Good afternoon, everybody. Thanks so much for joining us at another of our fireside chats here at Guggenheim's Emerging Outlook Biotech Conference. We host this conference annually, and I'm really pleased to be joined by Inventiva again. CEO Andrew Obenshain is here with us today. You know, Andrew, maybe I'll just kick it off very quickly to note, you know, our previous company that was just up here has phase III study reading out. I think uniquely within our coverage, you guys also have phase III study reading out, which is not typical in biotech. So really exciting to kind of have that opportunity to see that card get turned over this year in MASH. But, you know, maybe you can just help us level set the playing field in terms of where Inventiva is today and where you see it going.
Yeah, absolutely. So, I mean, I think both Inventiva and the MASH field have evolved tremendously over the last couple of years. Let me start with maybe the MASH field. We all know that we, you know, this is an area that has had a lot of clinical failures in the past, and we've seen some clinical success in the last couple of years. Two approvals. We've seen Madrigal prove that this could be a billion-dollar market for F2, F3 market. We've seen three acquisitions in the space. So, really validation of the space and of the commercial potential. And during that time, we've seen Inventiva also mature. So Inventiva, for the last 18 months, 18 months ago, was a completely different company. It started with a recapitalization in October of 2024 to really give the company some proper cash runway.
And since then, our board chair, Mark Pruzanski, who is a longtime MASH veteran, the former CEO of Intercept, has brought in starting with a clinical management team, a head of R&D, and a head of regulatory with tremendous experience in getting drugs approved and commercializing, and then myself coming in to focus much more on the fundraising and the commercial and the G&A. We've put a structure around this company that can really make it succeed in this market. And so now we're really looking forward to reading out for lanifibranor in the second half of this year with phase III. it's a pan-PPAR agonist for F2 and F3 patients. And I think we're going to be really well positioned to be used probably on top of the backbone of GLP-1s that I think all and being oral and backbone of GLP-1s for the F2 and F3 patients.
We're super excited to be bringing this forward.
Awesome. So, you know, I guess in your role in your new role in the CEO seat, you know, help us understand, you know, goals for the first few months, what your learnings have been, and, you know, what you're particularly focused on at this point as the trial advances.
Yeah. Well, I think I'm privileged to have the privilege that there's such a strong asset here at Inventiva. This is a product that was rationally designed as a pan-PPAR agonist based on 10 years of pan-PPAR biology. So taking the lessons from previous compounds, making it into a, you know, trying to address some of the safety concerns that other PPARs have had, and then improving the efficacy as well. And the phase II that read out absolutely did that. I think what I, you know, when I looked at Inventiva coming in as a kind of a new CEO, what I saw is a wonderful product that could really make a difference for patients that needed the company that needed a little bit of care. Right? And number one, you know, biotechs survive on cash.
And so the first order of business was raising some capital to make sure that we actually had a proper cash runway to be able to bring this product forward and then also to bring in some new talent as well. So people experience actually bringing phase III into commercial. So that's really been my focus. It's a, I always say it's people and money. Right? People and money are what actually makes a biotech hum. And now we've got the right team in place at Inventiva, and we've got the cash runway to bring it forward. And now we're executing on the trial. It is phase III trial that is fully enrolled.
We're in the process of cleaning the data that we have, getting ready for database lock, getting ready for that top-line data and the NDA filing, and bringing in the people that know actually how to do that well.
Got it. Great. You know, in terms of where lani fits, before we get into kind of the specifics of the product itself, where it fits best, can you just sort of talk about that and what you're particularly excited about? You've talked about a $15 billion market opportunity, you know, not reflected in the market cap, obviously, at this point. But, you know, walk us through that a little bit.
