On Monday, Inventiva (NASDAQ:IVA) discussed quarterly financial results during its earnings call. The full transcript is provided below.
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The full earnings call is available at https://edge.media-server.com/mmc/p/utvoidph/
Summary
Inventiva reported a strong financial position with €233.9 million in cash and equivalents as of June 30, 2026, and completed significant capital structure optimization.
The company is advancing its lead drug, lanafibranor, towards Phase 3 top-line results expected in Q4 2026 for NASH, with potential regulatory filings in 2027.
Lanafibranor is designed to address both metabolic and hepatic drivers of MASH, with promising Phase 2b data showing significant improvements in fibrosis and MASH resolution.
Inventiva aims to be commercially ready for a potential U.S. launch in 2028, with ongoing preparations for regulatory submissions.
The NATIVE3 trial is fully recruited, and the company is confident in the trial design, which includes sensitivity analyses for potential therapeutic drop-ins like GLP-1s and SGLT2 inhibitors.
Full Transcript
OPERATOR (Operator)
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 Nikodem, Head of Investor Relations for Inventiva. Please go ahead.
David Nikodem, Ph.D. — Head of Investor Relations & Special Projects
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 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 Malcomes, 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.
Andrew Obenshain, Chief Executive Officer
Thank you, David, and welcome everyone. Today I'll start by providing an update on the company and our priorities. Jason will overview our lanafibranor 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 lanafibranor toward the Phase 3 top-line results readout in NASH 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 lanafibranor 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 lanafibranor is designed to address both through a single once-daily oral therapy. In our NATIVE Phase 2b study, lanafibranor showed improvement across all key histological endpoints.
Next is validation. We designed the NATIVE3 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 lanafibranor 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 lanafibranor 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 one driver. That is the unmet need we believe lanafibranor 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 NASH.
The differentiated mechanism of lanafibranor, modulating both pathways, is reflected in compelling clinical data in our Phase 2b study. After six months, lanafibranor delivered an 18% placebo-adjusted improvement in fibrosis, 26% MASH resolution, and 24% on the composite endpoint. Those results are the foundation for NATIVE3. We are now testing the same approach in a larger, controlled Phase 3 population of patients with F2 and F3. That is what makes NATIVE3 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. 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. A compelling opportunity for lanafibranor, if approved. Turning to Slide 9 to see where lanafibranor 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 NASH and cardiometabolic risk, such as type 2 diabetes. This is a population with high unmet medical need where the mechanism of action of lanafibranor can be compelling in that it targets both the liver and the metabolic driver simultaneously. In our Phase 2b trial, lanafibranor 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 lanafibranor could potentially offer an opportunity to intervene earlier in the course of the disease, if approved. Moving to the top-right quadrant. By extension, lanafibranor could be well positioned in patients with F3 fibrosis without significant cardiometabolic risk.
Here, that fibrosis itself is the primary concern and lanafibranor may have the potential to address the underlying liver disease before progressing. Taken together, these three quadrants represent a large population with significant unmet need and, if approved, we believe lanafibranor 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 lanafibranor, let me lay out three key priorities we are focused on to unlock new opportunities for patients with MASH.
First, the NATIVE3 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 NASH 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 best-in-class products to be ready for the potential launch in 2028. We believe we are moving forward with lanafibranor from a position of strength and with the potential for a differentiated profile, a late-stage validation opportunity with NATIVE3, 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 lanafibranor and our clinical program.
Jason Campagna (Chief Medical Officer and President of R&D)
Jason, thank you Andrew, and greetings everyone. I'll 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've observed in the positive NATIVE Phase IIb 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 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 antifibrotic 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 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. The result is a once-daily oral therapy intended to deliver a physiologic balance between achieving pan-PPAR activation while avoiding any one 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 three histologic endpoints, showing that the drug worked equally well in both early and later-stage disease—and 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 2b clinical trial.
