Okay, thanks everyone for joining us today at the Pliant Fireside Chat at the 44th annual TD Cowen Health Care Conference. I'm covering analyst Ritu Baral, and with us today from Pliant, we have President and CEO, Bernard Coulie, and CMO, Éric Lefebvre. Thank you for joining us today, guys. I want to start with your, not going to start with your most recent data. I'm going to start with the major value driver, as most people see it, in your stock, your lead program for lead candidate, bexotegrast, which is in a Phase IIb clinical, in Phase IIb clinical development for IPF. So it's an alpha V beta 1, alpha V beta 6 integrin inhibitor.
At the IPF PH panel on Monday that we held, there was some discussion about the IPF market and how many numbers floating out there are old. Bernard, can you talk about your most up-to-date market intelligence on the US IPF market? I mean, not long ago, the US TAM was 50,000-70,000 patients, 100,000 in its most generous. What's been happening with awareness and diagnosis?
First, thanks for having us, Ritu. So we weren't at the panel, but obviously it's a question that's been asked a lot. I think it's important to make a distinction between number of treated patients and then the TAM numbers, right? I mean, it's the incidence is what it is. It's about 140, 150 thousand patients with IPF in the U.S. We know that about 40% of them are not being treated. So if you look at the treated population with the two standard-of-care drugs, and the majority of them with Ofev, if you look at the revenues is about 60%. Persistence rates, or let's say, discontinuation rate, is anywhere between 30% and 50%. So at some point, half of those patients, again, are not being treated.
I think that's kind of the reality, what it is. Still, despite the fact that, of course, Esbriet as well, are suffering from, you know, tolerability issues, it's a $4 billion market. Today, those two drugs combined, but the majority Ofev, is $4 billion.
What does that tell you about the market? Because these are just drugs that prevent decline and have the GI issues.
Absolutely, and I would say completely unsaturated, right? I mean, there's a lot of opportunity, a lot of upside. We and others have looked at the overall global market. IPF alone, if you think about, potential new entries like ourselves, mainly driven, I think, by novel oral treatments-
Mm-hmm
... with proper safety and tolerability profiles, it's anywhere between $6 billion-$10 billion. I mean, recent analyst notes have done, notably for us, bexotegrast, an analysis, and their forecast is $3 billion peak sales. Of course, that will include, you know, that's kind of how you look at the overall population and who could be on our drug. I think the way we see this is that this could be potential first line. Could be second line as a preferred switch, could be second line in terms of, you know, starting, or on top of standard of care. And I think that's kind of... The market has a tremendous potential, but right now, to your point, patients just don't stay on drug or being dose deescalated.
Why do you think Ofev is doing better than Esbriet? Does that crystallize the importance of efficacy, or does that underscore better GI tolerability, do you think?
The safety tolerability profile is very similar.
It's marketing.
It's marketing-
Mm-hmm
... and it's their approval in progressive pulmonary fibrosis-
Right
... which has allowed physicians to start prescribing the drug without having final diagnosis of IPF.
Okay.
So patients get to drug quicker. The average time to get the diagnosis in IPF is somewhere between six months and a year.
Mm-hmm.
So I'm not saying it's off-label use, but they basically, because the label has been expanded into Progressive Pulmonary Fibrosis, you don't need IPF as a diagnosis, and so patients get the drug quicker.
Got it.
But overall, if you look at the discontinuation rates, dose de-escalation is very similar between Esbriet and Ofev. The fact that Roche, we don't know what that exactly means, but I think last week there was an article. I mean, it was a press release, I think, about Roche looking for a buyer.
Mm-hmm
... right, for Esbriet. So maybe it will have a second life, we don't know.
Mm-hmm.
Right now, of those, I mean, the $4 billion that we mentioned, I think $3.5 billion is entirely driven by Ofev.
Yeah. So you're running your Phase IIb on background standard of care, stratifying by each drug. Do you see these two drugs continuing to stay standard of care if this next generation of IPF drugs is successful, just given the GI side effect profile, and given that, as our doctor emphasized on Monday, you guys have such clean safety and tolerability? We'll get into this later, but he's like, "If they show nothing better on efficacy, this is already a gimme, just based on tolerability." So you think they'll even continue, even if they're generic, based on that?
