title: Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Bristol-Myers Squibb, Research and Development, Hopewell, NJ, USA. richard.nettles@bms.com
authors.forename: Richard E
authors.initials: RE
authors.lastname: Nettles
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Marc
authors.initials: M
authors.lastname: Bifano
authors.forename: Ellen
authors.initials: E
authors.lastname: Chung
authors.forename: Anna
authors.initials: A
authors.lastname: Persson
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Marbury
authors.forename: Ronald
authors.initials: R
authors.lastname: Goldwater
authors.forename: Michael P
authors.initials: MP
authors.lastname: DeMicco
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.forename: Apinya
authors.initials: A
authors.lastname: Vutikullird
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fuentes
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Lopez-Talavera
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002219:Carbamates; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012367:RNA, Viral / Q000097:blood; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D012367:RNA, Viral; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir