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

Authors


  • Potential conflict of interest: Drs. Nettles, Gao, Bifano, Chung, Lopez-Talavera, Grasela, and Persson own stocks in Bristol-Myers Squibb. Dr. Rodriguez-Torres consults for Genentech. He received grants from Vertex, Valeant, GlaxoSmithKline, Novartis, Wyeth, Bristol-Myers Squibb, Virochem-Pharma, Idera, Intarcia, Sanofi-Aventis, Merck, Pfizer, Human Genome Sciences, Gilead, Johnson & Johnson, Zymogenetics, and Medtronics. He also consults for and received grants from Anandys, Roche, Pharmasset, Abbott, and Akros. Dr. Lawitz received grants from Abbott, Achillion, Anadys, Biolex, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix, Idera, Inhibitex, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, Schering-Plough, Santaris, Scynexis, Tibotec, Vertex, ViroChem, and ZymoGenetics.

  • Supported by Bristol-Myers Squibb.

  • §

    See Editorial on Page 1898

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 log10 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

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