It's a good question. I think, I mean, we assume they are here for a while... and definitely it will still be there if we would to market at the time of NDA and launch. But ultimately, they may disappear. Obviously, as Esbriet starts to kind of disappear, maybe revive. And of course, Boehringer is pushing their PDE4 inhibitor quickly, right? They are ahead of us, they are ahead of BMS. So it all depends on what Boehringer is going to do with their own Ofev, versus, you know, once they have their PDE4 on the market, if that will make it. Also, Ofev will go off patent, will be generic probably 2025, 2026.
Our KOL indicated that you couldn't combine the two because of overlapping talks.
Diarrhea, I see the issue.
So-
Yeah, doubles.
Yeah, exactly.
Yeah.
So that's, that's a no-go. So you could have differentiated tolerability on background-
Yeah
... if anybody was too nervous. Okay, so for Bexo, but as we look at this combination from a biochemical perspective, is there rationale for additive benefit on top of a kinase?
Yes, I mean, we haven't looked versus PDE4, but we definitely have looked versus-
Yeah
... nintedanib, so Ofev, as well as, as pirfenidone. And obviously, we still see, we still generate, a beneficial effect in terms of FVC decline-
Mm-hmm
... or reduction of FVC decline, or even FVC improvement on top of standard of care.
Yeah.
So whether we are looking at the pure effect of Bexo or whether this is kind of a combined effect is unclear, because our placebo group with, you know, standard of care didn't do well, right? So and we saw a clear improvement there. So, but for sure, unlike some of the other data we saw recently, on top of standard of care, we don't lose any effect.
Yeah.
I think that's the key, that's the key message, and we don't induce any additional tolerability issues. Any tolerability issues that we saw, which was mainly diarrhea, was all in patients, notably on Ofev.
Yeah.
We didn't see it in our monotherapy arm at all, so.
Um-
But biologically, coming back to your question-
Yeah
... very briefly, if you look at the pathways, it makes perfect sense to combine both.
For the kinase.
Yeah.
Okay. Given that we're talking about like 80,000, 90,000 treated patients and the potential for combination therapy, how many treatments do you think the market can support? And the answer is at least like 3 or 4, but-
I think so.
How much?
Yes. I think, I mean, I don't think, we don't believe that IPF is a single-agent market. It has to be a two-agent market because all the other agents never made it to that point.
Yeah.
So we have never experienced a situation like PAH or COPD or asthma, but we think that IPF, and by extension, ILD, so including progressive pulmonary fibrosis, which almost, not doubles, but adds another 30% to that group of patients, is, you know, can tolerate multiple entries and can tolerate multiple mechanisms. Whether it can tolerate multiple route of administrations remains to be seen. I mean, inhale, inhalation and IV is less obvious, I think.
Mm-hmm.
I mean, inhalation obviously is obvious in COPD and asthma, but in IPF, a bit of a challenge. IV, little bit of a challenge as well, as pulmonary centers don't have IV, infusion units like gastroenterologists have.
Mm-hmm.
But oral drugs, I think there could be multiple entries, and they can, as long as they can be combined or, you know, pulmonologists can kind of develop a combination schedule-
Yeah
... I think there is room for multiple entries.
One quick thing I'd like to add, that we haven't really focused on are what's the part of the treatment guidelines as well.
Yeah.
Because right now, you have pirfenidone and nintedanib that have conditional recommendation, right?
Yeah.
It's not a full recommendation, but you can easily see new drugs coming in and getting preferred recommendation, potentially also, with-
Yes
... you know, as time goes, that some of the agents that were preferred become less optimal and then-
Mm
... replaced by new agents.
So, Bernard, you bring up an interesting point. I'm about to go off script, so apologies. If PPF allows for an easier NRx for Ofev right now, and you have Bristol with its LPA1 going after PPF, and I'm sure Boehringer is going to do that with the... or is already doing that with the PDE4, does that mean you have to go after PPF to be commercially competitive for ease of prescription?
I think you have to, I mean, I think it would be for approved, and that's definitely how we see it.
