title: Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening.
abstract: 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).
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Université Pierre et Marie Curie, Hôpital Pitié Salpêtrière, Paris, France; Institute of Cardiometabolism and Nutrition, INSERM, UMRS 938, Paris, France. Electronic address: vlad.ratziu@upmc.fr.
authors.forename: Vlad
authors.initials: V
authors.lastname: Ratziu
authors.affiliation: Department of Medicine, Gastroenterology and Hepatology Service, Brooke Army Medical Center, Fort Sam Houston, Texas.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Harrison
authors.affiliation: Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Francque
authors.affiliation: Department of Pathology, Hôpital Beaujon, University Paris-Denis Diderot, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.affiliation: Department of Psychiatry, the University of Melbourne, Melbourne, Australia; Faculty of Economics, University of Louvain UCL, Belgique, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lehert
authors.affiliation: Université Pierre et Marie Curie, Hôpital Saint-Antoine, Paris, France.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Serfaty
authors.affiliation: Unit for the Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Sevilla.
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gomez
authors.affiliation: Hepatology Department, University Hospital and LUNAM University, Angers, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Boursier
authors.affiliation: Duke University, Durham, North Carolina.
authors.forename: Manal
authors.initials: M
authors.lastname: Abdelmalek
authors.affiliation: Gastroenterology and Hepatology Division, University of Virginia, Charlottesville, Virginia.
authors.forename: Steve
authors.initials: S
authors.lastname: Caldwell
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Drenth
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Dean
authors.initials: D
authors.lastname: Hum
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Remy
authors.initials: R
authors.lastname: Hanf
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Roudot
authors.affiliation: Genfit SA, Loos, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Megnien
authors.affiliation: University of Lille, INSERM UMR1011, Institut Pasteur de Lille, European Genomic Institute for Diabetes, Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Arun
authors.initials: A
authors.lastname: Sanyal
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D047188:Chalcones / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D057194:Intention to Treat Analysis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016017:Odds Ratio; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011422:Propionates / Q000008:administration & dosage* / Q000009:adverse effects; D012074:Remission Induction; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: C585906:2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid; D015415:Biomarkers; D047188:Chalcones; D005765:Gastrointestinal Agents; D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates
keywords: NAFLD; PPARA; PPARD; fatty liver