Inventiva's investigational oral therapy lanifibranor has demonstrated significant improvements in both liver health and metabolic parameters when administered either as a monotherapy or in combination with Jardiance (empagliflozin) in patients with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes, according to new Phase 2 trial data.
The findings from the LEGEND clinical trial (NCT05232071) were presented at the European Association for the Study of the Liver's (EASL) Steatotic Liver Disease Summit 2025 in Portugal, marking a significant advancement in MASH treatment development.
Key Trial Findings and Metabolic Improvements
The LEGEND trial met its primary efficacy endpoint with both lanifibranor monotherapy and the lanifibranor-Jardiance combination showing significant reductions in HbA1c levels compared to placebo. Notably, more than half of the treated patients achieved an HbA1c below 6.5% - a crucial threshold in diabetes management - while no placebo group patients reached this target.
The trial enrolled 39 participants, who received either lanifibranor (800 mg), a combination of lanifibranor with Jardiance (10 mg), or placebo daily for approximately six months. These results confirmed earlier positive interim findings that had led to early trial completion.
Liver Health and Safety Outcomes
Multiple secondary endpoints demonstrated favorable outcomes, including improvements in:
- Markers of liver injury and inflammation
- Fibrosis indicators
- Hepatic steatosis
- Composite measures of MASH activity
The treatment showed an interesting effect on body composition, with the combination therapy avoiding the weight gain typically associated with PPAR activators. Both treatment arms demonstrated reduced ratios of visceral to subcutaneous fat, suggesting improved metabolic health. The therapy maintained a favorable safety profile with no new concerns identified.
Mechanism of Action and Disease Context
Lanifibranor functions as an oral small molecule activating three major PPARs (peroxisome proliferator-activated receptors), targeting multiple disease processes including inflammation, scarring, and metabolic dysfunction. This comprehensive approach is particularly relevant for MASH, a severe form of fatty liver disease characterized by hepatic fat accumulation, inflammation, and fibrosis.
The condition is closely linked to cardiometabolic risk factors, including obesity, hypertension, and type 2 diabetes, making treatments that address both liver health and metabolic parameters particularly valuable.
Future Development and Market Potential
The positive LEGEND results support the ongoing Phase 3 NATIV3 trial (NCT04849728), which is evaluating lanifibranor in approximately 1,000 MASH patients with advanced liver fibrosis. This larger study, expected to report data in 2026 with top-line results in 2027, could support accelerated approval applications.
The NATIV3 trial is assessing two daily doses of lanifibranor (800 mg and 1,200 mg) against placebo over an 18-month period, followed by an extension phase. The primary endpoint focuses on MASH resolution and fibrosis improvement, with potential market availability targeted for 2028 if results prove positive.
These developments represent a significant step forward in addressing the unmet medical needs of patients with both MASH and type 2 diabetes, a growing population currently lacking approved therapeutic options.