Okay.
Whether you have to, I mean, we didn't really model that, but I think, you know, intuitively, I would argue yes.
I mean-
Definitely, it's part of our development plan, so.
'Cause the flip side of that is if you get PPF, at least in this day and age with the current IRA, you would lose your orphan exclusivity.
Yes, but we modeled that.
Okay.
And so-
And still
... the key will be-
Mm-hmm
... to have an approval in both indications as close as possible to each other.
Got it.
If you look at it as life cycle management, IRA is going to punish you.
Yes.
But we definitely have. We did the whole IRA calculation.
Mm-hmm.
Of course, we have orphan exception on-
Yeah
... on IPF.
Yeah.
PPF, it's big enough to generate additional NPV. I mean, it's not the same as this. This would be pre-IRA.
Yeah. Yeah, but-
But it's definitely going to be sufficient to justify-
It's enough
... the development and to compensate for the R&D costs that you will make to kind of do-
Got it
... do a PPF trial. Because the advantage of a PPF trial is that we, we still see this as a separate trial. We had a question re-... whether you could run one trial-
Mm-hmm.
ILD, all comers.
Yeah.
Which I think is a risk.
Mm-hmm.
Because you will have to power it up to kind of thousands of patients. BI doesn't do it, BMS doesn't do it. If they don't do it, I don't think we should do it, because that means that they had feedback from the FDA that suggests that they shouldn't do it.
Okay.
In any case, if you think about it, you can run it in exactly the same centers, with exactly the same physicians, because it's exactly the same patient population-
Mm-hmm
... ILD patients. And I would argue, your screen failures in IPF become your-
Yeah, yeah
... patients in your PPF trial.
Yeah. Okay, that makes sense. Where, when does it make sense to start that PPF development?
I would say concurrently with our phase 3 development.
Okay.
So in IPF. It would be once we have phase 2b data in IPF, that's when we would start PPF.
Yeah. So let's move to BEACON-IPF, the phase 2b. How is enrollment going? How's site activation going? Our KOL mentioned that with all the trials, enrollment is getting competitive. Of course, BI has that tolerability issue, which is a headwind, but how do you see site activation, allowance of background treatment, and just competition?
Yeah, I mean, I think that we're in a very good position. We're very happy with the progress in terms of activation and enrollment, and hopefully soon we'll be able to provide more, more clear guidance-
Mm-hmm
... on when we expect to be fully enrolled. But we're in a good time period right now because Boehringer has fully enrolled their-
Right
... IPF study, so we're not competing for those patients. United Therapeutics is enrolling their study-
Yeah
... but it's taking a while, probably because of also the mode of ac, you know-
Mm-hmm
... the mode of action, and the-
Yeah
... the dosing administration there.
Yeah.
And BMS is just starting in terms of their phase III, but for IPF, there's a little bit less excitement, I would say, around the data that was generated from their phase IIb 26-week trial.
Mm-hmm.
The results were, you know, good but not great, and I think we have an opportunity there, to really play a very like, to really deliver on our deliverables, if you know what I mean. Just getting to-
Mm-hmm
... Phase IIb data.
When we think about, like, an inhaled treprostinil for IPF, what's different about the IPF patient's cough? They cough more. Do they like doing... no.
No, I mean, it's, it's one of the side effects is-
Yeah
... just the formulation itself is irritating.
Uncomfortable.
Uncomfortable, and-
Yeah
... they need to get to 12 inhalations a day.
Yeah.
Which is a lot.
Yeah.
And published data by United have shown that you need to get to 10 inhalations at least in order to be effective, to see an effect in IPF and in ILD, and about 50% of patients get there.
Mm-hmm.
Most of the patients, actually, half of the patients don't even get to 10 inhalations a day, and so you are, like, suboptimal dosing from an efficacy perspective. So again, I mean, I think it's a real contender.
Mm-hmm.
It's a marketed product, so-
It's potentially combination-
Exactly.
Mm-hmm
Mechanism.
Exactly. We, I mean, we can combine, but of course, they have PAH plus ILD as-
Yeah
... an approved product. So, I'm not, you know, dismissing-
Mm-hmm
... at all, United Therapeutics, but it's the inhaled route is definitely a challenge, notably with 12 inhalations a day.
