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.
Article first published online: 30 NOV 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 6, pages 1956–1965, December 2011
How to Cite
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. and 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: 1956–1965. doi: 10.1002/hep.24609
Supported by Bristol-Myers Squibb.
See Editorial on Page 1898
- Issue published online: 30 NOV 2011
- Article first published online: 30 NOV 2011
- Accepted manuscript online: 11 AUG 2011 09:27AM EST
- Manuscript Accepted: 1 AUG 2011
- Manuscript Received: 26 MAY 2011
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