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Thank you. Good day and thank you for standing by. Welcome to Inventiva's First Half of 2026 Financial Results Conference Call. At this time all participants are in listen only mode. After the speaker's presentation there will be a question and answer session. As a reminder, today's conference call is being recorded. I would now like to hand the call over to David Nicodem, Head of Investor Relations for Inventiva. Please go ahead.

Thank you. Good morning. Good afternoon. Thank you for joining Inventiva's first half 2026 financial results and business update. This morning we issued our press release reporting our full financial results for the first half of 2026. A replay of this webcast will be available in the investor section of our website following the call. Before we begin, a quick reminder that the statements we make today, including during the Q&A, may include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements reflect our views only as of today and should not be relied upon at any later date. Please refer to slide 2 and to our filings with the SEC and the AMF for discussion of the associated risks.

Joining me today are Andrew Obenshain, our Chief Executive Officer, Dr. Jason Campagna, our Chief Medical Officer and President of R&D, and Axel-Sven Malkomes, our Chief Financial Officer. Chris Benecki, our recently appointed Chief Operating Officer, will be joining us for the Q&A portion of the call. With that, I'll turn the call over to Andrew.

Thank you, David, and welcome everyone. Today I'll start by providing an update on the company and our priorities. Jason will overview our Lanifibranor Development Program. Axel will walk through our first half of 2026 financial highlights, and then we will open the call for Q&A. The first half of 2026 has been a defining period for Inventiva. We have stayed focused on our near-term objectives, advancing Lanifibranor toward the Phase 3 top line results readout in MASH expected in Q4 2026, preparing for regulatory filing while building your organization to support a potential commercial launch. Let me start with why we believe in the potential of Lanifibranor and why a potential new therapy for MASH is so important.

It comes down to 3 key elements, differentiation, late stage validation, and market opportunity. Let's begin with differentiation. MASH is driven by both intrahepatic and extrahepatic processes, and Lanifibranor is designed to address both through a single, once-daily oral therapy. In our NATIVE Phase 2b study, Lanifibranor showed improvement across all key histological endpoints. Next is validation. We designed the NATIVE 3 Phase 3 trial to build on the foundation established in our positive Phase 2b study. We look forward to reporting top-line data in the fourth quarter of this year. And finally, market opportunity. The market is being built in front of us. If Lanifibranor is approved, we will enter an established therapeutic area with a market potential expected to exceed $15 billion by 2035.

However, significant unmet need remains, and this represents a meaningful opportunity for Inventiva to bring a potentially differentiated treatment option with Lanifibranor to people diagnosed with MASH, if approved. Let me take each in turn and then lay out our priorities for the year ahead. Let's start with differentiation, and it begins with understanding the biology of the disease. MASH is not simply a liver problem. It is the hepatic expression of a broader systemic metabolic dysfunction. As slide 6 shows, the disease is driven by multiple interconnected pathways, both outside and inside the liver. These include insulin resistance, adipose dysfunction, and dyslipidemia on the extrahepatic side, and steatosis, inflammation, and fibrosis within the liver itself.

That has clear implications for treatment. If the disease is driven by several processes at once, there is an opportunity for next-generation treatment to target more than just 1 driver. That is the unmet need we believe Lanifibranor could address if approved. Our aim is not only to target the liver, it is to modulate pathways across both the metabolic and hepatic components of the disease and bring a differentiated treatment option to patients with MASH. The differentiating mechanism of Lanifibranor modulating both pathways is reflected in compelling clinical data. In our Phase 2b study, after 6 months, Lanifibranor delivered an 18% placebo-adjusted improvement in fibrosis, 26% on MASH resolution, and 24% on the composite endpoint. Those results are the foundation for NATIVE 3.

We are now testing the same approach in a larger controlled Phase 3 population of patients with F2 and F3. That is what makes NATIVE 3 so impactful. It was designed to confirm at pivotal scale the biology and activity we observed in our Phase 2b study. And we are pursuing this in a market with substantial and growing unmet need. As slide 8 shows, there are an estimated 18 million Americans living with MASH, yet only 10% are diagnosed. That is changing fast. As the treatment landscape has matured, diagnosis has increased, up roughly 25% versus 2024. And that is translating into a larger population being actively identified and managed.

Today, approximately 374,000 patients with F2 or F3 disease are already in treatment or under the care of a physician. The picture is clear. A large, prevalent patient population expanding rapidly as awareness and testing improve, and it could a compelling opportunity for Lanifibranor if approved. Turning to slide 9, to see where Lanifibranor may fit in the treatment paradigm, it helps to think about MASH in terms of 2 factors that are top of mind for physicians. Severity of fibrosis, and the cardiometabolic factors that can influence the risk of disease progression. Put fibrosis on 1 axis and cardiometabolic risk on the other, and 4 clinically distinct populations come into view. Start with the lower right quadrant. We have patients with F3 MASH and cardiometabolic risk, such as type 2 diabetes. This is a population with high unmet medical need.

With the mechanism of action of Lanifibranor could be compelling in that it targets both the liver and the metabolic driver simultaneously. In our Phase 2b trial, Lanifibranor demonstrated an 18% placebo-adjusted improvement in fibrosis at just 6 months. Similarly, in the lower left, although these patients have earlier stage F2 fibrosis, their cardiometabolic risk factors can put them at risk for more rapid disease progression. For these patients, physicians may also want to act urgently and Lanifibranor for potentially offer an opportunity to intervene earlier in the course of the disease if approved. Moving to the top right quadrant. By extension, Lanifibranor could be well positioned in patients who have F3 fibrosis without significant cardiometabolic risk. Here, the fibrosis itself is the primary concern, and Lanifibranor may have the potential to address the underlying liver disease before it progresses.

Taken together, these 3 quadrants represent a large population with significant unmet need. And if approved, we believe Lanifibranor has the potential to play an important role in addressing the needs of these patients. With that overview of why we believe in the potential of Lanifibranor, let me lay out 3 key priorities we are focused on to unlock new opportunities for patients with MASH. First, the NATIVE 3 trial. We remain on track to report top-line data in the fourth quarter of 2026. Earlier this month, the last patient completed their final, second-to-final, and final 72-week visit. The main cohort enrolled 1,009 participants, all with biopsy-confirmed non-cirrhotic MASH and F2 or F3 fibrosis. Second, regulatory readiness. We are advancing our preparations now to support a potential NDA submission with the FDA in the first half of 2027, positioning us to move quickly into regulatory interactions if the top line data readout is positive.

And third, commercial readiness. We are building a commercial organization with the depth and breadth of experience with the best disease products to be ready for the potential launch in 2028. We believe we are moving forward with Lanifibranor from a position of strength and with the potential for a differentiated profile, a late-stage validation opportunity with NATIVE 3, and a significant market opportunity if approved. I'm truly energized by the potential to make a real difference for millions of people living with this serious disease. With that, let me hand it over to Jason to take you through the science behind Lanifibranor and our clinical program.

Thank you, Andrew, and greetings, everyone. I'll spend a few minutes on 4 aspects of our Lanifibranor development program in MASH. 1, how Lanifibranor is designed to address the spectrum of disease. 2, what we've observed in the positive NATIVE Phase 2b clinical trial. Third, how our NATIVE 3, Phase 3 trial is built to confirm that Phase 2 study. And lastly, where we're thinking of taking the program next. Let me start with the molecule. Slide 11 shows Lanifibranor as a potential novel new chemical entity, structurally and mechanistically distinct from both fibrates and thiazolidinediones, and recognized by the FDA with both Breakthrough Therapy and Fast-Track designations.

It was informed by decades of research on PPAR biology and the development learnings of prior compounds. And it rests on 1 critical concept, balance. Lanifibranor engages all 3 PPAR isoforms, alpha, delta, and gamma, in a low-potency, balanced manner such that no single receptor biology dominates. It was also engineered to have only partial agonism of the PPAR gamma receptor. The combination of this balanced low-potency pharmacology and partial PPAR gamma agonism are the keys to our differentiation. This is what lets Lanifibranor modulate in harmony the metabolic, inflammatory, and antifibrotic pathways of MASH combined rather than forcing 1 mechanism or receptor at the expense of the others. The 2 charts on the right illustrate this design pharmacology. On the first panel, we see the balanced activation profile and the approximately 80% gamma activation with Lanifibranor, while on the far right, the cofactor recruitment fingerprint that sets Lanifibranor apart from full TZD gamma agonists. Result is a once-daily oral therapy intended to deliver a physiologic balance between achieving PAN-PPAR activation and avoiding any 1 receptor dominance.

Moving now to our Phase 2b NATIVE Clinical Trial Data. Andrew shared our overall histology efficacy data, but that included patients with lower risk earlier F1 disease. When we exclude these patients with earlier stage disease, we continue to see robust effects across all 3 histologic endpoints, showing that the drug worked equally well in both early and later stage disease. And these results were achieved after only 6 months of treatment. Looking more closely at the data for the composite endpoint, you can see that treated patients were roughly 8 times more likely than placebo patients to achieve dual histologic improvement in the type 2 diabetes subgroup. Thank you. This tells us that spontaneous regression of the disease was uncommon and that the treatment effect of Lanifibranor was strong. Together with the early and late stage data, these results underscore the potential of Lanifibranor to perform across the disease spectrum, including in patients with the most urgent disease.

Let me now turn to safety and tolerability. On slide 13, we show the most frequently reported adverse events by investigators in our NATIVE Phase 2b clinical trial. Lanifibranor was generally well tolerated across the totality of our Phase 2 program, but the adverse event profile in NATIVE 2b tracked closely with the underlying scientific design of Lanifibranor. Consistent with our preclinical toxicology data, we saw minimal classic alpha or delta toxicities. Gamma-related effects, weight gain, edema, and hemoglobin decline, these were present but attenuated relative to the full TZD class gamma agonists. The weight gain we observed in patients treated with Lanifibranor is biphasic. Early on, the partial PPAR gamma activation acts on a sodium channel in the kidney, resulting in sodium and water retention.

While in a later phase, that same partial PPAR gamma activation drives improved insulin sensitization and adipose remodeling, reflected in the rise in adiponectin, tied to histologic efficacy. Both phases are consistent with the known pharmacology of PPAR gamma engagement, and based on our legend study, these gamma-related effects were mitigated by adding an SGLT2 inhibitor, empagliflozin, while also preserving the metabolic benefit of Lanifibranor. This brings me to NATIVE 3. This is a Phase 3 global registrational trial, and it was deliberately designed to build on our Phase 2b, the same 2 doses, a similar patient population, and a primary composite endpoint of MASH resolution and at least 1 stage fibrosis improvement in the same patient. Secondary endpoints include MASH resolution and fibrosis improvement of 1 stage or more. The trial enrolled approximately 1,400 patients across 2 cohorts, a placebo-controlled randomized portion consisting of 1,009 patients with biopsy-confirmed F2 or F3 MASH. And an exploratory cohort of 410 patients with predominantly F1 or F4 disease. Both cohorts were treated for 72 weeks.

All patients who completed the trial are eligible for an active treatment extension to support a longer-term view of the safety and tolerability of Lanifibranor. The main cohort will serve as the basis for global marketing registration, and the primary endpoint is powered at 90% on deliberately conservative assumptions with a higher placebo response and a lower treatment effect than we observed in the Phase 2b NATIVE trial. It is stratified by fibrosis stage and diabetes status. This main cohort also reflects the real world. The NATIVE 3 population is a contemporary MASH population, with higher diabetes prevalence, more advanced fibrosis, and more use of GLP-1s and SGLT2 inhibitors compared to our Phase 2b trial. As Andrew noted, it has been fully recruited, and the last patient visit for the week 72 portion of the trial was completed earlier this month. And as Andrew shared, we are excited for top-line data in the fourth quarter of this year.

Subject to positive Phase 3 results, we intend to file for accelerated approval with the FDA and conditional approval with the EMA. We will also be initiating a confirmatory clinical outcomes trial designed to evaluate the effects of Lanifibranor in patients with more advanced disease. That's worth pausing on because everything I've described targets the core pathophysiology of MASH. That same pathophysiology also underlies Compensated Advanced Chronic Liver Disease, or CACLD, due to MASH. These are patients who have progressed to advanced fibrosis or early histologic cirrhosis, yet they remain clinically compensated but have evidence of clinically significant portal hypertension. The primary driver of adverse liver-related outcomes. This subgroup of patients has no approved disease-modifying therapy. It is a significant area of high unmet need in the disease. We believe that Lanifibranor is mechanistically compelling in CACLD because the same PPAR isoforms that drive the histologic and metabolic effect in the non-cirrhotic MASH population also act on the vascular biology that underpins portal hypertension in this more advanced group. And in CACLD, portal pressure matters because as the disease advances, portal hypertension and not fibrosis alone becomes a key driver of these hard clinical outcomes, including bleeding, ascites, and liver transplant.