Can you remind us of BEACON-IPF powering?
Yes.
What you said about placebo assumptions, which is another topic of conversation.
Right. So, I mean, we're treating the BEACON-IPF study as it could be one of two pivotal studies.
Mm-hmm. Yep.
We're powering it at 80%, at least 80%, to show difference between active and placebo. We're using the approvable endpoint, which is the absolute change in FVC, and we're using the time point of 52 weeks. That's the standard. We will have 30% of patients that will not be on background therapy. They could, they could have been on them, but discontinued-
Mm-hmm
... or be treatment naive, potentially, so we'll capture that information. And then, the other aspect is, as you mentioned, we stratify for use of background or not, in our study, and also, GAP stage, which is a predictor of mortality because we're looking at key secondary endpoints, outcomes, time to, you know, all-cause mortality, time to respiratory hospitalization, and what have you. So, you know, we've had a recent, or late last year, we had an interaction with the FDA, the respiratory division, and they've really been very complimentary of the design of Beacon, and have also provided some suggestions we might want to consider for our statistical analysis plan down the road.
Because they, they do want us, the way—to use their language, "We want to help you leverage as much as this trial, this robust phase 2b evaluation." So that's kind of, for us, reading between the lines was a bit of a pat on the back.
Yeah.
Continue doing what you're doing, and that's kind of the approach we're taking. And for the effect size or the, you know-
Yeah
... we haven't disclosed that, but what we've seen, let's say, at, 24 weeks for the 320 milligram group-
Mm-hmm
... is something we're hoping to replicate at week 52. So we're conservative in that assessment, in the way that we haven't expected the trajectory downwards that, we've seen on the placebo-
Yeah
... group would continue at the same rate.
Got it. One of the things our KOL said, I asked him, you know, "Who are the placebo patients?" Right? Are they the ones declining on background therapy, or are they just the, you know, the type A patients who just want to do everything possible and just so motivated? And he said he thinks that they're the type A.... So he thinks, they're not the decliners, and they would lose 100 mL's a year, essentially. Is that, is that a fair way? Is that the going assumption right now as you put Beacon together?
One piece of information that not everybody, I think, has picked up on yet is, so in the Galapagos Phase III study that they published, there's a significant proportion of patients on background therapies that are not on—they're on dose reduction.
Mm-hmm.
They're not on the approved dose.
Yes.
It varies from 40%-50%.
Yes
... which is quite striking.
Yeah.
So that could also play a role, potentially, in explaining why background is not performing as well as it did in the registrational trials. We also have heard from our advisors, I mean, there's this idea of a selection bias as well. So maybe they're the type, some of the type A patients, I think it's probably fair to say that, but there's also probably patients that doctors are more concerned with-
Uh-huh
... that are on background, and that's why they're offering clinical trials to them.
Got it. Got it. Okay. Do you think you're going to see dose response between the 160 and 320?
We hope so. Certainly, I think we know from all our translational work that the 320-
Yeah
... milligram achieves near saturation of the target. And what we've modeled is also looking at the time above IC 50, IC 80, IC 90. So the 320 does provide more time above IC 90 than-
Mm-hmm
... the 160, and it also provides higher trough levels. There's a lot of things that really seem to play in its favor, and when we look at the results of the trial as well, it points that there, you know, the 320 did the best, right?
Mm-hmm.
So I think the question I've and you may have heard me say this before, but in our BEACON study, you know, if we see the high dose, is it gonna be more effective in the setting of monotherapy than the low dose?
Mm-hmm.
If it is, is it as well tolerated with background therapy as-
Yeah
... the 160? Because ultimately you want one dose to market, right? So I think it's-
Why wouldn't, I mean, just based on every doctor I've spoken to who's been involved in your studies, like, this is so clean.
Yeah.
It's so clean. So why wouldn't it? Is there-
Well, I hope they're right, and-
Okay
... and so do I. But, you know, you never know-
You never know.
... until you do these large studies, right?
Yeah.
If there's something that, you know, something can come up. But the point is that I think we're in very good shape with the 160 and 320 to be able to decide which dose goes into phase 3.