Lanifibranor was generally well tolerated across the totality of our Phase II 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. 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 NATIVE 3. This is a Phase 3 global registrational trial, and it was deliberately designed to build on our Phase 2b: the same two doses, a similar patient population, and a primary composite endpoint of NASH 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 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 pause on, because everything I've described targets the core pathophysiology of MASH, but 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 NASH 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. These are exploratory analyses, but they add to our conviction to pursue further advanced disease states in MASH. With that, I'll hand it over to Axel.
David Nikodem, Ph.D. — Head of Investor Relations & Special Projects
And I will pick up for Axel here.
Axel Sven Malcomes (Chief Financial Officer)
Yeah, I'm sorry, I lost my text. Please go ahead.
David Nikodem, Ph.D. — Head of Investor Relations & Special Projects
Yep. 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? Okay. As of June 30, 2026, we had 233.9 million euros 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, 2026 press release.
Axel Sven Malcomes (Chief Financial Officer)
I'm ready to take over.
David Nikodem, Ph.D. — Head of Investor Relations & Special Projects
Please go ahead.
Axel Sven Malcomes (Chief Financial Officer)
As part of this optimization, we secured new debt financing of up to 130 million euros in three committed tranches, subject to conditions, with an initial drawdown of two 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 Depositary Shares, generating gross proceeds of 103 million euros.
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 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, our cash runway would extend to the start of the first quarter of 2028.
R&D expenses were 46.2 million euros in the first half of 2026, brought in line with the prior year and reflecting continued clinical development of lanifibranor in MASH. Marketing and business development expenses increased to 2.6 million euros, and G&A expenses increased to 22.2 million euros. 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, Chief Executive Officer
Thank you, Axel. This is truly an exciting time for Inventiva. Our differentiated results we saw in the NATIVE Phase IIb trial and the robust design of our NATIVE 3 Phase 3 trial provide a strong foundation as we approach the milestones ahead. The next major milestone is our NATIVE 3 top-line results readout expected in the fourth quarter of this year. If 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 are 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 NASH 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 (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 re-enter the queue. We'll now move to our first question, and our first question comes from the line of Yasmin Rahimi from Piper Sandler.
Please go ahead. Your line is open.
Yasmin Rahimi, Analyst at Piper Sandler
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 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 one other one that sometimes comes up is that the higher dose had a phenomenal histological benefit, but then when we compared the NITs the two 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 a few of the investors that have been asking us that.
Andrew Obenshain, Chief Executive Officer
Thank you, Yasmin, and good morning. So two questions in there. First one I think more of a commercial question which I'll take and then I'll pass it on for the correlation with histology and dose to Jason in a second. But first, if you know, 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 there could be scenarios in which the difference between the two makes sense to bring both to market — potentially one for F2 patients, or one you could think of earlier-stage patients that are less urgent and so therefore would be okay with, if there's a dose response, lower efficacy and more tolerable. And if another one, if there's 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 of NITs.
Jason Campagna (Chief Medical Officer and President of R&D)
Sure. Happy to, Yasmin, 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 evident — this reflects hepatocellular injury. But 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 the collagen peptide — and the Pro-C3 marker actually tracked quite nicely with the 1200 mg 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 laying down, resorbing some existing scar. And lastly on the TE, the range — it's very difficult to compare trials, Yasmin, 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 kPa placebo-adjusted change all the way up to like 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 that's one, 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 Echosens manuals, about being cautious about getting liver stiffness data after a meal or in the presence of fluid loading.
And at six 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-adjusted 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.
Yasmin Rahimi, Analyst at Piper Sandler
Thank you so much.
OPERATOR (Operator)
Thank you. We'll now move on to our next question. And our next question comes from the line of Seamus Fernandez from Guggenheim Securities. Please go ahead, your line is open.
Seamus Fernandez, Analyst at Guggenheim Securities
Oh great. Thanks for the question. So 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 NATIVE 3 study, and 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 but by gross change very consistent with what you 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 NATIVE 3 study. Thanks so much.