Yeah. So first of all, the market opportunities, there are over 15 billion—sorry, 15 million patients with MASH in the U.S. This diagnosis rate is increasing dramatically with these new launches and the awareness of MASH. And I think this is a market that's going to continue to expand. But let's just come to the present right now. So presently, there's 375,000 patients that we think are addressable in F2 and F3. And if we say, where does lanifibranor fit in that? I, you know, I always paint a very simple grid for people to understand. You have F2 and F3 patients on one axis. They're split about evenly. And you have non-diabetics and diabetics on the other axis. And it makes a, and that's about 40% non-diabetic, 60% diabetic. It makes a nice two-by-two grid with roughly equal number of patients in each one.
The way we see the market shaping up is that many of those patients will be on a GLP-1 backbone, either have tried it on it now or will try it soon, and they'll be looking for an oral, either Rezdiffra or lanifibranor, to lay on top of that to address the fibrosis. If the patient that walks in is an F3 patient standing in front of the doctor, what's that doctor really worried about? They're worried about that patient going from F3 to cirrhosis to F4. They want to stop us. They want to pick up the biggest hammer they can find to go after that fibrosis. That's where lanifibranor showed in phase II-B an 18% effect size after 6 months versus Rezdiffra has a 12% effect size after 12 months. They're going to pick up lanifibranor.
They're especially going to pick it up for that diabetic patient because that diabetic we, you know, lanifibranor has shown an ability to reduce HbA1c as well and address the metabolic part of the disease. So that makes doubly sense to pick up lanifibranor. Same is probably true in the F2 diabetes patient population. Again, you want to address the metabolic underpinnings of the disease in addition to the liver. And I think where you're going to see where Rezdiffra might remain a kind of an equal choice is in that F2 non-diabetic patient population. So that's how we see the market shaping up.
Great. You know, the NATiV3 study has been running for quite some time. Can you talk about what the team is doing actively to ensure enrollment kind of stays at a high threshold? Have there been any challenges with keeping patients in the study? Just trying to understand, you know, what the risks, if you think there are any, to the study, you know, how you're mitigating those risks?
Yeah. So when NATiV3 was powered, it was powered pretty conservatively. So what and I'll get to the dropout rate in a second. It was, you know, looked at the placebo rates that we saw and took the most the highest. Right? Looked at the effect size we saw and took lower and looked at the dropout rate and said, OK, this was a six-month trial. What it's going to be an 18-month trial. This is going to be a longer chance for patients to drop out. And so the I think we announced publicly that threshold was it had we powered it so that a 30% dropout rate would still be OK. And in fact, when we did our funding, the second tranche of funding that came in was in order to be able to for us to get it, we had to be at 30% or below.
We announced, I believe it was last spring, that in fact, we were below 30%. We didn't say how much, but we were below that 30%. The trial was powered for that 30%. So we're well within the power of the trial. And I'll just say that I think our experience is within range of experience in MASH in general.
OK, great. You know, maybe just walk us through the trial design itself and, you know, the population that you're targeting. I know there's some interesting characteristics to the study that allows for an expanded look at F4 patients. Maybe help us understand a little bit of that as well.
Yeah, absolutely. So randomized trial 1:1:1. Right? Placebo 800 mg daily, 1,200 mg daily, 1,009 patients in that main cohort. So enrolled into one of the three arms. Patients stay on drug for 18 months, liver biopsy at the beginning, liver biopsy at the end, using some NITs in between to measure the patient. And then if the patient screen fails because of the biopsy, if they're F1 or F4 instead of F2 or F3, they get enrolled in a different cohort, which we have about 400 patients in. Majority of those patients are F1. About roughly 100 of those patients are F4. So again, that part of the trial is blinded as well. And we should get some read out there for on what a potential impact is on F1 and F4 patients in addition to the F2 and F3.
The F2 and F3 is the registrational cohort. F1, F4 is exploratory, will help inform our outcomes trial. That would be in F4 as well.
OK, great. And, you know, when we sort of look at the phase II data and the powering of the study, you know, what aspects of that there are different kind of fibrosis benefits between the 800 and the 1,200 dose. So can you just talk about the results in the study and some of the, you know, what effect size you're really powered for?
