Evaluation of VCH-759 monotherapy in hepatitis C infection.
OBJECTIVE
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.
Cooper
Curtis
C
The Ottawa Hospital, Division of Infectious Disease, Ottawa, ON, Canada K1H 8L6. ccooper@ottawahospital.on.ca
Lawitz
Eric J
EJ
Ghali
Peter
P
Rodriguez-Torres
Maribel
M
Anderson
Frank H
FH
Lee
Samuel S
SS
Bédard
Jean
J
Chauret
Nathalie
N
Thibert
Roch
R
Boivin
Isabel
I
Nicolas
Olivier
O
Proulx
Louise
L
D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D016174:Hepacivirus / Q000145:classification / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D002264:Carboxylic Acids; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C542785:VCH-759; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase