Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′-C-Methylcytidine to Hepatitis C Virus-Infected Chimpanzees

ABSTRACT Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide, and the current standard of care, a combination of pegylated interferon alpha and ribavirin, is efficacious in achieving sustained viral response in ∼50% of treated patients. Novel therapies under investigation include the use of nucleoside analog inhibitors of the viral RNA-dependent RNA polymerase. NM283, a 3′-valyl ester prodrug of 2′- C -methylcytidine, has demonstrated antiviral efficacy in HCV-infected patients (N. Afdhal et al., J. Hepatol. 46 [Suppl. 1] : S5, 2007; N. Afdhal et al., J. Hepatol. 44 [Suppl. 2] : S19, 2006). One approach to increase the antiviral efficacy of 2′- C -methylcytidine is to increase the concentration of the active inhibitory species, the 5′-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2′- C -methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacy in vivo , the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by ∼1.4 log 10 IU/ml and by >3.6 log 10 IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.