Good morning, everyone. Welcome to our Piper Sandler Healthcare Conference, the stage three of our conference. My name is Yaz Rahimi. I'm a senior biotech analyst here at Piper. Really thrilled to have the team from Pliant Therapeutics here and excited very much in 2025.
Lots to cover over the next 25 minutes, but a great place to start off is a key milestone that's upcoming for the company with the BEACON-IPF study, getting it to enrollment completion in Q1 2025. So if you could just talk about where you are as things are wrapping up to bring it to the finish line, that would be great.
Yeah, I think from a high level, we are very much on track according to our projections. So the study is enrolling very well. It's basically a global footprint. So it's, you know, North America, Latin America, Europe, and Asia. And so all those countries have come basically online, literally, and we start to, you know, have this kind of diverse group of patients being enrolled. So we anticipate to have it fully enrolled first quarter. And so that guidance is still accurate.
Okay. And maybe we could spend some time on the study design. I think, could you talk about, I think you have publicly said that you're going to have pirfenidone and nintedanib, which is standard of care therapies, patient stratified. What is the stratification protocol going to look like between these standard of care treatments?
Yeah, so indeed, we stratify in the study for use of background therapies or not. And if the patients are using background therapies, we also capture the information whether they're on pirfenidone or nintedanib.
So we really want to have a balanced mix of these two agents across all the treatment groups because we've seen in a recent trial, at least mentioned when you think about the Galapagos phase 3 trial, ISABELLA, they had pointed to the fact that pirfenidone seems to potentially perform not as good as nintedanib in that trial. So we wanted to make sure that there's no confounding factor for efficacy in our study.
Okay. And could you maybe talk about once enrollment is complete, what you're hoping your target baseline FVC is going to be as that's going to be the key primary endpoint?
Yeah, so what we're looking for is really a difference between a stat sig between active and placebo. Our phase 2b part of BEACON-IPF, which is the late stage study, is powered to at least 80%. So we've also, and I think that comes in some of your questions as well, but we think that if we, you know, we've used the INTEGRAL-IPF study data and also looking at other trials for standard deviations to put our assumptions together.
But we think generally that if you have greater than a 50% decline, reduction in decline in FVC over the 52-week period with good safety and few discontinuations, that would really be a step forward. So hopefully we'll see more than that.
But, you know, if you think about our INTEGRAL-IPF study, certainly in the 320 milligram dose group, we saw a reduction of 80%, further reduction of 80%. So, you know, we'll see where we actually land, but that's really what we're thinking about.
Okay. And then, team, upon enrollment completion, you guys have also known the top line data would be then on track for mid 2026. Maybe some housekeeping question that we always ask is at the time of the data, what will you believe you'll have a top line? You guys have been always very data transparent. What are maybe measures that could maybe potentially come later? If you could talk about the type of data available.
Yeah, I think, you know, we're going to try to be as complete as possible. I think this is going to be very important information, obviously. And certainly we think that, you know, the main results would be communicated at the time of the readout. Possible that we may have, like we'll follow up with a manuscript and that we're still, we haven't, you know, gone that far in terms of additional things that we would share later. But I think there probably wouldn't be any incremental data that you would see later.
What do you hope to show to have a competitive product profile in your primary endpoint?
Yeah, so I think, you know, the bar currently is low for existing agents. And so I think that if we're able to show really not only the effect, statistically significant effect in the entire patient population, but if we see very strong effects in subgroups, patients not on background therapy, which will represent at least 30% of our patient population, and on standard of care, that would be really great.
And you may recall that in the INTEGRAL-IPF study and also the Collagen PET study that we disclosed this year, there was a reduction in cough severity that would be important. And then, you know, looking at respiratory related hospitalizations and things like that. So we'll look. I think we might need the whole data set from phase 2b and phase 3 to really interrogate things like respiratory related hospitalizations and also mortality. But certainly subgroup information and symptomatic relief as well.
I think also what will be important is in the coming months. I think probably around ATS 2025, our main competitor being Boehringer will hopefully disclose their data of their FIBRONEER phase 3 study. Then I think we also have a benchmark and can have kind of a meaningful conversation about where we hope to be compared to them. I mean, we heard a lot of, you know, through the grapevine stuff, but I mean, the press release was very kind of opaque. It's very little that we learned from that.
Team, when you speak with physicians, what do they consider sort of a clinically meaningful difference in FVC given that it's a progressive declining disease?