Andrew Obenshain, Chief Executive Officer
So a couple elements of 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 3 trial on weight gain? And then I could take it from there. Jason, go ahead.
Jason Campagna (Chief Medical Officer and President of R&D)
Yeah, sure. So Seamus, good morning. So we previously disclosed back when the structured financing back in 2024, some data on our Phase 2 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. And in that trial we showed that the weight gain was similar up to six months to what we saw in the NATIVE Phase 2b trial and thereafter — where NATIVE 2b stopped at six months — and 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 NATIVE 3 in any manner. And 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. And that, Seamus, you're really getting at what's the potential impact of things like weight gain and edema. I think that that's the right question. And when you look in the NATIVE trial, about half of all patients in that trial had no weight gain defined as anything beyond or -5%.
So 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's 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 approximately 30 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, 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, Chief Executive Officer
Well, I don't think I can say it better than you, Jason. That was perfect. So I think we can move on to the next question.
OPERATOR (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, Analyst at TD Cowen
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 NASH patients and that risk-benefit around sort of extremitous edema versus any potential issue of fluid load?
Andrew Obenshain, Chief Executive Officer
So I'll start out, then I'll hand it to Jason as well. So a very similar answer to before — the edema is mechanistically understood, is consistent with known PPAR gamma pharmacology, and that makes physicians who, especially those who use pioglitazone in the market, very comfortable with managing those types of effects. And we are looking for, in the larger NATIVE 3 data set, to provide a more comprehensive safety characterization overall. But in general, physicians know that they can mitigate the effects linked to fluid retention, weight, hemoglobin by addition of an SGLT2 if they want to manage it.
So we do view this as a profile that is very commercially attractive. Jason, do you have anything to add to that?
Jason Campagna (Chief Medical Officer and President of R&D)
I do, just briefly. I think so. 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 2 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 and a similar MASH population — you're somewhere in the mid-20s, 20 to 25% edema range.
So that's a prevalence. In terms of the severity, which I think, Ritu, was where your question was headed, generally these events are considered mild to moderate. And going back to the NATIVE 2b clinical trial, these were not primary drivers of patients discontinuing treatment. So 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. And most importantly, the difference between a pure PPAR gamma 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 than you would see with a full TZD-class agonist.
Ritu Baral, Analyst at TD Cowen
Would you expect it to be transient?
Jason Campagna (Chief Medical Officer and President of R&D)
I'm sorry, Ritu, do I expect it to be?
Ritu Baral, Analyst at TD Cowen
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 (Chief Medical Officer and President of R&D)
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, so to the extent that patients may or may not have been already on a pre-existing agent like SGLT2s or thiazide diuretics, that may impact it. And also mild changes in diet or in 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.
And maybe I'll make the simple point: pioglitazone is a generic therapeutic at this point. It's still used in about 4 million scripts a year in the United States, 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, Analyst at TD Cowen
Understood. Thank you.
OPERATOR (Operator)
Thank you. We'll now move on to our next question. And the next question comes from Thomas Smith from Leerink Partners. Please go ahead. Your line is open.
Thomas Smith, Analyst at Leerink Partners
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's 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 native 3 on a blinded basis.
And then just a bit on your market research, you highlighted the 374,000 F2–F3 patients diagnosed under the care of a specialist. That's a bit lower than the 460,000 we've heard from a competitor. I was just wondering if you could talk a little bit about the differences there, and how you're thinking about patient targeting relative to Rezdifra. Thanks so much.
Andrew Obenshain, Chief Executive Officer
Yeah, thanks for the question, Thomas. So let me handle the first two, then hand it over to Jason on the active treatment role. We're not commenting on that yet. We haven't publicly disclosed that information on the patient population. Yes, there's some range of estimates out there. The 374,000 is certainly on the low end of that. We haven't updated that number, but certainly I think the real message here is that it's 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 (Chief Medical Officer and President of R&D)
Yeah, Thomas, good morning. Good question. There's no formal management algorithm or treatment algorithm in the native 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, Analyst at Leerink Partners
Understood. Super helpful. Thanks, guys. Looking forward to the data.