Yeah. So we saw if we just look at the fibrosis endpoint in phase II-B. By the way, phase II-B was the primary endpoint was an SAF score. In fact, it wasn't improvement of fibrosis or steatosis or the dual endpoint. But we did measure those in the phase II. And so phase III endpoint is a dual endpoint, is you have to improve fibrosis by a stage and improve steatosis as well, fatty liver, basically. And so you have to improve both, which is a harder hurdle to hit. That effect size of that dual endpoint in the phase II is actually 24%. The effect size of fibrosis only was 18%. I'm not going to say what we powered to, but just that we powered more conservatively. But the primary endpoint is that dual endpoint in the phase III.
We think that's important because it's much harder for the placebo that controls for the placebo effect. It's much harder for a placebo patient to see both improvement in the fatty liver and in the fibrosis. Sorry, I forgot the rest of your question. But.
I mean, I think you pretty much covered the majority of it. I think the only other thing would be, you know, the comparison of the patients recruited into the NATiV3 study versus your phase III.
Yeah. So there was two main differences actually, three main differences. Number one, we had F1 patients in the phase II. We do not have them in phase III. when we took a look at what the effect sizes were, if you removed the F1 patients, they were actually the same to slightly better. Similarly, we have more diabetes patients in phase III. that's mostly because we enrolled in the U.S., where there's a higher diabetes patient population. Again, if you look at how we performed the diabetes patient population, the effect size is actually the same to slightly better in a diabetes patient, again, which took the more conservative powering there. The third difference is that GLP-1s were not available when we ran our phase II.
And we about 14% of our patients actually came into the study on a stable GLP-1 dose. And that should be equally balanced between the placebo and the treatment arms. And just important to note, that's the lower of the GLP-1 dose. That's the diabetes or obesity dose. It's not the MASH dose, which is higher.
Got it. OK. And in terms of, you know, just maybe to follow up on that, risk of drop-in on GLP-1s. So you may have had 14% at baseline. But do we know if there was drop-in onto either an SGLT2 or, you know, or other drugs that might have some effect on MASH?
Yeah. So yes, it was allowed for patients to go onto an SGLT2 or a GLP-1 in the study, not at the MASH dose, though. So it had to be at the lower dose.
To control their diabetes.
To control their diabetes.
Got it.
So that was allowed. There was, I think, a mid-single digit percentage points of GLP-1 addition during the study.
OK, great. There's, you know, in terms of safety and tolerability, so many questions around PPARs over the years. Maybe just separate the historical experience of TZDs and dual PPARs from lanifibranor.
Yeah. So this is a novel chemical class. This is not on the TZD backbone at all. Right? It was developed; it is a different chemical entity, a different drug. But it's actually; it was designed with all those lessons in mind. Right? So what we've learned over time about PPARs is take gamma, for example. Gamma is the, you know, that was rosiglitazone. That was a really, really tight gamma binder and ended up being withdrawn from the market. And I'm going to get it wrong. It's either U.S. or Europe. One of the two. I can't remember which one due to toxicity. Whereas you look at pioglitazone, which is still widely prescribed as a diabetes drug, it had a much more modest binding. Right? So the lanifibranor binding of the gamma element looks much more like pioglitazone.
It then brings in also some modest binding on the alpha and delta as well. And the PPARs, there's three isoforms. They're all networked. They work together. So you actually want to hit them all together in order to get the best efficacy for MASH and reduce the possibility of toxicity. So it was rationally designed for that. And then you saw the outcomes in phase II-B, which seemed to validate that design choice.
OK. And I guess there's one side effect that, when we talk to physicians, comes up repeatedly, which is the risk of weight gain. I think, you know, can you just characterize the weight gain? And then separately, are there ways to actually manage it?