We recently published an analysis of our Phase 2b NATIVE trial showing a correlation in patient biopsies with vascular remodeling we've observed preclinically. Exploratory analysis, but they add to our conviction to pursue further advanced disease states in MASH. With that, I'll hand it over to Axel.

And I will pick up for Axel here.

Yes, I'm sorry. I lost my text. Please go ahead. Yep so good, I.

So this morning we issued our press release reporting our full financial results for the first half of 2026. Axel will focus on the key financial highlights and our financial position as we approach the NATIVE 3 top line readout. Axel, are you ready to take over? Not yet. Okay. As of June 30, 2026, we had €233.9 million of combined cash, cash equivalents, and short-term deposits. And we significantly strengthened our financial position through the comprehensive capital structure optimization that we announced in June. Under that, we bought back approximately 60% of the EIB warrants with anti-dilution protection for €50 million, and repaid our EIB loans for €63 million. In addition, the remaining EIB warrants with anti-dilution protection were cancelled and then Inventiva issued new EIB warrants in exchange described in the July 9, 2021.

I'm ready to take over. Please go ahead. As part of this optimization, we secured new debt financing of up to €130 million in 3 committed tranches, subject to conditions, with an initial drawdown of 2 tranches of €75 million gross, plus an additional uncommitted tranche of up to €20 million, as described in our press release of June 2, issued earlier this year. We also completed an underwritten public offering of our American Depository Shares, generating gross proceeds of €103 million. Together, these actions strengthened our balance sheet, extended the maturity of our debt, and simplified our capital structure. Our current financing assumptions, existing resources, and completed financing transactions provide cash runway until the end of the second quarter of 2027. Seeing us through key milestones, the Phase 3 top line data readout and potential NDA filing. Assuming full exercise of tranche 3 warrants on the back of a positive top line result, as well as successful completion of tranche C of the debt financing transaction, cash runway would extend to the start of the first quarter of 2028. R&D expenses were €46.2 million in the first half of 2026, brought in line with the prior year and reflecting continued clinical development of Lanifibranor and MASH. Marketing and business development expenses increased to €2.6 million and G&A expenses increased to €22.2 million. Overall, we entered the second half of 2026 with a strengthened balance sheet and financial visibility for the company.

With that, I'll turn the floor back to Andrew for his closing remarks.

Thank you, Axel. This is truly an exciting time for Inventiva. Our differentiated mechanisms of action, the results we saw in the NATIVE Phase 2b trial, and the robust design of our NATIVE Phase 3 trial provide a strong foundation as we approach the milestones ahead. The next major milestone is our NATIVE 3 Topline Results Readout expected in the fourth quarter of this year. Positive it could support a U.S. regulatory filing in the first half of 2027 and a potential EU filing to follow. And if approved, we're prepared for a potential U.S. commercial launch in 2028 with the goal of bringing a new treatment option to patients with significant unmet need. We also expect to initiate an outcomes trial, which could support a potential opportunity for Lanifibranor to expand into more advanced disease populations. Stepping back, what does this all mean for Lanifibranor? Let me bring it back to where I started. Why Lanifibranor and why now? Lanifibranor was designed to target both the metabolic and hepatic drivers of MASH in 1 oral medicine.

NATIVE 3 top line results readout is imminent in Q4 this year. The market is established and significant unmet need remains. We have established the foundation to build a launch-ready organization and prepare for the next stage of development, moving forward from a position of strength with the discipline and the urgency that people living with MASH deserve, and I'm genuinely excited about what lies ahead. With that, let me hand it back to the operator to begin Q&A. Operator?

Thank you. We will now open lines for questions. [Operator Instructions] We'll now move to our first question. And our first question comes from the line of Yasmeen Rahimi from Piper Sandler. Please go ahead.

Good morning, team. Congrats on all the updates, and thank you so much for walking us through some of the key questions. Maybe we've been lately getting questions from investors how we should be thinking about the 2 doses in the NATIVE study, and the NATIVE 3 study, and whether it would even make sense commercially if both showed a clinically meaningful difference to move forward. Would love to get your thoughts, and maybe 1 other 1 that sometimes comes up is that the higher dose had a phenomenal histological benefit, but then when we compared the NITs, the 2 doses looked more the same. So would love if you could maybe comment on both. That would be very helpful, as it's on top of you of the investors that have been asking us that. Thank you.

Thank you, Yasmeen, and good morning. So 2 questions in there. First 1, I think more of a commercial question, which I'll take, and then I'll pass it on for the correlation with histology and those to Jason in a second. If both doses are positive, are statistically significant positive, I think it would make sense to bring both forward in the market. It's going to depend on the data. So we'll clearly look at what the efficacy is with each dose and the tolerability of each dose. And if there is a there were to be scenarios in which the difference between the 2 makes sense to bring both the market potentially 1 for 2 patients or 1 you could think of as earlier stage patients that are less urgent and so therefore would be okay with a dose response of lower efficacy and more more tolerable, and if another 1, if you have, if there's a tolerability difference between low and high, then a higher dose with still tolerable, but a slightly different profile, you could see bringing both forward.

But that's really remains to see in the data. It's a little bit too early to speculate until we get the actual data to see it. Jason, let me hand the second question over to you, the correlation of NITs.

Sure, happy to Yasmeen, good morning. So in the NATIVE Phase 2 trial, generally speaking, the histology endpoints tracked well with most, but not all, of the clinical biomarker endpoints. Obviously, ALT-AST reduction was evidence. This reflects a hepatocellular injury, but moving into fibrosis, you can see that the Think of the data that we had as looking at both new scar being laid down and active scar resorption. PRO-C3 is the best example of new scar being laid down. It's a fragment of the collagen peptide, and the PRO-C3 marker actually tracked quite nicely with the 1,200 milligram histology efficacy endpoint. Similarly, when we look at ELF, the hyaluronic acid was a little noisy at baseline, but the 2 other components actually tracked very nicely in a dose-dependent manner, representing that we were, in this case, laying down, resorbing some existing scar. And lastly, on the TE, the range, you know, it's very difficult to compare trials, Yasmeen, as you know, across different sponsors, but when you look at the data ranging from 6 months to 18 months, the range in TE, liver stiffness measurement, ranges from about a 1% placebo-adjusted change all the way up to like a high, uh, sorry 1 kPa up to a high of 3 kPa.

So that's somewhere around 10% to 30%. Lanifibranor came in at the lower end of that range, and it's our belief that do that's 1. It's just early in the disease to really have movement on liver stiffness, the composite view of what's going on in the liver. And more importantly, we know that Lanifibranor has some confounding due to that fluid retention. This is a known concern with liver stiffness in general, listed in the the ECHO SENS manuals about being cautious about getting liver stiffness data after a meal or in the presence of fluid loading, and at 6 months, the dynamic fluid flux that's still happening due to the PPAR gamma, we believe is likely impacting some of that. So we landed at about a 10% reduction in liver stiffness, about a 1 kPa placebo, which just a number, and we're confident that with a longer treatment duration, the underlying fibrosis improvements will, in the end, dominate that signal by 18 months.

Thank you so much. Thank you. We'll move on to our next question. Our next question comes from the line of Rami Katkhuda from Fisai Capital. Please go ahead. The line is open.

Hi, guys. Thanks for taking my questions as well. Maybe going off a comment Jason made earlier, can you touch on the time course of Lanifibranor-associated weight gain, particularly the timing of early fluid retention versus later adipose remodeling and when each typically plateaus? And then secondly, I know it's a bit early, but how are you thinking about design of the confirmatory outcomes trial, and are there any key learnings from ongoing studies that could help inform patient selection?

Yes, thanks, Rami. So, 2 questions there just on the time course, which I'm just a preemptive. We can't really say much more than we've already said on this call. I think we've answered that question pretty thoroughly. So, maybe we could focus, Jason, on the F4 and the confirmatory study and what we're thinking there.

Yes, I'm happy to. I think, look, we're looking forward to talking more the confirmatory study after top line, but I think for now, what we're trying to communicate is 1 that will be focused on this decompensated chronic advanced compensated liver disease population, those with clinically significant portal hypertension. We know now that there are very, very good ways to assess and identify these patients in the wild using non-invasive methodologies like a combination of liver stiffness measurements and platelets. They're captured in criteria that providers use routinely in the care of patients with advanced liver disease. So the inclusion of patients with clinically significant portal hypertension, attention is the goal. Second, you ask what what evidence might we have from our clinical program that will inform that trial? Good question. The exploratory cohort I mentioned during the scripted portion of the call, we have approximately 75 to 100 cirrhotic patients in that trial that will have been exposed to Lanifibranor for at least and if they complete the active treatment extension, they could be on for up to 4 years. We think that those data from a safety and tolerability perspective and pharmacology will be helpful.

And lastly, we have completed nearly a quarter a dozen Phase 1 clinical trials with Lanifibranor over the years, including dedicated hepatic impairment study in patients with Child-Pugh A, B and C. And the results of those studies, although we haven't published them, we are comfortable and confident around the safety of the drug in those Phase 1 trials at the doses. We're presently using. And when combined with that exploratory cohort of about 75 to 100 patients, we think we'll have a really good opportunity to build and conduct a strong outcomes trial in this CACLD population.

Awesome. Thank you, guys. Thank you. We'll move on to our next question. And our next question comes from the line of Sylvie for Sushila Hernandez from Van Lanschot Kempen. Please go ahead, your line is open.

Hi, this is Sylvie on for Sushila. Thank you so much for taking your questions. So with the Lanifibranor Phase 3 NATIVE top line readout in MASH expected in the next quarter, we were wondering what kind of data we can expect at the top line. So will there be data on the treatment response in patients on GLP-1 and on SGLT2? GLP inhibitor or on the weight gain. And then if I could just ask another question, we were also wondering, how do you expect the placebo response to evolve with the longer treatment duration? Thank you.

So, Sylvie, thank you for the question. We are not guiding on the top line data right now. I think we, as you can tell on this call, we are very well aware of the interest and with 10 points and a tolerability profile elements I'm sure people are interested in seeing and I'm sure we will be looking to address a lot of the questions that were on the call today, however we're not yet guiding on what's in that readout. In terms of the placebo response, the composite endpoint was deliberately chosen as the primary endpoint as it controls better for placebo response. It's very difficult for a placebo patient to achieve resolution by themselves on both on fibrosis and all the clinical endpoints of MASH. Therefore, that was why that placebo rate was chosen. Really I'm not going to speculate on what the placebo rate will be after an 18-month trial versus a 6-month trial, but certainly it's our expectation that having that composite endpoint does help mitigate any fluctuation in the placebo rate.

Yes, okay, thank you so much. We will now go to our last question, and that question comes from the line of Jason for Andy Chen from Wolfe Research. Please go ahead, your line is open.

Hi, thank you so much. This is Jason taking it for Andy. And we just wanted to ask another question about GLP-1. And do you guys think the baseline GLP-1 subgroup is large enough to meaningfully assess whether Lanifibranor provides incremental histological benefits on top of the therapy? And how would that sensitivity analysis be presented?

If you could provide some color on that, thank you. Yes, so first of all, a clarification, the GLP-1's drop-ins that were allowed in the trial were not at the MASH dose. So they were at a lower dose, so there should be no histological impact of the GLP-1, on the GLP-1. So I think that in terms of doing a subset analysis So I think that answers the question that we don't anticipate that there should be a histological effect of the GLP-1.

Jason, would you like to add to that? No, I do, Andrew. Just, Andy, a good question. Just referring you back to earlier in the Q&A around the sensitivity analyses and that this is a question, the form of the question. How is it that other therapeutics that are dropped into a late-stage clinical trial may affect the primary endpoint? This is routinely handled in Phase 3 trials, not in the primary endpoint. Not only outside like in atopic dermatitis and use of steroids, but also within MASH. So the sensitivity analyses that we'll run are completely routine and standard for a Phase 3 program facing those kinds of questions. Got you. Thank you.

Thank you. There are no further questions at this time, so I'll hand the call back to Andrew for closing remarks.

I want to thank everyone for joining today and for the questions. We are, you know, Inventiva at an inflection point right now. We are very excited to be approaching the top line results in Q4 this year, and the potential to bring a therapy forward for a large patient population with a large unmet need and bring a new therapy option. So thank you everyone for your interest and we will see you the next time we talk will be on. So thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.

This live transcript is auto-generated without human intervention or review.

Well, thank you for joining me today at this fireside chat with CEO of Inventiva, Andrew Obenshain; and the CMO, Jason Campagna. I will do a quick disclosure from Morgan Stanley. So for important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

Without further ado, let's get started. Andrew, before we get into the details, could you give us a brief update on where Inventiva stands today and what investors should understand about the company as you approach a very pivotal Phase III readout?