OPERATOR (Operator)
Thank you. We'll now move on to our next question. And our next question comes from the line of Michael Yee from UBS. Please go ahead. Your line is open.
Kyle Yen, Analyst at UBS
Hey, guys. Good morning. This is Kyle Yen for Michael Yee. Just two for us. The first one is on the F2–F3 migration. So we did notice that native 3 enrolled a meaningfully higher proportion of F3 patients relative to native 2. So 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. So you previously disclosed roughly 10% GLP-1 dropping rate during this study. How do you think that could potentially impact the outcomes on both the drug arms and placebo?
Thank you.
Andrew Obenshain, Chief Executive Officer
Yeah, absolutely. So let me just set the stage. I'm going to hand it over to Jason to answer this. So in the F2, F3, the mix was indeed different in the phase 3. We enrolled more patients in the US in the phase 3 than we did in the phase 2, and the patient population just looks a little bit different in the US. There's more diabetes, and diabetes and F3 track together, so therefore we had slightly more diabetic patients and slightly more F3 patients in the study.
We have looked at our phase 2 and actually removed the F1 patients from our phase 2. We saw a slightly better response rate in the F2 and F3 combined than we saw when it was combined with the F1, which gives us confidence that a drop in the F1s from the study will not impact the patient population. And I'll have Jason comment in a second just on the split between F2 and F3. On the 10%—9%—drop-ins on GLP-1s, we do not anticipate that to impact the trial, as they drop in at a lower dose.
Jason, over to you.
Jason Campagna (Chief Medical Officer and President of R&D)
Yeah, thank you, Andrew. So just adding on to Andrew's response there on F2–F3, I agree. We don't have any expectation that the larger prevalence of F3 patients should impact the primary efficacy readout. I think three additional reasons: one, there's nothing in the sort of biology of F2 or F3 disease that's different from each other; it's just a more advanced version of the exact same biology. I think, second, that lanifibranor has direct antifibrotic actions to hepatic stellate cells in the liver.
That direct action, meaning it doesn't depend on extrahepatic elements in order to achieve fibrosis—things like weight loss or glucose metabolism—they're 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 into that. So we're pretty comfortable with that 18-month duration for native 3.
And lastly, the FGF21 analogs like efruxifermin have shown similar efficacy in F2 and F3, and I highlight them because those drugs, although very different mechanism of action, actually have similar impact on both intra- and extrahepatic drivers to some degree. So although not a complete overlap with pan PPAR agonist, there are some elements that do, and I think that's support for the fact that, by getting both direct action in the liver and modulating some extrahepatic drivers of disease, this difference between F2 and F3 is unlikely to be a concern.
OPERATOR (Operator)
Thank you. We'll now move on to our next question. And our next question comes from the line of Annabel Samimy from Stifel. Please go ahead. Your line is open.
Annabel Samimy, Analyst at Stifel
Hi, thanks for taking my questions. I guess one question: with the patients on the GLP-1s and SGLT2s, are there any prespecified analyses of these patients? And 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? And I guess you touched on this before, but how you might account for any changes in the background mid-trial, and 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, Chief Executive Officer
So on the—thank you, Annabel, for the question. On the second, it's a little bit too early to comment on any sort of guidance to physicians post data, but let me go for the first part. Jason, let me hand it to you.
Jason Campagna (Chief Medical Officer and President of R&D)
Sure. So there are several questions there. Let's go through it. Yes, there are sensitivity analyses that we have prespecified in the SAP to allow us to look at the impact, if any—again, as Andrew said, we don't expect any, but the analyses are there—on the use of these non-match 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 mentioned before, the powering detail there.