Yep, absolutely. So just first of all, the facts about, so 50% of patients don't have any weight gain. 20% have modest; it's under 5% weight gains. And then all 30% have 5% or more. And it's actually not that much more than 5% or more. It is mechanistically the; it is the weight gain goes kind of goes up and it plateaus after about six months, unlike pioglitazone that keeps on going, for example. And the reason is that first, you get some volume expansion, like you get from a salty meal or elevation or something like that at first. And then there's actually a change in how the fat's distributed. It goes away from the gut and goes to the periphery. And the muscle comes on board as well. And so that's why you see the tapering overall.
So there's a redistribution metabolic redistribution and muscle coming on board. And that's why you see the tapering. So from, you know, then the question is, well, how does that, in fact, impact the profile? Right? What are physicians going to say about that? Oh, sorry. Let me go to the mitigation first. We did a study with SGLT2 when you combine with SGLT2. And that mitigated the weight gain completely. So that's an option. But if I go back to that segmentation and the physician's talking to a patient, that patient is an F3 patient, needs fibrosis regression, is a diabetes patient, that, in terms of a weight gain, as part of the profile, is completely acceptable to a physician. Right?
Then you take the opposite extreme, which is non-diabetic F2, that's where there might be a patient preference for something that maybe doesn't have weight gain. That's why I think that's how the market's going to segment out. The other two segments, again, I've said, I think are more appropriate for lanifibranor in that profile. And so that's how we view the market going forward. And that's how the feedback we've gotten from physicians, too. I'm actually going to note one thing just on it. It's actually not; it's more a tolerability issue than a safety issue. If you look at our phase II trial, there's about 30% of patients that gained that weight. But it was only reported as an adverse event around low double digits as a percentage. The physicians don't view that as an adverse event.
It only made the adverse event table in a very small set of patients.
OK. So the tolerability, despite the weight gain, is quite good.
Yeah, it's quite good. Yeah.
What we saw with TZDs was actually accumulation of fluid that typically also had some accumulation of fluid on the heart, unfortunately, that then catalyzed a lot of the concerns around those programs.
Exactly, especially with the type like the rosiglitazones of the world.
Right. OK. And yeah, so I mean, again, what's your general sense so I know that there's kind of a strategic component here that's worth thinking about. You know, strategically, why, what would be the gating factor to a, you know, strategic move of partnership or a large pharma coming in and taking Inventiva very seriously immediately after phase III data? Obviously, you'll have to read out phase III data. That's got to happen, I would think. But is there a negative view of PPARs in general that needs to be kind of crossed by phase III data? Or is that, do you think that's a fallacy?
No. So I think there is an executive in every pharmaceutical boardroom that has been burned by PPAR. So I think that's a very real, but the data will speak for itself. Right? The phase II data already speaks itself. phase III speaks for itself. And it hopefully will speak for itself. And I think that will overcome any hurdles. It's a big trial. Right? And so we'll get a very, very good signal.
Great. You know, let's talk a little bit about F4. And, you know, what could we possibly learn from C in 100 patients? How might that compare to, you know, a phase II trial that might be conducted in F4 or, you know, some of the learnings that we might get from some of the upcoming outcomes studies from other competitors?
So let me start with kind of the end in mind. We do intend to run an F4 outcomes trial with lanifibranor. We have a really strong reason to believe that there's mechanistically this should work. We've shown in preclinical models that we can address portal hypertension. We can address basically the stiffness of the liver that leads to the liver backing up and the liver outcomes in cirrhosis. So if we can identify a patient population that has portal hypertension, I mean, that means they're sick enough that they're going to get outcomes soon, but not so sick that we can't reverse it with lanifibranor. All right? And so what we're hoping to see is validation of that thesis in the exploratory cohort.
Now, probably the patients that we enrolled in F4 that we've kind of with the screen fails, they won't all necessarily have the portal hypertension we're looking for. So there'll probably have to be some parsing of that data. Right? So I wouldn't expect the top line F4 to show, you know, in 100 patients to show an impact on outcomes in that study. That's not what we're going to show. But we are going to show that it's probably safe and effective, hopefully, in that F4 patient population, at least from some biomarker standpoint, noninvasive tests and to give us confidence to go into that outcomes trial.
