Inventiva (IVA) Q2 2026 Earnings Call Transcript

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DATE

Sept. 28, 2026

CALL PARTICIPANTS

• Head of Investor Relations-David Nikodem
• Chief Executive Officer-Andrew Obenshain
• Chief Medical Officer and President of R&D-Dr. Jason Campagna
• Chief Financial Officer-Axel-Sven Malkomes
• Chief Operating Officer-Chris Benecchi

TAKEAWAYS

• Combined Cash and Short-term Deposits -- €233.9 million as of June 30, 2026, providing a cash runway through the second quarter of 2027.
• Net Loss -- €69.5 million for the first half of 2026, compared to a net loss of 175.9 million in the first half of 2025.
• Research and Development Expenses -- €46.2 million for the first half of 2026, representing a 3% increase over the prior year due to the continued development of lanifibranor.
• General and Administrative Expenses -- €22.2 million for the first half of 2026, reflecting a €7.5 million increase driven by higher personnel costs and commercial preparations.
• NATiV3 Trial Enrollment -- 1,009 patients in the main cohort with biopsy-confirmed non-cirrhotic MASH and F2 or F3 fibrosis.
• Exploratory Cohort Enrollment -- 410 patients with predominantly F1 or F4 disease, intended to support safety and broader efficacy data.
• Phase IIb Clinical Efficacy -- 18% placebo-adjusted improvement in fibrosis and 26% resolution of MASH without worsening of fibrosis after six months of treatment.
• Market Potential -- Management estimated the MASH therapeutic area could exceed $15 billion by 2035, with current diagnosis rates increasing 25% compared to 2024.
• Equity Offering Proceeds -- €103 million in gross proceeds generated from a public offering of American depositary shares to strengthen the balance sheet.
• Debt Financing -- Secured up to €130 million in committed tranches, with an initial drawdown of €75 million to support clinical milestones.
• NATiV3 Top-line Readout Timeline -- Expected in the fourth quarter of 2026 following the completion of the last patient's 72-week visit in September 2026.
• Regulatory Submission Target -- Planned for the first half of 2027 for a New Drug Application with the U.S. Food and Drug Administration.
• Commercial Launch Target -- Potential U.S. commercial launch in 2028 if regulatory approval is obtained following positive clinical results.
• GLP-1 Medication Usage -- 9% of patients in the NATiV3 trial utilized GLP-1 therapies, which were permitted at non-MASH doses.
• Expected Cash Runway Extension -- Financing could extend until the first quarter of 2028 if all warrants are exercised and additional debt tranches are completed.
• Patient Dropout Rate -- Management reported the dropout rate for the NATiV3 trial was comfortably below 30% as of mid-2025 assessments.
• SGLT2 Inhibitor Baseline Usage -- 10% of NATiV3 participants utilized SGLT2 inhibitors at the start of the study, consistent with modern patient management.
• Phase III Powering Assumptions -- 90% based on conservative models of higher placebo response and lower efficacy than Phase IIb results.
• EIB Loan Repayment -- €63 million paid to resolve European Investment Bank loans as part of a comprehensive capital structure optimization.
• Warrant Repurchase -- €50 million utilized to buy back approximately 60% of anti-dilution warrants from the European Investment Bank.
• Headcount -- 73 employees as of the reporting period, focused on clinical development and commercial readiness.

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RISKS

• Management stated that as of the reporting date, "current cash and cash equivalents are not sufficient to cover operating needs as currently planned for the next twelve months," noting that further funding is dependent on positive clinical milestones and additional financing tranches.

SUMMARY

Management at Inventiva S.A. (NASDAQ:IVA) reported progress toward the Phase III top-line results for lanifibranor, which are expected in the fourth quarter of 2026. The company completed the last patient's final visit in the NATiV3 trial, positioning it for a potential regulatory submission in the first half of 2027 and a commercial launch in 2028. Financial results for the first half of 2026 included a significant strengthening of the balance sheet through a 103 million equity offering and a new 130 million debt facility. Management stated that these actions simplified the capital structure and extended the cash runway through the second quarter of 2027. The company is also preparing to expand its pipeline into compensated advanced chronic liver disease, targeting a therapeutic area with no currently approved disease-modifying treatments.

• CEO Obenshain stated, "The market is being built in front of us," noting that only 10% of 18 million Americans with MASH are currently diagnosed, a figure that is growing rapidly.
• Dr. Campagna explained that lanifibranor is designed to achieve a "physiologic balance" across three PPAR isoforms, avoiding the receptor dominance common in earlier chemical classes.
• Management indicated that weight gain associated with the drug is biphasic and typically plateaus between week 24 and week 30 of treatment.
• The company reported that approximately 374,000 patients with F2 or F3 disease are already under physician care, representing the initial target population for a potential launch.
• Management noted that results from the LEGEND study showed that adding an SGLT2 inhibitor mitigated weight gain and edema while maintaining metabolic efficacy.
• The company intends to file for accelerated approval with the FDA and conditional approval with the EMA if the NATiV3 top-line results confirm the findings of the Phase IIb study.