The third—I think the important point I think we want to convey here—is that there's nothing unusual or different that we are doing in this phase 3 trial than any other sponsor in any other phase 3 trial would do to account for therapeutic drop-ins. You know, 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 answer. 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, Analyst at Stifel
Okay, great, that's helpful. And 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, Chief Executive Officer
Axel, go ahead.
Axel Sven Malcomes (Chief Financial Officer)
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 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 three 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, you know, the data readout now in Q4. Two, we can fund it until the NDA filing. On top of that, we do not guide on any, you know, future raises. But with what we currently have, we believe we have strengthened the balance sheet, simplified the cap structure, lengthened, you know, prolonged the debt maturity, and with that, we are basically solidly financed prior to the data release.
Annabel Samimy, Analyst at Stifel
Okay, thank you.
OPERATOR (Operator)
Thank you. We'll now move on to our next question. And our next question comes from the line of Prakar Agrawal from Cantor. Please go ahead. Your line is open.
Prakar Agrawal, Analyst at Cantor Fitzgerald
Hi. Thank you so much for taking my questions and congratulations on all the progress. So 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 3 MASH trials? And a couple on weight gain—maybe mechanistically, why does the weight gain plateau for lanifibranor and not for PPAR gamma/pioglitazone? And if I remember correctly, the company had previously shared interim weight gain data from the ongoing phase 3 a couple of years back—realize it was interim, but was a decent enough sample size—so why shouldn't we use that as a reference for understanding what the weight gain profile could look like in the final analysis in the phase 3? Thank you so much for taking my questions.
Andrew Obenshain, Chief Executive Officer
Yeah, so thank you for the questions, Prakar. So let me actually address the—you asked about a biopsy completion rate. What we've guided on publicly is a dropout rate for the trial overall. So we powered the trial such that we could tolerate up to a 30% dropout rate. In the trial we guided in, I believe it was April 2005—April/May 2005—that dropout rate was below 30%, and we confirmed that that dropout rate is comfortably below 30% at that time. We're not giving more guidance beyond that. Regarding the weight gain, you had a question about the plateau and the difference with pioglitazone, and then I missed the second part, but I'm hoping Jason picked it up to be able to talk about both those points. Jason, go ahead.
Jason Campagna (Chief Medical Officer and President of R&D)
Yeah, I agree. Prakar, we'll come back to the reference—I missed that. But on the question of plateau, our view is that it's a combination of the partial gamma component of lanifibranor—so not a full agonist—and that has important consequences for long-term activation of that sodium channel. And second, and more importantly, the pan-PPAR agonism 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, and that utilization actually prevents that sugar from being stored. You get a sort of metabolic pop from that alpha/delta which helps to keep the scale weight plateauing over time. Again, Prakar, if you could just get to the last question—the reference part of it—I missed it.
Prakar Agrawal, Analyst at Cantor Fitzgerald
So if I remember correctly, a couple of years back, the company had previously shared blinded interim weight gain data on a pooled basis from the ongoing phase three. It was interim, but I thought it was a very large sample size. Why shouldn't 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 three? Thank you so much.
Jason Campagna (Chief Medical Officer and President of R&D)
Sure. So you are correct, Prakar, that several years ago something like that was done. I think, just correcting language, it was no interim read of anything. It was an early look at approximately 100 blinded patients that had achieved week 72. To the extent that anyone on the outside world took comfort or not in that, I think those days are in the past. You ask why don't we do that again? It's our view that utilizing blinded data from a 1,000-plus patient clinical trial is fraught with error of interpretation, and it's not something that we think would be helpful.
It's more importantly not something that we are guiding on, regardless.
Prakar Agrawal, Analyst at Cantor Fitzgerald
Got it. Thanks for clarifying.
OPERATOR (Operator)
Thank you. We'll 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, Analyst at Truist Securities
Guys, thank you so much for taking my question, and congratulations on all the progress done this year. I have a question on fibrosis expectations. How much importance should we place on not hitting the statsig endpoint but on the magnitude of fibrosis improvement independent of the MASH resolution? You talked earlier about Lani's antifibrotic effect. What level of response would convince you that this is a meaningful antifibrotic effect rather than improving the metabolic inflammatory component of the disease?