Thank you. And those last words are the keywords. We are approaching a Phase III readout for our sole asset, lanifibranor, and we've guided that, that readout will happen in Q4. So it is imminent. And for those of you that don't know Inventiva, we are a single product company based in France, and lanifibranor is our lead product. It is a product that treats the disease of NASH, which is 1 disease, but that has 2 disease drivers and lanifibranor addresses both those drivers. Let me just give you a little bit of an overview of NASH.

NASH is liver disease and it's the second leading cause of liver transplant in the U.S. There's 2 drivers of disease. There's the scarring of the liver itself, the scar deposit and the lack of scar dissolving and that can progress up until cirrhosis and it can be death sentence if you get to cirrhosis. But it's really driven by metabolic dysfunction, by dyslipidemia, by sugars, by adipose tissue health. And the existing therapies on the market right now really address one of those 2 drivers that either address the liver directly or they address the metabolism. There's no therapy that actually does both. And lanifibranor is really the first that addresses both. And we were very excited to see our readout in the Phase II, which is published in the New England Journal of Medicine, which showed the leading oral efficacy in this disease with an 18% reduction of fibrosis. We're looking forward to try to duplicate that in the Phase III.

That's really super interesting. And you've talked about this kind of dual mechanism for lanifibranor. MASH is often thought of primarily as a liver disease, and you described it slightly differently. So why does understanding MASH as a systemic metabolic disease MASH when you think about how you're going to treat it?

So the -- if you address just the liver, you are addressing just 1/2 of the disease. You're not addressing both. And there's a -- there's been some studies that have shown that you could give a patient the best liver drug that exists, which is a liver transplant, but a healthy liver into a patient with MASH. And within 5 years, they will all have MASH again. And about half of them all have fibrosis because you haven't addressed the metabolic dysfunction. So in order to really get at a long-term solution for disease, you need to be able to address both, and that's what lanifibranor has the possibility of doing.

So with that in mind, like what is fundamentally different about lanifibranor's pan-PPAR mechanism? And why do you think that it could like why do you believe that difference matters clinically?

I'm actually going to hand that over to Jason.

Yes. So we've known for a better part of 25, 30 years now that the PPAR pathway, alpha, delta and gamma are generally metabolic reprogrammers. They manage sort of the state of energy metabolism in an organism. So you think about glucose production, adipose tissue function, energy metabolism, et cetera. The pathways are very clear on what PPARs do. What's new is that as Andrew was leading to that in the last decade or so, since really Intercept came on the scene with the very first attempt at getting a drug approved in NASH, we've gone from thinking that this is primarily a liver-centric or liver-dominant disease. And it's more that the liver is sort of one organ manifestation of a larger metabolic problem. It's an important organ, and it's one that's really severely affected. But when you think about a drug like lanifibranor that can target multiple nodes or axis in this pathway, it makes a very compelling argument that you may have a really better way to get control of both the intrahepatic and those extrahepatic drivers. It's not the only way to do that, but it's certainly a very compelling way to do it.

Okay. And so there are already 2 therapies approved and on market that got a significant amount of clinical data attached to them. Do you think there's still a need for additional MASH therapy?

So absolutely. So the -- it is the market is actually being built in front of us. If you go back a couple of years, there was a question about whether or not there was a real market for F2 and F3 treatment. And now we have 2 therapies that have shown actually tremendous progress in proving that, that market exists. And we have actually built a company in Inventiva with the people to actually go and bring lanifibranor into this growing market as well. Again, these 2 therapies that are on the market, they address either one element of disease or the other, not both. They either address the liver aspect of it or the metabolic aspect, but not both together, and that's where lanifibranor really can make a difference.

And so what do you think the future of MASH treatment is going to look like?

So I think that right now, there's a greater understanding of the need to treat both of these elements, and we're going to see a lot more combinations. There's a lot of more people on GLPs right now, combined well with the GLP-1. We'll actually in our trial, have a number of patients actually on a GLP-1. And so physicians are going to be looking to do those combinations going forward.

And so you've touched on GLP-1 therapies. I think the number of people that are on it, both kind of prescribed but also DTC, and it's really transforming the obesity and metabolic medicine landscape. Do you think the emergence of GLP-1 change the opportunity for MASH-specific therapies like yours?

Well, I think there's a couple of elements in terms of the answer to that question. So the -- in order -- so the GLP-1s have an impact on MASH. But in order to have an impact, you have to be on a higher dose of GLP-1 and you have to be on it for the course over a year before you see a difference. So certainly very useful in terms of treating the disease. But if you have a patient that has F3, for example, so that's a patient that's pretty close to cirrhosis, you want something that's going to act fairly quickly. In our Phase IIb, we showed an effect after 6 months. So I think it's going to be unlikely that physicians are going to really want to wait a full year for effect with the GLP-1, especially for an F3 patient.

And so working through one of those PPAR pathways, actually weight gain is a sign of clinical efficacy. And so you've seen that in some of your trials. How do you think about lanifibranor's weight profile in the treatment landscape that's increasingly focused on kind of weight loss?

Actually going to hand that over to you, Jason.

Yes. I think it's a fair question, but it gets, I think, to the core of what we're trying to accomplish. So I just step back a little bit. We knew for a long time that bariatric surgery, if it's effective at weight loss, can also be effective at improving NASH. So you look at histology, whether it's NASH resolution or fibrosis, we knew that bariatric surgery can do that. So GLP-1s have clearly changed that landscape. The point is that it changed in one very particular way, weight loss through the GLP-1 pathway, muscle, et cetera, does appear to be resetting a lot of that programming that's a problem. That's a very good thing.

With lanifibranor or the weight gain that we see actually has nothing to do with that pathway. It's really around a PPAR gamma mediated effect, which is well known and well understood around fluid retention. The impact of that fluid, the goal of the lanifibranor program initially was to show that on the one hand, we can capture all of that biology in a single drug, alpha, delta and gamma. But on the other hand, the drug as designed could lead to a softer gentler gamma effect. And I believe that's what we're seeing. So it's not that weight gain in the form of fluid is unimportant. It's that when you pair that more modest gamma effect with the benefits that a pan-PPAR agent might give you that, that benefit risk might make a lot of sense in a patient population, particularly the later-stage patients where the urgency to treat gets pretty high. So you're beginning to think at that point, not just, oh, you have NASH, but you have advanced fibrosis and you have several risk factors that if left unaddressed, can lead to pretty severe outcomes over a period of time, that urgency to treat makes a drug like lanifibranor with a more, say, muted or balanced PPAR gamma effect with the other benefits that we hope to see in the clinical program make a lot of sense.

And we already touched on there's already 2 assets approved and in the market. Lanifibranor obviously have its clinical data this year and hopefully, it is soon to be on the market. But there is several years, obviously, that the 2 that are already on market have in terms of kind of commercial but also real-world experience. Do you think that lanifibranor is any kind of disadvantage for not being that kind of first mover? Or how do you see this the commercial landscape?

No, I think quite the opposite, actually. I think what this did it is the entry of these 2 therapies on the market has grown the physician appreciation for the need to treat. As you've seen actually this was not something that published drugs were readily available before. So it has, I think, increased the diagnosis, right, that you see more machines and offices that can do diagnosis now. It's actually increasing the patient pool that's under treatment. And as we come to the market with a therapy that can address the multimodal etiology of this disease, we'll have an opportunity to go into that growing market as well.

Let's turn to the exciting data that's coming up. So NATiV3, what do you think you need to see in the Phase III data to confirm and build on the results that you've already demonstrated in Phase II, which was very impressive.

Yes. So in the Phase II, just as a reminder, Phase IIb, we demonstrated an 18% improvement in fibrosis versus placebo. And we believe that if we duplicate that 18% that we have a very successful therapy on our hands for patients. Specifically, if we -- the way we think about this market is that we do a very simple 2x2 grid. On one axis, you have severity, so F2 and F3, right, just before you get to cirrhosis. On the other axis, you have risk of progression. And for that, we use as a proxy diabetes because you have nondiabetics and diabetics. If you have diabetes, you are at a higher risk for progression, you move faster. And we imagine a future where a patient walks into a physician's office and the -- let's say, the patient gets diagnosed with F3 and they have diabetes. We think that lanifibranor is the first product that doctors are going to reach for and they're going to reach for it for 2 reasons.

Number one, you want to pick up the biggest hammer you've got on fibrosis at that point in order for that patient not to go to F4, which can be a death sentence. And we have an effect of 18% versus the competitors that are in the low double digits. So that's the first reason. The second reason is we do address, we do lower HbA1c. We do address diabetes. That physician -- that is one element for a reason that the physician is going to pick up lanifibranor. The other is they're really worried about that patient progressing quickly because they have diabetes. And they know in our Phase IIb, we showed that we can work as quickly as 6 months. So that is another reason to pick up lanifibranor.

Now so we think that, that is the patient -- that is a very natural place for us to start. And then by extension, the physician will think about lanifibranor in those F3 nondiabetic patient populations. They want the biggest hammer and in that F2 diabetic patient population that they want to address the underlying diabetes.

And so what gives you confidence that what you saw in Phase II is going to be reproducible in the NATiV3 study?

Jason, let me hand that to you.

So I think the first begins and ends with the trial design. So NATiV3 is largely very similar to NATIVE in most of the key elements. So very similar, if not identical patient population. We've narrowed it from F1 through F3 to only F2, F3. The baseline demographics are largely similar when you look at the severity of disease and the comorbidities, et cetera. Third, we are treating for longer, which is a good thing given that the mechanism of action of PPARs do take some time. So 6 months was aggressive and early, and we've already seen an effect. But there are transcriptional modulators, so they take time to work. And the underlying biology takes a little bit of time to work on the liver itself. So the 18 months favors both of those. But from a structural program, the trial looks largely similar to what we did in NATIVE, and we're letting it run longer with both doses. I think all of that lines up to give us a fair bit of confidence that if there's biology that's there, we should be able to see it and identify it.

Great. And so we touched a little bit on the safety profile and talking about weight gain and that we see in the Phase IIb results. There have been concerns and given the historical safety with some PPARs. What are you expecting to see in Phase III? Like weight gain we talked about decrease in hemoglobin, peripheral edema. And what are your expectations?

Yes. I'm going to start and I'm going to hand it to Jason. I think when physicians look at this profile, the thing that they think about versus the efficacy where they want to use it. And you bring up some tolerability issues that we have with the drug in terms of weight gain, which is really fluid retention. So there's a class of physicians that have been using pioglitazone, which is another PPAR gamma and it's still 4 million to 5 million scripts a year, especially with endocrinologists who are very familiar with how to handle this type of profile. And they have -- and there's no concerns in terms of the management in their minds because they -- and they look primarily at the efficacy.

Having said that, the fluid -- I'm going to go ahead and take this. I'm sorry, Jason. If you take a look at the fluid retention, which is what leads to the weight gain, it's mechanistically understood, it's relatively modest, and it can be managed. So mechanistically, as I said, pioglitazone has a PPAR gamma, physicians are comfortable with it, mechanism, modest or slightly attenuated version. We have about 80% PPAR agonist versus pioglitazone, which is not 100%. So the edema that you see with pioglitazone, we have a more modest amount than pioglitazone.

And then lastly, if you actually give a patient SGLT2 or loop diuretic SGLT2 when you combine these, that weight gain is totally mitigated due to the fluid being essentially peed out.

And frankly, with the comorbidities that a lot of these patients have, there's every likelihood they may already be on one of these therapies.

There's a very high likelihood, yes.

And so assuming NATiV3 is successful, how do you see lanifibranor fitting into the kind of the future MASH treatment landscape?

Yes. So I think why I talk about that F3 patient with diabetes being a very natural place. I think that if we are able to show that greater than 18% effect size, just we up into the 20s into low 20s, then I think actually the whole market, all of the 400,000 patients that are currently have F2 and F3 physicians care are patients that would -- should consider lanifibranor. So I think it could be -- and these are things that combine very well with the GLP-1, with SGLT2s. So really, you can look at this as kind of the foundation of MASH therapy for the future.

And it's oral, it's very easy to take and a lot going for it. And there's an increasing focus on compensated cirrhosis and that F4 population. How do you think about the opportunity for lanifibranor beyond the F2, F3 population being studied in NATiV3?

Jason, go ahead.