INDUSTRY GLOSSARY

• MASH: Metabolic dysfunction-associated steatohepatitis, a progressive chronic liver disease formerly known as NASH.
• cACLD: Compensated advanced chronic liver disease, a stage where liver fibrosis has progressed to early cirrhosis but remains clinically managed.
• PPAR: Peroxisome proliferator-activated receptors, proteins that regulate gene expression related to metabolism, inflammation, and fibrosis.
• NATiV3: The name of Inventiva's global registrational Phase III clinical trial for lanifibranor in MASH.
• SGLT2: Sodium-glucose cotransporter-2, a class of medications used to treat type 2 diabetes that may also mitigate fluid retention.
• Fib-4: A non-invasive clinical test used to estimate the severity of liver fibrosis based on patient age and laboratory values.

Full Conference Call Transcript

Operator: 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 Nikodem, Head of Investor Relations for Inventiva. Please go ahead.

David Nikodem: 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 two and to our filings with the SEC and the AMF for a 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 Benecchi, 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.

Andrew Obenshain: 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 III top-line results readout in MASH expected in Q4 2026, preparing for regulatory filing while building the 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 three 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 II-B study, lanifibranor showed improvement across all key histological endpoints. Next is validation. We designed the NATiV3 phase III trial to build on the foundation established in our positive phase II-B study. We look forward to reporting top-line data in the fourth quarter of this year. 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 six 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 one 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 differentiated mechanism of lanifibranor modulating both pathways is reflected in compelling clinical data.

In our phase II-B study, after six months, lanifibranor delivered an 18% placebo-adjusted improvement in fibrosis, 26% on MASH resolution, and 24% on the composite endpoint. Those results were the foundation for NATiV3, where we are now testing the same approach in a larger control phase III population of patients with F2 and F3. That is what makes NATiV3 so impactful. It was designed to confirm at pivotal scale the biology and activity we observed in our phase II-B study, and we are pursuing this in a market with substantial and growing unmet need. As slide eight 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 a compelling opportunity for lanifibranor if approved. Turning to slide nine. To see where lanifibranor may fit in the treatment paradigm, it helps to think about MASH in terms of two factors that are top of mind for physicians, the severity of fibrosis and the cardiometabolic factors that can influence the risk of disease progression.

Put fibrosis on one axis and cardiometabolic risk on the other, and four 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, where the mechanism of action of lanifibranor could be compelling in that it targets both the liver and the metabolic drivers simultaneously. In our phase II-B trial, lanifibranor demonstrated an 18% placebo-adjusted improvement in fibrosis at just six 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 could 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 with 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 three 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 three key priorities we are focused on to unlock new opportunities for patients with MASH. First, the NATiV3 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 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 read out as positive. Third, commercial readiness.

We are building a commercial organization with the depth and breadth of experience with the best in 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 a potential for a differentiated profile, a late-stage validation opportunity with NATiV3, and a significant market opportunity if approved. I am 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. Jason?

Jason Campagna: Thank you, Andrew, and greetings, everyone. I will spend a few minutes on four aspects of our lanifibranor development program in MASH. One, how lanifibranor is designed to address the spectrum of disease. Two, what we have observed in the positive NATIVE phase II-B clinical trial. Third, how our NATiV3 phase III trial is built to confirm that phase II study. Lastly, where we are thinking of taking the program next. Let me start with the molecule. As Slide 11 shows, lanifibranor is 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 one critical concept, balance. Lanifibranor engages all three 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. It is what lets lanifibranor modulate in harmony the metabolic, inflammatory, and anti-fibrotic pathways of MASH combined rather than forcing one mechanism or receptor at the expense of the others. The two charts on the right illustrate this designed 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. The result is a once-daily oral therapy intended to deliver a physiologic balance between achieving pan-PPAR activation and avoiding any one receptor dominance. Moving now to our phase II-B 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 three histologic endpoints, showing that the drug worked equally well in both early and later stage disease.

