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. Gournay & 49 others E. 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, Sanjaya 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

233 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1147-1159.e5
JournalGastroenterology
Volume150
Issue number5
DOIs
StatePublished - May 1 2016

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

All Science Journal Classification (ASJC) codes

  • Hepatology
  • 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, Sanjaya; 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. 1147-1159.e5.

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. 1147-1159.e5. 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, Sanjaya ; 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. 1147-1159.e5.
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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.",
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 Sanjaya 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",
year = "2016",
month = "5",
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",
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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, Sanjaya

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 <.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.

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 <.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.

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DO - 10.1053/j.gastro.2016.01.038

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JO - Gastroenterology

JF - Gastroenterology

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