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Abstract Details
GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study
Rodriguez-Torres M1, Glass S2, Hill J3, Freilich B4, Hassman D5, Di Bisceglie AM6, Taylor JG7, Kirby BJ7, Dvory-Sobol H7, Yang JC7, An D7, Stamm LM7, Brainard DM7, Kim S8, Krefetz D9, Smith W10, Marbury T11, Lawitz E12. J Viral Hepat. 2016 Mar 9. doi: 10.1111/jvh.12527. [Epub ahead of print]
Author information
1Fundación de Investigación, Rio Piedras, Puerto Rico.
2PRA Health Sciences, Philadelphia, PA, USA.
3Avail Clinical Research, LLC, DeLand, FL, USA.
4Kansas City Research Institute, Kansas City, MO, USA.
5Comprehensive Clinical Research, Berlin, NJ, USA.
6Saint Louis University Medical Center, Saint Louis, MO, USA.
7Gilead Sciences, Inc., Foster City, CA, USA.
8WCCT Global, Costa Mesa, CA, USA.
9PRA Health Sciences, Marlton, NJ, USA.
10New Orleans Center for Clinical Research, University of Tennessee Medical Center, Knoxville, TN, USA.
11Orlando Clinical Research Center, Orlando, FL, USA.
12Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
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.