(VX-497) and Interferon-Α in Previously
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Antiviral Therapy 10:635–643 A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-α in previously untreated patients with chronic hepatitis C John G McHutchison1,2*, Mitchell L Shiffman3, Ramsey C Cheung4, Stuart C Gordon5, Teresa L Wright 6, John C Pottage Jr 7, Lindsay McNair7, Ene Ette7, Scott Moseley 7 and John Alam7 1Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA 2Division of Gastroenterology, Scripps Clinic, La Jolla, CA, USA 3Hepatology Section, Virginia Commonwealth University Health System, Richmond, VA, USA 4VAPAHCS, Palo Alto, CA, USA 5William Beaumont Hospital, Royal Oak, MI, USA 6VA Medical Center, San Francisco, CA, USA 7Vertex Pharmaceuticals, Cambridge, MA, USA *Corresponding author: Tel: +1 919 668 7177; Fax: +1 919 668 7164; E-mail: [email protected] Inhibition of inosine monophosphate dehydrogenase elevated alanine aminotransferase levels. No pharmaco- (IMPDH) is one of several proposed mechanisms of action kinetic interactions were evident between the two drugs. for ribavirin (RBV), a critical component of the current Analysis of covariance that adjusted for a baseline imbal- treatment for chronic hepatitis C (CHC). ance in HCV-RNA in the intent-to-treat population did This study was a double-blind, placebo-controlled dose- not show any significant differences between the treat- escalation study of a novel, selective, orally active small ment groups, or between MMPD plus IFN-α compared molecule inhibitor of IMPDH, merimepodib (VX-497 or with IFN-α alone. However, the per-protocol primary MMPD) in combination with standard interferon-alpha efficacy analysis based on treatment-compliant patients (IFN-α). Fifty-four treatment-naive patients with genotype- demonstrated a greater reduction in mean HCV-RNA in 1 CHC were randomized to receive IFN-α 3 MIU the combination of 100 mg MMPD plus IFN-α compared subcutaneously three times a week, alone or in combination with IFN-α alone (–1.78 log vs –0.86 log, P=0.037). with 100 mg or 300 mg (every 8 h) of MMPD for 4 weeks. In conclusion, the addition of a selective IMPDH inhibitor At the end of 4 weeks, all patients were offered 48 weeks of to IFN-α was well tolerated. In a low-dose range, the treatment with IFN-α/RBV. The objectives of the study were addition of MMPD may have the potential to add to the to evaluate the tolerability of the IFN-α/MMPD combina- antiviral efficacy of IFN-α. Larger, longer duration trials tion and to evaluate whether MMPD had an on-treatment incorporating pegylated IFN would be required to deter- effect on HCV-RNA, similar to RBV when added to IFN-α. mine whether this combination, alone or with RBV, would The drug combination was generally well tolerated; one increase either early or sustained virological response patient at the higher dose discontinued because of rates. Introduction The addition of ribavirin (RBV), a broad-spectrum When combined with either standard recombinant or antiviral agent, to interferon (IFN) therapy, has proven pegylated IFN-α, RBV seems to have two effects: to be a significant advance in the treatment of patients firstly, to increase the percentage of patients who with chronic hepatitis C (CHC) infection. When used achieve HCV-RNA undetectable status as compared alone, RBV decreases alanine aminotransferase (ALT) with IFN-α alone and secondly, of the patients who levels in most patients during treatment. However, liver achieve an undetectable level of HCV-RNA, to enzymes return to baseline values when treatment is decrease the rate of breakthrough/relapse during and discontinued and, when given alone, RBV has little if after treatment. The net effect of the addition of RBV to any effect on serum HCV-RNA concentrations [1]. IFN-α is that it substantially increases the sustained © 2005 International Medical Press 1359-6535 635 JG McHutchinson et al. virological response (SVR) rate [2–5]. Although the herpes simplex virus type-1 are 12.4 µM, 1.1 µM and side-effect profiles of these drugs preclude their use in 6.3 µM, respectively [6]. These values compare with some patients, the combination of pegylated IFN-α and 44.6 µM, 20.9 µM and 162 µM, respectively, for RBV. RBV is currently the most effective therapy for patients The combination of MMPD and IFN-α shows additive with CHC. activity against encephalomyocarditis virus, a single- The major limitation of RBV therapy is the develop- stranded RNA virus. The in vitro effects have been ment of drug-induced haemolytic anaemia, with the further explored in a hepatitis C viral subgenomic majority of patients demonstrating a 2–3 g/dl decrease replicon system based on Bartenschlager’s method [10]. in haemoglobin during treatment. Decreases in haemo- In this assay, the IC50 values for MMPD, RBV and globin concentrations to less than 10 g/dl, necessitating IFN-α are 0.5 µM, 41.8 µM and 3.1 