Yeah, so generally, I mean, people have been used to seeing a 50% reduction in decline in FVC, right? So that's, I think what they're used to. But if you have symptomatic relief, for example, on cough severity and things like that, that would really make a big difference.
And certainly showcasing, you know, the anti-fibrotic properties of our agents also will be important because if you think about the approved agents, there's no MOA for Pirfenidone. We know, of course, that Nintedanib is a multikinase inhibitor, but there's not a lot of translational data on these drugs.
And I think that will be important to build on what we've done to date. Because that's something that keeps coming up in conversations with KOLs and PIs is you've done more to characterize your drug than any other sponsor has. I think that is really what gets them excited about the program.
Given that you have upsized your study with the adaptive design, we'll talk about that. You also have 30% of the patients that are going to be not on background therapy. Will it have some statistical power to be able to show separation or will it be difficult if you see a trend it could inform you in terms of phase three preparations to potentially contemplate a first line therapy trial study design?
I mean, we think it's, let's say rewind a little bit. What we were a few years ago is assuming that it's in the non-standard of care subgroup that you have the greatest power to show a difference between active and placebo because it is pure placebo comparison in that setting.
And I mean, it's going to be really interesting to see what the FIBRONEER data show in that regard. But we really have the opportunity there to generate significant data. And we're going to look at the power that we have in that subgroup as well in phase 2b. And once we have, you know, we'll make determinations and does it make sense potentially to increase the size of a subgroup to really get the power you need to increase the likelihood of having that description in the product, in the package insert or the label.
So you have also an ability to promote to that because if you fast forward, let's say in 2027, 2028, what will physicians be asking? Can I use your drug without the previous therapies, right? So that's going to come up. And I think we want to be competitive from that perspective.
Okay. I think it's very clear to investors that, you know, Bexo is in pure anti-fibrotic mechanism. And so as we head into the Beacon-IPF study, what are measures beyond FVC, which is more functional that could really bring to light the anti-fibrotic activity of the drug? So what are the things that we should be looking for?
I mean, there are a number of biomarkers that are being measured, obviously, that are markers of collagen formation, same basically that we have measured before, like PRO-C3, et cetera.
And then we do QLF as well. So patients undergo high-resolution CT at start and end. And so basically it's the same measure as what we used in our phase 2a INTEGRAL-IPF study. So QLF, I think, remains a very meaningful measure. What we've learned is that it's, I mean, there is variability inherent to the measure. And obviously, we, you know, with the number of patients we have and over 52 weeks, I think we should see a meaningful change there based on anti-fibrotic activity of the drug. I don't know.
That is exactly right, and I think, you know, in a way, it's also data from other trials that we've done to illustrate the anti-fibrotic mechanism, like the Collagen PET study has been really quite compelling in that sense because it was the first time that we actually see a drug being able to reduce type one collagen in the lung of IPF patients over a 12-week period.
This was really a big, I think, novel data presented at ERS this year. It was really well received, so we want to build on that theme because it is, you know, it is really how we understand the drug to work.
So we'll just need to keep doing what we're doing and actually just educate physicians and maybe that are less familiar with this technology, but keep educating them because we're seeing more and more trials with this measure.
How accessible is QLF measures in the clinic? I remember when INTEGRAL-IPF read out, you know, investigators were excited. They were intrigued by the new technology. Have you noticed that there has been also an uptake in the clinical practices or more than utility in a clinical trial that has?
The latter. Whoops, sorry. The latter is true because it's not available. It's an algorithm, basically, you know, AI in a way, machine learning that determines the results there. So there's no human error in it, but it's not available like for treaters to use, right?
It's a clinical study tool.
But all the big, I mean, all the phase 3 studies are using it. So Boehringer has used it. I think it's in the BMS protocol as well. That's why we're using it as well.
What reminds us what is considered a clinically meaningful difference in QLF?
A change of 2%, whether it's a reduction, anything beyond 2%, either as a reduction or as an increase, is seen as a meaningful change. And that's looking at the entire lung or the lungs. And that's really well defined.
They've established the MCID, or minimally clinically important difference, a few years ago. And that's certainly some of the interesting data from the INTEGRAL study, if you recall. At 24 weeks, the Bexo treated patients did not exceed that 2% versus the placebo group, actually much exceeded it. So that's something that is well understood.