Yes. I think the F4 population is the most rapidly growing segment in the world now. And I think that's a function of 2 things. We're finding patients more frequently, which is great. But because the disease is chronic and it's subclinical, it's often very difficult to detect and therefore, diagnose when these patients are presenting, they're presenting very late in the stage of disease. I think the second driver is that the field has actually matured a fair bit in understanding what cirrhosis really looks like. So there's an anatomic distinction. I mean put a needle on somebody's liver, take it out, you look at it under a microscope, they have so-called bridging fibrosis or cirrhosis. But we also know that the physiology of cirrhosis, which is portal hypertension, actually appears much earlier than the scarring in the liver would suggest. So we now know that there's a proportion of F3s walking around that are late in their disease. Anatomically, they look like an F3. But physiologically, they behave and have the risk of an F4.

That's a problem in the world. That's the so-called urgency to treat, getting a therapeutic. So how we think about compensated cirrhosis is that we believe that in lanifibranor, the mechanism of action by the way that drug works hits on those nodes, those biologic nodes that drive the portal hypertension, the physiology that leads to these liver-related outcomes. So that when we're thinking about designing our F4 trial and the one that we would like to run, ideally, you want to include a population of patients that are F3 that have evidence of portal hypertension, they look exactly the same as the F4, except when you put the needle in the F4, they happen to be anatomically F4, but they're really the same patient. Those are clinically significant portal hypertension.

Right now, the field is very concentrated on being able to identify those patients. There are guidelines that are being put out on that. And then once you identify them, getting them in the clinical trials to methodically test whether or not you have a therapeutic that can avoid liver-related outcomes. We think that with lanifibranor, the mechanism of the drug, we've recently put out some really nice data over the last year or 2 talking about this. But we think that the mechanism of action of the drug strongly suggests that we might have a real meaningful impact there. So it's something we're actually really excited to do and to sort of get on with it. But step one is we got to get through the data first in NATiV3, and then we'll talk about that next year.

And as you said, Jason, it's a growing population, but it's also a population where there is very, very little available to actually treat the patients and the unmet need is significant.

We agree.

And what do you think investors misunderstand the most about Inventiva and lanifibranor today?

So we get a lot of questions about fluid retention, about weight gain. I think what's misunderstood is the physician choice here. The physicians -- the first thing the physician is looking at is the efficacy, right? And they understand how to manage fluid. They understand how to with diuretics with SGLT2, what they -- what the physicians are seeking is really an option with a higher efficacy and really to help those patients not flip in F4, and that's what lanifibranor offers.

I'll be a little bit more philosophical. We've -- recently, in the oncology world, there's been some beautiful data in pancreatic cancer, right, and the KRAS inhibitors. When you look at the company that did that, they had one mission to do that job. I think what people underestimate with Inventiva is that it's a 14-year-old company that was founded by a group of people that had one goal. They were PPAR biology experts. They had one goal. They wanted to make a drug that will solve the tolerability and safety issue that had plagued other PPAR therapeutics, not all of them, fenofibrate is successful, bezafibrate. There are a lot of successful drugs in PPARs, but they wanted to solve that problem and apply that therapeutic to the field of MASH. I think what people underestimate is that we've had people in Inventiva that have been there 35 years since long before the spinout, the inventor of lanifibranor was still at the company until last year. So I think people, although we're new to the management team, the sort of intellectual wiring diagram of that company goes back decades, and they have been on one mission to solve that problem.

I think when you find focused people like that, you sort of get out of their way because what they can do with that is pretty powerful. So I think we're very fortunate. We all believe in our management team that we're sort of the recipients of all of that. We don't want to mess it up in any way, but it's a pretty powerful story.

I mean it's amazing to hear that conviction and that belief in this asset.

Exactly, over a very long period of time. And a very difficult capital environment for the company. I think Andrew and I both joined on the tailwind of a group of people recapitalizing this company in 2024 because they believed in the data and the power of it. But while that company was in trouble, the what we'll call the old Inventiva, those people were still there, still working away in the offices in France and still working on that problem, good for them.

Absolutely. Happy to open it up to the audience for any questions for Andrew and Jason.

Firstly about the additional benefit in a longer follow-up period. Are there plans to follow any of the Phase II patients to gather any other long-term data on them?

You're asking about the Phase II patient population. No. So that trial is long closed and those patients are sort of off the follow-up. But in the Phase III study, we have 2 mechanisms to follow them. After the trial ends at week 72, they can go up to week 96 and remain on therapy for follow-up. And then if they choose, they're all eligible to roll into an active treatment extension that would get them out another 52 weeks. So we have 2 ways in which we can follow both the main randomized cohort and the exploratory cohort, about a total of 1,500 patients.

Well, Andrew, Jason, thank you very much for your time today and joining us at the Morgan Stanley Healthcare Conference. I think it goes without saying that there is an exciting couple of months coming out of the company. And I for one, I'm really looking forward to seeing what is certainly probably one of the most highly anticipated Phase III readouts after 2026. So best of luck.

Thanks.

Thank you, and thank you for having us.

Thanks a lot.

Good day, and thank you for standing by. Welcome to the Inventiva Full Year 2025 Financial Report Webcast and Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, David Nikodem, Head of Investor Relationship. Please go ahead.

Good morning, good afternoon, everyone, and thank for joining Inventiva's Full Year 2025 Financial Results and Business Update. Our press release was issued yesterday evening, and this webcast and slides will be available in the Investors section on our website following the call. Joining us on the call today are Andrew Obenshain, Chief Executive Officer; Jean Volatier, Chief Financial Officer; and Dr. Jason Campagna, Chief Medical Officer and President of R&D.

I would like to remind everyone that statements made during today's conference call and during the Q&A session may include forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Please refer to Slide 2 of the slides and our SEC and AMF filings for a discussion of associated risks. These statements reflect our views as of today and should not be relied upon as representing our views at any later date.

With that, I will now turn it over to Andrew, starting on Slide 3. Andrew?

Thank you, David. Good morning, good afternoon to everyone, and thank you for joining us. Since joining Inventiva 6 months ago, I've been struck by the depth of scientific conviction behind lanifibranor and the dedication of this team. Today, every resource, every decision and every member of this team is now aligned behind a single objective, advancing lanifibranor towards approval for patients with MASH.

Let me start with our main focus, our global Phase III clinical trial NATiV3. Enrollment was completed in April 2025 and represented a landmark operational milestone for this company. Today, we are updating the expected timing of our top line readout to Q4 2026, reflecting the disciplined sequencing of our clinical and biostatistical milestones. We believe the data from the NATiV3 trial, if positive, has the potential to carry weight with regulators, physicians and most importantly, with patients. And we believe we are running this program with the rigor and precision all stakeholders deserve.

On our pipeline and organizational focus, in the first half of 2025, we made the strategic decision to concentrate all of Inventiva's resources on lanifibranor and MASH. As part of this plan, in Q4 2025, we sold our global rights to odiparcil to Biossil and we may receive up to $90 million of potential regulatory and commercial milestone payments, as well as potential high single-digit royalties on future net sales if approved. While this transaction frees up our internal resources to fully focus on lanifibranor, we are pleased that odiparcil has found a new home where its development can continue, potentially in offering patients with MPS VI an opportunity for treatment.

At the same time, we strengthened our leadership team to align with the level this opportunity demands. Jason Campagna joined as CMO and President of R&D. Martine Zimmermann joined as new EVP and Head of Quality and Regulatory Affairs; and Nazira Amra joined as our Chief Commercial Strategy Officer. We are building towards launch in a lean and targeted way, advancing our readout and NDA preparations while laying the early groundwork for commercialization in anticipation of potential approval of lanifibranor. And the opportunity is real. MASH has been underdiagnosed and undertreated for too long, but that is changing. More patients are being identified, more being diagnosed and entering care. Awareness is growing, screening is improving and metabolic disease is finally getting the attention it deserves.

The numbers tell that story clearly. There are an estimated 18 million people in the U.S. living with MASH, but only around 10% have been diagnosed, and that number has grown by 25% compared to 2024 estimates. Among those diagnosed with clinically actionable F2 or F3 disease, only around 40% are currently under the care of a treating position. So while diagnosis rates are improving and the market is evolving, far too many patients with significant fibrosis remain without the care they need and face a real risk of progression to cirrhosis and liver failure. If our NATiV3 trial can replicate the 18% fibrosis improvement seen in Phase II, we believe lanifibranor could be well positioned as a potential best-in-disease oral therapy with significant commercial impact. Ultimately, our goal is to make a meaningful difference for patients and that is what drives everything we are doing.

I will now turn the floor over to Jason, who will give a brief update on lanifibranor, our differentiated oral anti-fibrotic, and a potential new treatment option that we believe addresses the remaining unmet medical needs in MASH.

Thank you, Andrew. Good morning and good afternoon, everyone. Let me start by reminding you of the mechanism of action and the development pathway of lanifibranor. Lanifibranor is a small molecule designed to induce anti-fibrotic, anti-inflammatory and beneficial vascular and metabolic changes by activating all 3 PPAR isoforms, alpha, delta and gamma in a balanced manner. This broad mechanism of action is designed to target the hepatic and extrahepatic drivers of MASH simultaneously and in one oral therapy. Lanifibranor was the first asset to achieve statistically significant improvement in the composite endpoint of both fibrosis improvement and MASH resolution in our Phase IIb NATIVE trial, after just 24 weeks of treatment with a favorable safety and tolerability profile.

On the basis of these results from our Phase IIb the FDA granted lanifibranor breakthrough therapy and fast track designations. NATiV3, our pivotal Phase III clinical trial was designed to confirm and extend those findings in a larger, more diverse global population over 72 weeks and is intended to provide the data to enable successful marketing authorization in the United States and Europe. NATiV3 is a randomized, double-blind, placebo-controlled trial in patients with biopsy-confirmed MASH and stages F2 or F3 fibrosis, the core of the MASH treatment population. Those with significant disease burden and a high risk of progression to cirrhosis, liver failure and liver-related mortality.

We specifically chose a clinically meaningful primary endpoint for NATiV3, fibrosis improvement and MASH resolution. And at 6 months in our Phase IIb the 1,200-milligram dose of lanifibranor showed a 24% treatment effect. NATiV3 was also deliberately designed to mirror the patient population of our positive Phase IIb and the real world as it exists today. A meaningful proportion of our patients have type 2 diabetes and other metabolic comorbidities, and a number are on background GLP-1 and/or SGLT2 inhibitor therapies, mirroring the patient's physicians actually see in their clinics, which we believe will ensure that we generate clinically meaningful data to support both NDA and MAA submission.

In April of 2025, we completed enrollment, exceeding our original targets with over 1,000 patients in the main cohort and additional 410 patients with MASH and fibrosis stages F1 through F4 in an exploratory cohort. We anticipate sharing the top line results of our pivotal Phase III trial in Q4 of this calendar year, a moment, I believe, will be significant for the field and for the patients who need new treatment options.

I will now turn the floor over to John for our financial review.

Thank you, Jason. Good morning and good afternoon, everyone. So yesterday evening, we issued our press release with our full financial results for the year ended December 31, 2025. I will focus on the highlights. As of December 31, '25, we held EUR 230.9 million, close to EUR 231 million in combined cash, cash equivalents and short-term deposits. This position was built by 2 significant financing events in '25. First, the execution of the second tranche of our 2024 structured financing in May generating approximately EUR 108 million in net proceeds.

And second, our U.S. registered public offering in November generating approximately EUR 139.4 million in net proceeds. We estimate that we are funded beyond our anticipated NATiV3 readout. Based on our current operating plan and cost structure, we estimate that our cash runway extends to the middle of Q1 2027 and to the middle of Q3 2027, assuming the full exercise of our tranche 3 warrants, which could generate up to an additional EUR 116 million. We confirm this way the cash guidance provided earlier. Our R&D expenses for the full year were EUR 87 million, primarily reflecting our pipeline prioritization and, to a lesser extent, the completion of NATiV3 enrollment in April 2025.

Marketing and business development spend increased to EUR 5 million primarily due to expenses related to a planned pre-commercial investment as we prepare for a potential launch of lanifibranor if approved. G&A expenses of EUR 47.9 million include approximately EUR 20.3 million of noncash share-based compensation tied to the governance and organizational transition we implemented this past year.

I will now turn the floor back to Andrew for closing remarks.

Thank you, Jean. Inventiva enters 2026, well-funded, operationally focused and ready for a consequential chapter in this company's history. NATiV3 is fully enrolled. We've built a leadership team with deep medical, regulatory and commercial expertise, and our regulatory and commercial readiness work is progressing in parallel. Our anticipated top line readout in the fourth quarter of this year represents a genuine inflection point, not just for Inventiva, but for the millions of patients living with MASH, who still have no adequate treatment options. We are truly executing with the discipline and urgency this moment demands.

Thank you for joining us today. We will now open the floor for questions. Operators, please go ahead and provide instructions for the Q&A session.

[Operator Instructions] We will now take our first question. And our first question for today comes from the line of Seamus Fernandez from Guggenheim.

