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


  • The METRO study (VX03-497-205) is registered with (NCT00088504). The METRO study was funded by Vertex Pharmaceuticals Inc., the developer of MMPD. The authors had full access to the study data, and the corresponding author had final responsibility to prepare and submit the manuscript for publication.

  • Potential conflict of interest: Dr. Lee reports receiving consulting fees from AstraZeneca Pharmaceuticals, Eli Lilly and Co., and Fibrogen Inc., and grant support from Bristol-Myers Squibb, Roche, Schering-Plough Corp. Siemens, and Vertex Pharmaceuticals; Dr. Lawitz, grant support from Abbott Laboratories Anadys Pharmaceuticals, Inc., Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline GlobeImmune Inc., Human Genome Sciences, Idenix Pharmaceuticals, Idera Pharmaceuticals Intarcia Therapeutics, Inc., Medarex Inc., Merck & Co., Inc., Novartis, Roche, sanofi-aventis Schering-Plough Corp., Valeant Pharmaceuticals International, Vertex Pharmaceuticals, ViroChem Pharma (now Vertex Pharmaceuticals), and ZymoGenetics; Dr. Gordon, consulting fees and grant support from Roche, Schering-Plough Corp., and Vertex Pharmaceuticals; Dr. Afdhal, consulting and advisory fees from GlaxoSmithKline, Idenix Pharmaceuticals, Schering-Plough, and Vertex Pharmaceuticals, lecture fees from Bristol-Myers Squibb, Gilead Sciences, and Schering-Plough Corp, and grant support from Gilead Sciences, Schering-Plough Corp., and Vertex Pharmaceuticals; Dr. Poordad, consulting and advisory fees, as well as grant support, from Roche and Vertex Pharmaceuticals, and lecture fees from Roche; Dr. Bonkovsky, consulting fees from Boehringer-Ingelheim Corp. and Novartis, advisory fees from Novartis, lecture fees from Ovation (now Lundbeck Inc.), and grant support from Novartis, Roche, and Vertex Pharmaceuticals; Dr. McHutchison, consulting fees and grant support from Roche, Schering-Plough Corp., and Vertex Pharmaceuticals. Drs. Aalyson, Alam, Chandorkar and McNair are former employees of Vertex Pharmaceuticals. Drs. Bengtsson, Gharakhanian, Harding and Kauffman are employees of Vertex Pharmaceuticals.


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. (HEPATOLOGY 2009.)