GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study

  • J Viral Hepat. 2016 Aug;23(8):614-22. doi: 10.1111/jvh.12527.
M Rodriguez-Torres  1 ,  S Glass  2 ,  J Hill  3 ,  B Freilich  4 ,  D Hassman  5 ,  A M Di Bisceglie  6 ,  J G Taylor  7 ,  B J Kirby  7 ,  H Dvory-Sobol  7 ,  J C Yang  7 ,  D An  7 ,  L M Stamm  7 ,  D M Brainard  7 ,  S Kim  8 ,  D Krefetz  9 ,  W Smith  10 ,  T Marbury  11 ,  E Lawitz  12
Affiliations
  • 1. Fundación de Investigación, Rio Piedras, Puerto Rico.
  • 2. PRA Health Sciences, Philadelphia, PA, USA.
  • 3. Avail Clinical Research, LLC, DeLand, FL, USA.
  • 4. Kansas City Research Institute, Kansas City, MO, USA.
  • 5. Comprehensive Clinical Research, Berlin, NJ, USA.
  • 6. Saint Louis University Medical Center, Saint Louis, MO, USA.
  • 7. Gilead Sciences, Inc., Foster City, CA, USA.
  • 8. WCCT Global, Costa Mesa, CA, USA.
  • 9. PRA Health Sciences, Marlton, NJ, USA.
  • 10. New Orleans Center for Clinical Research, University of Tennessee Medical Center, Knoxville, TN, USA.
  • 11. Orlando Clinical Research Center, Orlando, FL, USA.
  • 12. Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
PMID: 26957110 DOI: 10.1111/jvh.12527
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.

Keywords
GS-9857; NS3/4A protease inhibitor; hepatitis C virus.
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