@article{768600ae275445038093cff0071544d8,
title = "Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening",
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 <.001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group. Elafibranor was well tolerated and did not cause weight gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31 ± 1.19 μmol/L; P <.001). Conclusions A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov number: NCT01694849.",
keywords = "NAFLD, PPARA, PPARD, fatty liver",
author = "Vlad Ratziu and Harrison, {Stephen A.} and Sven Francque and Pierre Bedossa and Philippe Lehert and Lawrence Serfaty and Manuel Romero-Gomez and J{\'e}r{\^o}me Boursier and Manal Abdelmalek and Steve Caldwell and Joost Drenth and Anstee, {Quentin M.} and Dean Hum and Remy Hanf and Alice Roudot and Sophie Megnien and Bart Staels and Arun Sanyal and P. Mathurin and J. Gournay and E. Nguyen-Khac and {De Ledinghen}, V. and D. Larrey and A. Tran and M. Bourliere and M. Maynard-Muet and T. Asselah and J. Henrion and F. Nevens and D. Cassiman and A. Geerts and C. Moreno and Beuers, {U. H.} and Galle, {P. R.} and U. Spengler and E. Bugianesi and A. Craxi and M. Angelico and S. Fargion and M. Voiculescu and L. Gheorghe and L. Preotescu and J. Caballeria and Andrade, {R. J.} and J. Crespo and Callera, {J. L.} and A. Ala and G. Aithal and G. Abouda and V. Luketic and Huang, {M. A.} and S. Gordon and P. Pockros and F. Poordad and N. Shores and Moehlen, {M. W.} and K. Bambha and V. Clark and S. Satapathy and S. Parekh and Reddy, {R. K.} and Sheikh, {M. Y.} and G. Szabo and J. Vierling and T. Foster and G. Umpierrez and C. Chang and T. Box and J. Gallegos-Orozco",
note = "Funding Information: Conflicts of interest These authors disclose the following: VR reports consulting fees from Abbott, Astra-Zeneca, Boehringer-Ingelheim, Galmed, Genfit, Nimbus, Ionis, Pfizer Novartis, Roche-Genentech, Intercept, Sanofi Aventis-Genzyme, Takeda, Tobira, and research support from the European Community's Seventh Framework Programme ( FP7/2007-2013 ) under grant agreement number HEALTH-F2-2009-241762 for the project FLIP. SH reports consulting fees from AbbVie, Astra Zeneca, Galectin, Genfit, Nitto Denko, Nimbus, Salix, Tobira. SF reports consulting and speaker fees from MSD, Roche, Gilead, BMS, Astellas, Synageva, Genfit, Actelion, Fresenius, Abbvie. PL reports consulting fees from Genfit. LS has served on consulting, advisory committees or review panels for Abbvie, Janssen, Merck Sharp & Dohme (MSD), Roche, Bristol-Meyers Squibb (BMS), Gilead, Intercept, GlaxoSmithKline (GSK), Pfizer and Novartis and has received grant/research support from Roche and MSD and provided speaking and teaching for Roche, Abbvie, MSD, Gilead, BMS, Janssen and Aptalis. MRG reports consulting fees from Merck, Roche, Gilead, Abbvie, Janssen, BMS, Idenix, Ocera, Umecrine and research support from Merck , Roche , Gilead ; MA received consulting fees from Taiwan J Pharmaceuticals, Islet Sciences and research/grant funding from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases , Gilead Sciences , Taiwan J Pharma , Tobira , Immuron , Galmed , Arisaph Pharma , Intercept Pharma , Galactin , BMS , NGM , Synageva , Metabolon , and Genfit . SC reports consulting fees from Vital Therapy, Welstat, and research support from Gilead , Genfit , NGM , Taiwan J , Galmed , Immuron , Hyperion , Salix . JD reports consulting fees from BMS, Gilead, Janssen, and Merck and research grants from Abbvie and Janssen , all fees directed toward the Radboudumc Foundation. QA reports consulting fees for consultancy on behalf of Newcastle University from Genfit, Acuitas Medical, Intercept, Raptor Pharma, NewGene, and speaker fees from Abbott and Falk and research funding from GSK and Vertex . DH, RH, AR, SM are employees of Genfit SA. BS is a consultant of Genfit. AS has stock options in Genfit. He has served as a consultant to AbbVie, Astra Zeneca, Nitto Denko, Nimbus, Salix, Tobira, Takeda, Fibrogen, Immuron, Exalenz, and Genfit. He has been an unpaid consultant to Intercept and Echosens. His institution has received grant support from Gilead , Salix , Tobira , and Novartis . The remaining authors disclose no conflicts. Publisher Copyright: {\textcopyright} 2016 AGA Institute.",
year = "2016",
month = may,
day = "1",
doi = "10.1053/j.gastro.2016.01.038",
language = "English (US)",
volume = "150",
pages = "1147--1159.e5",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "5",
}