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

Authors


  • Potential conflict of interest: Dr. Shiffman is a consultant for, advises, is on the speakers' bureau of, and received grants from Roche. He also advises and received grants from Vertex. He received grants from Schering-Plough. Dr. Pockros is a consultant for, advises, is on the speakers' bureau of, and received grants from Roche. He is a consultant for, advises, and received grants from Wyeth and Idenix. Drs. Nelson and Everson are consultants for, advise, are on the speakers' bureau of, and received grants from Roche. Dr. Godofsky is on the speakers' bureau of and received grants from Roche. Dr. Rodriguez-Torres advises, is on the speakers' bureau of, and received grants from Roche. Dr. Fried is a consultant for, is on the speakers' bureau of, and received grants from Roche. Dr. Ghalib is on the speakers' bureau of and received grants from Schering-Plough and Roche. He is also in the speakers' bureau of Valeant. He received grants from Vertex and Coley. Dr. Harrison advises, is on the speakers' bureau of, and received grants from Roche. He also received grants from Schering-Plough and Valeant. Dr. Nyberg is on the speakers' bureau of and received grants from Schering-Plough. She also received grants from Roche, Vertex, Novartis, Idenix, and Human Genome Sciences.

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 (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log10 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.)

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