title: Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C.
abstract: Hepatitis C virus (HCV) protease inhibitors combined with pegylated alfa interferon-ribavirin have demonstrated improved efficacy compared with pegylated alfa interferon-ribavirin alone for the treatment of chronic hepatitis C. Asunaprevir (BMS-650032), a novel HCV NS3 protease inhibitor in clinical development, was evaluated for safety, antiviral activity, and resistance in four double-blind, placebo-controlled, sequential-panel, single- and multiple-ascending-dose (SAD and MAD) studies in healthy subjects or subjects with chronic HCV genotype 1 infection. In SAD studies, subjects (healthy or with chronic HCV infection) were randomized to receive asunaprevir in dose groups of 10 to 1,200 mg or a placebo. In MAD studies, healthy subjects were randomized to receive asunaprevir in dose groups of 10 to 600 mg twice daily or a placebo for 14 days; subjects with HCV infection received asunaprevir in dose groups of 200 to 600 mg twice daily, or a placebo, for 3 days. Across all four studies, headache and diarrhea were the most frequent adverse events in asunaprevir recipients. Asunaprevir at doses of 200 to 600 mg resulted in rapid HCV RNA decreases from the baseline; maximal mean changes in HCV RNA over time were 2.7 and 3.5 log(10) IU/ml in the SAD and MAD studies, respectively. No enrichment of signature asunaprevir-resistant viral variants was detected. In conclusion, the novel NS3 protease inhibitor asunaprevir, when administered at single or multiple doses of 200 to 600 mg twice daily, is generally well tolerated, achieving rapid and substantial decreases in HCV RNA levels in subjects chronically infected with genotype 1 HCV.
authors.affiliation: Bristol-Myers Squibb, Research and Development, Hopewell, New Jersey, USA. claudio.pasquinelli@bms.com
authors.forename: Claudio
authors.initials: C
authors.lastname: Pasquinelli
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.forename: Criselda
authors.initials: C
authors.lastname: Villegas
authors.forename: Katrina
authors.initials: K
authors.lastname: Sandy
authors.forename: Pamela
authors.initials: P
authors.lastname: Sheridan
authors.forename: Anna
authors.initials: A
authors.lastname: Persson
authors.forename: Shu-Pang
authors.initials: SP
authors.lastname: Huang
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernandez
authors.forename: Amy K
authors.initials: AK
authors.lastname: Sheaffer
authors.forename: Paul
authors.initials: P
authors.lastname: Scola
authors.forename: Thomas
authors.initials: T
authors.lastname: Marbury
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Ronald
authors.initials: R
authors.lastname: Goldwater
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.forename: Michael
authors.initials: M
authors.lastname: Demicco
authors.forename: David
authors.initials: D
authors.lastname: Wright
authors.forename: Michael
authors.initials: M
authors.lastname: Charlton
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kraft
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Lopez-Talavera
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D012367:RNA, Viral / Q000187:drug effects; D012093:Replicon; D018401:Sample Size; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D007546:Isoquinolines; D012367:RNA, Viral; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C571889:asunaprevir