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Phase 2 study of the combination of merimepodib with peginterferon-alpha2b, and ribavirin in nonresponders to previous therapy for chronic hepatitis C.

AbstractBACKGROUND/AIMS:
While combination of peginterferon-alpha (PEG-IFN) and ribavirin (RBV) therapy is the current standard of care for chronic hepatitis C (CHC), only 44-51% of genotype-1 patients achieve a sustained virological response (SVR), and both agents produce treatment-limiting toxicities. In the hepatitis C virus (HCV) replicon system, merimepodib (MMPD), a novel, selective inhibitor of inosine monophosphate dehydrogenase, has shown potent antiviral effects.
METHODS:
This randomized, placebo-controlled, double-blind study evaluated the safety and antiviral activity of PEG-IFN-alpha2b and RBV combined with either placebo, 25mg MMPD every 12h (q12h), or 50mg MMPD q12h in interferon-alpha (IFN) and RBV nonresponders. After 24 weeks of treatment, subjects with undetectable HCV RNA were proposed to continue assigned treatment for up to 24 additional weeks.
RESULTS:
The PEG-IFN-alpha, RBV, and MMPD combination was well tolerated at both doses. After 24 weeks, the proportion of HCV RNA undetectable subjects was 8/11 (73%) in the 50-mg MMPD group, 2/10 (20%) in the 25-mg MMPD group, and 3/10 (30%) in the placebo group (P=0.02, Jonckheere-Terpstra test for increasing dose response). Ten subjects entered and completed an extension study, at Week 48, 2 of 2 (100%) of the 25-mg and 3 of 5 (60%) of the 50-mg subjects remained HCV RNA undetectable, compared with 3 of 3 (100%) of the placebo subjects. At Follow-up Week 24, 2 (100%) of the 25-mg , and 1 (25%) of the 50-mg subjects remained undetectable, compared with 1 (33%) of the placebo subjects. Pharmacokinetic and pharmacodynamic analyses showed a correlation between MMPD exposure and early virological response at week 12, but not with hemoglobin decreases often associated with RBV.
CONCLUSIONS:
In conclusion, PEG-IFN-alpha2b and RBV combined with 50 mg MMPD q12h was well tolerated and induced virological response with undetectable HCV RNA in IFN-alpha and RBV nonresponders.
AuthorsPatrick Marcellin, Yves Horsmans, Frederik Nevens, Jean-Didier Grange, Jean-Pierre Bronowicki, Denis Vetter, Susan Purdy, Varun Garg, Leif Bengtsson, Lindsay McNair, John Alam
JournalJournal of hepatology (J Hepatol) Vol. 47 Issue 4 Pg. 476-83 (Oct 2007) ISSN: 0168-8278 [Print] Netherlands
PMID17629590 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Carbamates
  • Interferon alpha-2
  • Interferon-alpha
  • N-3-(3-(3-methoxy-4-oxazol-5-ylphenyl)ureido)benzylcarbamic acid tetrahydrofuran-3-yl ester
  • Phenylurea Compounds
  • Placebos
  • RNA, Viral
  • Recombinant Proteins
  • Polyethylene Glycols
  • Ribavirin
  • peginterferon alfa-2b
Topics
  • Adult
  • Antiviral Agents (therapeutic use)
  • Carbamates (pharmacokinetics, pharmacology, therapeutic use)
  • Drug Therapy, Combination
  • Female
  • Hepacivirus (isolation & purification)
  • Hepatitis C, Chronic (drug therapy)
  • Humans
  • Interferon alpha-2
  • Interferon-alpha (pharmacokinetics, pharmacology, therapeutic use)
  • Male
  • Middle Aged
  • Phenylurea Compounds (pharmacokinetics, pharmacology, therapeutic use)
  • Placebos
  • Polyethylene Glycols
  • RNA, Viral (blood)
  • Recombinant Proteins
  • Ribavirin (pharmacokinetics, pharmacology, therapeutic use)
  • Treatment Outcome

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