Evaluation of VCH-759 monotherapy in hepatitis C infection

Curtis Cooper, Eric J. Lawitz, Peter Ghali, Maribel Rodriguez-Torres, Frank H. Anderson, Samuel S. Lee, Jean Bédard, Nathalie Chauret, Roch Thibert, Isabel Boivin, Olivier Nicolas, Louise Proulx

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Background/Aims: VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC50 values versus genotype 1a/1b replicons. Methods: The antiviral activity, pharmacokinetics and tolerability of VCH-759 administered as monotherapy for 10 days with a 14 day follow-up period were evaluated in 31 treatment-nai{dotless}̈ve genotype 1 participants. Three cohorts received: 400 mg thrice (t.i.d.), 800 mg twice (b.i.d.), 800 mg t.i.d or placebo. Results: VCH-759 was well tolerated with the most frequent adverse event being gastrointestinal upset in both the active and placebo groups attributable, in part, to the dosing vehicle. VCH-759 was rapidly absorbed and trough plasma levels were at or above the IC90 (non protein-adjusted) for all dosing regimens. The mean maximal decrease in HCV RNA log10 (IU/mL) was 1.97, 2.30 and 2.46 for 400 mg t.i.d., 800 mg b.i.d. and 800 mg t.i.d. doses. Viral polymerase genotypic sequencing revealed emergence of HCV variants in a majority of participants that coincided with on-treatment viral rebound. Conclusions: VCH-759 was well tolerated and achieved a ≥ 2 log10 decline in HCV RNA with 800 mg b.i.d. and t.i.d doses. In a subset of participants, viral rebound was observed and associated with resistant variants. This data supports further evaluation of VCH-759 in combination with interferon-ribavirin treatment.

Original languageEnglish (US)
Pages (from-to)39-46
Number of pages8
JournalJournal of Hepatology
Volume51
Issue number1
DOIs
StatePublished - Jul 2009
Externally publishedYes

Keywords

  • Antiviral activity
  • Non-nucleoside NS5b inhibitor
  • Pharmacokinetics
  • Proof-of-concept study
  • Safety and tolerability
  • Variant identification

ASJC Scopus subject areas

  • Hepatology

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