Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1

Richard E. Nettles, Min Gao, Marc Bifano, Ellen Chung, Anna Persson, Thomas C. Marbury, Ronald Goldwater, Michael P. Demicco, Maribel Rodriguez-Torres, Apinya Vutikullird, Ernesto Fuentes, Eric Lawitz, Juan Carlos Lopez-Talavera, Dennis M. Grasela

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159 Scopus citations

Abstract

The antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS-790052, a nonstructural protein 5A (NS5A) replication complex inhibitor, were evaluated in a double-blind, placebo-controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log 10 IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once-daily dosing with median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing. BMS-790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters. Conclusion: BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1. (HEPATOLOGY 2011

Original languageEnglish (US)
Pages (from-to)1956-1965
Number of pages10
JournalHepatology
Volume54
Issue number6
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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    Nettles, R. E., Gao, M., Bifano, M., Chung, E., Persson, A., Marbury, T. C., Goldwater, R., Demicco, M. P., Rodriguez-Torres, M., Vutikullird, A., Fuentes, E., Lawitz, E., Lopez-Talavera, J. C., & Grasela, D. M. (2011). Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology, 54(6), 1956-1965. https://doi.org/10.1002/hep.24609