title: GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study.
abstract: GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.
authors.affiliation: Fundación de Investigación, Rio Piedras, Puerto Rico.
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez-Torres
authors.affiliation: PRA Health Sciences, Philadelphia, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Glass
authors.affiliation: Avail Clinical Research, LLC, DeLand, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hill
authors.affiliation: Kansas City Research Institute, Kansas City, MO, USA.
authors.forename: B
authors.initials: B
authors.lastname: Freilich
authors.affiliation: Comprehensive Clinical Research, Berlin, NJ, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hassman
authors.affiliation: Saint Louis University Medical Center, Saint Louis, MO, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Di Bisceglie
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Taylor
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Kirby
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: An
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Stamm
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: WCCT Global, Costa Mesa, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.affiliation: PRA Health Sciences, Marlton, NJ, USA.
authors.forename: D
authors.initials: D
authors.lastname: Krefetz
authors.affiliation: New Orleans Center for Clinical Research, University of Tennessee Medical Center, Knoxville, TN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Smith
authors.affiliation: Orlando Clinical Research Center, Orlando, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Marbury
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lawitz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D003521:Cyclopropanes; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D047028:Macrocyclic Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D011392:Proline / Q000031:analogs & derivatives; D011810:Quinoxalines; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D010919:Placebos; D011810:Quinoxalines; D013449:Sulfonamides; C000619503:voxilaprevir; D011392:Proline; D007930:Leucine
keywords: GS-9857; NS3/4A protease inhibitor; hepatitis C virus