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A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in previously untreated patients with chronic hepatitis C.

Abstract
Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC). This study was a double-blind, placebo-controlled dose-escalation study of a novel, selective, orally active small molecule inhibitor of IMPDH, merimepodib (VX-497 or MMPD) in combination with standard interferon-alpha (IFN-alpha). Fifty-four treatment-naive patients with genotype-1 CHC were randomized to receive IFN-alpha 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-alpha/RBV. The objectives of the study were to evaluate the tolerability of the IFN-alpha/MMPD combination and to evaluate whether MMPD had an on-treatment effect on HCV-RNA, similar to RBV when added to IFN-alpha. The drug combination was generally well tolerated; one patient at the higher dose discontinued because of elevated alanine aminotransferase levels. No pharmacokinetic interactions were evident between the two drugs. Analysis of covariance that adjusted for a baseline imbalance in HCV-RNA in the intent-to-treat population did not show any significant differences between the treatment groups, or between MMPD plus IFN-alpha compared with IFN-alpha 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-alpha compared with IFN-alpha alone (-1.78 log vs -0.86 log, P=0.037). In conclusion, the addition of a selective IMPDH inhibitor to IFN-alpha was well tolerated. In a low-dose range, the addition of MMPD may have the potential to add to the antiviral efficacy of IFN-alpha. 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 rates.
AuthorsJohn G McHutchison, Mitchell L Shiffman, Ramsey C Cheung, Stuart C Gordon, Teresa L Wright, John C Pottage Jr, Lindsay McNair, Ene Ette, Scott Moseley, John Alam
JournalAntiviral therapy (Antivir Ther) Vol. 10 Issue 5 Pg. 635-43 ( 2005) ISSN: 1359-6535 [Print] England
PMID16152757 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antiviral Agents
  • Carbamates
  • Interferon-alpha
  • N-3-(3-(3-methoxy-4-oxazol-5-ylphenyl)ureido)benzylcarbamic acid tetrahydrofuran-3-yl ester
  • Phenylurea Compounds
  • IMP Dehydrogenase
Topics
  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Antiviral Agents (administration & dosage, therapeutic use)
  • Carbamates (administration & dosage, therapeutic use)
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Hepatitis C, Chronic (drug therapy)
  • Humans
  • IMP Dehydrogenase (administration & dosage, antagonists & inhibitors, therapeutic use)
  • Injections, Subcutaneous
  • Interferon-alpha (administration & dosage, therapeutic use)
  • Male
  • Middle Aged
  • Phenylurea Compounds (administration & dosage, therapeutic use)

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