III trial, but 40%-50% had dose reduction, if they were on approved agents. So that could explain also the less optimal performance of the placebo group just because these patients are not taking the optimal dose.
Right. Makes sense. And then maybe just one last question on the data. I know in some of the analyses, including FVC, there was, you know, one, I guess one of the patients wasn't counted in the analysis. It sounds like that from the slides, that patient didn't have adequate FVC measurements. But can you maybe elaborate a little bit more on that and the reason for exclusion?
Yeah. That patient had a good baseline. Unfortunately, the measurements after that were not of quality, so they couldn't be reproduced. So that's why it was left out. That patient was left out of the FVC curve.
Okay. Got it. And then maybe shifting gears, you recently talked about the acceptance of phase IIb, an adaptive study design by European regulators. How much can this shorten the development timeline? And can you talk a little bit more about maybe how the FDA might, could be thinking about the regulatory path in IPF?
Yeah. I think, I mean, Eric can speak to that or I can answer the question. 24 months is what we anticipated will shorten the overall development timeline. If you think about it, so phase III will start enrolling by the time phase IIB is fully enrolled, which will be first quarter 2025. Basically, that cuts out a number of delaying or white space in the timeline, the development timeline. To start with, you don't have an end-of-phase II meeting. You don't have startup time for your phase III because you have to reopen centers, etc. Actually, the phase III will start enrolling at the time that the phase II is at its max in terms of enrollment rate. So those same centers will just continue to enroll, but now in the phase III.
and so if you look at the overall win gain, it is about 24 months, potentially towards NDA.
Okay.
The FDA right now, as you know, hasn't accepted that kind of study design. I think their main concern is having too many patients exposed to the drug at the same time during that overlapping phase without having a clear view on safety from your Phase IIB trial. I would argue safety is the main driver of that concern. While we don't have any safety issues, obviously, we understand why they think like this because this is actually the first time this type of study design is being applied in an IPF patient population. I don't think it's drug-specific, although maybe in the past, some of the competitor drugs like Biogen may not have helped our case. But again, we haven't seen any of that. And so our plan is very clear.
It's like knowing that that's their concern, at times that we have our DSMB cuts, and so we will have safety data. We plan to consider going back to the FDA and have that conversation again.
Okay.
So it's only the US, the rest of the world, allows us to do kind of this adaptive, seamless type of design. This is not one study. I want to be clear about this. The phase IIB and the phase III are separate studies. So both of them could be potentially registration.
Got it. And then I guess what's your latest thinking on the overall IPF market opportunity in the—in the evolving competitive landscape, based on what—what we've seen so far? Where are kind of the biggest unmet needs with regards to standard of care?
Yeah. I think, I mean, I would say it's huge. And you and your team put out a very, I think, very well-informed note. I think it was in March. So I looked at those numbers again, and they were a little bit higher than we thought it would be. But I think let's start with what's the—what's the medical need? The medical need is clear. I think current treatment allows a lot of room for improvement. Discontinuation rates anywhere between mid-30s, I would say high 30s, mid-50s, something like, let's say 30%-50%. Even one of the, you know, basically Roche has put out a paper in terms of their own discontinuation rates on pirfenidone, which was close to 30%.
Yeah.
So I think it's safe to assume that the numbers are actually higher. And discontinuation is entirely driven by tolerability issues, mainly GI side effects for both drugs. I mean, there are additional toxicities as they relate to liver, but the main issue is diarrhea in the case of Nintedanib, so Ofev, or nausea in the case of Pirfenidone. There's also phototoxicity, etc. I mean, a number of issues that play a role. So there is a tremendous room for improvement there. Then we have looked at, and others have looked at, what is the total market potential in the next 5-10 years, anywhere between $6 billion and $10 billion. And this is driven by incidence increase. So it's an organic growth of the population because they're getting older. And IPF is mainly a disease of older people.
At the same time, I think new entrants like ourselves, oral drugs, small molecules, without the safety and tolerability issues of the existing drugs, will just increase uptake. If we think about our own drug, we see four patient populations. I mean, the addressable market is about $140-$150 in the US. We anticipate that will increase. The reason for that is a group of patients that is not being treated today and does not start treatment for the simple reason of the perceived or real tolerability issues. A physician decides that a patient will not be treated because of that. That is almost close to, I think, your numbers were pretty close to what we thought it would be. About 60% of newly diagnosed patients don't get in standard of care. So what do we think are the four populations that we can address?
The first one, it's an obvious one, is switch. So we could be the preferred switch. Patients that discontinue, which is anywhere between 30%-50% on a yearly basis, could switch to our drug. It's well tolerated. It works, assuming that what we have seen so far continues to be shown in a phase IIB trial. Second, patients that are seeking treatment, so newly diagnosed, so very much first-line treatment for patients that are seeking treatment that normally would be put on standard of care, but in this case, there is an alternative which is safe and works. Third patient population is combo therapy. So we have shown, and we are one of the very few that have shown an additional additive effect on top of standard of care on FVC.
