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

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Peroxisome Proliferator-Activated Receptors
Fibrosis
Placebos
Odds Ratio
Confidence Intervals
Non-alcoholic Fatty Liver Disease
Intention to Treat Analysis
Lipid Metabolism
Liver Cirrhosis
Insulin Resistance
Homeostasis
Logistic Models
Inflammation
Biopsy
Safety
Glucose
Liver

Keywords

  • fatty liver
  • NAFLD
  • PPARA
  • PPARD

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. / Ratziu, Vlad; Harrison, Stephen A.; Francque, Sven; Bedossa, Pierre; Lehert, Philippe; Serfaty, Lawrence; Romero-Gomez, Manuel; Boursier, Jérôme; Abdelmalek, Manal; Caldwell, Steve; Drenth, Joost; Anstee, Quentin M.; Hum, Dean; Hanf, Remy; Roudot, Alice; Megnien, Sophie; Staels, Bart; Sanyal, Arun; Mathurin, P.; Gournay, J.; Nguyen-Khac, E.; De Ledinghen, V.; Larrey, D.; Tran, A.; Bourliere, M.; Maynard-Muet, M.; Asselah, T.; Henrion, J.; Nevens, F.; Cassiman, D.; Geerts, A.; Moreno, C.; Beuers, U. H.; Galle, P. R.; Spengler, U.; Bugianesi, E.; Craxi, A.; Angelico, M.; Fargion, S.; Voiculescu, M.; Gheorghe, L.; Preotescu, L.; Caballeria, J.; Andrade, R. J.; Crespo, J.; Callera, J. L.; Ala, A.; Aithal, G.; Abouda, G.; Luketic, V.; Huang, M. A.; Gordon, S.; Pockros, P.; Poordad, F.; Shores, N.; Moehlen, M. W.; Bambha, K.; Clark, V.; Satapathy, S.; Parekh, S.; Reddy, R. K.; Sheikh, M. Y.; Szabo, G.; Vierling, J.; Foster, T.; Umpierrez, G.; Chang, C.; Box, T.; Gallegos-Orozco, J.

In: Gastroenterology, Vol. 150, No. 5, 01.05.2016, p. 1147-1159e5.

Research output: Contribution to journalArticle

Ratziu, V, Harrison, SA, Francque, S, Bedossa, P, Lehert, P, Serfaty, L, Romero-Gomez, M, Boursier, J, Abdelmalek, M, Caldwell, S, Drenth, J, Anstee, QM, Hum, D, Hanf, R, Roudot, A, Megnien, S, Staels, B, Sanyal, A, Mathurin, P, Gournay, J, Nguyen-Khac, E, De Ledinghen, V, Larrey, D, Tran, A, Bourliere, M, Maynard-Muet, M, Asselah, T, Henrion, J, Nevens, F, Cassiman, D, Geerts, A, Moreno, C, Beuers, UH, Galle, PR, Spengler, U, Bugianesi, E, Craxi, A, Angelico, M, Fargion, S, Voiculescu, M, Gheorghe, L, Preotescu, L, Caballeria, J, Andrade, RJ, Crespo, J, Callera, JL, Ala, A, Aithal, G, Abouda, G, Luketic, V, Huang, MA, Gordon, S, Pockros, P, Poordad, F, Shores, N, Moehlen, MW, Bambha, K, Clark, V, Satapathy, S, Parekh, S, Reddy, RK, Sheikh, MY, Szabo, G, Vierling, J, Foster, T, Umpierrez, G, Chang, C, Box, T & 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, vol. 150, no. 5, pp. 1147-1159e5. https://doi.org/10.1053/j.gastro.2016.01.038
Ratziu, Vlad ; Harrison, Stephen A. ; Francque, Sven ; Bedossa, Pierre ; Lehert, Philippe ; Serfaty, Lawrence ; Romero-Gomez, Manuel ; Boursier, Jérôme ; Abdelmalek, Manal ; Caldwell, Steve ; Drenth, Joost ; Anstee, Quentin M. ; Hum, Dean ; Hanf, Remy ; Roudot, Alice ; Megnien, Sophie ; Staels, Bart ; Sanyal, Arun ; Mathurin, P. ; Gournay, J. ; Nguyen-Khac, E. ; De Ledinghen, V. ; Larrey, D. ; Tran, A. ; Bourliere, M. ; Maynard-Muet, M. ; Asselah, T. ; Henrion, J. ; Nevens, F. ; Cassiman, D. ; Geerts, A. ; Moreno, C. ; Beuers, U. H. ; Galle, P. R. ; Spengler, U. ; Bugianesi, E. ; Craxi, A. ; Angelico, M. ; Fargion, S. ; Voiculescu, M. ; Gheorghe, L. ; Preotescu, L. ; Caballeria, J. ; Andrade, R. J. ; Crespo, J. ; Callera, J. L. ; Ala, A. ; Aithal, G. ; Abouda, G. ; Luketic, V. ; Huang, M. A. ; Gordon, S. ; Pockros, P. ; Poordad, F. ; Shores, N. ; Moehlen, M. W. ; Bambha, K. ; Clark, V. ; Satapathy, S. ; Parekh, S. ; Reddy, R. K. ; Sheikh, M. Y. ; Szabo, G. ; Vierling, J. ; Foster, T. ; Umpierrez, G. ; Chang, C. ; Box, T. ; Gallegos-Orozco, J. / Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. In: Gastroenterology. 2016 ; Vol. 150, No. 5. pp. 1147-1159e5.
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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",
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TY - JOUR

