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A
Dose Escalation Study of Merimepodib (VX-497) Plus Interferon
Alfa among Treatment-naïve HCV Patients
Inhibition
of inosine monophosphate dehydrogenase (IMPDH) is one of several
proposed mechanisms of action for ribavirin (RBV), which is a critical component of the current
standard of care for treatment of chronic hepatitis
C (CHC).
The current report was a double-blind, placebo-controlled
dose escalation study
of an orally active small molecule inhibitor of IMPDH, merimepodib
(MMPD), aka VX-497.
Fifty-four
treatment-naive patients with genotype1 CHC were randomized to receive standard
IFN-alfa 3 MIU subcutaneously three times a week, alone or in combination with
100 mg or 300 mg (every 8 h) of MMPD for 4 weeks.
At
the end of 4 weeks, all patients were offered 48 weeks of
treatment
with IFN-alfa/RBV.
The
objectives of the study were to evaluate the tolerability
of the IFN-alfa/MMPD
combination and to evaluate whether MMPD had an on-treatment effect on HCV RNA,
similar to RBV when added to IFN-alfa.
Results
· The
drug combination was generally well tolerated. One patient
at the higher dose discontinued because of elevated alanine
aminotransferase (ALT) levels.
· No
pharmacokinetic
interactions were evident between the two drugs.
· Intent-to-treat
analysis did not show any significant differences between
the treatment groups, or between MMPD plus IFN-alfa compared
with IFN-alfa alone.
· However,
the per-protocol primary efficacy analysis based on treatment-compliant
patients demonstrated a greater reduction in mean HCV RNA
in the combination of 100 mg MMPD plus IFN-alfa compared with
IFN-alfa alone (–1.78 log vs –0.86 log, P=0.037).
“The
addition of a selective IMPDH inhibitor to IFN-alfa was well
tolerated,” write the authors in their conclusion. Further,
they state, “In a low-dose range, the addition of MMPD may
have the potential to add to the antiviral efficacy of IFN-alfa.”
“Larger,
longer duration trials incorporating pegylated
IFN would be required to determine whether this
combination, alone or with RBV, would increase either early
or sustained
virological response (SVR) rates.”
09/23/05
Reference
J
G McHutchison and others. A randomized, double-blind, placebo-controlled
dose-escalation trial of merimepodib (VX-497) and interferon-alpha
in previously untreated patients with chronic hepatitis C.
Antiviral Therapy 10(5): 635-643. September 2005.
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