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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.

Abstract：

BACKGROUND/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.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Marcellin P,Horsmans Y,Nevens F,Grange JD,Bronowicki JP,Vetter D,Purdy S,Garg V,Bengtsson L,McNair L,Alam J

doi

10.1016/j.jhep.2007.03.028

subject

Has Abstract

pub_date

2007-10-01 00:00:00

pages

476-83

issue

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(07)00345-5

journal_volume

pub_type

杂志文章,多中心研究,随机对照试验

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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.