IU/ml, respectively. a reduction in the dose of RBV, have also been In the same assay, MMPD has demonstrated additive observed in approximately 8% of patients receiving activity when combined with either RBV or IFN-α [11]. combination therapy [3]. Given both the benefits and The clinical activity of MMPD monotherapy has limitations of RBV therapy, a drug that captures the been explored over the dose range 100–400 mg when clinical antiviral effects of RBV without the toxicity administered for 28 days to patients with hepatitis C would be an advance in the treatment of hepatitis C. who had previously failed treatment with IFN-α [12]. RBV was originally described as an inhibitor of the MMPD was well tolerated with only generally mild human enzyme inosine monophosphate dehydrogenase digestive system adverse events. A statistically signifi- (IMPDH), which catalyses the rate-limiting step in the cant reduction in end-of-treatment serum ALT de novo biosynthesis of guanine nucleotides. Inhibition compared with baseline was observed in patients of IMPDH reduces the intracellular levels of guanine receiving 200 mg and 400 mg MMPD. No demon- nucleotides, which are required for RNA and DNA strable change in HCV-RNA was noted. These results synthesis. Depletion of guanine nucleotides subse- are similar to those seen with RBV monotherapy. quently leads to antiproliferative and antiviral proper- The primary objective of the study was to evaluate ties. In various in vitro antiviral assays, the activity of the safety and tolerability of the IFN-α/MMPD combi- RBV is partially reversed when exogenous guanosine is nation; the secondary objective was to examine added, indicating at least some of the antiviral effect of whether MMPD had an on-treatment effect similar to RBV may be attributed to IMPDH inhibition [6]. that of RBV, that is, whether the combination of IFN-α However, the lack of full reversal indicates other mech- and MMPD enhanced the on-treatment antiviral anisms are involved and in vivo mechanisms may be activity when compared with IFN-α alone. Standard distinct from what is seen in vitro. Other proposed therapy was deferred for 4 weeks; therefore, the poten- mechanisms include inhibition of viral polymerase, tial for on-treatment effects was evaluated as change in activity as a viral mutagen and activity as a modulator HCV-RNA over 4 weeks of treatment. of TH1/TH2 (antiviral/inflammatory cytokines) responses [6–9]. The relative contribution of IMPDH Patients and methods inhibition versus other mechanisms to the clinical activity of RBV is unknown. Male and female patients aged 18–70 years with geno- Merimepodib (VX-497 or MMPD) is a novel, selec- type-1 CHC infection, not previously treated with tive and reversible inhibitor of IMPDH. MMPD antiviral therapy and candidates for IFN-α/RBV uncompetitively inhibits both isoforms of IMPDH with therapy, were enrolled in this study. All patients had Ki values that are approximately 25-fold lower than detectable serum HCV-RNA as determined by reverse those observed with RBV (7–10 nM versus 250 nM). transcription PCR, compensated liver disease (as The rationale for the development of MMPD in evidenced clinically, and by normal albumin, hepatitis C includes the possibility that a selective prothrombin time and bilirubin levels), and had no IMPDH inhibitor could lead to the clinical antiviral histological evidence of cirrhosis on liver biopsy activity of RBV without its associated toxicity, and that obtained within 3 years of study entry. Exclusion a more potent IMPDH inhibitor might have a greater criteria included a white blood cell (WBC) count <1500 antiviral effect. cells/mm3, a platelet count <100 000/mm3 and haemo- The antiviral activity of MMPD has been evaluated globin <9.5 g/dl. In addition, patients with a history of in vitro against a host of viruses including a flavivirus haemoglobinopathies or coinfection with either related to hepatitis C virus [6]. Data from these studies hepatitis B or HIV were excluded, as were those with indicate that MMPD possesses more potent broad- other causes of liver disease. In order to determine spectrum antiviral activity than RBV under the experi- whether or not the inhibition of IMPDH could add to α mental conditions. The IC50 for bovine viral diarrhoea the antiviral activity of IFN- , a high degree of study virus (a flavivirus), respiratory syncytial virus and medication compliance was required. 636 © 2005 International Medical Press Merimepodib and IFN in subjects with hepatitis C The study protocol was reviewed and approved by Assay methods institutional review boards at each of the respective Serum HCV-RNA concentrations were performed study sites, and informed consent in writing was using the quantitative NGI Superquant® RT-PCR assay obtained from each patient prior to screening and enroll- with a lower limit of detection of less than 100 ment into the study.