These results were achieved after only six months of treatment. Looking more closely at the data for the composite endpoint, you can see that treated patients were roughly eight times more likely than placebo patients to achieve dual histologic improvement in the type 2 diabetes subgroup. 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 II-B clinical trial. Lanifibranor was generally well-tolerated across the totality of our phase II program, but the adverse event profile in NATIVE IIb tracked closely with the underlying scientific design of lanifibranor. Consistent with our preclinical toxicology data, we saw minimal classic alpha or delta toxicities. On 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, which is itself tied to histologic efficacy. Both phases are consistent with the known pharmacology of PPAR gamma engagement. 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 NATiV3. This is a phase III global registrational trial, and it was deliberately designed to build on our phase II-B. The same two doses, a similar patient population, and a primary composite endpoint of MASH resolution and at least one-stage fibrosis improvement in the same patient.

Secondary endpoints include MASH resolution and fibrosis improvement of one stage or more. The trial enrolled approximately 1,400 patients across two 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 II-B NATIVE trial. It is stratified by fibrosis stage and diabetes status. This main cohort also reflects the real world. The NATiV3 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 II-B 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.

As Andrew shared, we are excited for top-line data in the fourth quarter of this year. Subject to positive phase III 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.

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 II-B NATIVE trial showing a correlation in patient biopsies with vascular remodeling we've observed preclinically. These are 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.

Andrew Obenshain: I will pick up for Axel here.

Axel-Sven Malkomes: I'm sorry, I lost my text. Please go ahead.

Andrew Obenshain: Yes. 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 NATiV3 top line readout. Axel, are you ready to take over?

Axel-Sven Malkomes: Not yet.

Andrew Obenshain: Okay. As of June 30, 2026, we had EUR 233.9 million of combined cash equivalents, and short-term deposits. 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 EUR 50 million, and repaid our EIB loans for EUR 63 million. In addition, the remaining EIB warrants with anti-dilution protection were canceled. Inventiva issued new EIB warrants in exchange, as described in the July 9, 2026, press release.

Axel-Sven Malkomes: I am ready to take over.

Andrew Obenshain: Please go ahead.

Axel-Sven Malkomes: As part of this optimization, we secured new debt financing of up to EUR 130 million in three committed tranches, subject to conditions with an initial drawdown of two tranches of EUR 75 million gross, plus an additional uncommitted tranche of up to EUR 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 depositary shares, generating gross proceeds of EUR 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 III 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, our cash runway would extend to the start of the first quarter of 2028. R&D expenses were EUR 46.2 million in the first half of 2026, brought in line with the prior year and reflecting continued clinical development of lanifibranor MASH.

Marketing and business development expenses increased to EUR 2.6 million, and G&A expenses increased to EUR 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.

Andrew Obenshain: Thank you, Axel. This is truly an exciting time for Inventiva. Our differentiated mechanism of action, the results we saw in the NATIVE phase II-B trial, and the robust design of our NATiV3 phase III trial provide a strong foundation as we approach the milestones ahead. The next major milestone is our NATiV3 top-line results readout, expected in the fourth quarter of this year. If positive, it could support the U.S. regulatory filing in the first half of 2027 and a potential EU filing to follow. 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 is designed to target both the metabolic and hepatic drivers of MASH in one oral medicine. Our pivotal 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.

We are 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?

Operator: Thank you. We will now open lines for questions. To ask a question, you will need to press star one and one on your telephone and wait for your name to be announced. To withdraw your question, please press star one and one again. You are kindly asked to limit yourself to one question and one follow-up. If you wish to ask any further questions, you may reenter the queue. We'll now move to our first question. Our first question comes from the line of Yasmeen Rahimi from Piper Sandler. Please go ahead. Your line is open.

Yasmeen Rahimi: 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 two doses in the NATiV3 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. Maybe one other one that sometimes comes up is that the higher dose had a phenomenal histological benefit, but then when we compare the NITs, the two doses look more the same. Would love if you could maybe comment on both.

That would be very helpful as it's on top of a few of the investors that have been asking us that. Thank you.

Andrew Obenshain: Thank you, Yasmeen, and good morning. So two questions in there. First one, I think more of a commercial question, which I'll take, then I'll pass it on for the correlation with histology and dose to Jason in a second. First, if both doses 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 with each dose.

There could be scenarios in which the difference between the two makes sense to bring both to the market, potentially one for two patients or one you could think of as earlier stage patients that are less urgent and so therefore would be OK with a dose response or lower efficacy and more tolerable. If another one, if you have a tolerability difference between low and high, then a higher dose with still tolerable but a slightly different profile, we could see bringing both forward, but that 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 with NITs.