So patients that are in standard of care and well tolerate standard of care and do not want to discontinue may benefit from our drug on top of theirs. And then finally, patients that I just mentioned, about 60% potentially of patients with IPF, newly diagnosed IPF, will never get on standard of care. This is kind of that unaddressable market within the old treatment paradigm that may open up. If you take all of that together, according to your numbers, with relatively, I would say, low capture rates, pretty-pretty moderate capture rates, could be $3 billion. This is just IPF. If we take just the two top populations, it's about $1.5 billion. And that's, I would say, kind of the comfort zone. That's kind of the-the low end of the potential spectrum of what Bexo could generate.
There's one more point that I wanted to make, but PPF.
Yeah.
So PPF, progressive pulmonary fibrosis, adds potentially 40% to that. I think if you look at ILD, about 60% IPF, 40% patients with non-IPF, type of lung fibrosis, how many of those are truly progressing remains to be seen.
Okay.
but at least it allows an earlier kind of start of treatment because for IPF drugs that are approved specifically for IPF, you need to confirm diagnosis, which takes anywhere between six months and one year. With progressive pulmonary fibrosis, you can start right away. Competition, Boehringer Ingelheim, PDE4 inhibitor, I think the main disadvantage of that drug is diarrhea. And so on top, it's the same tolerability issue that they have with their approved drug. The other one is BMS. We have heard, it's not in the public domain, that they will not continue IPF treatment development, but they will focus on progressive pulmonary fibrosis. If they continue IPF, which is possible, I think the main issue is efficacy on top of standard of care, which was moderate. It was about 28 milliliters, I think, at 12 weeks.
In our case, it's 140 milliliters, delta between active and placebo. And then United Therapeutics, of course, Tyvaso is being studied in IPF as well. There was a recent Lancet publication showing that the only FVC benefit with Tyvaso is in patients with increased pulmonary vascular resistance. Actually, patients with PH have improvement in FVC.
Right. Right.
All the others not.
Okay. I know we only have a few minutes left. I want to make sure to get to PSC.
Oh, sorry.
I know you're coming up on the.
Run the clock.
You're coming up on the PSC data. Oh, what should we be looking for with the 24-week data cut? What are you going to be reporting out? And how informative do you think the comparison to placebo will be at that time point, just given this small number of patients on placebo who are carried out for the full 6 months?
I mean, for us, the key information from the 24-week analysis is going to be to support the long-term safety of bexotegrast in patients with liver disease that are, you know, we know that that's a really vulnerable patient population. So showing good safety there, that's consistent with what we've shown to date, would really provide us very strong rationale for going to late-stage development should we go there, right? And so that's the key aspect of it. And then we'll be reporting on the other assessments, including the biomarker imaging, the MRI imaging we've done, and also the biomarkers ELF and PRO-C3. But we do, like you just mentioned, you know, we will be hampered by the fact that our placebo group, the only plus part of the or placebo patients that went beyond 12 weeks were those in that cohort.
So it's a third of that, actually a fourth of that cohort, in fact. So it will limit our ability to, to show stats on some of these comparisons. And then the 12, I mean, what we saw, the 12-week results is that all doses were effective, right? They seemed to blunt the fibrosis markers, compared to placebo. So I, I, you know, whether we'll be able to see more dose response here, potentially, potentially not, but certainly safety is the key aspect.
Okay. And what, how are you thinking about potentially moving forward in PSC? I guess what do you want to see both from a data standpoint and it sounds like it's mostly on the safety side. And then from a regulatory standpoint, do we have any updated clarity on what the FDA may be looking for? And I guess what would in terms of the potential scenarios there would trigger a go versus no-go decision in this indication?
I mean, I think us and the entire field would benefit from having more creative endpoints and shorter studies because right now, I mean, we, the sponsors are asked to look at histology-based endpoints, two-year duration, non-invasive play a supportive role, but they don't play, you know, they don't qualify for surrogate endpoints. And we know also about the reluctance of patients to undergo liver biopsies in this disease. So that's why we're engaging with the FDA. We have a, you know, we're planning for a meeting mid-year, and we hope to get clarity on what's their appetite for considering, you know, non-invasive as primary endpoint, what would maybe support that choice as well, and how much histology do we need to show?
We are thinking that we need to do additional dose ranging in late-stage, given the fact that we weren't able to show a clear dose response at 12 weeks. But, the big game changer for us would be non-invasive endpoints and short duration.
Okay. Great. Well, we're running up on time. So, Bernard, Eric, thank you guys so much.
Thanks, Brian.
Thank you so much.