T1 - Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

AU - Ratziu, Vlad

AU - Harrison, Stephen A.

AU - Francque, Sven

AU - Bedossa, Pierre

AU - Lehert, Philippe

AU - Serfaty, Lawrence

AU - Romero-Gomez, Manuel

AU - Boursier, Jérôme

AU - Abdelmalek, Manal

AU - Caldwell, Steve

AU - Drenth, Joost

AU - Anstee, Quentin M.

AU - Hum, Dean

AU - Hanf, Remy

AU - Roudot, Alice

AU - Megnien, Sophie

AU - Staels, Bart

AU - Sanyal, Arun

AU - Mathurin, P.

AU - Gournay, J.

AU - Nguyen-Khac, E.

AU - De Ledinghen, V.

AU - Larrey, D.

AU - Tran, A.

AU - Bourliere, M.

AU - Maynard-Muet, M.

AU - Asselah, T.

AU - Henrion, J.

AU - Nevens, F.

AU - Cassiman, D.

AU - Geerts, A.

AU - Moreno, C.

AU - Beuers, U. H.

AU - Galle, P. R.

AU - Spengler, U.

AU - Bugianesi, E.

AU - Craxi, A.

AU - Angelico, M.

AU - Fargion, S.

AU - Voiculescu, M.

AU - Gheorghe, L.

AU - Preotescu, L.

AU - Caballeria, J.

AU - Andrade, R. J.

AU - Crespo, J.

AU - Callera, J. L.

AU - Ala, A.

AU - Aithal, G.

AU - Abouda, G.

AU - Luketic, V.

AU - Huang, M. A.

AU - Gordon, S.

AU - Pockros, P.

AU - Poordad, F.

AU - Shores, N.

AU - Moehlen, M. W.

AU - Bambha, K.

AU - Clark, V.

AU - Satapathy, S.

AU - Parekh, S.

AU - Reddy, R. K.

AU - Sheikh, M. Y.

AU - Szabo, G.

AU - Vierling, J.

AU - Foster, T.

AU - Umpierrez, G.

AU - Chang, C.

AU - Box, T.

AU - Gallegos-Orozco, J.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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

AB - 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

KW - fatty liver

KW - NAFLD

KW - PPARA

KW - PPARD

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U2 - 10.1053/j.gastro.2016.01.038

DO - 10.1053/j.gastro.2016.01.038

M3 - Article

AN - SCOPUS:84960140218

VL - 150

SP - 1147-1159e5

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 5

ER -