Just a few quick questions. First, can you update us on how the performance of the trial has been in terms of dropouts? I know that there were some requirements from the tranches that were coming in that were successfully completed. But just wanted to get a sense of where the dropout rate was as you were kind of wrapping up enrollment.

Second question is, can you help us understand how you're thinking about the performance of the 800 versus the 1,200-milligram dose in terms of both weight gain and then ultimately on fibrosis? Is the sort of change from a more typical 12-month endpoint to the 18-month endpoint geared to have the 800-milligram dose catch up to the 1,200 but also manage the potential tolerability or weight gain issues?

And then to the last question is just what you're seeing in terms of the overall market interest. Madrigal continues to see very strong uptake in the U.S. How are you thinking about the opportunity to compete with Madrigal? What do you think is the threshold necessary? Andrew, you mentioned 18%. Just interested to know if you think 18% is the threshold where the impact is going to be substantial or is that more reference to the powering of the study?

So, Morning, Seamus. Thanks for the questions. I'm actually going to take your third one first and then hand the first 2 over to Jason. So yes, just to be really direct, we think that if we replicate the Phase II trial and have an 18% effect on a fibrosis, we have an excellent drug. That is the clearing efficacy that we need for in order to have a very attractive market opportunity. We continue to see a lot of market growth, thanks to the entry of the 2 approvals and a lot of awareness around MASH. And there still continues to be unmet need, especially we see in that F3 diabetic patient population, where we think there'll be a very good entry point for lanifibranor.

And then at 18% of fibrosis effect with our HbA1c lowering, we have a very good profile for that. Let me then turn the question over to Jason first on the drop-offs and what we've last discussed publicly there. And then the second question about the 800 catching up the 1,200 dose.

Seamus. So let's take the first one. So you are correct. As part of the structured financing from 2024, there were covenants in there around the release of follow-on tranches that the early termination rate for the trial needed to be below 30%. That number was selected because the original powering analysis from the trial was built allowed for up to a 30% dropout rate. So that was the metric that was used, and we have disclosed publicly at the time of both the first and the second tranche release, which would have been in April of 2025, that we were below that threshold.

I think now that we're tightening the guidance to Q4 of this calendar year, I think we were able to confirm we are well within that range and feeling quite good about where we've landed and are reaffirming that the trial is well powered to detect the primary endpoint with the size of the trial that we have and the early termination that we've seen.

So the second question you asked about the 2 doses, I think you're landing sort of in the right mixture of elements that are important to us. So we agree with you that in theory, with additional time just because of the way PPARs work and the biology of the liver that that 800-milligram dose will have time to sort of catch up to the 1,200. It was already quite a good dose back in NATIVE, as you recall. But 6 months is relatively thin for a PPAR, which is a transcriptional modulator to sort of do its work. So the idea that you could see a deeper effect with that 800 dose at 18 months, it's very reasonable.

But I think where you're landing around the potential dose responsiveness of the tolerability concerns, that is also very important to us. So take weight gain, which you mentioned. Weight gain is a traditional PPAR gamma mediated fluid retention event, and we know that, that fluid retention is highly likely to be dose dependent just from what's been shown with other PPAR agonists and our own data from NATIVE. So we think that potential to have really strong efficacy with both doses, which we were able to show in NATIVE, but may have a different tolerability profile at the lower dose could be meaningful for patients. So it's our hope that both will be positive, and we'll have that opportunity to discuss that with regulators.

Our next question comes from the line of Yasmeen Rahimi from PSC.

This is Dominic on for Yas. The first one, we know that NATiV3 is a very large data set. As we're getting closer to top line data in 4Q, what are some of the quality control, I guess, protocols going on in the background to analyze the biopsy samples and what procedures are in place to ensure timely and thoughtful assessment of these biopsies?

And then our second question is, can you just talk or help us understand, I guess, how you have how -- if you had any recent safety monitoring committed? And are you seeing anything on a blinded basis on the safety profile? Any color there would be helpful.

Good morning, Dominic. So 2 questions. Let me take the second one first, and the first one over to Jason. Just on safety monitoring, there are periodic monitoring committee meetings every 6 months. You would know if they had said anything. Other than that, we really can't say anything about those meetings. Go ahead, Jason, on the biopsy.

Yes. Thanks, Andrew. Dominic, so quality control and biopsy. Let me start by saying that the team we have here is outstanding. The clinical operation, the clinical development team have been immersed in the world of MASH clinical trials for the better part of a decade. So this is something that they know well and we carried that expertise forward. So you could think of quality control biopsy around 3 issues. Are we hurting the patient? Meaning at the bedside, are we doing the right things. Second, are we capturing the biopsy according to standard practice? So that's the length of the biopsy, the overall quality of the core, if you will. There's measurements and things that sort of go in and say check or not check. We have reviewed all of those and continue to do so right up until when we get to last patient, last visit later this year.

And then lastly, finally, when the slides are sectioned prior to going off and being read, there's a quality control set there that looks at what actually gets made on to the slide. Afterwards, at that point, we are obviously blinded to all of that information. But there is a quality check in terms of are the reviewers, the readers staying on time and on track reading biopsies in the paired matter that's specified both in the protocol and the analysis plan. So I like the teams that we have in front of it and more importantly, I think that they are doing exactly the right work to keep us on track.

Our next question for today comes from the line of Ritu Baral from TD Cowen.

I want to drill down a little bit more upon final powering. You guys disclosed the over 1,000 final patient number. I think it's 1009 and the 90% powering. What's the effect size that, that powering is for on the primary combined endpoint? And what are your expectations for potential movement around placebo of that, I think it was 7% at the 6 month upon the final primary endpoint? And then I have a follow-up on market expectations around that F3 diabetic population that was mentioned.

Thank you, Ritu. Jason, why don't you go ahead and answer that question?

On the first one, we are not guiding to the actual effect size, but I can reiterate for you and for everyone what we have been saying. So first, we are with the sample size of over 1,000 patients. We are powered to over 90% on a primary endpoint of the composite fibrosis improvement 1 stage or more MASH resolution. That one has a higher placebo response than we showed in NATIVE, which as you know, was 7%; and two, a smaller treatment effect than we showed in NATIVE data about the 1,200 milligram dose. So that means the overall effect size that we are powered to is smaller. So a much more conservative view than the actual data that we showed in the Phase II program.

We just talked earlier with Seamus that, that alongside our comfort with the early termination rates we have, we feel very good that the trial is structurally sound and that will give us an answer to the question one way or the other. Did lanifibranor work first at the 1,200-milligram dose? The testing is hierarchical. We can't get to the 800, unless you went on the 1,200. But that is the core question. We think the trial was well set up to deliver an answer to that question that is well powered and highly confident.

I think to your second question around placebo response. The individual endpoints of fibrosis alone. I think everybody on the call knows this, fibrosis alone improvement or MASH resolution alone can be quite noisy. It's not clear after all these years of study why that is, but we do know that they're noisy. On the other hand, the composite endpoint, the primary endpoint of NATiV3, are with us and other sponsors have shown that, that endpoint is much less prone to placebo response. And that makes sense, Ritu, biologically, right? You have in 1 patient, they may on a placebo response move their fibrosis stage by 1 point or more, but the idea that they can also resolve their MASH spontaneously.

What that 7% tells you was that in the wild, in the real world, that's incredibly uncommon and that makes total sense with the actual way that patients walk in. It's unusual if you leave them sort of sitting along without treatment, that both of those things will get better on their own. So the placebo response there actually reflects, we believe, the underlying biology, and it should remain very low. We've seen it by precedent, and it's our expectation for the trial that we're running.

Very helpful. And then, Andrew, a question on how you guys and your own market research is viewing that F3 diabetic population. Do you have an approximate patient number? How is the diagnosis rate in that population changing versus the overall MASH population given the ADA focus on MASH and its messaging to diabetologists?

Thanks for the question, Ritu. So in terms of size, there's about 375,000 patients total F2, F3, in under treatment of care right now. The largest segment is -- one of the largest segments is that F3 diabetic patient population, being 55% to 65% of the patients are diabetic, and about it splits roughly 50-50 in our market research between F2, F3. So that patient population is quite a large patient population overall. In terms of growth, we don't have the granularity down to that segment. However, I would just know anecdotally that F4 is one of the fastest-growing segments. And I think the diagnosis rates are increasing quite a bit overall for F2, F3, F4, just to the number of entrants into the market. So they are growing a minimally proportionate with the market in that segment.

To that point, Andrew, can you tell us of the 410 expansion cohort patients, how many are F4. Do you know at this point?

I'll pass that question.

Yes. Confirming you're talking about the exploratory cohort, correct?

The exploratory cohort, yes.

We do have F4s in that cohort. They would have screen failed in that case, by histology, potentially other lab values for the actual main cohort in NATIVE. So they represent a sort of range of F4 from. They're all compensated by definition, meaning they have no clinical outcome events, decompensation events. But the range of severity with portal hypertension can be from none to evidence of clinically significant. And those -- that data is going to be quite interesting to us. We're not yet guiding on when we'll have an opportunity to get those data out. It's unclear right now if we have them at top line per se, or in the weeks that follow it in one way or another. But I think as we get closer to top line data, we should be guiding on that more tightly.

Our next question today comes from the line of Thomas Smith from Leerink Partners.

Just wanted to follow up on that F4 population. And I know you're capturing some of those patients in the exploratory cohort. Can you just expand a little bit on what you hope to learn from that exploratory cohort and how you're thinking about planning for the outcome study in F4s pending the NATiV3 data and perhaps how you're thinking about perhaps how some of those plans could change. We know we're going to get F4 outcomes data for Rezdiffra also in 2027. So some interesting timing around that data set relative to when you're planning on starting this F4 outcome study.

Thanks for the question, Tom. Jason, go ahead.

So there's a lot there. Let me make sure I get it all for you. So one, just in general, what are we expecting to learn from that cirrhotic population in the exploratory cohort. First, above all safety of lanifibranor in that population. Clearly, right, if you're going to bring in a new therapeutic into a more, let's say, sicker population, you want to obviously want to have safety headroom to do that. So approximately 75 patients we have in that cohort safety above all else.

Second, it's not that, as you know, that cohort is not tracked systemically -- systematically, excuse me, for efficacy. That being said, we do anticipate having data of things on like LFTs, transaminases and other things that would point directionally towards whether the drug is biologically active. So really a pharmacology question, very important. We have done hepatic impairment studies with the drug, but looking at it in a real world and a clinical trial would be incredibly helpful.

And I think lastly, it will give us a sense in our own hands of how those patients progress over time to later-stage disease. You could read about it, you can model it, you can look at other people's trial, but in your own trial we will see how many of those patients go on to actually have liver related or other events. And that will be incredibly helpful as we think about powering and sizing of an outcome-driven trial, which is what we're right now calling NATiV4, for lack of a better term. But make sure that, that gets to your question, Tom, on the value of that cohort to us?

Yes, that's helpful.

Great. So now look, you know the Madrigal data coming. I think yet we acknowledge that. We agree. I think our view is that positive data, if Madrigal were to show it, would only be helpful for the field period, full stop. The idea that we have now finally shown that the surrogate endpoint does correlate with clinical outcomes would be an enormous one for the field. Look no further than what happened in the cardio renal division with proteinuria in the last 6 years. Proteinuria was issued as a surrogate in 2019. I have 5 or coming 6 approved therapeutics for IgAN, that's an enormous win for patients. So we expect something like that would hope would happen here.

But clearly, that would influence our thinking about how we think about populations and the ones that are most likely to develop liver-related outcomes because we want to get more of them since we know that the sort of door is open to show that the histology will map to clinical outcome.

Our next question comes from the line of Michael Yee from UBS.

I have [ 32 ] myself. First question is on weight gain, can you remind or confirm the views that based on the phase II also, I think what you're sort of said in the ongoing Phase III that there is some initial weight gain, but that it plateaus and that you don't really see anything beyond a modest increase in some patients, at least in the phase II, and that plateaus and that was initially seen in the Phase III, and therefore, no concerns.

The second question is, is there any view that either because of other drugs or because of longer time duration of 18 months versus 6 months here that, that could actually come down in some of those patients or at least come back down to baseline, is that possible?

And then the third question is around getting the regulators comfortable with that, what I guess fluid retention effect in some patients and that there would be presumably no at least initial cardiac imbalance in any of the arms that you see and which you'll be able to talk about no imbalance in any cardiovascular events numerically or any SAEs of that nature when you disclose the data in the fourth quarter?

