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Antiviral activity of the non-nucleoside polymerase inhibitor, VCH-759, in chronic Hepatitis C patients:Results from a randomized, double-blind, placebo -controlled, ascending multiple dose study
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Reported by Jules Levin
AASLD, Nov 2-6, 2007, Boston, MA
C. Cooper1; E. J. Lawitz2; P. Ghali3; M. Rodriguez-Torres4; F. H. Anderson5; S. S. Lee6; L. Proulx7
1. Department of Internal Medicine, Division of Infectious Disease, The Ottawa Hospital, Ottawa, ON, Canada.
2. Alamo Medical Research, San Antonio, TX, USA.
3. Department of Gastroenterology and Hepatololy, McGill University Health Center, Royal Victoria Hospital, Montréal, QC, Canada.
4. Fundacion de Investigacion de Diego, San Juan, PR, USA.
5. Liver and Intestinal Research Center, Vancouver, BC, Canada.
6. Liver Unit, University of Calgary, Calgary, AB, Canada.
7. ViroChem Pharma Inc, Laval, QC, Canada.
ABSTRACT
Background: VCH-759 is a novel, orally bioavailable non-nucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase. It has demonstrated sub-micromolar IC50s against the HCV replicons of genotype 1a and 1b.
Methods: This multiple ascending dose study was designed to assess the effect on viral kinetics, viral resistance, pharmacokinetics, safety and tolerability of VCH-759 given as monotherapy for 10 days with a 14-day follow-up period. Three cohorts of treatment-naive chronic hepatitis C patients infected with HCV genotype 1 received either placebo, 400 mg tid, 800 mg tid or 800 mg bid. Viral loads were determined using the Roche Amplicor assay (lower limit of quantification=600 IU/ml).
VCH-759 plasma levels were assessed over 6 hours for the tid regimen and over 12 hours for the bid regimen on Days 1 and 10 and daily, prior to the morning dose, on Days 1 to 11.
Results: Thirty-two (32) subjects were enrolled and completed the study (9: placebo, 9: 400mg tid, 9: 800 mg tid, 5: 800 mg bid). VCH-759 was rapidly absorbed with peak plasma levels of 1857 ± 773 ng/ml, 3,675 ± 2,213 ng/ml and 4,627 ± 1688 ng/ml at Day 1 for the 400 mg tid, 800 mg tid and 800 mg bid doses respectively.
All subjects had more than a one log reduction with values ranging between 1.4 and 2.6 log10 for the 400 mg tid dose, 1.5 and 2.9 log10 for the 800 mg bid dose and 1.2 and 3.3 log10 for the 800 mg tid dose. The mean maximal decrease in HCV RNA log10 was 1.9, 2.3 and 2.5 for the 400 mg tid, 800 mg bid and 800 mg tid doses respectively. The plasma levels at trough (before the morning dose) were higher than the IC90 (420 ng/ml) between Days 2 and 11 for 800 mg tid and between Days 2 and 7 for 800 mg bid.
VCH-759 was well tolerated with the most frequent adverse events being gastrointestinal disorders (most likely due to the formulation vehicle used) reported in both the active and the placebo groups.
Conclusions: VCH 759 achieved a 2 log10 or larger decline in HCV RNA at doses of 800 mg tid and bid. VCH-759 was well tolerated with no serious adverse events and no discontinuation. Genetic sequencing of NS5B is ongoing. Further studies combining VCH-759 with current therapies are warranted.
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