By Melane Sampson
Inventiva (Euronext Paris and Nasdaq: IVA) is advancing development of an oral treatment for metabolic dysfunction-associated steatohepatitis (MASH) with its investigational next-generation pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, lanifibranor, designed to simultaneously target the fibrosis, inflammation, and metabolic dysfunction that drives disease progression.
“MASH is a growing international health crisis, affecting millions of people worldwide, and it’s expected to become the leading cause of liver transplants in the U.S. alone,” Andrew Obenshain, CEO of Inventiva, says in an interview with BioTuesdays.
“It is a disease that doesn’t occur in isolation. MASH is closely associated with obesity, Type 2 diabetes, dyslipidaemia, and insulin resistance,” he adds.
Formerly known as NASH (nonalcoholic steatohepatitis), the terminology was updated to MASH in 2023 to better reflect the disease’s metabolic origins.
Mr. Obenshain explains that MASH is increasingly understood as far more than a liver disorder. Rather, it is a systemic cardiometabolic disease in which metabolic dysfunction causes fat to accumulate within the liver, triggering inflammation, fibrosis, and ultimately irreversible liver damage. Left untreated, patients can progress from early fibrosis to cirrhosis, liver failure, hepatocellular carcinoma, and the need for a liver transplant.
“These systemic conditions drive fat accumulation in the liver and perpetuate a cycle of inflammation and cellular injury,” he says. “This is why MASH is increasingly viewed not as a purely hepatic disease, but a manifestation of broader cardiometabolic dysfunction with consequences that extend throughout the body.”
Approximately 30% of adults worldwide are estimated to have some degree of fatty liver disease, with roughly one-quarter of those individuals progressing to MASH. The company estimates that roughly 18 million people in the U.S. fall within the broader MASH disease spectrum, although many remain undiagnosed.
Inventiva’s current development focus is patients with stage F2 or F3 fibrosis, where intervention has the greatest potential to prevent progression toward cirrhosis while patients remain relatively asymptomatic.
“Patients at F2 or F3 often look healthy and feel generally well,” Mr. Obenshain notes. “That’s exactly when physicians want to intervene—before they progress to cirrhosis, where the consequences become more serious.”
He points out that MASH diagnosis is expected to improve with the increasing adoption of non-invasive technologies such as FibroScan—a device that measures liver stiffness, allowing physicians to identify patients with progressive fibrosis before irreversible damage takes place.
For Inventiva, this trend reinforces both the medical need and the commercial potential of lanifibranor. “With greater recognition of MASH as a systemic cardiometabolic disease rather than only a liver disorder, we believe physicians will seek therapies that could address both hepatic fibrosis as well as the underlying metabolic abnormalities driving disease progression—a combination lanifibranor was specifically designed to achieve,” Mr. Obenshain explains.
The company estimates that approximately 375,000 MASH patients in the U.S. with F2 or F3 fibrosis are currently diagnosed and under the care of a physician and expects that number to grow by roughly 10% annually as awareness increases and screening becomes more routine.
Inventiva is focused on addressing the underlying biology responsible for disease progression rather than a single pathway. According to Mr. Obenshain, the company’s founders evaluated decades of research and set out to develop a next-generation molecule designed to improve upon the safety or tolerability concerns associated with earlier PPAR therapies.
The result was lanifibranor. Granted FDA Breakthrough Therapy Designation, lanifibranor is a new chemical entity engineered to deliver balanced activation across all three PPAR isoforms—alpha, delta, and gamma. Unlike earlier compounds that primarily activated a single isoform or dual isoforms, lanifibranor was intentionally designed as a next-generation pan-PPAR agonist to produce coordinated engagement of all three isoforms, aiming to address multiple pathways involved in MASH while avoiding receptor dominance.
“We designed what we believe is the physiologic sweet spot,” Mr. Obenshain contends. “We fully activate alpha and delta, and partially activate gamma. We also use a completely different chemical scaffold than earlier PPAR drugs, so while we interact with the same receptors, this is a fundamentally different molecule—designed to deliver balanced receptor activation at a lower potency while maintaining broad biological activity.”
The design was supported by extensive preclinical testing where the company observed no evidence of the cardiovascular, renal, skeletal, muscular, or carcinogenic toxicities that complicated development of some earlier agents within the class. These findings helped support confidence in advancing next-generation PPAR agonists. “Those findings gave us the confidence to advance into clinical studies evaluating both safety and biological activity,” Mr. Obenshain says.
He emphasizes that the subsequent Phase 1 program suggested the strategy was succeeding. “Investigators observed substantially less fluid retention than had historically been associated with PPAR agonists while also demonstrating improvements across several metabolic markers, reinforcing the rationale for advancing into a pivotal efficacy study.”
A Phase 2b trial ultimately provided the first clinical evidence supporting the company’s approach.
Published in The New England Journal of Medicine, the Phase 2b study evaluated lanifibranor over six months in patients with MASH and demonstrated improvements across multiple clinically meaningful measures. Most notably, patients receiving lanifibranor experienced an 18% greater reduction in fibrosis by at least one stage compared with placebo after just 24 weeks of treatment.
Moreover, in the Phase 2b study, lanifibranor demonstrated a 24% improvement compared with placebo in the proportion of patients achieving the combined endpoint of both fibrosis improvement and MASH resolution, something no previous compound studied in Phase 2 had ever demonstrated. Inventiva believes this endpoint provides a more rigorous assessment of treatment effect because achieving both outcomes simultaneously is less likely to occur simultaneously.
