Novel HCV Polymerase Inhibitor VCH-759 Monotherapy
Demonstrates Promising Antiviral Activity In
an attempt to improve sustained treatment response rates in people with chronic
hepatitis C, researchers continue to explore new directly targeted antiviral
agents. Data
on one such agent, VCH-759, were reported in a late-breaker presentation at the
58th Annual Meeting of the American Association for the
Study of Liver Diseases in Boston (November 2-6, 2007).
VCH-759 is
a novel orally bioavailable non-nucleoside inhibitor of HCV RNA-dependent RNA
polymerase. In laboratory studies to date, it has demonstrated activity against
genotype 1a and 1b HCV replicons at sub-micromolar concentrations
Investigators
undertook a multiple ascending-dose study to assess the effect on HCV viral kinetics,
viral resistance, pharmacokinetics, safety, and tolerability of VCH-759 given
as monotherapy for 10 days, with a 14-day follow-up period.
In this trial,
3 cohorts of treatment-naive chronic hepatitis C patients with HCV genotype 1
received either placebo or VCH-759 at doses of 400 mg three-times-daily, 800 mg
three-times-daily, or 800 twice-daily. In total, 32 subjects were enrolled and
completed the study (9 each in the placebo and the 2 three-times-daily VCH-759
dose groups; 5 in the twice-daily dose group).
HCV viral load was determined
using the Roche Amplicor assay with a lower limit of quantification of 600 IU/mL.
VCH-759 plasma levels were assessed over 6 hours for the three-times-daily regimen
and over 12 hours for the twice-daily regimen on days 1 and 10, and daily, prior
to the morning dose, on days 1 to 11.
Results
• VCH-759 was rapidly absorbed, with
peak plasma levels at day 1 of 1857 ng/mL for the 400 mg three-times-daily dose,
3675 ng/mL for the 800 mg three-times-daily dose, and 4627 ng/mL for the 800 mg
twice-daily dose.
• All participants
experienced a greater than 1 log reduction in HCV RNA, with values ranging from
1.4 to 2.6 log10 for the 400 mg three-times-daily dose, 1.5 to 2.9 log10 for the
800 mg twice-daily dose, and 1.2 to 3.3 log10 for the 800 mg three-times-daily
dose.
• The mean maximal decreases
in HCV RNA were 1.9 log10 for the 400 mg three-times-daily dose, 2.3 log10 for
the 800 mg twice-daily dose, and 2.5 log10 for the 800 mg three-times-daily dose.
• VCH-759 trough plasma levels
before the morning dose were higher than the 90% inhibitory concentration (420
ng/mL) between days 2 and 11 for the 800 mg three-times-daily dose and between
days 2 and 7 for the 800 mg twice-daily dose.
•
VCH-759 was well tolerated, with the most frequent adverse events
being gastrointestinal disorders reported in both the active drug and placebo
groups.
Conclusion
VCH-759
achieved a 2 log10 or larger decline in HCV RNA at doses of 800 mg [three-times-daily]
and [twice-daily]," the investigators concluded. "VCH-759 was well tolerated
with no serious adverse events and no discontinuation."
They added
that genetic sequencing of NS5B is ongoing, and recommended that, "Further
studies combining VCH-759 with current therapies are warranted."
Ottawa
Hospital, Ottawa, Ontario, Canada; Alamo Medical Research, San Antonio, TX; McGill
University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada; Fundacion
de Investigacion de Diego, San Juan, PR; Liver and Intestinal Research Center,
Vancouver, BC, Canada; University of Calgary, Calgary, Alberta, Canada; ViroChem
Pharma Inc, Laval, Quebec, Canada.
12/07/07 Reference
C
Cooper, EJ Lawitz, P Ghali, and others. 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.
58th Annual Meeting of the American Association for the Study of Liver Diseases.
Boston, MA, November 2-6, 2007. Abstract LB11.
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