Interim results from the Phase 3 NATiV3 trial indicate that lanifibranor, an investigational oral treatment, is showing signs of improved liver health in patients with metabolic-associated steatohepatitis (MASH). The blinded analysis of pooled data from the placebo-controlled study, which included 664 participants, revealed positive trends in biomarker assessments and liver scarring evaluations after up to 72 weeks.
Promising Early Findings
The NATIV3 study (NCT04849728) is a global trial evaluating lanifibranor in adults with MASH and moderate to advanced liver fibrosis. While it remains unknown whether the observed benefits are from the treatment or placebo groups, these early findings align with final data from the Phase 2b NATIVE trial (NCT03008070), suggesting that lanifibranor is exhibiting its anticipated therapeutic effects, according to Inventiva, the therapy's developer.
Frédéric Cren, chairman, CEO, and co-founder of Inventiva, expressed confidence in the progress of the Phase 3 NATiV3 clinical trial, acknowledging the efforts of key partners and clinical trial sites. The trial has enrolled 837 patients, representing 85% of its target enrollment, across nearly 360 sites in 24 countries. Top-line study results are expected by late 2026.
Lanifibranor's Mechanism of Action
Lanifibranor is an orally available small molecule with antifibrotic, anti-inflammatory, and metabolic properties. It functions by activating three PPAR isoforms (PPAR-alpha, PPAR-delta, and PPAR-gamma), which regulate genes involved in MASH-related processes. MASH, formerly known as nonalcoholic steatohepatitis (NASH), is characterized by the accumulation of fat in the liver, leading to inflammation and fibrosis. The disease is often associated with metabolic syndrome risk factors, including obesity, hypertension, dyslipidemia, and type 2 diabetes.
Prior Clinical Evidence
In the Phase 2b NATIVE study, daily administration of 1,200 mg lanifibranor significantly reduced disease activity without worsening fibrosis in adults with highly active MASH and type 2 diabetes or moderate to advanced liver fibrosis after 24 weeks. Another Phase 2 trial, LEGEND (NCT05232071), evaluated lanifibranor, with or without Boehringer Ingelheim’s Jardiance (empagliflozin), against placebo in MASH patients with poorly controlled type 2 diabetes. Interim data indicated that lanifibranor safely reduced blood sugar levels and improved signs of liver disease.
NATiV3 Trial Design and Objectives
The NATiV3 trial includes two sequential phases: an initial placebo-controlled phase followed by an active treatment extension phase. Enrolled patients were randomized to receive either 800 mg or 1,200 mg of lanifibranor, or a placebo, once daily for 72 weeks. A recent analysis indicated that the study's statistical powering exceeded 95% for both doses, suggesting that differences between lanifibranor and placebo should be detectable.
Clinical characteristics of NATiV3 participants at baseline were consistent with those in the NATIVE trial. Notably, 13% of enrolled patients were on a stable dose of GLP-1 receptor agonists. Inventiva believes that including these patients will provide valuable insights into the potential benefits of combining this class of products with lanifibranor.
The primary endpoint of NATiV3 is to assess the proportion of patients achieving MASH resolution and reduced fibrosis at week 72, based on MASH CRN scores. The blinded analysis of pooled data from the treatment and placebo groups included 545 patients at week 24 and 119 patients at week 72. Results demonstrated improved liver function, reduced fibrosis (assessed via Fibroscan), and lower blood fat and glucose levels.
Weight gain, observed in the NATIVE trial after six months, appeared to plateau and stabilize in NATiV3 after 24 to 36 weeks. If confirmed, this finding would differentiate lanifibranor from pioglitazone, which activates PPAR-gamma alone and has not shown such a plateau effect, according to Inventiva. NATiV3 also includes an exploratory group of MASH patients whose liver biopsy did not confirm fibrosis, which Inventiva believes may provide additional data to support future regulatory submissions.