“At the time, people didn’t think you could observe that level of fibrosis improvement so quickly,” Mr. Obenshain says. “Those were really dramatic Phase 2 results.”
Importantly, the benefits extended beyond liver histology. Improvements were also observed across liver enzymes, glycaemic control, lipid parameters, and other cardiometabolic biomarkers, supporting the hypothesis that treating the underlying metabolic dysfunction may generate benefits throughout the body rather than exclusively within the liver.
“All of the markers moved in the same direction,” he says. “We weren’t just seeing changes on biopsy—we were seeing evidence that the patient’s overall liver and metabolic health was improving.”
The company views fibrosis as the primary driver of long-term outcomes in MASH, but Mr. Obenshain argues that physicians must also consider the metabolic conditions responsible for disease progression. Patients with Type 2 diabetes, in particular, tend to develop more aggressive fibrosis and progress more rapidly toward cirrhosis, making effective metabolic control an important component of treatment.
“If you’re treating a patient with F3 fibrosis and Type 2 diabetes, the physician isn’t always thinking only about the liver,” he says. “They’re also thinking about controlling the underlying disease that’s driving the fibrosis.”
That is where Inventiva anticipates lanifibranor may offer a differentiated profile. In addition to reducing fibrosis, the therapy has demonstrated improvements in HbA1c, triglycerides, HDL cholesterol, and adiponectin—markers that collectively reflect healthier metabolic function.
“We think physicians are going to want the strongest agent they can find to improve fibrosis, particularly in patients with F3 disease, while also considering the metabolic comorbidities that influence disease progression, such as Type 2 diabetes,” Mr. Obenshain says. “That’s where we believe lanifibranor can be particularly compelling.”
He adds that the principal adverse events observed to date—including modest weight gain, peripheral oedema, and mild anaemia—appear to reflect fluid retention, a known effect of PPAR gamma activation. According to the company, these events have generally been modest in severity, manageable and consistent with the mechanism of action and expected pharmacological effect of lanifibranor, without revealing unexpected safety signals during clinical development.
Leveraging the encouraging results of the Phase 2b study, lanifibranor is currently being evaluated in a Phase 3 study. “We understand the side-effect profile very well,” he says. “We don’t expect to see new safety findings in Phase 3, and we believe physicians will weigh those manageable effects against the potential efficacy, particularly in patients at highest risk of disease progression.”
Inventiva’s pivotal trial is designed to evaluate whether lanifibranor can deliver meaningful improvements in patients with progressive fibrotic MASH, with a focus on the population most likely to benefit from an intervention before irreversible liver damage occurs.
The global Phase 3 trial is enrolling 1,009 patients across 23 countries, including the U.S., Europe, Latin America, South Africa, Australia, and China. The 72-week study is evaluating two doses of lanifibranor and uses paired liver biopsies to measure changes in fibrosis and MASH resolution.
Unlike earlier studies that evaluated fibrosis improvement or MASH resolution as separate measures, Inventiva selected the composite endpoint for its Phase 3 program that reflects what the company sees as the most clinically meaningful outcome for patients and physicians.
“When you think about how physicians treat these patients, they care about two things: reducing the scarring and improving the underlying disease activity,” Mr. Obenshain says. “For the first time, we were able in our Phase 2b to demonstrate improvement in both MASH resolution and fibrosis improvement in the same patients, and that’s why we selected the dual composite endpoint for Phase 3.”
He adds that the Phase 3 population also reflects lessons learned from earlier development. The study includes a greater proportion of patients with Type 2 diabetes and advanced fibrosis, a group considered to have particularly high unmet need and increased risk of progression.
“We designed Phase 3 around the patients who need are the greatest risk of progression to adverse liver outcomes,” Mr. Obenshain says. “Patients with F3 fibrosis and Type 2 diabetes progress faster, and we believe that is where a potential therapy like lanifibranor could have the greatest impact.”
Topline Phase 3 data are expected in the fourth quarter of 2026. If successful, Inventiva plans to submit a New Drug Application to the FDA in the first half of 2027, with commercialization targeted for 2028.
Beyond the initial F2 and F3 MASH population, the company is already exploring the potential of lanifibranor in patients with more advanced disease. Inventiva plans to initiate an outcomes study in compensated advanced chronic liver disease (cACLD) due to MASH, a population with significant unmet need and limited treatment options.
Unlike the Phase 3 registration trial, which relies on biopsy-based endpoints, the outcomes study is designed to evaluate whether lanifibranor can alter the natural history of the disease by reducing clinically meaningful events such as liver decompensation, transplantation, and death.
“We want to go beyond improving a biopsy result,” Mr. Obenshain says. “The ultimate goal is to show that we can change the course of the disease and prevent patients from progressing to the point where they need a transplant.”
The potential opportunity in advanced liver disease reflects Inventiva’s broader vision for lanifibranor as a potential disease-modifying therapy rather than simply a treatment for a specific stage of fibrosis.
Well-financed by a syndicate of life science investors, Mr. Obenshain says Inventiva has the resources in place to complete its Phase 3 program while enabling the company to sharpen its operational focus.
The company believes that its single-asset focus, strengthened balance sheet, and experienced management team provide a clear path forward as it approaches a critical clinical milestone.
“We are a focused company with one product, a strong management team, and the resources needed to execute,” Mr. Obenshain says. “We have a near-term opportunity to potentially bring an important new therapy to patients.”
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