title: Randomized, placebo-controlled, single-ascending-dose study of BMS-791325, a hepatitis C virus (HCV) NS5B polymerase inhibitor, in HCV genotype 1 infection.
abstract: BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC50], 3 nM) and 1b (EC50, 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.).
authors.affiliation: Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA karen.sims@bms.com.
authors.forename: Karen D
authors.initials: KD
authors.lastname: Sims
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Lemm
authors.affiliation: Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Menping
authors.initials: M
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Berglind
authors.affiliation: Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Sherman
authors.affiliation: The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: WCCT Global LLC, Cypress, California, USA.
authors.forename: Apinya B
authors.initials: AB
authors.lastname: Vutikullird
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tebas
authors.affiliation: Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pasquinelli
authors.affiliation: Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001552:Benzazepines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D015331:Cohort Studies; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D006207:Half-Life; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007372:Interferons; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012367:RNA, Viral / Q000097:blood; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: C587012:8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide; D000998:Antiviral Agents; D001552:Benzazepines; D007211:Indoles; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D007372:Interferons; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
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