Great. Welcome everyone. Very excited to have Inventiva here with us today. Ahead of a very exciting year for you into a Phase III readout. We're getting a lot of investor questions on this, so a lot to talk about today. I'm Ellie Merle, one of the biotech analysts here at Barclays. Joining us from Inventiva is CEO Andrew Obenshain. Obenshain I'm so sorry if I butchered your name. Chief executive officer and Jason, chief medical officer. Thank you both so much for joining us today. To begin with, can you give us an overview of lanifibranor and the design of your Phase III trial as we head into the data later this year? Maybe I'll start at a high level and I'll Jason for the phase III design. Lanifibranor, we are a one-asset company. Lanifibranor is a pan-PPAR agonist that we're developing in a Phase III study for MASH. It is a product that's been in development for quite a number of years. It's a rationally designed molecule designed to design out the liabilities of former PPARs. Learn from Actos and Avandia, for example, and designed out the liabilities by making it a more moderate gamma binder, and then also to balance PPAR. Another insight was that these PPARs are networked, and if you affect one, you affect them all, and therefore you want to hit them all in a balanced way. Before we go into the Phase III, I do wanna comment on the fact that we were required by the FDA to do quite an extensive toxicology work, two years in animals, that was due to the past PPAR experience. Those came out that we press-released those. Those actually had Actos (pioglitazone). They would not have survived. We showed that we had a very good tolerable profile. Went into the clinic. We've done five or six Phase I trials, had a positive Phase IIB trial published in the New England Journal of Medicine. Quite an extensive background before we even got into this Phase III. Jason could talk about then how we've started studying Phase III. Natural handoff. That's great. Yeah. Andrew said, NATIVE 2 was a successful Phase IIB trial, published in the New England Journal of Medicine now about five years ago, 2021. I think in that era, the excitement, it's sort of lost, you know, five years later, but it was the first drug ever in NASH to not only show meaningful effect at six months, but it had done so on a dual co-primary endpoint of both NASH resolution and fibrosis improvement in the same patient. NATiV3 just builds on the strength of that study. NATiV3 is largely similar, in many cases, identical to NATIVE 2. Obviously, it's longer, it's 18 months, but it's still the same basic construct, three arms, one-to-one to one, two doses of lanifibranor against placebo. The primary endpoint is somewhat unique, though, in the NASH field. It's the composite of both NASH resolution and fibrosis improvement of one stage and more in the same patient. We think that reflects some of that unique Andrew was sort of hinting at, and that, the ability of the drug to get both intrahepatic and extrahepatic drivers of MASH showed in NATIVE 2 that we can, in the same patient, resolve all of the features of MASH. Therefore, we brought that forward as our primary endpoint in Phase III. How should we think about the powering of this study? Well, it's well-powered. For a Phase III study, we've been guiding that we are powered to above 90%, on the co-primary endpoint of MASH resolution and fibrosis improvement. What we are not giving too much specifics about is, you know, what's the effect Jason, but what we can say is that we took a more conservative approach than NATIVE 2. Our effect size was 24% there with a placebo response rate of about 7%. What we did was we took a higher placebo response rate and therefore a lower treatment effect and powered to that. Then we over-enrolled the trial slightly, and we build in a 'cause it's an 18-month trial, and it was getting going during COVID, so we were a little nervous. We built in a much larger sort of dropout rate than what otherwise be expected in a Phase III, up to 30% dropouts, and we would still maintain and preserve that power. Okay. In my view, and, you know, jump in if I'm wrong, that sounds like quite conservative powering, where if you're 90% powered to show, what, the 18% placebo-adjusted effect size in Phase II, you probably could show meaningfully lower than that and still be statistically significant. Fair? Fair. Yeah. Yeah. You know, another way to say that is in 247 patients, we hit statistical significance on all three MASH endpoints, and now we have a 1,007 patient double-blind randomized controlled trial. We are very well-powered. At a much longer time point where you should. Exactly right. increasing effects over time. That's right. How should we think about that, how much the effect? I think broadly speaking, I mean, we don't know. In the end, there's a rational argument to be made that longer treatments kinda result in deeper effect. I think the three lines of evidence that support that are pretty straightforward. Other sponsors have shown it. Akero has shown it, for example, when they went from six months out to longer. Intercept showed it back in the day when they revealed top-line data on fibrosis improvement. You know, 18 months later, they continued to follow those patients, and they had deepening