Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1–infected patients†

Hepatology
Volume 54, Issue 1, pages 50–59, July 2011

Frank Wagner 1,‡, Robert Thompson 2, Constantino Kantaridis 3, Paul Simpson 4, Philip J. F. Troke 4, Shyla Jagannatha 5, Srividya Neelakantan 5, Vivek S. Purohit 5, Jennifer L. Hammond 5,*,§

Article first published online: 24 JUN 2011
DOI: 10.1002/hep.24342
Copyright © 2011 American Association for the Study of Liver Diseases

Author Information
1 Charité Research Organisation, Charité Universitätsmedizin Berlin, Berlin, Germany
2 University of Florida, Center for Clinical Trials Research, FL
3 Pfizer Clinical Research Unit, Pfizer, Brussels, Belgium
4 Pfizer Global Research, Sandwich, Kent, UK
5 Pfizer Worldwide Biopharmaceuticals, New London, CT

Email: Jennifer L. Hammond (jennifer.hammond@pfizer.com)

* Correspondence: Jennifer L. Hammond, Worldwide Biopharmaceuticals, Specialty Care, Pfizer, Inc., 50 Pequot Avenue, New London, CT 06320

Abstract

More effective and better-tolerated therapies are needed for chronic hepatitis C virus (HCV) infection. Among the direct-acting anti-HCV agents in development is the nonstructural 5B protein (NS5B polymerase) non-nucleoside inhibitor filibuvir. We investigated the antiviral activity, pharmacokinetics, safety, and tolerability of multiple doses of filibuvir in treatment-naive and treatment-experienced patients who were chronically infected with HCV genotype 1 in two phase 1b clinical studies (study 1 was a randomized, placebo-controlled dose escalation study and study 2 was a nonrandomized, open-label study). The filibuvir doses evaluated ranged from 200-1400 mg daily, and the duration of dosing ranged from 3-10 days. Genotypic changes in the NS5B nucleotide sequence following short-term filibuvir therapy were also assessed. Filibuvir potently inhibited viral replication in a dose-dependent manner. Mean maximum HCV RNA change from baseline ranged from −0.97 log10 IU/mL with filibuvir given at 100 mg twice daily to −2.30 log10 IU/mL with filibuvir given at 700 mg twice daily in treatment-naive patients. In treatment-experienced patients, an HCV RNA reduction of 2.20 log10 IU/mL was achieved with filibuvir given at 450 mg twice daily. Filibuvir was well tolerated in both studies. Adverse events were mild or moderate in severity. No discontinuations, serious adverse events, or deaths were reported. NS5B sequencing identified residue 423 as the predominant site of mutation after filibuvir dosing. Conclusion: Filibuvir administration resulted in significant reductions in HCV RNA concentrations at doses that were well tolerated in patients infected with HCV genotype 1. Filibuvir is currently being evaluated in combination with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients. (Hepatology 2011;)

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