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.”

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.