of the fibrosis effect by TE, so that's very good. Lastly, the biology of lanifibranor, the way that PPAR agonists work, they're sort of metabolic reprogrammers that work at the level of DNA transcriptional activation, that just takes time. six months, no doubt we saw an effect. We're very confident in that, but it's really early for gene regulation and transcriptional activation to show themselves fully. If all those three things line up, we think it's reasonable to think we're gonna get a deeper effect. How do you expect the patient baselines to compare in Phase II versus phase three? Yes. I'll start. It's largely similar. The big difference is we enroll more patients in the U.S. Therefore, there's more diabetes patients in the U.S. We have 55% diabetes patients in the trial, 42% were in Phase II. Actually, the stage of disease, F3, travels with diabetes. The more metabolically dysfunctional a patient, the more likely they are to have later-stage disease. You see that with a higher baseline of F3 patients in the trial. The other difference in the trial was that GLP-1s really weren't around during the Phase II. We had 14% of patients that started on a baseline GLP-1, not the MASH dose, the low dose for diabetes. Those came in on a stable dose. We had another about 10% of patients that dropped out during the trial, but it should be balanced by arm. Mm-hmm. across placebo and drug. Anything else? Okay. Great. That's helpful. Sorry for jumping into the trial design questions. You can tell where we're getting a lot of questions. Yeah. Maybe taking a step back, my favorite topic, MASH. Mm-hmm. How do you see the landscape? There's a lot of drugs in development. You have Rezdiffra, you have GLP-1s, now available, and then, of course, FGF-21's coming along. Where does lanifibranor fit in the development landscape? Yeah, absolutely. Just to take a step back first, broadly, we're at the very beginning of this market, right? We've just had two approvals recently, more that are gonna be coming. We are in the very beginning of what will eventually be multiple classes of drug and multiple drugs in those class and growing quite substantially, as a market. Where we are today is we think there's about 375,000 patients in that F2, F3 space, where lanifibranor will compete. In that space, we believe there's gonna be a baseline use of GLP-1s. GLP-1s for us are friend, not foe, and then physicians will layer on an oral to address the fibrosis on top of that, either Rezdiffra or lanifibranor. We'll get back to that in a second and how we see that playing out. Just to comment on the FGF-21s, we really view those as staying in F4 for a number of reasons. First of all, we believe the pharmaceutical companies will premium price those, and they're injectables competing in an oral market. They've got some toxicities, both bone density and GI that are gonna really prevent them from moving into that F3 market. We really see them staying in the F4 market. Bring us back to the F2, F3 market. How does a physician choose between lanifibranor and Rezdiffra? The way we segment this 375,000 patients is into four boxes, right? It's a two-by-two grid. You can think about F2 and F3, and they're roughly equal, 50% in each. You can think about non-diabetic, diabetic, and it's about 40% non-diabetic, 60% diabetic. You end up with four equally sized boxes, relatively equal, a little bit bigger for the diabetic. Where, what's the natural habitat for these drugs? Well, if you think about an F3 diabetic patient, right, a physician, you know, let's say lanifibranor has just launched, and a patient walks in, and the doctor needs to make a decision about what oral to put that physician, that patient on. Let's say we duplicated our Phase II and say, "Okay, well, super worried about fibrosis because I don't want that patient to go to F4. I wanna pick up the biggest hammer I have on fibrosis, and that's gonna be lanifibranor, 18% versus 12% if we duplicate the Phase II. This patient's got diabetes. I know that's driving the disease. The metabolic dysfunction is driving this disease, and I need to address that. They're probably already on diabetic medications, but why not add something that can reduce HbA1c even further? Lanifibranor becomes a very natural choice there. A patient walks in that's, you know, the day after lanifibranor launches, and there's a F2 non-diabetic patient. Well, that's probably a patient I'm still gonna put on Rezdiffra for now, right? It's a proven drug. He's comfortable with it, doesn't have diabetes. I'm not worried about the fibrosis going to F4 overnight. I'll stick with it there. You can see that as a physician gains experience, that a very natural place for lanifibranor to go is then to the other F3 patients without diabetes or to the diabetes patients with F2, and that's where we see the market evolving over time. If we end up getting better efficacy than 18%, maybe we double what Rezdiffra has, and then that you migrate into that whole market. Mm-hmm. Yeah, that 18% was at 24 weeks, no? That's correct. It was 18% after six months versus 12% after twelve months. In phase three, you're looking at 18 months. Yep, correct. We do expect a deepening of effect and hopefully some better results. How do you think about the breakdown