The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis

Michael Cooreman (1, 2) , Javed Butler (3) , Robert Giugliano (4, 5) , Faiez Zannad (6, 7, 8, 9) , Lucile Dzen (1, 2) , Philippe Huot-Marchand (1, 2) , Martine Baudin (1, 2) , Daniel Beard (10) , Jean-Louis Junien (1, 2) , Pierre Broqua (1, 2) , Manal Abdelmalek (11) , Sven Francque (12, 13)

1 Research and Development, Inventiva, New York
2 Inventiva [Daix]
3 BSWRI - Baylor Scott & White Research Institute
4 HMS - Harvard Medical School [Boston]
5 Brigham and Women's Hospital [Boston]
6 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
7 CIC-P - Centre d'investigation clinique plurithématique Pierre Drouin [Nancy]
8 INI-CRCT - Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy]
9 Cardiovascular & Renal Clinical Trialists - CRCT - French-Clinical Research Infrastructure Network - F-CRIN [Paris]
10 Translational Medicine Academy
11 Mayo Clinic [Rochester]
12 UZA - Antwerp University Hospital [Edegem]
13 UA - University of Antwerp

Abstract Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits.

Domaines: Sciences du Vivant [q-bio]

Michael Cooreman, Javed Butler, Robert Giugliano, Faiez Zannad, Lucile Dzen, et al.. The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis. Nature Communications, 2024, 15 (1), pp.3962. ⟨10.1038/s41467-024-47919-9⟩. ⟨hal-04577955⟩