Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

Vlad Ratziu, Stephen A. Harrison, Sven Francque, Pierre Bedossa, Philippe Lehert, Lawrence Serfaty, Manuel Romero-Gomez, Jérôme Boursier, Manal Abdelmalek, Steve Caldwell, Joost Drenth, Quentin M. Anstee, Dean Hum, Remy Hanf, Alice Roudot, Sophie Megnien, Bart Staels, Arun Sanyal, P. Mathurin, J. GournayE. Nguyen-Khac, V. De Ledinghen, D. Larrey, A. Tran, M. Bourliere, M. Maynard-Muet, T. Asselah, J. Henrion, F. Nevens, D. Cassiman, A. Geerts, C. Moreno, U. H. Beuers, P. R. Galle, U. Spengler, E. Bugianesi, A. Craxi, M. Angelico, S. Fargion, M. Voiculescu, L. Gheorghe, L. Preotescu, J. Caballeria, R. J. Andrade, J. Crespo, J. L. Callera, A. Ala, G. Aithal, G. Abouda, V. Luketic, M. A. Huang, S. Gordon, P. Pockros, F. Poordad, N. Shores, M. W. Moehlen, K. Bambha, V. Clark, S. Satapathy, S. Parekh, R. K. Reddy, M. Y. Sheikh, G. Szabo, J. Vierling, T. Foster, G. Umpierrez, C. Chang, T. Box, J. Gallegos-Orozco

Research output: Contribution to journalArticle

Abstract

Background & Aims Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis (NASH). Methods Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 weeks at sites in Europe and the United States. Clinical and laboratory evaluations were performed every 2 months during this 1-year period. Liver biopsies were then collected and patients were assessed 3 months later. The primary outcome was resolution of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score. Results In intention-to-treat analysis, there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02-5.24; P =.045), based on a post-hoc analysis for the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 (n = 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22-8.13; P =.018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32-9.40; P =.013). Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolution (mean reduction of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P

Original languageEnglish
Pages (from-to)1147-1159e5
JournalGastroenterology
Volume150
Issue number5
DOIs
Publication statusPublished - May 1 2016

Keywords

  • fatty liver
  • NAFLD
  • PPARA
  • PPARD

ASJC Scopus subject areas

  • Gastroenterology

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    Ratziu, V., Harrison, S. A., Francque, S., Bedossa, P., Lehert, P., Serfaty, L., Romero-Gomez, M., Boursier, J., Abdelmalek, M., Caldwell, S., Drenth, J., Anstee, Q. M., Hum, D., Hanf, R., Roudot, A., Megnien, S., Staels, B., Sanyal, A., Mathurin, P., ... Gallegos-Orozco, J. (2016). Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology, 150(5), 1147-1159e5. https://doi.org/10.1053/j.gastro.2016.01.038