And as we think, and we had asked on the panel again, as we think about the landscape, the desire for combo therapy, are there development stage mechanisms that would not be combinable, or leaving side effects aside, which, according to our doctor, you don't have at all. But as putting that aside, if we think about the LPA1 mechanism, the PDE4 mechanism, I think the Hedgehog, all of these that we asked about, is there anything that wouldn't be additive? Autotaxins are kind of dead, from what I understand.
Yeah. So I, actually we can, we can combine with any of these mechanisms.
Okay.
And, I think it's important to remind everybody that we don't have any drug-drug interaction potential-
Yeah
... so we can be combined with anything.
Okay. All right, in our under seven minutes, let's move to PSC, your most recent data. Can you, can you help frame the PSC market? Just a brief demographic overview on patients, and is this, is this one of those underdiagnosed diseases that, as awareness and maybe a treatment option, becomes available, might actually grow in prevalence?
I think, I mean, Éric can speak to it as well, of course, but, I mean, the demographics are, to start with, it's a much younger population, obviously, than IPF. These are people that often get or remain undiagnosed-
Mm-hmm
... but being treated for their inflammatory bowel disease. 70% of patients with PSC have IBD, and so obvious, and that's kind of an obvious disease. So they are being treated and followed by GI docs, and at some point, someone will start to develop abnormal liver tests.
Mm-hmm.
And that ultimately may lead to the diagnosis of PSC.
Okay.
The diagnosis itself, I mean, obviously, the disease has to be a little bit more progressed than really from the start, but is easy to make, at least with imaging, you can diagnose, sorry, you can diagnose PSC. You don't need a biopsy. By the way, these patients don't see biopsies, which is another challenge in clinical settings.
Yes
... of course. But, there, you know, it's estimated about 30,000 patients in the U.S. Could it be more? Could be more, because sometimes you hear of cases of patients that are diagnosed with cholangiocarcinoma, and die because of cholangiocarcinoma. And there is, like, no history of PSC-
Yeah
...that, which sounds a little bit, because cholangiocarcinoma is really linked to PSC-
Mm-hmm
... which suggests that you have maybe patients that, you know, are subclinical-
Yes
... or don't get diagnosed, and then suddenly there is cholangiocarcinoma. Right. So, with once treatment becomes available, obviously, that's what happens all the time, is that maybe the diagnostic, you know, effort will go up as well.
Okay.
So...
What do you think the dose range is for PSC? I mean, you have, you have much better drug exposure, in the liver compartment. What, so what are those doses that you are thinking about taking forward?
Yeah, that's a great question. I mean, obviously, to be upfront, I mean, we think that given the lack of dose response we've seen.
Mm-hmm
... in the biomarkers and INTEGRIS-PSC argues for doing additional dose ranging in late stage.
Yeah.
Right? So that's the approach that we're taking as well. And we haven't, you know, we'll wait till we have our interaction with the agency as well before we disclose some of this, you know, information, but we will have an FDA meeting and hoping to be, we're planning for it to be in mid-year, where we'll have that discussion around doses as well.
Mm-hmm.
But it's possible that the dose for late stage, a low dose would be lower than the 160, right?
Right.
That's possible because, certainly, we've seen good results across all doses in the PSC study. So there's probably some rationale, especially to try to see what the minimum-
Mm-hmm
... effective dose is as well there.
As you're approaching that FDA meeting, are you approaching it as an end of a traditional end of phase 2 meeting, with like a phase 3 proposed draft trial design in hand? Or just given PSC, the fact that there's no published guidance, the fact that there's no precedent, do you have to approach it sort of more flexibly and conversationally?
No, we want to be very, well, let's say, graphic with the FDA and what we want to do-
Okay
... in the sense that it's, you know, we want to focus on the path to registration.
Mm-hmm.
We want to understand that.
Mm-hmm.
We could-
You're going to go in with a proposal?
With a proposal.
Yeah.
Would this be sufficient to grant us approval?
Mm-hmm
... if everything plays out in the way we want, we hope it to be? But we want to force these conversations. Certainly, one of the important topics we want to cover is what's the appetite for noninvasive as a pivotal endpoint-
Yeah
... in phase three?
