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

• Published in: Journal of hepatology 2007-10, Vol.47 (4), p.476
• Main Authors: Marcellin, Patrick, Horsmans, Yves, Nevens, Frederik, Grange, Jean-Didier, Bronowicki, Jean-Pierre, Vetter, Denis, Purdy, Susan, Garg, Varun, Bengtsson, Leif, McNair, Lindsay, Alam, John
• Format: Article
• Language: English
• Subjects: Adult; Antiviral Agents - therapeutic use; Carbamates - pharmacokinetics; Carbamates - pharmacology; Carbamates - therapeutic use; Drug Therapy, Combination; Female; Hepacivirus - isolation & purification; Hepatitis C, Chronic - drug therapy; Humans; Interferon-alpha - pharmacokinetics; Interferon-alpha - pharmacology; Interferon-alpha - therapeutic use; Male; Middle Aged; Phenylurea Compounds - pharmacokinetics; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Placebos; Polyethylene Glycols; Recombinant Proteins; Ribavirin - pharmacokinetics; Ribavirin - pharmacology; Ribavirin - therapeutic use; RNA, Viral - blood; Treatment Outcome
• ISSN: 0168-8278

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. 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. 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. 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.