Mike. You were a little soft, so I'm just going to repeat some of it. So there was a question about does weight gain indeed plateau and number one, if in the Phase II. Number two, does that weight gain -- is there a chance of that weight gain would actually go down in the Phase III, either due to concomitant medications or longer treatment? And then number three, some of the weight gain do -- if the weight gain is due to fluid is there any concerns about a cardiac imbalance in the trial. So for those 3 questions, I'll hand it over to Jason.

Yes. Mike, good to talk to you again. So we have previously said and we'll reaffirm it here that the data that we have previously shown from the blinded look at NATiV3 back in September of 2024, and that we also disclosed at that time the FASST clinical trial in systemic scleroderma, which was a year trial with treatment of lanifibranor same doses in NATiV3, 800, 1200 milligrams, that the weight -- the fluid retention weight gain appear to plateau. I think we don't have any additional information to guide on that publicly, but I think that is what we've seen in both of the clinical trials so far.

I think second, do we expect the weight to come down? It's well possible. I think there are a couple of factors at play. Take the LEGEND study, for example. We show that when patients are given SGLT2 inhibition in parallel with lanifibranor that there's almost no weight gain at all. There are many patients in the trial that are on SGLT2 inhibition and do not have the number for you off the top of my head. And we know that patients can be started on those therapeutics for management of diabetes or any other reason. So it is entirely possible and reasonable to believe that if patients are getting SGLT2 inhibitors or other diuretics to manage blood pressure, et cetera, that, that weight gain either the fluid retention, could be blunted or resolved so that the final landing spot, if you will, for any patient, might be lower than the peak weight gain that they had in the trial. But I think we'll see what the data show.

Lastly, in terms of regulators, I think I can't speak for the FDA, but I can only speak to what I've read of everything they've put out. The fluid retention is a known phenomenon with PPAR gamma agonism, the thing about lanifibranor is it was designed to be different than other PPAR gammas, and we'll see what the data show. Our view is that it is a very different type of PPAR agonist. But that being said, the PPAR gammas is a known effect. It is on target. It is not idiosyncratic in any way. So FDA has shown with labeling and other work that they are comfortable with fluid retention, I think you're hitting on the right point, the cardiac. And as we've talked about and guided publicly over the years, we are not seeing congestive heart failure as a clinical issue in our program. It doesn't mean that we don't follow it.

And it doesn't mean that you're thinking about how fluid retention may lead to that. That's certainly in the PPAR labels today, the gamma agonist, but it is just not something that we are generally seeing in our program, but we will be paying careful attention to it, and it's a dialogue we'll have with FDA.

[Operator Instructions] Our next question comes from the line of Ellie Merle from Barclays.

This is Jasmine on for Elie. So as kind of a follow-up to Ritu's question. You talked about the overlap of MASH in type 2 diabetes as a segment where lanifibranor can be particularly attractive. But do you have a specific bar for what competitive data would look like in this population? And then specifically, how many type 2 diabetes patients do you think have undiagnosed MASH, and how do you plan to work to increase the diagnosis in this population and unlock that segment?

So I'll take those 2 questions. First of all, just the diabetes and overlap with MASH, it is enormous, right? And there's -- I think there's about 18 million patients in the U.S. with undiagnosed MASH. At least half of those or more have diabetes at it's obviously way, way more than 375 under the treat or care. The way we see the market evolving is we've seen since about 2004 that market has grown about 20%. So it's clearly quite robust growth, and we do anticipate that to grow nicely. We, as a company, probably will not be pushing diagnosis, at least initially, there are enough patients coming in that we can focus on the patients being diagnosed -- the existing patients being diagnosed. That would obviously, maybe a later marketing strategy would be to actually increase diagnosis.

And then your first question about -- I'm sorry, I forgot your first question already.

Just if you have like a specific bar in that population for what competitive data looks like?

Yes. So the -- in terms of competitive data, the way we look at this is that the differentiated profile that we have is we work both on the liver and we're extrahepatic. We work on the body and we work on the liver. So we have direct anti-fibrotic effect. Again, as I said, that an 18% effect size, if we duplicated that in the Phase III trial, we feel it's a very competitive drug. And then the other thing we'll be looking at is HbA1c lowering, which was on average across the whole patient population, diabetic and nondiabetic in the Phase II, with just over 0.5 point, that would be an approvable diabetes medication years ago.

So that combination of HbA1c lowering, combined with triglyceride lowering, HDL raising and the fibrosis effect, we think, has an extremely attractive profile for that diabetic F3 patient.

Our next question comes from the line of Lucy Codrington from Jefferies.

Just one left, please. Regarding the confirmatory trial, just wanted to confirm, do you have an understanding with the FDA in terms of what underway means when it comes to granting accelerated approval? Is it enough just to have started that trial? And does this need to be by the time you file or by the time you get to approval? And then related to that, is starting that trial included in that mid 3Q cash runway with the third tranche of warrants?

Yes. So yes, it is included. Starting that trial is included in the cash runway of that mid-Q3 runway. Jason, you want to talk about what's necessary for the trial?

Yes. Lucy, I think you have the broad brushstrokes of it, right, but just something on the language. So accelerated approval is only at the time of the review. What we're looking to get is conditional approval under Subpart H, which is you've got marketing authorization and then the trial, as you note, confirms your surrogate and then you get full approval. Whether accelerated is only a question of how long it takes the FDA to actually review the file.

With that, I'm just trying to make sure that we're all clear on that, that we -- you have the broad brushstrokes, right? But the individual rules are discussed with each sponsor at the time of the pre-NDA meeting and then during the mid-cycle review. But the general framework is you need to have most of the trials structurally in place, protocol approved at the time you were filing the drug and it needs to be moving on the definition of moving is going to be something FDA will define for us. We will be prepared. We have our CROs selected, the protocol is approved, may even have sites open. All of that is in the future.

But at the time we file, we will meet the FDA position of trial meaningfully underway. And then at the mid-cycle review, you need to show continued progress on that. So they will check again that made a much more detailed look around enrollment nerves, site activation curves, et cetera. Again, each sponsor has their own detailed agreement with FDA on that, and it is our plan, of course, not only to have those conversations, but to make sure that we're meeting those requirements. So that when we are offered if we're fortunate enough to make it there, and we offered, the conditional approval, that trial will be well underway at that point.

Got it. Thank you, and thank you for clarifying on the terminology.

Our next question for today comes from the line of Annabel Samimy from Stifel.

This is Jayed on for Annabel. Congrats on the progress. Just 2 for me. The first one is around the use of background GLP-1 in the trial. What are your expectations on the potential impact of having that background GLP-1 use on [ lani ] effect size of those patients? And my second question is around the AIM-MASH tool that was nearly FDA qualified as a supportive tool to help with histological assessments. Do you have any plans to maybe leverage that to control or minimize variability?

Yes. Thanks, and thanks for the question on the impact on the lani effect size based on background GLP-1 and the tools. So go ahead, Jason.

Yes. So in confirming we do have, and we've previously shared that we have about 14% or so of the population in NATiV3, that's across both cohorts, that have background GLP-1 use at the time of randomization. That could be semaglutide, older drugs, liraglutide, dulaglutide, et cetera. So it's not only limited to the modern GLP-1. And I think its effect on treatment response should be minimal, and that should -- it will sound tongue in cheek, it's not intended to be. It's because that when you enter the clinical trial independent of what drugs you're on, whether you've lost weight by any other measure, independent of a GLP-1, you're entering the trial issue have that F2, F3 disease with active MASH.

So whatever it is, one, those drugs are not doing it for you or your lifestyle modifications; and second, that the doses that we're using are really the diabetic doses. So they don't -- they are not anticipated to have much of an effect at all. We're simply seen that in the clinical trial data. I think to the second question about the tools, are you talking about PathAI specifically or just more general non-invasives?

Yes, no, it's the PathAI tool.

Yes. It's an interesting idea, right? But if you -- looking at it really simply, what PathAI lets you do is substitute one human pathologist for a digital pathologist and then you need a second pathologist to read. It's still the same idea of 2 plus 1 consensus. In this case, 1 of the 2 is PathAI. It's interesting. It's not something that in NATiV3, we anticipate taking much advantage of. But it is something we're thinking very closely about for NATiV4, potentially using that as the -- in the exploratory cohort presently from NATiV3 to see how we may be going to pull more data out of those patients that happen to have a biopsy.

Our next question for today comes from the line of Rami Katkhuda from LifeSci Capital.

I guess can you remind us of lanifibranor's FC and F2 versus F3 patients in the Phase II study and how those differences may impact expectations for NATiV3 just given the higher proportion of F3 patients enrolled?

Go ahead, Jason.

Rami, just to qualify, you want the proportion of patients in NATiV2 or the responses of the F2, F3?

The responses, please, between the F2s and F3s.

The sample sizes are simply too small to break out what we have done. We think the analysis that's more helpful, it's in our corporate materials, is that when you strip away the F1s in that trial. You get down to about 188 F2, F3 across all 3 arms. You can see that the effect size actually slightly goes up. What we guide to is that it remains unchanged. So the drug seems to work equally well in more advanced fibrosis in patients with earlier disease. So you're not getting much of a free glide on those F1s, if you will.

I think second, when we look at NATiV3, as Andrew talked about earlier, this is a contemporary MASH market. The majority of patients showing up and clinics today that have F3 disease, will have diabetes. So we think that aligns pretty well with the outside world. And we're pretty comfortable with what we've seen from our Nature publication back in 2024, that the drug not only works equally well in earlier and late-stage disease, but the adiponectin levels actually go up equally well across all cohorts and it's that adiponectin that's really driving, we think, well correlated with the clinical response. So we like where we're landing with NATiV3 and the likelihood of efficacy in both those F2 and F3 patients.

And as a reminder, we're stratified by fibrosis stage and diabetes and NATiV3, so we're going to cut those data in a number of different ways to sort of get where you're headed with your question.

Our next question comes from the line of Srikripa Devarakonda from Truist Securities.

This is Anna on for Kripa. So 2 questions from us. First, looking ahead a little bit in terms of the MASH guidelines, would you expect an update on the MASH guidelines this year? And how are you thinking about getting [ lani ] into the MASH guidelines? And then second question, in terms of cash, what kind of needs to happen for you to have access to that third tranche? Is it based on kind of Phase III success only? And are you looking at any other non-dilutive sources of funding such as partnerships?

Thanks for the questions. So on the MASH guidelines, I think we will wait -- we need to get data first before we have any conversations about putting lanifibranor into the MASH guidelines. On cash, the tranche 3 is a positive endpoint, and we hit a positive endpoint in our trial, and then when those 77 million shares of EUR 50 become exercisable, and the investors have 45 days to exercise them. So that's how that mechanically works. So positive trial equals cash coming in, so as long as the stock price is above the EUR 50. We are always looking for ways to increase our cash runway. And we've obviously in a very strong cash position right now.

In terms of partnerships, right now, our plan is to commercialize lanifibranor ourselves. Going forward, we think that there's plenty of access to capital, either in the equity markets or other kind of capital sources that we don't necessarily need to partner lanifibranor.

Our next question comes from the line of Sushila Hernandez from Van Lanschot Kempen.

Could you elaborate on your regulatory and commercial infrastructure? What steps are you taking to act with speed once the data is here, also considering your cash runway?

Yes, good question. So yes, so we are being very careful stewards of our capital right now before data. So a lot of -- the regulatory team is fully staffed, and I would include the quality team on that, too, because that's necessary, to make a really good filing with the FDA. So we have invested. We've increased the size of that team and the talent on the team in the course of this year.

From a commercial standpoint, really focused on strategic commercial execution. So being led by Nazira Amra, really focused on market access, the market research. I'm going to include in the broad commercialization medical affairs there. So the strategic role that won't really set us up for success in the future. We will not staff up aggressively in commercial until we have positive data.

This concludes today's question-and-answer session. I will now hand the call back to Andrew Obenshain, CEO of Inventiva for closing remarks.

Thank you so much. Thank you, everyone, for joining the call this morning. We certainly have an exciting remainder of the year coming up for Inventiva, and we look forward to engaging with you all as we go forward. Thank you.

This concludes today's conference call. Thank you for participating. You may now all disconnect.

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, 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?

Yes. So maybe I'll start at a high level, and I'll hand it to Jason for the Phase III design with lanifibranor. So we are a one-asset company. Lanifibranor is a pan-PPAR agonist that we're developing in a Phase III study for [ MASH ]. We -- 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. So learned from Actos and Avandia, for example, and designed out the liabilities by making a more moderate gamma binder. And then also it's a balanced PPAR. Another insight was that these PPARs are networks. 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 want to comment on the fact that we were required by the FDA to do quite an extensive toxicology work, 2 years in animals that were -- that was due to the past PPAR experience. Those came out that we press released those. Those actually had Actos and Avandia, going through those. They would not have survived. And we showed that we had a very good tolerable profile, went into the clinic. We've done 5 or 6 Phase I trials. We had a positive Phase IIb trial published in the England Journal of Medicine. So quite an extensive background before we even got into this Phase III. But maybe, Jason, you can talk about then how we've started...

