Source

Bristol-Myers Squibb, Research and Development, Hopewell, NJ.

Abstract

Hepatitis C virus (HCV) protease inhibitors combined with pegylated interferon alfa/ribavirin have demonstrated improved efficacy compared with pegylated interferon alpha/ribavirin alone for the treatment of chronic hepatitis C. Asunaprevir (BMS-650032), a novel HCV NS3 protease inhibitor in clinical development, was evaluated for safety, antiviral activity, and resistance in four double-blind, placebo-controlled, sequential-panel, single (SAD) and multiple ascending dose (MAD) studies in healthy subjects or subjects with chronic HCV genotype 1 infection. In SAD studies, subjects (healthy or with chronic HCV infection) were randomized to receive asunaprevir in dose groups of 10 to 1200 mg, or placebo. In MAD studies, healthy subjects were randomized to receive asunaprevir in dose groups of 10 to 600 mg twice daily, or placebo for 14 days; subjects with HCV infection received asunaprevir in dose groups of 200 to 600 mg twice daily, or placebo, for three days. Across all four studies, headache and diarrhea were the most frequent adverse events in asunaprevir recipients. Asunaprevir at doses of 200 to 600 mg resulted in rapid HCV RNA decreases from baseline; maximal mean changes in HCV RNA over time were 2.7 and 3.5 log(10) IU/mL in the SAD and MAD studies, respectively. No enrichment of signature asunaprevir-resistant viral variants was detected. Conclusion: The novel NS3 protease inhibitor asunaprevir, when administered at single or multiple doses of 200 to 600 mg twice daily, is generally well tolerated, achieving rapid and substantial decreases in HCV RNA levels in subjects chronically infected with genotype 1 HCV.