TY - JOUR
T1 - A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis
AU - Friedman, Scott L.
AU - Ratziu, Vlad
AU - Harrison, Stephen A.
AU - Abdelmalek, Manal F.
AU - Aithal, Guruprasad P.
AU - Caballeria, Juan
AU - Francque, Sven
AU - Farrell, Geoffrey
AU - Kowdley, Kris V.
AU - Craxi, Antonio
AU - Simon, Krzysztof
AU - Fischer, Laurent
AU - Melchor-Khan, Liza
AU - Vest, Jeffrey
AU - Wiens, Brian L.
AU - Vig, Pamela
AU - Seyedkazemi, Star
AU - Goodman, Zachary
AU - Wong, Vincent Wai Sun
AU - Loomba, Rohit
AU - Tacke, Frank
AU - Sanyal, Arun
AU - Lefebvre, Eric
N1 - Funding Information:
Received April 13, 2017; accepted August 13, 2017. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.29477/suppinfo. The CENTAUR study was sponsored by Tobira Therapeutics, a subsidiary of Allergan plc. The sponsor provided funding for the study and provided the study drug. Authors who were employees of Tobira Therapeutics were involved in study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analyses; obtained funding; administrative, technical or material support; and study supervision. *These authors contributed equally as first co-authors. **These authors contributed equally as senior co-authors. ClinicalTrials.gov no: NCT02217475 (CENTAUR).
Funding Information:
Copyright VC 2017 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.29477 Potential conflict of interest: Dr. Friedman consults for, advises for, and received grants from Tobira and Allergan. Dr. Goodman received grants from Allergan, Gilead, Conatus, Galectin, Exalenz, and Alexion. Dr. Kowdley consults for, advises for, is on the speakers’ bureau for, and received grants from Gilead. He consults for, advises for, and is on the speakers’ bureau for Intercept. He consults and received grants from NGM Biopharma. He consults for Enanta and Verylx. He advises for Allergan and Conatus. He received grants from Galectin, Immuron, and Tobira. Dr. Tacke advises for and received grants from Tobira and Allergan. Dr. Ratziu consults for Allergan, Genfit, Intercept, Novartis, Boehringer Ingelheim, and Pfizer. He received grants from Gilead. Dr. Wong advises for and received lecture fees from Gilead. He consults for Allergan and Pfizer. He advises AbbVie, Janssen, and Perspectum. He received lecture fees from Bristol-Myers Squibb, Echosens, and Merck. Dr. Sanyal is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect. He has served as a consultant to AbbVie, Astra Zeneca, Allergan, Nitto Denko, Ardelyx, Conatus, Nimbus, Amarin, Salix, Tobira, Takeda, Sanofi, General Electric, Fibrogen, Jannsen, Gilead, Boehringer, Lilly, Zafgen, Novartis, Pfizer, Immuron, Exhalenz and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Novo Nordisk, Affimune, Chemomab, Nordic Bioscience and Bristol Myers Squibb. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, Astra Zeneca, Malinckrodt, Cumberland and Novartis. . He receives royalties from Elsevier and UptoDate. Dr. Harrison consults and received grants from Genfit. He consults for Allergan, Cirius, NGM, Madrigal, and Perspectum. He advises for Intercept, Conatus, Echosens, Galmed, Gilead, Pfizer, and Fibrogen. He is on the speakers’ bureau for Alexion. Dr. Abdelmalek advises and has received grants from Allergan. Dr. Fischer is employed by Allergan. Mrs. Melchor-Khan is employed by Allergan. Dr. Wiens is employed by Allergan. Dr. Lefebvre is employed by Allergan. Dr. Vig is employed by Allergan. Dr. Seyedkazemi is employed by Allergan.
Publisher Copyright:
© 2017 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
PY - 2018/5
Y1 - 2018/5
N2 - The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of CC chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1-3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2-point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent-to-treat population and resolution of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, respectively). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. Conclusion: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (Hepatology 2018;67:1754-1767).
AB - The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of CC chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1-3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2-point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent-to-treat population and resolution of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, respectively). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. Conclusion: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (Hepatology 2018;67:1754-1767).
UR - http://www.scopus.com/inward/record.url?scp=85041240874&partnerID=8YFLogxK
U2 - 10.1002/hep.29477
DO - 10.1002/hep.29477
M3 - Article
C2 - 28833331
AN - SCOPUS:85041240874
SN - 0270-9139
VL - 67
SP - 1754
EP - 1767
JO - Hepatology
JF - Hepatology
IS - 5
ER -