OK, great. And, you know, when we look more, you know, sort of is there an opportunity in F1? Does that make sense? You know, or is that, you know, sort of the sweet spot for GLP-1s?
That's probably I would say, as of now, that's the sweet spot for GLP-1s. We could be proven wrong. Right? If we show very safe and we have some effect in F1, that could change. Right now, our thought is we're more likely to move in the F4 direction.
OK. And then, you know, when you and this is a very effective drug. But the 800 versus the 1200, any thoughts around the need for those two doses? And, you know, what would you if there were an ideal outcome in your study, what would that look like for the 800 and the 1200?
Right. So we did see a dose effect in phase II-B. there's reason to believe that this is just kind of receptor occupancy and that if you waited over time, the 800 would approach the 1200 in terms of efficacy. I kind of like the idea of having two because of the patient segmentation that I talked about. Right? For an F3 diabetic patient, maybe you go with a 1200, even if it has maybe some little more weight gain. Maybe the 800 has less weight gain. And that's the one you use for the F2 non-diabetic. So that's it could provide some nice segmentation. That's a fantasy. Right? We have to see what the data says.
Right, sure.
But I think having the two doses only gives us optionality.
Was there any dose response as it relates to weight gain or the pace of weight gain?
I actually can't not answer that. I don't think we parsed that out to that degree.
OK, got it. You know, maybe just as we think about kind of the closing discussion here, you know, I think we have maybe just as a starting point, we have a sense of the powering. But what we've heard from physicians is something in the low to mid 20s is kind of what they're hoping to see from a fibrosis improvement perspective. That would kind of match up with resmetirom. What's your hope for the data? And, you know, what do you think is that a reasonable threshold?
Yeah, I think if we look at effect size over placebo in MASH if we hit 18% from the phase II, we absolutely have a drug. That's still better than resmetirom. And it's 12% at 12 months. That would be, I think, a really viable drug. I think if we start to double resmetirom if we get up to that low 20s, low to mid 20s, I think that we have a market winner. Absolutely. That there's not a lot of reason that you could see not to use lanifibranor at that point.
OK, perfect. And then maybe just to wrap up, combinations. We're seeing a lot of oral drugs kind of come into the market. Oral GLP-1s are advancing. You know, what would you say are the obvious fixed dose combinations or combinations that make the most sense to you?
Yeah. So I don't know about fixed dose. But combinations, obviously I think looking I mean, we did a study in SGLT2s already. But the GLP-1s make a ton of sense. And all oral regimen of GLP-1 plus lanifibranor, I think, makes a lot of sense. If you look at the use right now of Rezdiffra, it is 50% or so, I think they've said publicly, is with the GLP-1s. You don't necessarily need the data to do it. They haven't studied it. It's going to happen anyway. But I think there's a lot of opportunity for this therapy to be combined with others.
OK. And remind us on the cash runway and, you know, the—I guess the, you know, the path as we move through the phase III.
Yep. We are structuring ourselves to be able to launch this ourselves. That was part of the rationale with the fundraise in the fall. That gave us a nice cash runway out to Q3 2027, assuming we get our if the data is positive, we get a third tranche of funding of EUR 118 million. That includes that EUR 118 million. That gives us some nice breathing room to, after getting the data, to consider our next steps. Right? That could be a very large fundraise to really fund the NDA approval and commercial launch.
Yep, great. So not without dilution, but dilution from a much higher threshold after phase III data. Well, it's definitely an exciting year for Inventiva. Exciting year for you, I'm sure, because you'll have become CEO and almost be on the cusp of or actually be looking phase III data at your one-year anniversary. So that's pretty exciting.
Exactly.
All right. Thanks so much, Andrew.
Thank you.
Great seeing you.