Alisporivir, a cyclosporin derivative that selectively inhibits cyclophilin, for the treatment of HCV infection

Abstract

HCV infection is the primary cause of chronic liver disease. Host cell cyclophilins (Cyps) are essential for efficient HCV replication in hepatocytes, and thus Cyps are regarded as a new target for anti-HCV therapy. Alisporivir (Debio-025), a non-immunosuppressive cyclosporine A derivative that selectively inhibits Cyps, is being developed by Debiopharm SA for the potential oral treatment of HCV infection. In the HCV subgenomic replicon system, alisporivir suppressed viral replication more potently than cyclosporine A. A phase II clinical trial demonstrated that treatment with alisporivir alone or combined with PEGylated IFNalpha2a reduced the viral load in patients with chronic HCV infection. The drug was also generally well tolerated. In contrast, a phase I trial of alisporivir monotherapy in patients with HIV-1 infection suggested that the drug has a limited effect on HIV-1 viral load. Alisporivir was also investigated in animal models of muscular dystrophy, acute myocardial infarction and brain disorders. At the time of publication, two phase II trials, evaluating alisporivir alone and in combination with PEGylated IFNalpha2a or with PEGylated IFNalpha2a and ribavirin, were ongoing in treatment-naïve patients with HCV-1 infection and in patients with chronic HCV-1 infection who were prior non-responders to PEGylated IFNalpha or ribavirin.