icon-folder.gif   Conference Reports for NATAP  
  HEP DART 2003: Frontiers in drug development for Viral Hepatitis
December 14-18, 2003
Kauai, Hawaii
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Merimepodib (VX-497), New HCV Drug
  Reported by Jules Levin
At the conference there were a number of presentations on early ongoing research into new drugs for treatment of HCV including polymerase inhibitor programs. Clearly, there is a large commitment from drug companies in conducting research and development for new HCV drugs.
A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial of Merimepodib (VX-497) and Interferon Alfa in Previously Untreated Patients with Chronic Hepatitis C: Final Results
JG Muhutchison (Duke University Medical Center), Vertex Pharmaceuticals and colleagues.
Inhibition of inosine monophospahe dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin., a critical component of current treatment for chronic hepatitis C (CHC). This study looks at a novel selective, orally active small bioavailable molecule inhibitor of IMPDH, merimepodib. Preliminary results of this study were presented at AASLD in 2001. These are the final results. Following this is a report from a Phase II study of this drug also presented at HEP DART.
54 treatment-naïve patients with genotype-1 CHC were randomized to receive interferon alpha (IFN-a), 3 million units subcutaneously three times a week, alone or in combination with 100 mg or 300 mf q8h of merimepodib for 4 weeks. At the end of 4 weeks all patients were offered 48 weeks of treatment with IFN-a/ribavirin.
The combination of IFN-a and merimepodib was generally well tolerated; one patient at the higher dose discontinued because of elevated ALT levels. No pharmacokinetic interactions were evident between the two drugs. The “intent to treat” (ITT) analysis showed a small but not statistically significant decrease in log HCV RNA from baseline to the end of treatment. However, the primary efficacy analysis specified in the study protocol was based on treatment compliant patients (“evaluable for efficacy”), analysis of which demonstrated an enhanced antiviral effect at the 100 mg merimepodib dose level compared to placebo (evaluable-for-efficacy p=0.037; mean log reduction: -0.86 for IFN-a and –1.78 for IFN-a/merimepodib).
Lesser reductions in HCV RNA levels were seen at the 300 mg dose level. Twelve patients achieved a sustained virologic response at 6 months follow-up after completing IFN-a/ribavirin treatment, with equal distribution across the treatment arms.
The authors concluded that the addition of a selective IMPDH inhibitor to IFN-a was tolerated and at a low dose may lead to an additional antiviral effect. Larger, longer duration treatment trials are nowrequired to further evaluate the efficacy of this combination alone with or witho ribavirin. A clinical study evaluating the merimepodib in combination with pegylated interferon and ribavirin is ongoing.
A second study was also presented at HEP DART.
A Phase II, Placebo-Controlled Study of Merimepodib (VX-497), Pegylated Interferon-Alfa, and Ribavirin in Patients with Chronic Hepatitis C Non-Responsive to Therapy with Interferon-alfa and Ribavirin: week 24 results
P Marcellin (Hopital Beaujon, Clichy, France), Vertex Pharma and colleagues.
This study evaluates the addition of MPH to pegylated IFN and ribavirin (RBV), in patients who were non-responders to IFN and RBV.
31 patients with genotyp 1 CHC who showed no response to prior IFN and RBV were randomized to receive MPB, 25 or 50 mg q12h or placebo orally, in combination with pegylated IFN (PegIntron 1.5 ug/kg/wk) and RBV (800, 1000 or 1200 mg/day based on body weight) for 24 weeks (core study). HCV RNA was assessed in the quantitative Roche Amplicor assay. Any samples testing below the lower limit of quantification (600 IU/ml) were tested in the qualitative assay to confirm undetectable status. Patients with no detectable virus at week 24 received the same treatment for an additional 24 weeks, then were followed post-treatment to ascertain sustained response. This report presents the anti-viral and safety data from the core study. Blinded treatment and follow-up is continuing.
The combination of PegIntron, RBV and MPB was well tolerated. Mild to moderate diarrhea and abdominal pain, and mild rash appeared to be associated with MPB because they were reported in recipients and in 18024% of MPB recipients. There were no clinically notable differences across treatment groups for hemotologic parameters. Median HCV viral load and ALT were similar in the three treatment groups at baseline. Across the three treatment groups, a dose-dependent increase in the proportion of patients with undetectable HCV RNA at week 24 was evident: 33% in the placebo and 25 mg MPB groups, and 86% in the 50 mg MPB group (p=0.03); Jonckheere-Terpstra test). Median HCV RNA at week 24 was 5.16, 5.96, and 2.48 log IU/ml for the placebo, 25 mg and 50 mg treatment groups, respectively. Median ALT was lower at week 24 in the 50 mg MPB group (18.5 U/L) compared to placebo (45 U/L) and the 25 mg MPB group (41 U/L).
The authors concluded that the addition of MPB to pegylated IFN and RBV was well tolerated and showed an enhanced anti-viral effect as compared with pegylated IFN and RBV alone at week 24 in an IFN-RBV non-responder population. These clinical data, are consistent with recent replicon data suggesting a potential mechanism for synergistic enhancement of the anti-viral effect of RBV by IMPDH inhibition. Follow-up of patients in this study is continuing, to assess end of treatment and sustained response.