Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C

Claudio Pasquinelli, Fiona McPhee, Timothy Eley, Criselda Villegas, Katrina Sandy, Pamela Sheridan, Anna Persson, Shu Pang Huang, Dennis Hernandez, Amy K. Sheaffer, Paul Scola, Thomas Marbury, Eric Lawitz, Ronald Goldwater, Maribel Rodriguez-Torres, Michael DeMicco, David Wright, Michael Charlton, Walter K. Kraft, Juan Carlos Lopez-TalaveraDennis M. Grasela

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Hepatitis C virus (HCV) protease inhibitors combined with pegylated alfa interferon-ribavirin have demonstrated improved efficacy compared with pegylated alfa interferon-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-and multiple-ascending-dose (SAD and 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 1,200 mg or a placebo. In MAD studies, healthy subjects were randomized to receive asunaprevir in dose groups of 10 to 600 mg twice daily or a placebo for 14 days; subjects with HCV infection received asunaprevir in dose groups of 200 to 600 mg twice daily, or a placebo, for 3 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 the 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. In 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.

Original languageEnglish (US)
Pages (from-to)1838-1844
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2012

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Pasquinelli, C., McPhee, F., Eley, T., Villegas, C., Sandy, K., Sheridan, P., Persson, A., Huang, S. P., Hernandez, D., Sheaffer, A. K., Scola, P., Marbury, T., Lawitz, E., Goldwater, R., Rodriguez-Torres, M., DeMicco, M., Wright, D., Charlton, M., Kraft, W. K., ... Grasela, D. M. (2012). Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C. Antimicrobial Agents and Chemotherapy, 56(4), 1838-1844. https://doi.org/10.1128/AAC.05854-11