Jason Campagna: Sure. Happy to. Yasmeen, good morning. So in the NATIVE phase II trial, generally speaking, the histology endpoints tracked well with most, but not all of the clinical biomarker endpoints. Obviously, ALT/AST reduction was evidenced. This reflects hepatocellular injury. Moving into fibrosis, you can 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 procollagen 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 two other components actually tracked very nicely in a dose-dependent manner, representing that we were, in this case, resorbing some existing scar. Lastly, on the TE, it's very difficult to compare trials, Yasmeen, as you know, across different sponsors. When you look at the data ranging from six 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, sorry, 1 kPa up to a high of 3 kPa. So that's somewhere around 10%-30%.

Lanifibranor came in at the lower end of that range, and it's our belief that's, one, it's just early in the disease to really have movement on liver stiffness. It's a composite view of what's going on in the liver. 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 Echosens manuals about being cautious about getting liver stiffness data after a meal or in the presence of fluid loading. At six months, the dynamic fluid flux that's still happening due to the PPAR, we believe is likely impacting some of that.

So we landed at about a 10% reduction in liver stiffness, about a 1 kPa placebo-adjusted number. We're confident that with a longer treatment duration, the underlying fibrosis improvements will, in the end, dominate that signal by 18 months.

Yasmeen Rahimi: Thank you so much.

Operator: Thank you. We'll now move on to our next question. Our next question comes from the line of Seamus Fernandez from Guggenheim Securities. Please go ahead. Your line is open.

Seamus Fernandez: Oh, great. Thanks for the question. Just wanted to get a sense of the information that you guys have on a blinded basis as it relates to weight gain throughout the NATiV3 study. If you might be able to share what's with your expectations for potential weight gain. What we've heard from thought leaders is 18% would be a highly differentiated threshold for fibrosis change, very consistent with what you've commented on. But I think there is the trade-off of potential weight gain and edema that some physicians have commented on and may have a higher bar for fibrosis difference over time.

Just interested to know what information you guys have on the weight gain and edema, how patients actually feel on drug that has any meaningful impact on the durability and sustainability of the use of lanifibranor in the NATiV3 study. Thanks so much.

Andrew Obenshain: Yeah. A couple elements to that question. Let me hand it to Jason to talk about the first part, which is what have we shown from a blinded basis from the phase III trial on weight gain, and then I can take it from there. Jason, go ahead.

Jason Campagna: Yeah, sure. Seamus, good morning. We previously disclosed back when the structured financing back in 2024, some data on our phase II clinical trial in the scleroderma population. This is a non-metabolic population treated for a year with the same doses of lanifibranor that are in the MASH program. In that trial, we showed that the weight gain was similar up to six months to what we saw in the NATIVE phase II-B trial and thereafter, where NATIVE II-B stopped at six months. Thereafter, the weight gain appeared to plateau right around the week 24 to week 30 and remained stable there out through to the end of the study at week 48.

We're not guiding any additional data or input on NATiV3 in any manner. I think, Andrew, to turn this over to you, I think that the data that we have in NATIVE is actually really representative of some of the questions Seamus asked, and I'll answer that and turn it back to you. Seamus, you're really getting at what's the potential impact of things like weight gain, edema? I think that's the right question. When you look in the NATIVE trial, about half of all patients in that trial had no weight gain defined as anything beyond plus or minus 5%.

Among the patients, therefore, that did have weight gain, when you look at the adverse event reporting in that trial, only about 10% of the reports related to weight gain. That is consistent with the idea that weight gain is not seen by patients or providers as a safety or tolerability concern. And in that trial, we had about 30 approximately dropouts, and weight gain was not a primary driver of the tolerability concern there and discontinuing treatment. So our view is that at least from the completed NATIVE clinical trial, that weight gain is not an impediment to patients staying on treatment.

And the perception of weight gain by both providers and patients is not one around safety and tolerability. Andrew, over to you.

Andrew Obenshain: Well, I do not think I could say it better than you, Jason. That was perfect. I think we can move on to the next question.

Operator: Thank you. And our next question comes from the line of Ritu Baral from TD Cowen. Please go ahead. Your line is open.

Ritu Baral: Good morning, guys. Thanks for taking the question. I guess I have the same question, in terms of edema, which is, I guess, related but separate in the sense that, I think KOLs see that less as a true safety issue, but potentially a tolerability issue. Is this something you guys have interrogated in your market research insofar as what level and severity that the edema becomes inconvenient or unacceptable to MASH patients and that risk-benefit around sort of extremitous edema, versus any potential issue of fluid load. Thanks.

Andrew Obenshain: I will start out, then I will hand it to Jason as well. A very similar answer to before. The edema is mechanistically understood, is consistent with known PPAR gamma pharmacology. That makes physicians, especially those who use pioglitazone in the market, very comfortable with managing those types of effects. We are looking for in the larger NATiV3 data set to provide a more comprehensive safety characterization overall. But in general, the physicians know that they can mitigate the MFX linked to fluid retention, weight, edema, hemoglobin, by addition of an SGLT2, if they want to manage it. We do view this as a profile that is very commercially attractive. Jason, do you have anything to add to that?

