A phase 1, randomized, dose-ranging study of GS-5816, a once-daily NS5A inhibitor, in patients with genotype 1-4 hepatitis C virus

E. Lawitz, B. Freilich, J. Link, P. German, H. Mo, L. Han, D. M. Brainard, J. McNally, T. Marbury, M. Rodriguez-Torres

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

GS-5816 is an inhibitor of the hepatitis C virus (HCV) NS5A protein that has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. The aim of this study was to evaluate the safety, antiviral activity and pharmacokinetics of once-daily doses of GS-5816 in patients with genotype 1-4 HCV infection. Patients with genotype 1-4 HCV infection were randomized to 3 days of GS-5816 at doses ranging from 5 to 150 mg or placebo. Adverse events were recorded, and plasma samples obtained for analysis of pharmacokinetics, HCV RNA and NS5A sequencing studies. GS-5816 5-150 mg for 3 days was well tolerated and resulted in rapid declines in HCV RNA that were sustained over the dosing period. In patients treated with the 150 mg dose of GS-5816, the mean maximal HCV RNA declines were 4.0, 4.0, 4.4, 3.3 and 3.5 log10 IU/mL in patients with genotype 1a, 1b, 2, 3 and 4 HCV infection, respectively. Pretreatment NS5A resistance-associated polymorphisms were detected in 31% (22/70) of patients. Genotype 1 and 3 HCV-infected patients without pretreatment NS5A resistance-associated polymorphisms had greater declines in HCV RNA than patients with resistance-associated polymorphisms. Plasma pharmacokinetics were supportive of once-daily dosing. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.

Original languageEnglish (US)
Pages (from-to)1011-1019
Number of pages9
JournalJournal of Viral Hepatitis
Volume22
Issue number12
DOIs
StatePublished - Dec 2015

Keywords

  • GS-5816
  • NS5A inhibitor
  • hepatitis C virus

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases
  • Virology

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