A randomized, placebo‐controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis

Abstract

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).

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

“…However, adverse effects may limit the treatment potential, e.g., glitazones are associated with phenotypical weight gain [136] and obeticholic acid induced pruritus and elevated LDL-C [137], the latter a potential concern in patients already at risk for cardiovascular disease. Cenicriviroc—despite not meeting its primary endpoint of NAFLD activity score improvement—[138] and obeticholic acid [137] were both able to improve hepatic fibrosis, and were currently undergoing phase III investigation. In addition, promising results have been reported for several phase II clinical trials and additional trials are currently ongoing, reflecting the growing research effort in developing novel treatments for NASH.…”

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

“…Although current anti‐inflammatory approaches have yet to bear fruit in BA, it is possible that there are subsets of BA patients who would benefit from selective agents after detailed cellular and molecular immunotyping. Several antifibrotic agents are currently undergoing study in liver diseases, including the chemokine (C‐C motif) receptor 2/5 antagonist cenicriviroc, which has improved fibrosis in nonalcoholic steatohepatitis in the recently completed CENTAUR trial …”

Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

“…For example, cenicriviroc, a dual CCR2/CCR5 antagonist improved hepatic inflammation and fibrosis in a murine model of NASH. 77 A phase IIb trial of cenicriviroc in patients with NASH patients with fibrosis 78 showed improvement of fibrosis without worsening of steatohepatitis. Furthermore, the pharmacological MLK3 inhibitor URMC099 reduced circulating CXCL10 and attenuated murine NASH.…”