between the different prescribers, especially given this effect that you're seeing in diabetic patients as well as maybe more physician familiarity from endocrinologists with the PPAR class? Mm-hmm. As you think about the segmentation, I mean, it seems like right now most of the MASH patients that are being treated are being treated by Hep/GIs, less so in the endocrinology segment. Where do you see this evolving in the coming years? Because, I mean, correct me if I'm wrong, but I would guess that a lot of MASH patients are sitting with endocrinologists right now. Certainly, the endocrinologist is probably keeping them in the opinion of the GI and the hepatologist, probably keeping them too long. This is something we won't make a decision now about how we do this, but we'll definitely be monitoring it. Overall, we're not gonna be looking to get switches in terms of patients off of Rezdiffra on lanifibranor. We're looking for new patients. We'll monitor closely kinda how the market is growing, where the diagnosis is happening, and where those new Rx are. I think GIs and heps are clearly gonna be a call point, a starting call point for us, and whether we add endocrinologists at the time of launch remains to be seen or to what scale. I think certainly there's at least a subset of endocrinologists that should be in that targeting at launch. Mm-hmm. What proportion of patients do you expect in your Phase III to be on GLP-1s at baseline? Based on GLP-1 use in NATiV3 is a little less than 15%. They needed to be stable treatment, non-NASH dosing. You're talking one, it's not all SEMA, and they've got all eyes and heat and light around SEMA, but it's not only SEMA. There's liraglutide, dulaglutide as well. Whatever it is, they need to be on stable dosing, and it needs to be the diabetes dose because it's for concomitant comorbidities, diabetes in this case, and not for NASH. We like that data set across both. We have two cohorts, the main 1000-patient randomized, double-blind, and then a sort of expansion cohort for screen fails of about 400 patients. That would give us a data set of about 300 patients. I think Andrew mentioned earlier, GLP-1s are gonna be the backbone for therapy, particularly patients entering at that F1, F2 side. Ones that are caught later by the heps, GIs, not clear that they'll be on GLP-1s, but clearly the earlier ones will be. The idea that we'll be able to have data that say that we work and play well with GLP-1s will be fantastic. We think it's gonna be a good data set. The mix of F2, F3 patients in your trial that you expect? It's contemporary, so we have roughly two-thirds, one-third, two-thirds F3, one-third F2, which is fairly similar to what Madrigal had in their Phase III program. It's a little different than our Phase II, but the world has changed. As Andrew said, we have more diabetics today that both have NASH, so that's also reflected in the diabetes status. We have about 55% diabetics in the NATiV3 trial compared to about 45% in NATIVE 2. Both of those really reflect the contemporary practice today. That's helpful because you're enriching for the patients that were better responders in Phase II. Well, it's interesting. We actually did a responder analysis. We published it after the NEJM article in 2024. Independent of diabetes status, the drug actually works equally well. Even if you strip out the F1s from NATIVE 2, the drug works slightly better in F2, F3, but I'll say here that it works equally well. One, we're not getting a free ride on the back of the sort of lesser severity patients. Second, diabetes isn't giving us the kinda tailwind. On the other hand, in the presence of diabetes or hemoglobin A1c reductions, like in our LEGEND study, approach one full point. That has all the makings of a drug that could be valuable to endocrinologists as they're trying to manage both diseases. Although it doesn't work better on histology, it does have the glycemic effects in the diabetics. Right. Makes sense. That's helpful. A question that we get from investors a lot is around safety- Mm-hmm. Particularly the history that the PPAR class has had with safety. Can you walk us through the history of the safety of the PPAR class briefly? I know there's a lot to go through with PPARs. Just kind of an overview of that and where you see lanifibranor falling and your confidence in the safety. Yeah. I'm gonna hand that one to you. Well, that's so kind of you. Yeah. Thank you. I'll actually pick up where Andrew left off. Lanifibranor was rationally designed by a group of chemists that were PPAR biology founders. They had created fenofibrate back in the day, and their goal was to sort of get the biology that these metabolic reprogrammers, PPARs, could do, but without a lot of the baggage of some of the therapeutics that had been on the market. The stepwise approach was design the molecule. Second, run the toxicology data in conjunction with FDA to say what's true for this drug and what's not true. Back in 2019, we had publicly talked about that toxicology program Andrew mentioned, full two years. two-year rodent, one-year non-human primate, discharge many of the traditional PPAR risks. Things like cancer, muscle damage, kidney damage sort of went away. That it showed that as predicted from the structure of