• Sven M Francque, Pierre Bedossa, Vlad Ratziu, Quentin M Anstee, Elisabetta Bugianesi, Arun J Sanyal, Rohit Loomba, Stephen A Harrison, Rozalina Balabanska, Lyudmila Mateva, Nicolas Lanthier, Naim Alkhouri, Christophe Moreno, Jörn M Schattenberg, Diana Stefanova-Petrova, Luisa Vonghia, Régine Rouzier, Maeva Guillaume, Alexander Hodge, Manuel Romero-Gómez, Philippe Huot-Marchand, Martine Baudin, Marie-Paule Richard, Jean-Louis Abitbol, Pierre Broqua, Jean-Louis Junien, Manal F Abdelmalek, and NATIVE Study Group.
• From 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.).
• N. Engl. J. Med. 2021 Oct 21; 385 (17): 1547-1558.

BackgroundManagement 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.MethodsIn 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.ResultsA 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.ConclusionsIn 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.).Copyright © 2021 Massachusetts Medical Society.

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