Jason Campagna: I do just briefly. Edema, as Andrew mentioned, is a known on-target consequence of PPAR gamma. I want to make a distinction between the prevalence of edema in the NATIVE II trial, the unadjusted prevalence, meaning independent of assessment, ranged between 7% and 10% on the two doses, and the drug-related edema was about 2%. Contrast that with what we know from pioglitazone in a similar MASH population, you are somewhere in the mid 20s, 20%-25% edema range. So that is a prevalence. In terms of the severity, which I think, Ritu, was where your question was headed, is that generally these events are considered mild to moderate.

Going back to the NATIVE II-B clinical trial, these were not primary drivers of patients discontinuing treatment. Most of the edema in the experience of our clinical program is so-called peripheral edema. It happens in the lower extremities, where present occasionally periorbital around the eyes, but generally this is a mild to moderate view. Most importantly, the difference between a pure PPAR agonist like pioglitazone, for example, is fairly large, which is consistent with our view that this is a more blunted or more attenuated gamma effect that you would see with a full TZD class agonist.

Ritu Baral: Would you expect it to be transient?

Jason Campagna: I'm sorry, Ritu, do I expect it to be?

Ritu Baral: Sorry. Would you expect the edema to be transient, and if so, would it be during the full 18 months, and would that be communicated?

Jason Campagna: I think we're not giving any guidance on what we expect over time. I think that 18-month trials are long. The fluid is due to salt and water. To the extent that patients may or may not have already on a pre-existing agent like SGLT2s or thiazide diuretics, that may impact it. Also mild changes in diet around salt intake and/or fluid can impact that. I think our view is that the pharmacology is well understood here and the overall mechanism, and that going back to your core point, we don't view it as a tolerability concern or gating in any way to patients staying on it. Maybe I'll make the simple point.

Pioglitazone is a generic therapeutic at this point. It's still used about 4 million scripts a year in the U.S., and that's with very minimal histologic efficacy on anything outside of MASH. I think the question you're really asking is, if we added an 18% one-stage improvement of fibrosis or more to that profile, would people use more or less of it? I would argue they would use more. I think even better evidence that it's much less of a tolerability concern in the market than we see it in the clinical program.

Ritu Baral: Understood. Thank you.

Operator: Thank you. We will now move on to our next question. The next question comes from Thomas Smith from Leerink Partners. Please go ahead. Your line is open.

Thomas Smith: Hey guys, good morning. Congrats on the progress and thanks for taking our questions. First, from a compliance perspective, can you just remind us, is there any protocol or counseling that is built into the study for patients that are experiencing weight gain or edema to help them manage this and stay on the study? Also wondering if you have any visibility into the proportion of patients who have rolled over into the active treatment extension portion of NATiV3 on a blinded basis. Then just a bit on your market research. You highlighted the 374,000 F2, F3 patients diagnosed under the care of a specialist. That is a bit lower than the 460,000 we have heard from a competitor.

I was just wondering if you could talk a little bit about the differences there and how you are thinking about patient targeting relative to Rezdiffra. Thanks so much.

Andrew Obenshain: Yeah. Thanks for the question, Thomas. Let me handle the first two, then hand it over to Jason. On the active treatment role, we are not commenting on that yet. We have not publicly disclosed that information. On the patient population, yes, there are some range of estimates out there. The 374,000 is certainly on the low end of that. We have not updated that number, but certainly, I think the real message here is that it is a very sizable population, and growing rapidly. So that number will continue to evolve. Jason, over to you on how weight gain was managed in the trial.

Jason Campagna: Yeah. Thomas, good morning. Good question. There's no formal management algorithm or treatment algorithm in the NATiV3 protocol. However, investigators are educated as to the mechanism. Generally, once they know that the protocol does allow them, if they choose to manage the weight gain, the fluid retention with the use of either diuretics or SGLT2s. Keep in mind, patients in this population are already on, many of them are already on diuretics for hypertension control, et cetera. So the providers have the opportunity to utilize therapeutics that may already be in use to manage, but there's no formal management algorithm that they're required to follow.

Thomas Smith: Understood. Super helpful. Thanks, guys. Looking forward to the data.

Andrew Obenshain: Yep.

Operator: Thank you. We'll now move on to our next question. Our next question comes from the line of Michael Yee from UBS. Please go ahead. Your line is open.

