title: A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in previously untreated patients with chronic hepatitis C.
abstract: Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC). This study was a double-blind, placebo-controlled dose-escalation study of a novel, selective, orally active small molecule inhibitor of IMPDH, merimepodib (VX-497 or MMPD) in combination with standard interferon-alpha (IFN-alpha). Fifty-four treatment-naive patients with genotype-1 CHC were randomized to receive IFN-alpha 3 MIU subcutaneously three times a week, alone or in combination with 100 mg or 300 mg (every 8 h) of MMPD for 4 weeks. At the end of 4 weeks, all patients were offered 48 weeks of treatment with IFN-alpha/RBV. The objectives of the study were to evaluate the tolerability of the IFN-alpha/MMPD combination and to evaluate whether MMPD had an on-treatment effect on HCV-RNA, similar to RBV when added to IFN-alpha. The drug combination was generally well tolerated; one patient at the higher dose discontinued because of elevated alanine aminotransferase levels. No pharmacokinetic interactions were evident between the two drugs. Analysis of covariance that adjusted for a baseline imbalance in HCV-RNA in the intent-to-treat population did not show any significant differences between the treatment groups, or between MMPD plus IFN-alpha compared with IFN-alpha alone. However, the per-protocol primary efficacy analysis based on treatment-compliant patients demonstrated a greater reduction in mean HCV-RNA in the combination of 100 mg MMPD plus IFN-alpha compared with IFN-alpha alone (-1.78 log vs -0.86 log, P=0.037). In conclusion, the addition of a selective IMPDH inhibitor to IFN-alpha was well tolerated. In a low-dose range, the addition of MMPD may have the potential to add to the antiviral efficacy of IFN-alpha. Larger, longer duration trials incorporating pegylated IFN would be required to determine whether this combination, alone or with RBV, would increase either early or sustained virological response rates.
authors.affiliation: Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA. mchut001@mc.duke.edu
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Shiffman
authors.forename: Ramsey C
authors.initials: RC
authors.lastname: Cheung
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Gordon
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Wright
authors.forename: John C
authors.initials: JC
authors.lastname: Pottage
authors.forename: Lindsay
authors.initials: L
authors.lastname: McNair
authors.forename: Ene
authors.initials: E
authors.lastname: Ette
authors.forename: Scott
authors.initials: S
authors.lastname: Moseley
authors.forename: John
authors.initials: J
authors.lastname: Alam
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002219:Carbamates / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007168:IMP Dehydrogenase / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D016898:Interferon-alpha; C407002:N-3-(3-(3-methoxy-4-oxazol-5-ylphenyl)ureido)benzylcarbamic acid tetrahydrofuran-3-yl ester; D010671:Phenylurea Compounds; D007168:IMP Dehydrogenase