Volume 150, Issue 5, Pages 1147-1159.e5 (May 2016) 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, 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, 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 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, 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, 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  Gastroenterology  Volume 150, Issue 5, Pages 1147-1159.e5 (May 2016) DOI: 10.1053/j.gastro.2016.01.038 Copyright © 2016 AGA Institute Terms and Conditions

Figure 1 Trial profile. ITT, intention to treat; PP, per protocol. Gastroenterology 2016 150, 1147-1159.e5DOI: (10.1053/j.gastro.2016.01.038) Copyright © 2016 AGA Institute Terms and Conditions

Figure 2 Changes from baseline in liver enzymes (A−C) and plasma lipids (D−F) in treatment groups of the Per Protocol set (n = 237). Results are expressed in mean values of changes from baseline during treatment with placebo (n = 77), elafibranor 80 mg (n = 82) and elafibranor 120 mg (n = 78). Error bars represent 95% CIs. ALT, alanine aminotransferase (A); Gamma-GT, γ-glutamyltranspeptidase (B). LDL, low-density lipoprotein. Gastroenterology 2016 150, 1147-1159.e5DOI: (10.1053/j.gastro.2016.01.038) Copyright © 2016 AGA Institute Terms and Conditions

Figure 3 Elafibranor-induced changes in glucose homeostasis markers in type 2 diabetic patients. Type 2 diabetic patients account for 40% of the ITT population (n = 94). Mean changes vs baseline in elafibranor 80 mg (n = 31) and elafibranor 120 mg (n = 35) groups were compared with the changes in placebo group using a mixed model with group as fixed factor and baseline value as a covariate. The effect size compared with placebo was calculated and expressed as LSMean. Error bars represent 95% CIs. #P < .05 vs placebo; ##P < .01 vs placebo. FFA, free fatty acids; FPG, fasting plasma glucose. Gastroenterology 2016 150, 1147-1159.e5DOI: (10.1053/j.gastro.2016.01.038) Copyright © 2016 AGA Institute Terms and Conditions

Supplementary Figure 1 Overall improvement in liver histology in patients who achieved the primary outcome according to the modified definition of response in the elafibranor 120-mg arm. Results are expressed as mean values of changes from baseline during treatment in responders (n = 17) and nonresponders (n = 61) to elafibranor 120 mg. Error bars represent 95% CIs. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Gastroenterology 2016 150, 1147-1159.e5DOI: (10.1053/j.gastro.2016.01.038) Copyright © 2016 AGA Institute Terms and Conditions

Supplementary Figure 2 Changes from baseline in inflammatory markers (Sup2A) and in noninvasive scores of fibrosis and steatosis (Sup2B) in treatment groups in the per protocol analysis (n = 237). Results are expressed as mean values of changes from baseline during treatment with placebo (n = 77), elafibranor 80 mg (n = 82) and elafibranor 120 mg (n = 78). Error bars represent 95% CIs. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001 vs baseline. #P < .05; ##P < .01; ###P < .001 vs placebo. Gastroenterology 2016 150, 1147-1159.e5DOI: (10.1053/j.gastro.2016.01.038) Copyright © 2016 AGA Institute Terms and Conditions