Jason Campagna (Chief Medical Officer and President of R&D)
Thank you. So, Kripa, let me— I think I understand the question. We believe 18% improvement is meaningful in fibrosis, basically duplicating our phase two in the phase three with that profile, with an 18% improvement of one stage or more in fibrosis. That's 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 of an 18% fibrosis effect would be— this would be a differentiated product for those patients.
Kripa Devarakonda, Analyst at Truist Securities
Thank you.
OPERATOR (Operator)
Thank you. We'll move on to our next question. Our next question comes from the line of Rami Catheda from Maisai Capital. Please go ahead. The line is open.
Rami Catheda
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? And then secondly, I know it's a bit early, but how are you thinking about the design of the confirmatory outcomes trial? And are there any key learnings from ongoing studies that could help inform patients who—
Andrew Obenshain, Chief Executive Officer
Yeah, thanks, Rami. Two questions there. Just on the time course—I'm going to be 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, what we're thinking there.
Jason Campagna (Chief Medical Officer and President of R&D)
Yeah, I'm happy to. Look, we're looking forward to talking more about the confirmatory study after topline, but for now what we're trying to communicate is, one, that it 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 noninvasive 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 is the goal. Second, you asked what evidence we might 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. And lastly, we have completed nearly a dozen phase 1 clinical trials with lanifibranor over the years, including a dedicated hepatic impairment study in patients with Child-Pugh A, B, and C. 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.
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.
Rami Catheda
Awesome. Thank you, guys.
OPERATOR (Operator)
Thank you. We'll move on to our next question. Our next question comes from the line of Susheela Hernandez from Van Lanschot Kempen. Please go ahead. Your line is open.
Zoe, Analyst at Van Lanschot Kempen
Hi, this is Zoe on for Sushila. Thank you so much for taking our questions. With the phase three NATiV3 topline readout in MASH expected in the next quarter, we were wondering what kind of data we can expect at the topline. Will there be data on the treatment response in patients on GLP-1 and on SGLT inhibitor, or on the weight gain? And then, if I could just ask another question, we were also wondering how you expect the placebo response to evolve with the longer treatment duration.
Thank you.
Andrew Obenshain, Chief Executive Officer
So thank you, Zoe, for the question. We are not guiding on the topline data right now. As you can tell on this call, we're very well aware of the interest— which endpoint and tolerability profile 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 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 fibrosis and all the clinical endpoints of MASH. Therefore, that was why that placebo rate was chosen. 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 the placebo rate.
Zoe, Analyst at Van Lanschot Kempen
Yeah. Okay. Thank you so much.
OPERATOR (Operator)
We will now go to our last question. That question comes from the line of Andy Chen from Wolfe Research. Please go ahead. Your line is open.
Jason, Analyst at Wolfe Research
Hi, thank you so much. This is Jason taking it for Andy. 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? And how would that sensitivity analysis be presented? If you could provide some color on that. Thank you.
Jason Campagna (Chief Medical Officer and President of R&D)
Yes. First of all, clarification: the GLP-1 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 to the GLP-1. 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. No, I do— Andrew, just— Andy, good question. Just referring you back to earlier in the Q&A around the sensitivity analyses and this 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 three trials, not only outside, like any topic and the use of steroids, but also within maximum. So the sensitivity analyses that we'll run are completely routine and standard for a phase three program facing those kinds of questions.
Jason, Analyst at Wolfe Research
Gotcha. Thank you.
OPERATOR (Operator)
Thank you. There are no further questions at this time. I will hand the call back to Andrew for closing remarks.
Andrew Obenshain, Chief Executive Officer
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 topline 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. I think the next time we talk will be on the date of release. Thank you.
OPERATOR (Operator)
This concludes today's conference call. Thank you for participating. You may now disconnect.
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