That's great. As Andrew said, NATiV2 was a successful Phase IIb trial, published in the England Journal of Medicine now about 5 years ago, 2021. I think in that era, the excitement, it sort of lost 5 years later, but it was the first drug ever in NASH to not only show a meaningful effect at 6 months, but it had done so on a dual co-primary endpoint of both NASH resolution and fibrosis improvement in the same patients. So NATiV3 just builds on the strength of that study. NATiV3 is largely similar in many cases identical to NATiV2. Obviously, it's longer. It's 18 months, but it's still the same basic construct, 3 arms, 1:1:1, 2 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. And we think that, that reflects some of that unique biology Andrew was sort of hinting at and that we -- the ability of the drug to get both intrahepatic and extrahepatic drivers of NASH showed in NATiV2 that we can, in the same patient, resolve all of the features of NASH. And therefore, we brought that forward as our primary endpoint in Phase III.

And how should we think about the powering of the study?

Well powered. For a Phase III study, we are -- we've been guiding that we are powered to above 90% on the primary end, the co-primary endpoint of NASH resolution and fibrosis improvement. What we are not giving too much specifics about is what's the effect size, [ Jason ]. But what we can say is that we took a more conservative approach than NATiV2. 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. And then we overenrolled the trial slightly, and we built in -- because 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 would otherwise be expected in a Phase III up to 30% dropouts, and we would still maintain and preserve that power.

Okay. So in my view, and 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. Yes.

Another way to say that is in 247 patients, we hit statistical significance on all 3 NASH endpoints. And now we have a 1,007 patient double-blind, randomized controlled trial, we are very well powered.

And at a much longer time point where you should see increasing effects over time.

Exactly right.

And how should we think about that? How much that could...

I think broadly speaking, I mean, we don't know. In the end, it makes -- there's a rational argument made that longer treatment is going to result in deeper effect. I think the 3 lines of evidence that support that are pretty straightforward. Other sponsors have shown it. Akero has shown it, for example, when they went from 6 months out to longer. Intercept showed it back in the day when they revealed top line data on fibrosis improvement. 18 months later, they continue to follow those patients, and they had deepening of the fibrosis effect by TE. So that's very good.

And lastly, the biology of lanifibranor, the way that PPAR agonists work, the sort of metabolic reprogrammers that work at the level of DNA transcriptional activation, that just takes time. So 6 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. So if all those 3 things line up, we think it's reasonable to think we're going to get a deeper effect.

How do you expect the patient baselines to compare in Phase II versus Phase III?

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. So we have 55% diabetes patients in the trial, 42% were in Phase II. And actually, the stage of disease, F3 travels with diabetes. The more metabolically dysfunctional patient, the more likely they are to have later-stage disease. And you see that with the baseline of 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 in during the trial, but should be balanced by arm across placebo and drug. Anything else?

Great. That's helpful. Sorry for jumping into the trial design questions. You can tell where we're getting a lot of questions. But maybe taking a step back, my favorite topic, [ MASH ]. 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, FGF21 is coming along. Where does lanifibranor fit in the development landscape?

Yes, absolutely. So just to take a step back first, broadly, we're at the very beginning of this market, right? We've just had 2 approvals recently, more that are going to 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 going to 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. I'll get back to that in a second and how we see that playing out.

But just to comment on the FGF21s, 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 there injectables competing in an oral market. They've got some toxicities, both bone density and GI that are going to really prevent them from moving into that F3 market. So we're really seeing the staying in the F4 market. So bring us back to the F2, F3 market.

So how does the physician choose between lanifibranor and Rezdiffra? So the way we segment this 375,000 patients is into 4 boxes, right? It's a 2 x 2 grid. You think about F2 and F3 and they're roughly equal, 50% in each. And you can think about nondiabetic diabetic, and it's about 40% nondiabetic, 60% diabetic. So you end up with 4 equally sized boxes relatively equal, a little bit bigger for the diabetic. And where -- what's the natural habitat with these drugs? Well, if you think about an F3 diabetic patient, right, physician, let's say, lanifibranor has just launched and a patient walks in and the doctor needs to make a decision about what world to put that patient.

Let's say we duplicate our Phase II and say, okay, well, super worried about fibrosis because I don't want that patient to go to F4. I want to pick up the biggest hammer I have on fibrosis, and that's going to be lanifibranor, 18% versus 12% if we duplicate the Phase II. And if patients got diabetes, I know that's driving the disease. The metabolic function is driving this disease, and I need to address that, but probably already on diabetic medications, but why not add something that can reduce HbA1c even further. So lanifibranor becomes a very natural choice there. A patient walks in the day after lanifibranor launches, and there's an F2 nondiabetic patient.

Well, that's probably a patient I'm still going to put on Rezdiffra for now, right? It's a proven drug, it'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. And then you can see that as the 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 how we see the market evolving over time. And if we end up getting better F2 than 18%, maybe we double what Rezdiffra has, then I think that you migrate into that whole market.

Yes. And that 18% was at 24 weeks now, not...

That's correct. Yes. It was 18% after 6 months versus 12% after 12 months.

Great. And so -- and then in Phase III, you're looking at 18 months?

Yes, correct. And 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. As you think about the segmentation, I mean, it seems like -- right now, most of the NASH 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 NASH patients are sitting with endocrinologists right now.

Certainly, the endocrinologist is probably keeping them in the opinion of the GI and the hepatologists probably keeping them too long. So -- and this is something we will make a decision now about how we do this. We'll definitely be monitoring it. But overall, you can think of -- we clear that we're not going to be looking to get switches in terms of patients off of Rezdiffra, on lanifibranor. We're looking for new patients. So we'll monitor closely kind of how the market is growing, where the diagnosis is happening and where those new Rxs are. I think GIs and heps are clearly going to be a call point and a starting call point for us. And whether we add endocrinologists at the time of launch remains to be seen or to what scale. But I think certainly, there's at least a subset of endocrinologists that should be in the targeting and launch.

And what proportion of patients do you expect in your Phase III to be on GLP-1s at baseline?

So baseline GLP-1 use in NATiV3 is a little less than 15%. So they needed to be stable treatment, non-NASH dosing. So you're talking, one, it's not all sema. I think all eyes and heat and light are on sema, but it's not only sema, there's liraglutide, dulaglutide as well. But 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.

So we like that data set across both. We have 2 cohorts, the main 1,000 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. And I think as Andrew mentioned earlier, GLP-1s are going to be the backbone of the 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. So we think it's going to be a good data set.

And then the mix of F2, F3 patients in your trial that you expect?

It's contemporary. So we have roughly 2/3, 1/3, 2/3 F3, 1/3 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 NATiV2. So both of those really reflect the contemporary practice today.

And 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. So even if you strip out the F1s from NATiV2, the drug works slightly better in F2, F3, but I'll say here that it works equally well. So one, we're not getting a free ride on the back of the sort of lesser severity patients. And second, diabetes isn't giving us the kind of tailwind.

But on the other hand, in the presence of diabetes, or hemoglobin A1c reductions like in our LEGEND study approach one full point. So that has all the makings of a drug that could be valuable to endocrinologists as they're trying to manage both diseases. So 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, particularly the history that the PPAR classes have 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 on the PPARs, but just kind of an overview of that and where you see lanifibranor falling and your confidence in the safety.

I'm going to hand that one to you.

That's so kind I'll actually pick up where Andrew left off. So 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 without a lot of the baggage of some of the therapeutics that have been on the market. So 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.

And back in 2019, we had publicly talked about that, that toxicology program Andrew mentioned, full 2 years to 2-year rodent 1-year nonhuman primate, discharge many of the traditional PPAR risk, things like cancer, muscle damage, kidney damage sort of went away. And 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. So very good. Rubber meets the road in clinical trials. And what we showed in NATiV2 sort of confirmed all of that.

So if you look at an adverse event table in NATiV2, 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. But 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 in pioglitazone, and it tends to plateau after about 6 months or so, good. The peripheral edema that one sees associated with that weight gain appears to be less.

And the final arbiter of that is the congestive heart failure signal. Now obviously, we're running a blinded clinical trial, but based on NATiV2, we like that step off a lot, less weight gain, less edema and much, much less heart failure compared to sort of historic norms. So I think in summary, we like our safety profile, not because it's better than pioglitazone, it's our own. And it's been sort of matched with exactly what the people that designed the drug 15 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?

So why don't you start with the weight gain and then I'll go to pio.

So I think -- the first thing to understand is about 50% of patients in our Phase II did not gain weight. 20% gained very modest 2.5% to 5%. And there was 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 in many -- this is not perceived as an adverse event. It's really a tolerability issue and physicians actually only recorded 1 out of every 3 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 kind of what the biology is, and then I can talk about how we think this will play in the market.

Yes. So on the one hand, the gamma effect of pioglitazone and rosiglitazone, these are incredibly strong metabolic reprogrammers. 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've seen in the monitor. The problem was that it came along with this question of weight gain edema and congestive heart failure.

So what we see is, generally speaking, the weight gain that looks -- it's about proportionately numerically less than what you might see with pioglitazone. More patients tended to gain more weight with pioglitazone and it lasted a longer time. So 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 3 as opposed to something like maybe month 6 or 9, which is where we're landing. And the overall magnitude of the weight gain, which is what Andrew just showed is less.

And when you step that down, the peripheral edema, in some cases, looks to be fivefold lower than what we reported in some trials. But if you look at the label, for example, it might be two to threefold lower than what was reported. So 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. So 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.

But then I think just to bring it back to that market segmentation that I talked about, that it is so 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 the F2 nondiabetic, 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? So it just plays into that market dynamic.

We've seen in labels across the PPARs, black box warning for congestive heart failure associated with the edema in warnings for bladder cancer risk. As we think about your profile, what are the reasons why you think you're seeing a lower risk relative to pioglitazone?

So it's a tricky question, right? Because in the end, FDA gets a big vote, too. So -- and we don't have full data yet from NATiV3. So it's all highly speculative. But that being said, the 3 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. So we're not pio that also happens to have alpha and delta. We are 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. And 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, 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. But we actually think we're in a really good position to walk in with a straight face argument, not the same drug. We have our own data set. And 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. And what are your plans in F4?

I'm sorry.

Your plans in F4?

Do you want to start?

Yes. So we are -- 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 willing to find that a little bit more. So we'll start that trial after we get data. We have to have substantially started by the time we file our NDA. But 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 that we can't reverse the disease. And 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 to explain the biology.

Yes. I mean this is -- honestly, this is a really active area for those that are listening. It just -- it will develop over the next couple of years. But 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, as Andrew said, that you can identify them easily at the bedside really makes the possibility of putting them in clinical trials really attractive. So 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.

But 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 lani on the alpha, delta and gamma PPAR receptors, each of those pathways are driving some of that portal hypertension. So 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. So 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. So we're excited to begin to talk to FDA about this and build that trial.

Strategically, we've seen 3 acquisitions in the [ MASH ] space in the last year. You are a fraction of [ Madrigal's ] market cap. Those are just fast. 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 midsized biotech can commercialize successfully and drive to profitability. So we plan to follow that path. So you should expect us to -- if we have positive data to raise a lot of money to be commercializing ourselves. Now along the way, yes, you're right, there might be some strategic interest that might prevent us from realizing that mission. But 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?

So cash runway goes to about Q3 '27 right now, so well on the other side of data, which gives us a lot of room to make some strategic decisions post data.

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...

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 that the trial started. And 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. So it's not a get going and let us know how you're doing. It's active engagement with them at the prefiling meeting, the interim mid-cycle review meeting. But 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 out of time, but I appreciate both of you joining us today and certainly an exciting year ahead, ahead of the Phase III data.

Thank you. Thanks for having us.

Thank you.

Welcome, ladies and gentlemen. Welcome to the last day of JPMorgan Healthcare Conference and today's presentation from Inventiva. It's my pleasure to introduce Andrew Obenshain, CEO of Inventiva. We'll first do the presentation after that, there is time for some questions. So feel free to save those to the end.

And I'll leave it to Andrew to take us through.

Thank you very much, and thank you for having us at this conference, and thank you for ordering up some beautiful weather this week. I'm glad to see there's a sellout crowd of hundreds of people in the audience for those people online. A lot of interest in Inventiva today.

So again, I'm Andrew Obenshain, I'm the CEO of Inventiva. Today, I'm going to talk about the company and our lead asset, lanifibranor, which has the potential to be best in disease for MASH as an oral therapy. This is my disclaimer. This presentation contains forward-looking statements. I will not read the whole thing.

