Titre :

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

Auteur(s) :

Ratziu, Vlad [Auteur]
CHU Pitié-Salpêtrière [AP-HP]
Harrison, Stephen [Auteur]
Francque, Sven [Auteur]
Antwerp University Hospital [Edegem] [UZA]
Bedossa, Pierre [Auteur]
CHU Tenon [AP-HP]
Lehert, Philippe [Auteur]
Serfaty, Lawrence [Auteur]
CHU Saint-Antoine [AP-HP]
Romero-Gomez, Manuel [Auteur]
Boursier, Jérôme [Auteur]
Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques [HIFIH]
Abdelmalek, Manal [Auteur]
Caldwell, Steve [Auteur]
Drenth, Joost [Auteur]
Radboud University Medical Center [Nijmegen]
Anstee, Quentin [Auteur]
Newcastle University [Newcastle]
Hum, Dean [Auteur]
Hanf, Remy [Auteur]
Roudot, Alice [Auteur]
Megnien, Sophie [Auteur]
Staels, Bart [Auteur]
Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 [EGID]
Université de Lille
Institut National de la Santé et de la Recherche Médicale [INSERM]
Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Sanyal, Arun [Auteur]
Virginia Commonwealth University [VCU]

Titre de la revue :

Gastroenterology

Pagination :

1147-1159.e5

Éditeur :

Elsevier

Date de publication :

2016

ISSN :

0016-5085

Mot(s)-clé(s) en anglais :

Adult
Biomarkers
Biopsy
Chalcones
Double-Blind Method
Europe
Female
Gastrointestinal Agents
Humans
Intention to Treat Analysis
Liver
Liver Cirrhosis
Logistic Models
Male
Middle Aged
Non-alcoholic Fatty Liver Disease
Odds Ratio
PPAR alpha
PPAR gamma
Propionates
Remission Induction
Severity of Illness Index
Signal Transduction
Time Factors
Treatment Outcome
United States

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

<p><b>BACKGROUND &amp; AIMS: </b>Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, ...
Lire la suite ><p><b>BACKGROUND &amp; AIMS: </b>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).</p><p><b>METHODS: </b>Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n&nbsp;= 93), elafibranor 120 mg (n&nbsp;= 91), or placebo (n&nbsp;= 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.</p><p><b>RESULTS: </b>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&nbsp;= 2.31; 95% confidence interval: 1.02-5.24; P&nbsp;= .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&nbsp;= 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio&nbsp;= 3.16; 95% confidence interval: 1.22-8.13; P&nbsp;= .018) and the modified definitions (19% vs 9%; odds ratio&nbsp;= 3.52; 95% confidence interval: 1.32-9.40; P&nbsp;= .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 &lt; .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&nbsp;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 &lt; .001).</p><p><b>CONCLUSIONS: </b>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.</p>Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Collections :

• Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (RNMCD) - U1011

Source :

Harvested from HAL