Lanifibranor improves liver health in MASH with diabetes in trial
Results of now-completed LEGEND Phase 2 study presented at SLD Summit
Daily treatment with the investigational oral therapy lanifibranor — used alone or in combination with the diabetes medication Jardiance (empagliflozin) — led to improvements in metabolism and liver health for people with metabolic dysfunction-associated steatohepatitis (MASH), a severe type of fatty liver disease, and type 2 diabetes (T2D).
Developer Inventiva announced that these findings, from the now complete Phase 2 LEGEND clinical trial (NCT05232071), were discussed in an oral presentation at the Steatotic Liver Disease (SLD) Summit 2025. The summit, hosted by the European Association for the Study of the Liver (EASL), was held Jan. 23-25 in Portugal.
“The study met its primary efficacy endpoint, demonstrating a significant reduction in [three-month average blood sugar] levels … compared to [a] placebo,” Inventiva stated in a company press release. “Furthermore, therapeutic efficacy with statistical significance was observed across multiple secondary endpoints.”
The data are consistent with an interim report from last year. That analysis, conducted after half the planned number of participants had finished treatment, showed that the study had already met its main goals, and thus would not need to continue recruiting.
Meanwhile, an ongoing Phase 3 trial called NATIV3 (NCT04849728) is testing lanifibranor against a placebo in an estimated 1,000 MASH patients with advanced liver scarring, or fibrosis. Recruitment is wrapping up, but enrollment remains ongoing at hundreds of sites worldwide, including dozens in the U.S.
NATIV3 data are expected in 2026, with top-line results in 2027. Inventiva has indicated that should the findings be positive, they could support applications seeking accelerated approval of lanifibranor for MASH, with the goal of having it on the market in 2028.
Phase 2 study data also showed improvements in patients’ metabolism
MASH is a severe stage of fatty liver disease in which fat accumulation in the liver — medically known as hepatic steatosis — gives rise to inflammation and fibrosis. Over time, this can lead to serious liver damage and related symptoms.
Cardiometabolic risk factors such as obesity, high blood pressure, elevated fats in the blood, high blood sugar (glucose), or T2D are linked to MASH development and progression. In T2D, blood glucose is elevated because the body doesn’t respond normally to the glucose-regulating hormone insulin.
Lanifibranor is an oral small molecule designed to activate three major PPARs, a group of proteins that regulate genes implicated in MASH-associated processes. Such processes include inflammation, scarring, and metabolic factors.
The treatment candidate was shown in an earlier clinical trial to reduce disease activity for MASH patients. In another study involving people with fatty liver disease and T2D, the therapy led to metabolic improvements and reduced steatosis.
LEGEND, launched in 2022, was designed to evaluate the safety and efficacy of lanifibranor, given alone or in combination with Boehringer Ingelheim’s Jardiance, in MASH patients with poorly controlled T2D. Jardiance works to lower blood sugar in people with diabetes by inhibiting a protein called SGLT2, ultimately promoting the excretion of glucose in the urine.
The trial — initially slated to involve more than 60 participants, but which had its recruitment stopped after the positive interim analysis — enrolled 39 individuals. Each was randomly assigned to receive lanifibranor (800 mg), alone or in combination with Jardiance (10 mg), or a placebo. Treatment was given once daily for about six months.
As previously reported, both lanifibranor and the lanifibranor/Jardiance combination led to significant reductions in HbA1c, meeting the study’s main goal, or endpoint. HbA1c is a measure that reflects a person’s average blood sugar levels over the previous three months.
More than half of the patients in either treatment group achieved an HbA1C of less than 6.5%, whereas no patient in the placebo group achieved this, according to the presentation abstract. In general, an HbA1C of 6.5% or higher means a person meets the criteria for T2D.
Lanifibranor now being tested in global Phase 3 trial
A favorable treatment effect was observed across multiple secondary trial endpoints, including markers of liver injury, inflammation, fibrosis, and metabolic factors. Similar benefits were seen when lanifibranor was used alone or with Jardiance.
Significant reductions in hepatic steatosis and a composite measure of MASH activity and fibrosis were observed in both treatment groups. Spleen and liver volumes, which can increase with worsening liver disease, were also decreased.
There was a small observed average weight gain with lanifibranor alone — a known side effect of PPAR activators — but this did not occur in the combination treatment group.
In contrast to a slight increase with the placebo, both treatments were associated with reductions in the ratio of visceral fat, meaning deep in the organs, to subcutaneous fat, or that seen under the skin. According to the company, this can reflect a shift toward more metabolically healthy fat tissue.
Lanifibranor was well tolerated with no new safety concerns.
In the NATIV3 trial that’s ongoing, participants are randomly assigned to receive one of two daily doses of lanifibranor (800 mg or 1,200 mg) or a placebo for about 1.5 years. This is followed by an extension phase in which all will receive lanifibranor for about another year.
The main goal is to evaluate the proportion of patients who achieve MASH resolution and fibrosis improvement after 1.5 years.
A blinded interim analysis showed that trial participants were experiencing better liver function, reduced fibrosis, and improvements in metabolic factors, although those early findings did not distinguish whether the improvements were specifically seen in those given lanifibranor.
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