MK-0608 is an Orally Active Inhibitor of HCV Replication

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated morbidity and mortality worldwide. HCV associates with an increased incidence of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Especially, HCV is a small, enveloped, positive-strand RNA virus of the family Flaviviridae. HCV is the causative agent of non-A, non-B viral hepatitis. In particular, HCV chronic infection associates with an increased incidence of fibrosis, cirrhosis, and the development of hepatocellular carcinoma.

The development of HCV therapy evolves very rapidly in the last decade. Particularly,MK-0608 is a potent inhibitor of HCV replication in vitro. In the subgenomic-replicon assay, MK-0608 inhibits viral RNA replication at an EC50 of 0.3 μM (EC90=1.3 μM) in the absence of significant cytotoxicity. MK-0608 is a nucleoside analog potently inhibits replication of several mosquito-borne flaviviruses. These viruses include the dengue virus (DENV) and Zika virus (ZIKV). MK-0608 inhibits viral RNA replication in the subgenomic HCV genotype 1b replicon, with a EC50 of 0.3 μM (EC90=1.3 μM). Additionally, MK-0608 significantly improves the pharmacokinetic properties of animals.

There is a dose- and time-dependent decrease in plasma viral loads of HCV-infected chimpanzees in vivo. After 37 days of oral dosing, one chimpanzee with a high starting viral load experiences a reduction in viral load of 4.6 log10, and the viral load in the other chimpanzee fell below the limit of quantification (20 IU/mL). Importantly, viral load remains below the limit of quantification throughout the duration of dosing and for at least 12 days after dosing ended. In summary, the results demonstrate a robust antiviral effect on the administration of MK-0608 to HCV-infected chimpanzees.

Carroll SS, et al. Robust antiviral efficacy upon administration of a nucleoside analog to hepatitis C virus-infected chimpanzees. Antimicrob Agents Chemother. 2009 Mar;53(3):926-34.