Kyle Yang: Hey, guys. Good morning. This is Kyle Yang for Michael Yee. Just two for us. The first one is on the F2, F3 mix. We did notice that NATiV3 enrolled a meaningfully higher proportion of F3 patients relative to NATIVE phase II-B. How do you expect that to impact both efficacy on the drug arms and placebo arm? The second question is on GLP-1 drop-ins. You previously disclosed roughly 10% GLP-1 dropping rates during this study. How do you think that could potentially impact the outcomes on both the drug arms and placebo? Thank you.

Andrew Obenshain: Yeah, absolutely. Let me just set the stage. I am going to hand it over to Jason to answer that. On the F2, F3, the mix was indeed different in the phase III. We enrolled more patients in the U.S. in the phase III than we did in the phase II. The patient population looks a little bit different in the U.S. There is more diabetes, and diabetes and F3 track together. Therefore, we had slightly more diabetic patients and slightly more F3 patients in the study. We have looked at our phase II when next time we removed the F1 patients from our phase II.

We saw a slightly better response rate in the F2 and F3 combined than we saw in when it was combined with the F1, which gives us confidence that we are going into at least a drop in the F1s from the study will not impact the patient population. I will have Jason comment in a second just on the split in F2 and F3. On the 10% drop-ins, it is actually 9% drop-ins on GLP-1s. We do not anticipate that to impact the trial as when they dropped in, they drop in on the non-MASH dose. They have dropped in on a lower dose. Jason, over to you.

Jason Campagna: Yeah. Thank you, Andrew. Just adding on to Andrew's response there around F2, F3. I agree. We do not have any expectation that the larger prevalence of F3 patients should impact the primary efficacy readout. I think three additional reasons. One, there is nothing in the biology of F2 or F3 disease that is different from each other. It is just a more advanced version of the exact same biology. I think second, that lanifibranor has direct anti-fibrotic actions to hepatic stellate cells in the liver. That direct action, meaning it does not depend on extra hepatic elements in order to achieve fibrosis.

Things like weight loss or glucose metabolism, they are additive, but they are not required for fibrosis improvement. Third, the time duration of the trial actually will help to this extent. I think clearly, if the biology takes more time in an F3 patient to resolve, which is not unreasonable, a longer clinical trial should give us visibility into that. So we are pretty comfortable with that 18-month duration for NATiV3. Lastly, the FGF21 analogues like efruxifermin have shown similar efficacy in F2, F3, and I highlight them because those drugs, although very different mechanism of action, they actually have similar impact on both intra and extrahepatic drivers to some degree.

So although not a complete overlap with pan-PPAR agonists, there are some elements that do, and I think that is support for the fact that by getting both direct action in the liver and modulating some extrahepatic drivers of disease, this difference between F2, F3 is unlikely to be a concern.

Operator: Thank you. We will now move on to our next question. Our next question comes from the line of Annabel Samimy from Stifel. Please go ahead. Your line is open.

Annabel Samimy: Hi. Thanks for taking my questions. I guess one question, with the patients on the GLP-1s and SGLT2s, are there any pre-specified analyses of these patients? Are any of those subgroups powered to show any kind of difference or statistical analysis on how those patients perform with that background of GLP-1s or SGLT2s? I guess you touched on this before, but how you might account for any changes in the background mid-trial. Then how might that inform physicians on how to incorporate these drugs? Is there any specific protocol that you would be recommending going forward?

Andrew Obenshain: Thank you, Annabel, for the question. On the second, it is a little bit too early to comment on any sort of guidance to physicians by Inventiva post data. Let me go for the first part. Jason, let me hand it to you.

Jason Campagna: Sure. There are several questions there. Let us go through it. Yes, there are sensitivity analyses that we have pre-specified in the SAP to allow us to look at the impact, if any. Again, as Andrew said, we do not expect any, but the analyses are there on the use of these non-MASH dose of GLP-1s and the use of SGLT2s. I think second, no, none of those groups are in any way powered. We are powered on our primary endpoint. That is the intent of the trial. As I have mentioned before, the power in detail there.

Third, I think the important point I think we want to convey here is that there is nothing unusual or different that we are doing in this phase III trial than any other sponsor in any other phase III trial would do to account for therapeutic drop-ins. Even in the case of MASH, if you go back to Intercept's REGENERATE trial, the questions in that era were, what about statins and what about other antidiabetic drugs? Liraglutide had shown in the LEAN study that there was evidence that it could work. Pioglitazone.

The answers there were the same answers here, that for any drop-in that may theoretically impact your concern for efficacy, sensitivity analyses are built in to give us and FDA confidence that the treatment effect we see is due to lanifibranor and not due to any other agent that may be dropped in during the course of the trial.

Annabel Samimy: Okay, great. That's helpful. If I can ask one more quick follow-up for Axel. How are you guys preparing for the launch, and have you laid out what kind of funds you might need for the launch?