Great. Team, I think investors are aware of, you know, sort of the high discontinuation rates on standard of care. And given that 70% of the Beacon-IPF study is on standard of care, the question always comes up is like, how will you handle discontinuation rates in your current protocols? So if you could talk about, it's a large study, you're going to encounter discontinuation throughout the 52 weeks. So how were they handled? How were they handled? And remind us also on integral.
Yeah, so I think in terms of the, we have assumed a 25% dropout rate just based on other studies that have been run in the field, but I think we, you know, we should do much better than that. We're currently tracking very well in terms of discontinuations or dropouts, and we are requiring stable therapy for patients who are on background therapy when they come into our trial, so at least three months.
So typically that's the period where they tend to experience most of the side effects, so that's something that will help. In the patients not receiving background therapies, we don't expect to see so many discontinuations just based on our clinical experience now that it's over 800 study participants in phase one and phase two, we've seen very low discontinuation rates, so I think that's going to be important.
And one thing that we'll be doing as well is when if patients decide that, you know, sometimes patients decide to stop drugs, like that's what they do in the real world as well because they don't feel well. If that happens in our study, if patients stop study drug, we also encourage the investigator to reach out to us to discuss, like is it a concern that we can address?
Is it something we think is drug related? So making sure we have those conversations because the fewer discontinuations we have in the end, the more power we have to show difference, right? So that's really important for us.
Okay. And then have you spoken publicly around the statistical handling of discontinuations?
Yeah, I mean, technically discontinuations for any reason will be accounted for in your ITT analysis, right? That's usually how it goes. But we are capturing the reasons for discontinuations. And certainly we'll be, as part of any statistical analysis plan, you have quite a few sensitivity analyses. So those are things that we would do, for example, to look into the impact of patients discontinuing to adverse events and things like that.
Perfect.
But missing values will not be imputed. I mean, this is the mixed model of repeated measures that we use. I mean, it's an old discussion that sometimes comes back, but you know, if a patient drops out, a patient drops out and the values are not kind of continued.
Okay. Perfect. We'd love to kind of like pass the data, think about the implication of the seamless design, right? So 1 Q comes out, you guys say enrollment is done. You have the seamless protocol in all geographies outside of the U.S. Just remind us what that operationally means for sites outside of the U.S.?
Yeah. So I mean, for them, they won't feel a difference at all because their protocol includes outside ex-US. They have the phase 2b component and the phase 3 component. It truly is seamless. So once we've activated these sites and they're enrolling, they technically would not even know where those patients are coming from because they don't see all the big numbers that we see in terms of the total counts.
But for us, it's going to be making sure that we track this very closely to be able to tell our U.S. sites stop screening. We've got this phase 2b fully enrolled now. But the ex-US sites will just be instructed that now their patients that are enrolling will be part of the phase 3.
Okay, and how will the randomization towards the two doses proceed in the ex-U.S. geographies?
It's going to start as a two-dose study, phase 3, just like the phase 2b. So the 160 milligrams and 320 compared to placebo. And then the plan is that once we have the readout from the phase 2b component, then we would basically take the patients on the non-selected dose and roll them over into an open-label safety study where they will count for the safety database, right?
So that will be important from a safety perspective to keep these patients in that study. And then at that point on, there will only be a randomization for new patients from the selected dose or placebo.
Okay. Is there a reason to believe that you could warrant to move both doses forward in a registrational study?
There's a reason to believe that we might be fully enrolled, at least for what we expect will be the phase 3 sample size by the time that we read out the phase 2b. So we'll have to look at, you know, where do we see a strong dose separation in phase 2b? Do we need to see more? That will be something that we'll see when we see the phase 2b. But there is a possibility that we'll take the two doses to the end of, like to phase 3. But there is a possibility that we drop a dose. If the differentiation is very strong in phase 2b, that would really be a simple decision.
If it's not completely clear from phase 2b, we're, you know, going to interrogate the phase 2b data set very well to see are there subgroups where it makes a difference, and if we don't find it there, that might be that we need the entire sample size from phase 2b and phase 3 to interrogate the database, you know, for these things.
Is it possible based on the existing data to impute and help to understand whether we should expect a dose response in the Beacon-IPF study or what are your thoughts around?
I'm not sure, yeah.
Whether you expect a dose response? Like, do you expect a different response?
