The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of C—C 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).

The CENTAUR study was sponsored by Allergan plc. All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship. Authors who were employees of Allergan were involved in study concept and design; data acquisition; analysis

Introduction: Nonalcoholic steatohepatitis (NASH) is a sub-classification of nonalcoholic fatty liver disease (NAFLD) characterized by increased risk of progressive liver fibrosis. Cenicriviroc (CVC) is a novel, orally administered, potent chemokine 2 and 5 receptor antagonist currently in development for the treatment of liver fibrosis in adults with NASH. Methods and analysis: Efficacy and safety of CVC will be comprehensively evaluated in a global, Phase 3, multicenter, randomized, double-blind, placebo-controlled study (AURORA, NCT03028740) of subjects with NASH and Stage F2 or F3 fibrosis. Approximately 2000 adults (Part 1, 1200 subjects; Part 2, 800 additional subjects) aged 18-75 years with histological evidence of NASH with Stage F2 or F3 fibrosis (NASH Clinical Research Network classification system) will be randomized 2:1 to CVC 150 mg or placebo orally once daily. Primary efficacy endpoints will include the proportion of subjects with ≥1-stage improvement in liver fibrosis and no worsening of steatohepatitis at Month 12 relative to screening (Part 1), and time to first occurrence of any adjudicated event: death; histopathologic progression to cirrhosis; liver transplant; Model of End-Stage Liver Disease score ≥ 15; ascites; hospitalization due to liver decompensation (Part 2). Patient-reported outcomes will assess changes in health outcomes from baseline (Chronic Liver Disease Questionnaire-NAFLD; Work Productivity and Activity Impairment in NASH; 36-Item Short Form Health Survey version 2). Adverse events will be assessed throughout the study. As there are currently no approved treatments indicated for NASH, the AURORA CVC Phase 3 study addresses an unmet medical need.

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Background & Aims: The development of accurate non-invasive tests to detect and measure the extent of fibrosis and disease activity in patients with non-alcoholic steatohepatitis (NASH)the progressive phenotype of non-alcoholic fatty liver disease (NAFLD) is of great clinical importance. Herein, we aimed to validate the performance of PRO-C3 and ADAPT for the detection of moderate/ severe fibrosis within the CENTAUR screening population. Methods: PRO-C3 was assessed in plasma from the screening population of the phase IIb CENTAUR study (NCT02217475) in adults with NASH and liver fibrosis. The relation between PRO-C3 and histologic features of NASH was evaluated, as well as the demographics of patients with high and low levels of PRO-C3. The diagnostic ability of PRO-C3, as a standalone marker or incorporated into ADAPT, to identify patients with F> − 2 and NASH was estimated using receiver-operating characteristic analysis and logistic regression models. Results: A total of 517 individuals with matched biopsy and PRO-C3 measurements were included. Patients with PRO-C3 levels > − 20.2 ng/ml showed increased levels of insulin, HOMA-IR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and platelet count compared to patients with low PRO-C3 (p <0.05). PRO-C3 increased stepwise with increasing liver fibrosis, lobular inflammation, hepatocyte ballooning, steatosis, and NAFLD activity score (p <0.05), and could distinguish between NAFL and NASH (p <0.0001). PRO-C3 was independently associated with fibrosis and NASH when adjusted for clinical confounders. ADAPT outperformed Fibrosis-4, AST-to-platelet ratio index, and AST/ALT ratio as a predictor of advanced fibrosis and NASH (p <0.001). Conclusion: PRO-C3 was associated with NAFLD activity score and fibrosis. ADAPT outperformed other non-invasive scores for detecting NASH. These data support the use of PRO-C3 and ADAPT as diagnostic tools to identify patients with NASH eligible for inclusion in clinical trials. Clinical trial number: NCT02217475 Lay summary: PRO-C3 is a serological biomarker associated with liver disease activity and fibrosis. Its performance for the detection of disease activity and fibrosis is improved when it is incorporated into the ADAPT score. Herein, we showed that ADAPT was better at selecting patients with non-alcoholic steatohepatitis for inclusion in clinical trials than other noninvasive scores.