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 GS-1101 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 The current treatment selleck kinase inhibitor of chronic hepatitis C virus (HCV) infection, a regimen of

pegylated interferon alpha (PEG-IFN)-2a or -2b, and ribavirin 上海皓元医药股份有限公司 (RBV) remains unsatisfactory, particularly in the large number of patients with HCV genotype 1 infection, whose sustained viral response rates are currently ≈40%.1 However, treatment for HCV infection is rapidly evolving with the introduction of direct-acting antiviral (DAA) agents.2, 3 The combination of telaprevir, an HCV NS3 protease inhibitor, with PEG-IFN alpha-2a and RBV has been associated with sustained viral response rates of 61%-67% in patients with genotype 1 infection.2 Telaprevir is administered three times a day and has been associated with adverse events (AEs) such as rash and anemia.4 There continues to be an unmet medical need for additional DAA agents with different mechanisms of action and resistance patterns that are easy to administer, more effective, and well tolerated. Focusing on the critical importance of nonstructural protein 5A (NS5A) for HCV replication, BMS-790052 was identified as a potent and highly selective inhibitor of HCV based on inhibitor binding and mapping, inhibitor-induced resistant substitutions, and crystal structure modeling. In vitro data have shown that BMS-790052 inhibits HCV genotype 1 replicons with a median 50% effective concentration of ≤50 pM, whereas BMS-790052-resistant variants remain fully sensitive to interferon alpha and small-molecule inhibitors of HCV protease and polymerase.