A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4

Bradley Vince, John M. Hill, Eric J. Lawitz, William O'Riordan, Lynn R. Webster, Daniel M. Gruener, Ricky S. Mofsen, Abel Murillo, Eileen Donovan, Jie Chen, Joseph F. McCarville, John Z. Sullivan-Bólyai, Douglas Mayers, Xiao Jian Zhou

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Background & Aims Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) non-structural protein 5A (NS5A). This study evaluated the antiviral activity, pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects infected with HCV genotype 1-4. Methods Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized to receive for 3 days placebo or samatasvir 25-100 mg per day. Plasma samples for HCV RNA, pharmacokinetics and sequencing were collected up to day 10. Results Samatasvir achieved potent antiviral activity across genotypes: mean maximum reductions from baseline were 3.2-3.6 (genotype 1a), 3.0-4.3 (genotype 1b), 3.2-3.4 (genotype 3), and 3.6-3.9 (genotype 4) log10/ml respectively; no viral rebound was observed during the 3-day treatment period. For genotype 2 HCV, samatasvir was active in subjects with NS5A L31 polymorphism at baseline (individual range 2.5-4.1 log10/ml), but showed minimal activity in those with baseline M31 polymorphism. Samatasvir exhibited a long plasma half-life of approximately 20 h which supports once daily dosing. Samatasvir was well tolerated in all subjects with no safety-related discontinuations or serious adverse events. The most common adverse events included constipation, nausea and headache and occurred at similar frequency in active and placebo subjects. All events were mild or moderate in intensity. There were no patterns or dose dependence of adverse events, vital signs, laboratory parameters or electrocardiograms. Conclusions Samatasvir 25-100 mg monotherapy for 3 days was well tolerated and induced a rapid and profound reduction in plasma HCV RNA in subjects infected with HCV genotype 1-4. Samatasvir is being evaluated in combination with other direct-acting antiviral agents in subjects with HCV infection.

Original languageEnglish (US)
Pages (from-to)920-927
Number of pages8
JournalJournal of Hepatology
Volume60
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

Keywords

  • Chronic hepatitis C
  • Direct-acting antiviral agents
  • IDX719
  • NS5A
  • Pan-genotypic antiviral activity
  • Pharmacokinetics
  • Samatasvir

ASJC Scopus subject areas

  • Hepatology

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