Drug Discovery Opinion

Infection with hepatitis C virus (HCV) is a major cause of acute hepatitis and chronic liver disease, including cirrhosis and cancer. Current treatments are not able to cure all of those chronically infected with the virus, and there is a real need for new therapies. An interest in novel cyclophilin inhibitors for the treatment of HCV arose out of the observation that cyclosporin-A, which is widely used in the management of liver transplant recipients, also inhibits HCV replication. Scynexis has recently released top-line results of a Phase Ib study of its non-immunosuppressive cyclophilin inhibitor, SCY-635, in adults with chronic HCV infection. The randomized, double-blind, placebo-controlled study showed that treatment with SCY-635 for 15 days was well tolerated and produced a clinically relevant reduction in plasma HCV RNA.

Cyclophilins are ubiquitously expressed proteins with peptidyl prolyl cis-trans isomerase activity that play an important role in folding and isomerisation of proteins. Although the isomerase activity of cyclophilin is critical for HCV replication, it is not completely clear which viral protein is modified by the isomerase; interactions with both the NS5B polymerase and the non-structural protein, NS5A, have been proposed. Preclinical data have suggested that viral resistance to cyclophilin inhibitors may not arise as easily as resistance to polymerase and protease inhibitors. Other cyclophilin inhibitors that are being studied for the treatment of HCV infection include NIM811 and Debio-025. Positive clinical efficacy data have been reported for Debio-025, both as monotherapy and in combination with pegylated interferon-α.

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