Yes. I mean, based on all the data we have generated so far, there's no evidence at this point in time that, you know, we have reached, that we would have reached kind of the top of the dose response curve at 160. But it's possible that they're very close to each other, 160 and 320. And that it may be in a number of different measures that we have to look at to see the difference.
I mean, going back to the INTEGRAL-IPF data, there you saw a clear, you know, 320 was outperforming every other dose. And 160, we saw also a separation. But then the collagen data, although very small studies, I mean, sample, we saw a clear separation. And actually the FVC went positive again at 160. And it was a different patient population compared to INTEGRAL-IPF.
I mean, as you remember, this was a single-center study done at Mass Gen with patients that clearly had a, you know, were more progressed. At start, baseline FVC was lower compared to our INTEGRAL-IPF study. So again, let's see. But we anticipate there is a difference between the two, 160 and 320.
Okay. And then team, given that the seamless protocol has worked out almost everywhere outside of the U.S. geography, is there a need for working with the agency to get seamless in the U.S.? And where are you in those discussions?
I mean, I think that there's, you know, the U.S., the FDA actually is quite supportive on our program, and they've indicated that our phase 2b evaluation is robust and that that would, and that's in one of your questions, but that could potentially allow to go for a single phase 3. They've really indicated that to us, so it's really good news on that front. Right now, our understanding is from our conversations with them is that they really would like to see the phase 2b data because it's powered for efficacy.
Remember, our INTEGRAL-IPF study was not. It was a safety study, so that's where they're coming from because in their assessment, and it's not specific to our program, you know, this is a conservative division because they're dealing with also very vulnerable patients, right? They're older and have comorbidities and their prognosis is poor.
So that's where they're coming from. So they see phase 2b as the preliminary characterization of the benefit risk. And that's why they're taking that position with us. But we have continuous interaction with them. And if there's an opportunity to pull them in to the, you know, and change their minds, we would do it.
But if that didn't happen, it wouldn't be a substantial hurdle in our assessment because the Beacon trial is, first of all, the phase 2b part started in the U.S. first. We have quite a strong U.S. representation in that phase 2b part already. And then we're across all regions of the world. So from a diversity perspective, which is also something that the FDA is looking to see, then we have that. And importantly, FVC is a universal endpoint. So it's not different across the region.
So we think that good data from this program would really, like if we, even if we fully enroll the phase three, for example, and we haven't included U.S. patients in phase three, we don't think that would pose a significant challenge.
Okay. And so I just want to make sure I understood it. Upon success on Beacon-IPF, it could be deemed as one of your registrational studies. But that does not mean you're done and you can file. You still will have to do a.
Phase three.
Phase three.
Yeah.
Okay.
That's correct. Well, yes. But there is a possibility with the phase 2b data is not get out of the park completely. But that's, you know, that's a very positive scenario.
Yeah. That would be an amazing scenario. Yeah.
But if that would happen, we will definitely have that conversation with the FDA. But we assume like everybody, I mean, in the space, in the IPF, you know, development space, everybody is basically doing two pivotal trials.
And does Beacon-IPF have also a portion from open label beyond that? And if it does, like should we be expecting updates from that program or is the open label post the phase three?
No, the open label will be, yeah, phase three dose selection. Because we want to make sure that we have the right dose to initiate the open label safety study, right? So that's why we're waiting for that.
Okay. And then, team, would love to just broadly speaking, I think investors are aware of the Boehringer's ongoing phase three study. Do you believe that the elements of the design of the studies have changed, I think, as you think about preparation for phase three post mid 2026? Like, is there important considerations that have changed in the regulatory landscape or discussions?
I don't think so.
No. We basically use, I mean, we are using all the same protocol. Inclusion, exclusion, everything is almost identical. But like we're also very hoping to, like when we see that FIBRONEER data, that's something we'll be tracking, right?
No. I think that's great because we're going to see, you know, the approval of a new IPF drug and the market opportunity, which is very, very high. So I think it's going to be in the trend and it will be the translation of phase 2b to phase 3, right? Which will be very helpful.
Exactly.
And next year. And then maybe last question, what is the company's cash runway?
So at the end of last quarter was $403 million, I think, a little bit over $406. Sorry, I'm just looking at Keith here. $406 million, which, you know, basically funds the company through 2026.
Perfect. Well, let's applaud the team for a great discussion. Can't wait for next year and enrollment completion and lots of great activity. So thank you.
Thank you. Thank you for having us.
Thank you.