Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders

Abstract

on behalf of the MErimepodib TRiple cOmbination (METRO) study group Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) and ribavirin (RBV). We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P ‫؍‬ 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. Conclusion: The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.

Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models

“…Indeed, IMPDH inhibitors have shown antiviral activity in cell culture models of HCV infection 12, 56. However, at this time, no IMPDH inhibitors have obtained U.S. Food and Drug Administration approval for the treatment of hepatitis C, indicating that this may not be the only mechanism by which ribavirin exerts its antiviral activity 57, 58. Additional studies will be needed to determine if IMPDH inhibitors can effect ISG induction by IFN in cell culture models of virus infection as well as in patients.…”

Curing a viral infection by targeting the host: The example of cyclophilin inhibitors

“…If there is a significant difference in the target or pathway in vitro and in vivo , one might see a poor correlation of the effect. For example, the IMPDH inhibitor VX-497 potently inhibited HCV replication in vitro , but its efficacy in patients was more limited and variable ( McHutchison et al, 2005 , Rustgi et al, 2009 ). One possible explanation is that the level and supply of nucleotides, and thus the dependence of viral replication on their de novo synthesis, are very different in vitro and in vivo , which could significantly affect the efficacy of inhibitors modulating nucleotide metabolism.…”

Medicinal chemistry strategies toward host targeting antiviral agents

“…However, in a phase II triple combination study using 47, RBV, and IFN-α to treat genotype 1 CHC pegylated IFN and RBV nonresponders, the addition of 47 to IFN-alfa-2a and RBV failed to increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR. 107 Due to the unsatisfactory results, the clinical trials of 47 for HCV treatment was discontinued. Although 47 is a very selective IMPDH inhibitor with potent anti-HCV activity in vitro, it did not achieve similar magnitude of antiviral efficacy in patients.…”