the drug, we had gamma effects, but they looked a little muted and blunted compared to, like, pioglitazone or rosiglitazone. Very good. Rubber meets the road in clinical trials. What we showed in NATIVE 2 sort of confirmed all of that. If you look at an adverse event table in NATIVE 2, it looks like a lanifibranor adverse event table. It doesn't look like other PPARs. It's its own footprint. What's absent are a lot of the PPAR-alpha delta safety issues. Good. What is present are some of the gamma concerns, but they do appear to be muted compared to what you see with longer term, bigger studies with pioglitazone. We do have weight gain, for example, but it appears to be less than what you would see with pioglitazone, and it tends to plateau after about six months or so. Good. The peripheral edema that one sees associated with that weight gain appears to be less. The final arbiter of that is the congestive heart failure signal. Now, obviously, we're running a blinded clinical trial, but based on NATIVE 2, we like that step off a lot. Less weight gain, less edema, and much, much less heart failure compared to sort of historic norms. I think in summary, we like our safety profile not because it's better than pioglitazone, it's our own. It then sort of matched with exactly what the people that designed the drug fifteen years ago were hoping that they would get in the clinical environment. Stripped of a lot of the safety baggage, but still getting you the same intrahepatic and extrahepatic biology that made PPAR so interesting in the first place. What are you seeing in terms of weight gain, and how does that compare to what's seen with pioglitazone? Why don't you start with the weight gain. Yeah. I'll go to pio. I think absolutely. The first thing to understand is about 50% of patients in our Phase II did not gain weight. Mm-hmm. 20% gained very modest 2.5%-5%. There's a 30% they gained 5% or more. What's interesting is the way the doctors code that, right? If you look at the adverse event table, a weight gain is only 10% because, you know, in many, this is not perceived as an adverse event. It's really a tolerability issue, and physicians actually only recorded it one out of every three patients with that weight gain over 5%. So that's the facts of where it is. Maybe I can hand it to you to talk about kinda what the biology is, and then I could talk about how we think it's gonna play in the market. Yeah. On the one hand, the gamma effect of pioglitazone, rosiglitazone, these are incredibly strong metabolic reprogrammers. Mm-hmm. In fact, pioglitazone probably has some of the best glycemic data that exists ever. I mean, they're fantastic. They even had outcomes back in the day. It was in the 1990s. I don't think people think about outcomes in that regard, but they actually had really good outcomes in diabetics that had macrovascular disease when they looked at, like, what we would think of as sort of a MACE endpoint today. Hazard ratios look pretty similar to what we see in the modern. The problem was that it came along with this question of weight gain, edema and congestive heart failure. What we see is, generally speaking, the weight gain that looks, it's about proportionally numerically less than what you might see with pioglitazone. More patients tended to gain more weight with pioglitazone, and it lasted a longer time. If you follow those patients for years, like in the PIVENS study, the weight gain kept going up and up and up, and it reached a plateau maybe at year three, as opposed to something like maybe month six or nine, which is where we're landing. The overall magnitude of the weight gain, which is Andrew just shared, is less. When you step that down, the peripheral edema, in some cases, looks to be five-fold lower than what we reported in some trials. If you go look at the label, for example, it might be two to three-fold lower than what was reported. We like that. We call it a sort of blunted or attenuated gamma effect, but it still is very clearly a gamma effect, which is really just salt and water retention in the end. That's what all this comes back to, is that the gamma works by modulating salt reabsorption, and you get some peripheral edema and fluid retention. Mm-hmm. I think just to bring it back to that market segmentation that I talked about, a chance of weight gain is going to be part of the profile. For that F3 diabetic patient population, that is a perfectly acceptable part of the profile in terms of physician choice. For that F2 non-diabetic, that's probably where it becomes a little bit more of a liability unless your fibrosis score is so good that it overcomes that, right? It just plays into that market dynamic. We've seen in labels across the PPARs, you know, black box warning for congestive heart failure associated with the edema. Mm-hmm. We've seen warnings for bladder cancer risk. As you think about your profile, what are the reasons why you think you're seeing a lower risk relative to pioglitazone? It's a tricky question, right? Because in the end, FDA gets a big vote, too. We don't have full data yet from NATiV3, so it's all highly speculative. That being said, the three elements that matter are what's your drug, your class, what are your data, and can you manage the risk in a trial