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A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH
Sven M Francque1, Pierre Bedossa1, Vlad Ratziu1
1From Antwerp University Hospital and the Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp (S.M.F., L.V.), and Service d'Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (N.L.) and Cliniques Universitaires de Bruxelles-Hôpital Erasme, Université Libre de Bruxelles (C.M.), Brussels - all in Belgium; the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom (P. Bedossa, Q.M.A.); Pitie-Salpétriêre Hospital, Institute of Cardiometabolism and Nutrition, Sorbonne Université, Paris (V.R.), Centre Hospitalier Universitaire Rangueil, Toulouse (M.G.), and Inventiva Pharma, Daix (P.H.-M., M.B., M.-P.R., J.-L.A., P. Broqua, J.-L.J.) - all in France; the Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy (E.B.); Virginia Commonwealth University, Richmond (A.J.S.); the University of California San Diego, La Jolla (R.L.); Pinnacle Clinical Research, San Antonio, TX (S.A.H.); Acibadem City Clinic Tokuda Hospital (R.B.), University Hospital "St. Ivan Rilski," Medical University-Sofia (L.M.), and Diagnostic Consultation Center Alexandrovska (D.S.-P.) - all in Sofia, Bulgaria; Arizona Liver Health, Phoenix (N.A.); Metabolic Liver Research Program, Department of Medicine, University Medical Center, Mainz, Germany (J.M.S.); Cap Research, Quatre Bornes, Mauritius (R.R.); Monash Medical Centre, Clayton, VIC, Australia (A.H.); Virgen del Rocío University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville, Spain (M.R.-G.); and Duke University Medical Center, Durham, NC (M.F.A.).
Background:
Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH.
Methods:
In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis.
Results:
A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo.
Conclusions:
In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.).
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