Cenicriviroc versus placebo for the treatment of non-alcoholic steatohepatitis with liver fibrosis: Results from the Year 1 primary analysis of the Phase 2b CENTAUR study

Background: Cenicriviroc (CVC), an oral chemokine receptor CCR2/5 antagonist, has potent anti‐inflammatory and antifibrotic activity in animal models of acute and chronic liver diseases. Its efficacy and safety as a treatment for non‐alcoholic steatohepatitis (NASH) and liver fibrosis are being evaluated in adults at increased risk of progression to cirrhosis (CENTAUR; NCT02217475). Methods: Phase 2b, randomized, double‐blind, placebo‐controlled, ongoing 2‐year multinational study; primary analysis at Year 1. Subjects with histologically defined NASH, a non‐alcoholic fatty liver disease activity score (NAS) ≥4, liver fibrosis (stages 1‐3 NASH CRN), and diabetes or metabolic syndrome (MetS) were randomized to CVC 150 mg QD or placebo. NAS, resolution of steatohepatitis, and fibrosis stage were assessed on Year 1 liver biopsies. Markers of systemic inflammation, treatment‐emergent adverse events (TEAEs), and laboratory abnormalities were evaluated. Result: Two hundred eighty‐nine subjects were randomized: 53% female; 52% diabetes; 72% MetS; 74% NAS ≥5; 67% fibrosis stage 2‐3. Mean BMI (SD) was 34 kg/m2 (6.5). A similar proportion in each group achieved the NAS and resolution of steatohepatitis endpoints (Table 1). Improvement in fibrosis by ≥1 stage and no worsening of steatohepatitis was obtained in significantly more CVCtreated subjects than placebo overall (p = 0.023) and in subgroups with histologically advanced disease characteristics. Improvement in fibrosis by 2 stages was observed in 11 subjects (8 CVC; 3 placebo). Seven subjects progressed to cirrhosis (2 CVC; 5 placebo). IL‐6, hs‐ CRP, and fibrinogen levels were significantly decreased with CVC vs. placebo. Drug‐related, clinical TEAEs of Grade ≥2 severity occurring in ≥2% of subjects were fatigue (2.8%) and diarrhea (2.1%) for CVC; headache (3.5%) for placebo. There were no differences in laboratory abnormalities or premature discontinuations between CVC and placebo. Conclusion: In the ITT population, CVC was well tolerated and resulted in twice as many subjects achieving ≥1 stage improvement in fibrosis and no worsening of steatohepatitis vs. placebo, after only 1 year of treatment. Importantly, greater treatment benefits were observed in subjects with higher disease activity and fibrosis stage. (Table Presented).