environment or market environment? Number one, we have a different scaffold. We are not a TZD. We're a completely novel agent. We're not pio that also happens to have alpha and delta. We're a completely novel agent there. Second, we'll have our own data sets, as we just talked about. They will or they will not look differently in the end than pioglitazone. That will matter. Lastly, how are we doing in the clinical trial when the FDA ultimately looks at, were you able to manage whatever effects you see? If they're comfortable that it's a different drug and the data look different and you're managing risk well, then there's no reason for a box warning. That being said, FDA has decisions of their own, and they may still say, "You're going to get a box no matter what." We actually think we're in a really good position to walk in with a, you know, a straight-faced argument. Not the same drug. We have our own data set. We think we've done a really nice job in a trial environment of managing our risk. Therefore, this is the label that we're proposing based on our data. We'll see what we get. That's helpful. What are your plans in F4? I'm sorry? Your plans in F4. Do you want to start? We will be approved under conditional approval in the U.S. for F2 and F3, so we'd have to do an outcomes trial. We are choosing to do that outcomes trial in F4. I'm going to maybe define that a little bit more. We will start that trial after we get data. We have to have it substantially started by the time we file our NDA. We're looking to choose a patient population that is sick enough that it can progress to outcomes, we can measure outcomes, but not so sick that we can't reverse the disease. We've identified a patient subgroup that has portal hypertension that we believe is the right target for that trial. I'll hand that over to you to maybe go explain the biology. Yeah. I mean, this is honestly, this is the really active area for those that are listening. It'll develop over the next couple of years. This idea that we can now identify easily at the bedside a group of patients that are either advanced F3 or F4, but they have the physiology of cirrhosis, portal hypertension, Andrew Obenshain said. That you can identify them easily at the bedside really makes the possibility of putting them in clinical trials really attractive. This idea that you can have a group of patients in the trial that have the portal hypertension that puts them at much higher risk of liver-related outcomes, that's fantastic when you think about a trial design perspective. What we like the most about it is that that group of patients appears to match the biology of lanifibranor really nicely. The intrahepatic and extrahepatic modifying elements of lanifibranor on the alpha, delta, and gamma PPAR receptors, each of those pathways are driving some of that portal hypertension. We have a fair bit of preclinical data that we published over the years, including at The Liver Meeting last year, AASLD in Washington, sort of outlining that data. We're excited, and we have about 75 patients roughly in our expansion cohort in our Phase III program that was a really nice view of the safety of both doses of lanifibranor. We're excited to begin to talk to FDA about this and build that trial. Strategically, we've seen three acquisitions in the MASH space in the last year. You're a fraction of Madrigal's market cap. Mm-hmm. Those are just facts. I'm not speculating. How are you thinking strategically about your plans for commercialization and what might make the most sense, whether you go it alone or seek a partner? Well, Madrigal has really laid out the path for how a mid-sized biotech can commercialize successfully and drive to profitability. We plan to follow that path, right? You should expect us to, if we have positive data, raise a lot of money to be commercializing ourselves. Now, along the way, yeah, you're right, there might be some strategic interest that might prevent us from realizing that mission. We are planning to commercialize ourselves in the U.S. definitely, and then secondarily in Europe. What is your cash balance and cash runway currently? Our cash runway goes to about Q3 2027 right now, so well on the other side of data, which gives us a lot of room to make some strategic decisions post-data. Mm-hmm. Great. Just a question on the confirmatory study. How are you thinking about how you might design that and start it shortly before we might get the data for Madrigal? I can imagine that's not exactly. I think what FDA wants is very clear on this. You need to have the trial meaningfully underway at the time of approval. At the time of filing, you need to have the trial started. Then prior to that, we have a lot of opportunity to engage with FDA on exactly how they define that. That's the point of it. It's not a get going and let us know how you're doing. It's active engagement with them at the pre-filing meeting, the interim mid-cycle review meeting. Our plan is that clearly we will wait for data to have any meaningful start on that study, but we're already laying the groundwork for that now. Great. Awesome. Well, I think we're at time, but appreciate both of you joining us today and certainly an exciting year ahead of the Phase III data. Thanks. Thanks for having us.