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

• Published in: Hepatology (Baltimore, Md.) Vol. 54; no. 6; pp. 1956 - 1965
• Main Authors: Nettles, Richard E., Gao, Min, Bifano, Marc, Chung, Ellen, Persson, Anna, Marbury, Thomas C., Goldwater, Ronald, DeMicco, Michael P., Rodriguez‐Torres, Maribel, Vutikullird, Apinya, Fuentes, Ernesto, Lawitz, Eric, Lopez‐Talavera, Juan Carlos, Grasela, Dennis M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2011; Wiley; Wolters Kluwer Health, Inc
• Subjects: Adolescent; Adult; Antiviral Agents - administration & dosage; Antiviral Agents - pharmacokinetics; Biological and medical sciences; Carbamates; Double-Blind Method; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genotype & phenotype; Half-Life; Hepacivirus - drug effects; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatology; HIV; Human immunodeficiency virus; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacokinetics; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Middle Aged; Pyrrolidines; RNA, Viral - blood; Valine - analogs & derivatives; Viral Load; Viral Nonstructural Proteins - antagonists & inhibitors; Human; Typing; Genotype; Protein; Virus; Multiple dose; Infection; Microbiological investigation; Gastroenterology; Replication; Flaviviridae; Hepatitis C virus; Hepacivirus
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1002/hep.24609

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