Yeah, yeah.
Because the two sponsors that have gone to phase 3 have had to use histology. Histology is highly variable in PSC, and you also have the fact that you need to wait 2 years.
It's more variable in PSC than in NASH, I think.
Much more.
Yeah.
Much more because it's—I mean, the liver fibrosis in PSC is described as patchy.
Patchy.
So that means that whenever you're sticking the needle in the liver, you're not-
It's more variable.
... sure where you're, you know-
Yeah
... where you're hitting IPF. And is it really regression you're seeing or progression?
Mm-hmm.
You can't really be sure. So noninvasives would really open up the door there, but also the door to potentially more patient participation because they don't get biopsies.
Mm-hmm.
Also, potentially shorter studies because, you know, if you think about histology and the precedent is two years-
Mm-hmm
... that's a long time, right? So, why would maybe a noninvasive be able to be shorter, like a one-year duration for phase 3, and all these elements? So that's, that's a key part of what we want to find out. Because we know historically it's histology, but we've heard also that there's maybe an openness to-
Yeah
... think about PSC as more of a rare disease.
Right.
Because a lot of the trials that have been done in PSC were done by MASH sponsors-
Mm-hmm
... that tried out their drug in PSC, so that's why it ended up at the Hepatology-
Yeah
... and Gastroenterology Division. But, you know, we think there should be more creativity in a space where there's no drug approved. So these patients are without therapy, basically, and you know, how do we think about registration?
Are you going to file BLAs and NDAs in time to FDA, or is that too far?
I mean, there's definitely some, you know, imaging component that we'd love to do.
Mm-hmm.
I mean, MR contrast, MR is certainly something that merits a lot of consideration-
Mm-hmm
... given the results of our PSC study. Also, you know, MRE or MR elastography is something to think about.
Mm-hmm.
I mean, there's, and of course, FibroScan and what have you, but we think that having a lot of noninvasive assessments-
Mm-hmm
... even if we need to do some histology, could really set the stage for someday moving out of histology-
Mm-hmm
... in this field.
Okay.
I think also safety endpoints could be used as efficacy endpoints. Because the interesting observation we made, although in a very small group in our phase 2a, was that the incidence of cholangitis, ascending cholangitis-
Yeah, cholangitis
... was less.
You were reducing that, yeah.
And at 3:20, it was zero versus placebo. That was a safety observation, but you can kind of start thinking about this as a-
Mm-hmm
... as a secondary, because that's a consequence of-
Yeah
... better bile flow, right?
So you're doing this this year, but we've spoken before, you don't have any of your current $500 million earmarked for this.
No. No, no.
Are you going to wait for Beacon before deciding on the Beacon readout before deciding next steps, and PSC there?
No, the way we see it is first we need feedback from the FDA, right?
Yeah.
So we obviously, we will disclose more detail at a later point in time, but you already hear Éric kind of hinting towards kind of moving away from biopsies, shorter-term trials, kind of a rare disease approach, which means less patients. So this could cut the cost of any kind of trial that would move us quickly to a catalyst.
Mm-hmm
... to by two-thirds, right?
Yeah.
So still, that's not money that we will, you know, use out of our current cash-
Yeah
... but we are looking at non-dilutive funding, notably from some earlier-stage partnerships-
Mm-hmm
... and, you know, potential collaborations that we are actively working on around our oncology program, our DM D program-
Mm-hmm
... which are a bit out of scope-
Yeah
... but which could basically pay for a PSC-
Interesting
... development. If we have to start a PSC 24-month biopsy-only trial, the old-fashioned-
Yeah
... two doses, it's not going to happen.
Yeah. Okay. No one's coming to kick me out quite yet. Last question: If BEACON-IPF works, great p-value, clear treatment effect, is your next phase 3 an IPF study, or is it a PPF study?
Both.
It's both. It's a two-part.
Two different trials.
Two different part.
Yeah.
Two different, two-
Mm-hmm
... oh, two phase, 2 concurrent phase 3s at that point.
Mm-hmm.
Got it. Great! Well, thank you so-