Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis

ABSTRACT

Introduction: Nonalcoholic fatty liver disease (NAFLD) has an increasing prevalence worldwide. At present, no specific pharmacotherapy is approved for NAFLD. Simple steatosis and nonalcoholic steatohepatitis (NASH) can progress to liver fibrosis that is associated with mortality in NAFLD. The recruitment of inflammatory monocytes and macrophages via chemokine receptor CCR2 as well as of lymphocytes and hepatic stellate cells via CCR5 promote the progression of NASH to fibrosis.

Areas covered: I summarize preclinical and clinical data on the efficacy and safety of the dual CCR2/CCR5 inhibitor cenicriviroc (CVC, also TBR-652 or TAK-652) for the treatment of NASH and fibrosis. In animal models of liver diseases, CVC potently inhibits macrophage accumulation in the liver and ameliorates fibrosis. In a phase 2b clinical trial (CENTAUR) on 289 patients with NASH and fibrosis, CVC consistently demonstrated liver fibrosis improvement after 1 year of therapy and had an excellent safety profile, leading to the implementation of a phase 3 trial (AURORA).

Expert opinion: Preclinical and clinical data support the development of CVC as a safe and potent antifibrotic agent. However, open questions around CVC are the durability of antifibrotic responses, divergent effects on NASH versus fibrosis, potential long-term concerns and the expected path to approval.

KEYWORDS:

• NASH
• liver fibrosis
• macrophage
• monocyte
• NAFLD
• cenicriviroc

Box 1. Drug summary

Acknowledgments

The photographs of human liver were kindly provided by Dr. Olivier Govaere and Dr. Quentin Anstee (Newcastle University, Newcastle-upon-Tyne, UK). I cordially thank all members of my lab and collaborating scientists for helpful discussions.

Declaration of interest

Work in the lab of F. Tacke has received research funding by Tobira/Allergan, Galapagos and Noxxon. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the German Research Foundation (DFG; Ta434/3–1, Ta434/5–1, and SFB/TRR57) and by the Interdisciplinary Center for Clinical Research (IZKF) Aachen.