R1626 plus peginterferon Alfa‐2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin†

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Abstract
R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time‐dependent and dose‐dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa‐2a ± ribavirin in HCV genotype 1‐infected treatment‐naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] + peginterferon alfa‐2a; n = 21); DUAL 3000 (3000 mg R1626 bid + peginterferon alfa‐2a; n = 32); TRIPLE 1500 (1500 mg R1626 bid + peginterferon alfa‐2a + ribavirin; n = 31); or standard of care (SOC) (peginterferon alfa‐2a + ribavirin; n = 20). At 4 weeks HCV RNA was undetectable (10 IU/mL. Synergy was observed between R1626 and peginterferon alfa‐2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions. Conclusion: A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa‐2a ± ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa‐2a and ribavirin is underway. (HEPATOLOGY 2008.)