Evaluation of VCH-759 monotherapy in hepatitis C infection.

Abstract

BACKGROUND/AIMS:

VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC(50) 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 ve genotype 1 participants. Three cohorts received: 400mg 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 IC(90) (non protein-adjusted) for all dosing regimens. The mean maximal decrease in HCV RNA log(10) (IU/mL) was 1.97, 2.30 and 2.46 for 400mg 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> or =2 log(10) 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.

• Authors: 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
• Journal: Journal of hepatology (J Hepatol) Vol. 51 Issue 1 Pg. 39-46 (Jul 2009) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 19446909 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Carboxylic Acids
• Thiophenes
• VCH-759
• Viral Nonstructural Proteins
• NS-5 protein, hepatitis C virus

Topics

• Adult
• Antiviral Agents (adverse effects, pharmacokinetics, pharmacology)
• Carboxylic Acids (adverse effects, pharmacokinetics, therapeutic use)
• Double-Blind Method
• Female
• Hepacivirus (classification, genetics)
• Hepatitis C (drug therapy, virology)
• Humans
• Male
• Middle Aged
• Phenotype
• Thiophenes (adverse effects, pharmacokinetics, therapeutic use)
• Viral Nonstructural Proteins (antagonists & inhibitors)