And I want to start this presentation by just talking about the company a little bit instead of the product because Inventiva has really gone through a transformation in the last 18 months. We currently have a fully enrolled Phase III trial. That Phase III trial design was based off of a Phase IIb of well over 200 patients that was published in the New England Journal of Medicine with positive results and the design of the Phase III is largely similar, and we anticipate that readout in the second half of this year.

The company itself has received a substantial amount of funding over the last 18 months, starting with a $411 million raise in October of '24 and supplemented with $172 million in October. That's important because the history of Inventiva has been one of scraping together a couple of pennies to get to the next stage, and now we're actually fully capitalized to realize the full potential of lanifibranor.

Along with the first fund raise, Mark Pruzanski, the former CEO of Intercept, joined as the Board Chairman, bringing a lot of expertise in MASH. And he has proceeded to build up the management team, starting with addressing the medical and regulatory side. We brought in Jason Campagna, who is the former CMO of Intercept; and Martine Zimmermann, the former Head of Regulatory at Ipsen, where she got the PPAR approved. So very relevant experience to really shepherd lanifibranor through.

We've added commercial expertise with Nazira Amra from Intercept. And then I've joined -- my background is as a public company CEO, transitioning biotech companies from Phase III to commercial. So we now have a well-funded company, an experienced management team, a fantastic asset to bring forward into a very exciting MASH space.

So I'm going to start by just talking a little bit about MASH and what we think is needed to address the unmet need of these patients. So MASH is a chronic progressive disease. It's the #1 cause of liver-related death, but it's more than just liver disease. It's more than just liver scarring. It is a cardiometabolic disease. It's really part of the cardiometabolic metabolism. These patients have both a sick liver with scarring, but also a sick body. Over 60% of them have diabetes, obesity involved. And really to address the liver issues, you need to address both the sick liver and the sick body. We believe that lanifibranor is a product that is positioned to do just that.

In terms of the market, this is a market that's going to grow to $15 billion by 2035, but it's not there yet. It remains a market of a lot of opportunity. There's about 2 million diagnosed MASH patients in the U.S. right now, just under. That's only about 10% of the total population. But that diagnosis rate is increasing very, very quickly. Our current estimate of 2 million diagnosed is -- represents a growth of about 25% since 2024.

And the patient population that we'll target is the F2, F3 patient population. That's about 375,000 patients in the U.S. that are under care of a physician. And again, that represents growth of about 20% since 2024. But that patient population has been -- the patient population that's been sufficient to drive the first oral to the market to a run rate of over $1 billion in sales. So this is a market that is growing and a lot of opportunity.

Now one of the reasons the market is growing is because there's been a lot of activity and positive activity. There's been 2 approvals in this market recently, one GLP-1 and one THR beta. And that has increased the diagnosis rate and the awareness. But it also presents a question of where does lanifibranor fit in. And so the way we see the treatment of MASH evolving is that any patient that is F1, F2 or F3 will have tried, will soon try or will be on a GLP-1. That will be the backbone of therapy for these patients because GLP-1s really address the underlying metabolic issues.

There's also FGF21s. We view that those therapies are very promising therapies, but really will remain in F4 because they're injectable, they have some overlapping toxicities with GLP-1s. They're probably -- and this is speculation, going to be premium priced. So they really will stay in that F4 patient -- and we see the future as for F2 and F3 patients as a GLP-1 plus or minus an oral, and that oral will either be Rezdiffra or lanifibranor.

So let me go into lanifibranor and specifically how it was designed and the mechanism of action. So lanifibranor is a pan-PPAR agonist. It was rationally designed based on over a decade of PPAR biology and understanding. It was not made on the old TZD backbones, rather it's a new chemical entity, so it has its own properties. And really was designed with 2 goals in mind. First of all, to be a low potency binder across all 3 isoforms.

Now why is low potency? Why? We usually in drug development, we like high potency, we like tight binders. But it's been shown that especially for the gamma isoform, if it binds tightly and have a high potency binder, it leads to adverse events that we want to avoid, for example, peripheral edema. And this was the case with rosaglitazone, which was a tight gamma binder that was withdrawn from the market in Europe.

We also want to be balanced across all the isoforms. We want to recruit not only the liver effects, but the body effects and also the balance actually helps to -- these are networked receptors and hitting them all together leads to a much more balanced profile and safe profile. So -- and one of the reasons we want to be balanced across all 3 isoforms was we want to recruit both the liver effects and each isoform has different impacts on the body.

So we want to address steatosis, PPAR gamma, fibrosis, PPAR gamma and alpha, inflammation and ballooning, PPAR -- all the 3 PPARs and vascular gamma and delta. And then we also -- for MASH, especially want to address the metabolism. And a pan-PPAR addresses insulin sensitivity, it lowers HbA1c, increases HDL and lowers triglycerides. So that was the goal of the design of lanifibranor.

So let's turn to the clinical data. How this was the goal of design, how did the drug actually perform in patients? Well, in the Phase IIb study, which these were published in the New England Journal of Medicine, with only 6 months of treatment, so 24 weeks, lanifibranor improved fibrosis and key metabolic markers. So we saw an 18% effect size on fibrosis. And if we looked at both fibrosis and mass resolution, that actually grew to 24%. In addition to that, it improved the cardiometabolic glycemic and metabolic markers. So it did -- it delivered as promised in the clinic.

Now that Phase II trial was, again, 6 weeks, and it was 2 doses, 800 and 1,200. It included F1, F2 and F3 patients, and the primary endpoint was an SAF score, so a steatosis activity fibrosis score as measured. This is not what -- our Phase III is going to look very similar to this, but not quite identical. So I'm going to go through a couple of differences and maybe what impact those will have.

So let's start, let's reground ourselves in the efficacy. So on the dual endpoint, the resolution of MASH and improvement in fibrosis, that is what's going to be our primary endpoint, not the SAF score. And that is where we had that 24% effect size in the Phase II. Now our Phase III is going to include no F1 patients. It's just F2 or does include no F1 patients, just F2 and F3. So how do we do an effect size in that population? Well, roughly the same, slightly better. So we're confident that the elimination of the F1 patient population from the Phase III is actually -- has either no or positive impact.

Also, we're running the study or the study was run more in the U.S. than the Phase II, and therefore, there was more type 2 diabetes. So the patient population is slightly enriched for type 2 diabetes. And again, you see that the effect size remains similar, actually slightly better. So we're -- that Phase III patient population is -- we're confident that we can duplicate that Phase II data.

Now these are the histological findings from the study, but the biomarkers also support the same efficacy that we saw. So we saw a statistically significant decrease in liver enzymes, ALT, AST, gamma GT, and this was rapid and sustained improvement. And we also saw a number of extrahepatic benefits, including the lipid profile improving with HDL going up, triglycerides going down. There was no change in LDL. There was significant reduction in HbA1c. In fact, it went down by half -- just over 0.5 point that would have been an approval diabetes product back in the day. We saw significant improvements in hepatic and muscular insulin sensitivity. We saw a decrease in diastolic blood pressure that was not statistically significant, but something we'll be measuring. And we saw increases in adiponectin levels as well up to threefold and over threefold at the higher dose.

Now that's how we did on efficacy, which was quite compelling and really led the company to start that Phase III. And on safety, how did the rational design impact the safety of the molecule. So overall, what the concern about PPARs is peripheral edema. And if you look at the peripheral edema rates and drug-related peripheral edema rates in our Phase II, it was just at 2%. So it appears that the design seems to have mitigated some of the worst impacts of the gamma of PPARs.

We did also have weight gain in the study as has been reported with other PPAR agonists. That weight gain appears to have been milder than previous PPAR agonist. Half of patients gained no weight, so there was no impact. 20% gained less than 5% and 30% gained 5% or more. And this profile, remember the profile of really robust fibrosis efficacy, cardiometabolic benefits, we think -- when we talk to physicians, we think this is a very competitive profile in the MASH market.

So let me move to the Phase III. Again, this is a fully recruited trial. The last patient was enrolled in April of last year. The -- as opposed to being a 6-month trial, it is an 18-month trial. So a full extra year of follow-up, and we do hope for a deepening of effect over that extra 1 year. The main cohort has over 1,000 patients enrolled, so a very large trial, again, 2 doses. And the key differences between the Phase II and the Phase III are, as I mentioned, the type 2 diabetes, again, no F1s. And there are a number of patients, 14% that actually started the trial on a baseline of GLP-1, a steady dose of -- or a stabilized dose of GLP-1 as opposed to we had no patients in the Phase II as GLP-1s were really not used that much at that time.

So importantly, from this as well, we have an exploratory cohort where any screen fails, F1 or F4 go into an exploratory cohort. So we will have a population of F4s coming out of this, where we should have some data. And that is particularly important because the next step for Inventiva is an outcomes trial. So because we are using a histological endpoint, which is used as a surrogate endpoint by the FDA and the EMA, we do need to do a confirmatory trial. And we are going to start an outcome study in patients with compensated cirrhosis, MASH to confirm the clinical benefits. We have to measure either the prevention of progression to cirrhosis or a reduction in associated clinical outcomes, such as decompensation, cancer or liver transplant.

So we're actively designing that trial now. And some early thoughts on it are that we need to have a patient population that is sick enough so they can progress to get events, but not so sick that we cannot reverse the pathology of it, right? So there's got to be this Goldilocks patient population that we can study. Otherwise, we're doing a 10-year outcomes trial, which no one wants. And we do believe that there is a patient population of compensated advanced chronic liver disease or cACLD that meets that criteria. These are patients that have advanced fibrosis or cirrhosis, but no outward signs of liver disease. However, you can identify them through noninvasive tests.

And one of the key hallmarks is they have portal hypertension. In other words, the blood flowing into the liver is not flowing out as quickly. It's backing up into the circulation system of the body and leading to varices in the esophagus and other places. And importantly, preclinical data suggests that lanifibranor can address the etiology of that cACLD patient, that portal hypertension. So we'll be exploring this more and giving more details on this as we go through the year.

All right. So what can you expect from Inventiva in the next 24 months? Well, we will report out data this year. We will start our F4 outcomes trial at the beginning of next year sometime and then file with the FDA as well and the EMA. And we anticipate a potential market launch for lanifibranor in 2028. And we do so from a position of strength. We have a cash balance that runs us out to Q3 '27, and that assumes the third -- positive data and the third tranche from the PIPE that we did in October '24 coming in and funding the company. Just as a reminder, we own this asset fully with the exception of out-licensed in China, Japan and South Korea with a very low royalty burden. So this is a fully owned asset by Inventiva.

So to summarize, we have a wonderful -- asset that has -- a therapy that has the potential to have real clinical benefit in a very large unmet need patient population with a large potential. We have a company that is well funded with a really strong management team, and we're looking forward to giving you updates throughout the course of the year and having a very successful 2026.

And with that, I will hand it over to you, to our questions in the audience. Thank you.

Any questions from the audience here? Otherwise, I would like to kick it off. I mean, I sat here a year ago, it's great to see the progress since you started the job in October. Any first impressions? And how has it been going?

It's been -- so I would say that there is a -- this is a French innovation company that has done a wonderful job of progressing this asset as far as it has. I think it was a real pleasure and surprise to come in and just see how well this trial had been executed and just the potential impact on patients that it has this is in terms of actually reversing stages of fibrosis. I did not, as first time in the MASH market, appreciate just the damage that liver disease does to these patients and the impact that you can have by reversing it. So very impressed with what the company has done so far.

Great. And with the recent management changes, is Inventiva planning to becoming a U.S. company?

No, we're going to stay France based. While we build up our U.S. commercial infrastructure in the future, but we will be -- I think we'll move from a French innovation company to a transatlantic international company that's still based in France.

Great. That's -- pleased to hear. I see we've got one question from the webcast, which is, is there any -- I mean, you commented on the planned filing of the data. Do you see any risk factors, limiting factors that could result in a later filing?

So we are -- I always say that we're not Pfizer, we're not going to file it is in 1 day with a COVID vaccine. No, but we have -- I think right now, we are building up such a very strong team that has experience prosecuting these types of trials, collecting the data, cleaning the data, moving from last patient, last visit to top line data, moving from top line data to NDA filing. So I think we're going to move very efficiently going forward.

And what's the company currently doing to prepare for commercialization?

Yes. So this 2026 is a year of strategic preparation, doing a lot of market research, preparing some market access, thinking strategically about which geographies we want to be in at what point, probably building up a little bit of presence in medical affairs for 2026, really with the preparation to scale robustly in 2027 after data.

Good. Any further questions from the room? I think we leave it there. Thank you.

Yes. Well, thank you, everyone, for coming today. Don't jostle on the way out. And we will -- we look forward to giving updates through the course of the year. Thank you.

Thank you.