Andrew Obenshain: Axel, go ahead.

Axel-Sven Malkomes: Yeah, sure. Let's take a step back. We have done our capital transaction, as you all know, in June of this year, which gives us a solid funding until the end of Q2 2027. If we would have positive data, and we could, in addition, add the financing out of the structured financing Tranche 3 as well as the Tranche C out of the refinancing, we would extend that cash runway until the start of the beginning of Q1 2028. So with that, we basically can fund the following catalysts. Point one, the data read out now in Q4. Point two, we are funded until the NDA filing. On top of that, we do not guide on any future raises.

But with what we currently have, we believe we have strengthened the balance sheet, simplified the cap structure, prolonged the debt maturity. And with that, we are basically solidly financed prior to the data release.

Annabel Samimy: Okay. Thank you.

Operator: Thank you. We will now move on to our next question. Our next question comes from the line of Prakhar Agrawal from Cantor. Please go ahead. Your line is open.

Prakhar Agrawal: Hi. Thank you so much for taking my questions, and congratulations on all the progress. Maybe I had a couple of questions. Firstly, can you talk about the biopsy completion rate in the trial and whether that is tracking in line with some of the recent phase III MASH trials? A couple on weight gain. Maybe mechanistically, why does the weight gain plateau for lanifibranor and not for PPAR gamma pioglitazone? If I remember correctly, I think the company had previously shared interim weight gain data from the ongoing phase III a couple of years back. Realize it was interim, but was a decent enough sample size.

So why should not we use that as a reference for understanding what the weight gain profile could look like in the final analysis in the phase III? Thank you so much for taking my questions.

Andrew Obenshain: Yeah. Thank you for the questions, Prakhar. We will address the, you asked about a biopsy completion rate. What we have guided on publicly is a dropout rate for the trial overall. We powered the trial such that we could tolerate up to a 30% dropout rate in the trial. We have guided in, we believe it was April and May 2005, that dropout rate was below 30%, and we confirmed that dropout rate is comfortably below 30% at that time. We are not giving more guidance beyond that. Regarding the weight gain, you had a question about the plateau and the difference pioglitazone. We are hoping Jason picked it up to be able to talk about both those points.

Jason, go ahead.

Jason Campagna: Yeah, we agree. Prakhar, we will come back to the reference. We missed that. On the question of plateau, our view is that it is a combination of the partial PPAR gamma component of lanifibranor, so not a full agonist. That has important consequences for long-term activation of that sodium channel. Second, and more importantly, the pan-PPAR antagonism brings the alpha and delta components online, and they work to increase not to. The gamma will increase glucose storage via improved insulin sensitization, but the alpha and delta actually get to improved utilization of glucose by tissue.

That utilization actually prevents that sugar from being stored, and that you get a sort of metabolic pop from that alpha delta, which helps to keep the scale weight plateauing over time. Again, Prakhar, if you could just get to the last question, the reference part of it, we missed it.

Prakhar Agrawal: Yeah. If we remember correctly, a couple of years back, the company had previously shared blinded interim weight gain data, so on a pooled basis from the ongoing phase III. It was interim, but we thought it was a very large sample size. Why should not we use that as a reference for understanding the weight gain profile and the plateau effect and the time point of it for the final analysis in phase III? Thank you so much.

Jason Campagna: Sure. You are correct, Prakhar, that several years ago, something like that was done. We think just correcting language, it was no interim read of anything. It was an early look at approximately 100 blinded patients that have achieved week 72. We think to the extent that anyone on the outside world took comfort or not in that, we think those days are in the past. You ask, why do not we do that again? It is our view that utilizing blinded data from a 1,000+ patient clinical trial is fraught with error of interpretation, and it is not something that we think would be helpful. It is more importantly, not something that we are guiding on regardless.

Prakhar Agrawal: Got it. Thanks for clarifying.

Operator: Thank you. We will now move on to our next question. Our next question comes from the line of Kripa Devarakonda from Truist Securities. Please go ahead. Your line is open.

Kripa Devarakonda: Hi, guys. Thank you so much for taking my question and congratulations on all the progress end of year. I have a question on fibrosis expectations. How much importance should we place on not hitting the stat sig endpoint, but on the magnitude of fibrosis improvement independent of the MASH resolution? You talked earlier about lanifibranor's antifibrotic effect. What level of response would convince you that this is a meaningful antifibrotic effect rather than improving metabolic inflammatory component of the disease? Thank you.

Andrew Obenshain: Kripa, let me I think I understand the question. We believe 18% improvement is meaningful in fibrosis to basically duplicating our phase II into phase III. With that profile, with an 18% improvement of one stage or more in fibrosis, that is a secondary endpoint for us. We believe that we have those three segments that I discussed, the F3 diabetics or high cardiometabolic risk, the F3 non-diabetics, and the F2 diabetics as segments where that profile is an 18% fibrosis effect, this would be a differentiated product for those patients.

Kripa Devarakonda: Thank you.

Andrew Obenshain: Yeah.

Operator: Thank you. We will move on to our next question. Our next question comes from the line of Rami Katkhuda from LifeSci Capital. Please go ahead. The line is open.

Rami Katkhuda: 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 lani-associated weight gain, particularly the timing of early fluid retention versus later adipose remodeling and when each typically plateaus? Then secondly, I know it is a bit early, but how are you thinking about the design of the confirmatory outcomes trial? Are there any key learnings from ongoing studies that could help inform patient selection?

Andrew Obenshain: Yeah, thanks, Rami. So two questions there just on the time course, which I am just going to pre-empt it. We cannot really say much more than we have already said on this call. I think we have answered that question pretty thoroughly. So maybe we could focus Jason on the F4 and the confirmatory study and what we are thinking there.

Jason Campagna: Yeah, I am happy to. I think, look, we are looking forward to talking more about the confirmatory study after top line. But I think for now, what we are trying to communicate is, one, that we will be focused on this cACLD, chronic advanced compensated liver disease population, those with clinically significant portal hypertension. We know now that there are 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 are 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 is the goal.

Second, you ask 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 18 months, and if they complete the active treatment extension, they could be on for up to four years. We think that those data from a safety and tolerability perspective and pharmacology will be helpful. Lastly, we have completed nearly a dozen phase I clinical trials with lanifibranor over the years, including dedicated hepatic impairment study in patients with Child-Pugh A, B, and C.

The results of those studies, although we have not published them, we are comfortable and confident around the safety of the drug in those phase I trials at the doses we are presently using. When combined with that exploratory cohort of about 75 to 100 patients, we think we will have a really good opportunity to build and conduct a strong outcomes trial in this cACLD population.

Rami Katkhuda: Awesome. Thank you, guys.

Operator: Thank you. We'll move on to our next question. Our next question comes from the line of Sushila Hernandez from Van Lanschot Kempen. Please go ahead. Your line is open.

Sushila Hernandez: Hi, this is Zoe on for Sushila. Thank you so much for taking our question. With the lanifibranor phase III NATiV3 top line readout in MASH expected in the next quarter, we were wondering what kind of data we can expect at the top line. Will there be data on the treatment response in patients on GLP-1 and on SGLT inhibitor or on the weight gain? If I could just ask another question, we're also wondering how do you expect the placebo response to evolve with the longer treatment duration? Thank you.

Andrew Obenshain: Great. Thank you, Zoe, for the question. We are not guiding on the top-line data right now. I think as you can tell on this call, we are very well aware of the interest in the endpoints and the tolerability profile elements I'm sure people are interested in seeing. 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 a primary endpoint, as it controls better for placebo response.

It's very difficult for a placebo patient to achieve resolution by themselves 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 six-month trial, but certainly it's our expectation that having that composite endpoint does help mitigate any fluctuation in placebo rates.

Sushila Hernandez: Yeah. Okay. Thank you so much.

Operator: We will now go to our last question, and that question comes from the line of Andy Chen from Wolfe Research. Please go ahead. Your line is open.

Jason Zhang: Hi. Thank you so much. This is Jason taking it for Andy, and we just wanted to ask another question about GLP-1. 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? How would that sensitivity analysis be presented? If you could provide some color on that. Thank you.

Andrew Obenshain: Yeah. First of all, clarification, the GLP-1s drop-ins that were allowed in the trial were not at the MASH dose. They were at a lower dose. There should be no histological impact of the GLP-1 on the GLP-1. I think that in terms of doing a subset analysis, I think that answers the question that we don't anticipate that there should be a histological effect of the GLP-1.

Jason Zhang: Gotcha. Thank you.

Andrew Obenshain: Jason, would you add anything to that?

Jason Campagna: No, I do, Andrew. Andy, a good question. Just referring you back to earlier in the Q&A around the sensitivity analyses and that this 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 III trials, not only outside, like in atopic dermatitis and use of steroids, but also within MASH. So the sensitivity analyses that we will run are completely routine and standard for a phase III program facing those kinds of questions.

Jason Zhang: Gotcha. Thank you.

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

Andrew Obenshain: Yeah, I want to thank everyone for joining today and for the questions. Inventiva is 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. Thank you, everyone, for your interest, and we will see you, I think the next time we talk will be on the data release. Thank you.

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

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