Antiviral Activity and Safety of 3 Different Doses of Mifepristone in Hepatitis C Infected Patients

Hepatitis C Virus Infection Clinical Trial

Official title: A Randomized, Open-label Phase II Trial of the Anti-HCV Activity and Safety of VGX-410 (Mifepristone) at 3 Dose Levels in HCV Infected Patients

Status Completed

Clinical Trial Summary

Hepatitis C virus (HCV) infects approximately 170 million people worldwide. The current standard- of- care therapy of chronic HCV infection is a regimen of subcutaneously administered (pegylated)-interferon-α and ribavirin for 24 weeks (for genotypes 2 and 3) to 48 weeks (for genotype 1). The sustained viral response rates (SVR) in patients infected with genotypes 2 and 3 are ~80% but remain <50% in patients infected with genotype 1. The treatment is quite toxic with approximately 30% of patients experiencing adverse events (i.e. depression, fever, anemia, fatigue) requiring dose reduction or discontinuation of therapy. This regimen is contraindicated in women who are pregnant and in patients with decompensated liver disease. The absence of acceptable therapies for many patients with HCV infections makes new therapies desirable for this disease.

Clinical Trial Description

The 341-nucleotide 5' non-translated region is the most conserved part of the hepatitis C virus (HCV) genome. It contains a highly structured internal ribosomal entry site (IRES) that mediates cap-independent initiation of translation of the viral polyprotein by a mechanism that is unprecedented in eukaryotes. The first step in translation initiation is assembly of eukaryotic initiation factor (eIF) 3, eIF2, GTP, initiator tRNA and a 40S ribosomal subunit into a 43S preinitiation complex (1, 2). The IRES contains sites that bind independently with the eIF3 and 40S ribosomal subunit components of 43S complexes, and structural determinants that ensure the correct spatial orientation of these binding sites so that the 48S complex assembles precisely at the initiation codon. Since inhibiting this early translation of viral protein should block HCV replication downstream, this early critical step in replication is of great interest as a drug target. All genotypes of HCV use the same pathway; this drug target should be effective for all HCV genotypes.

VGX-410 represents the first drug in a novel class of HCV IRES inhibitors under development. VGX-410 is an orally active and bioavailable, small-molecule, organic drug. Because a related formulation of mifepristone has been previously approved by the FDA for another indication (medical abortion), there are pre-existing data from animal toxicity tests showing the safety of this compound at very high doses (5 mg/kg for 6 months in rats and macaques). In addition, chronic administration (up to 200 mg/day) of this compound for the experimental treatment of a variety of malignant and non-malignant conditions has been well tolerated in non-HCV-infected subjects for up to 1 year (3-6).

In cell culture tests, VGX-410 has been shown to be effective in inhibiting HCV replication with the 50% and 90% effective antiviral concentrations (EC50 and EC90) of 2 and 10 μM, respectively. Furthermore, VGX-410 was shown to act synergistically with interferon-a (IFN-a), the most widely-used drug treatment option available today. When used in combination with a low dose IFN-a at 1 IU/ml, EC90 of VGX-410 was reduced to 3 µM. Moreover, since VGX-410 inhibits viral replication by blocking the cellular protein complex for HCV IRES, there is reduced potential for viral mutation and resistance to this drug.

From these in vitro data, we would expect to observe 50 to 90% anti-HCV effects in humans at serum drug concentrations of 2 to 10 μM, respectively. Moreover, we compiled the drug concentration results from several previously-reported clinical data on the level of steady-state concentrations in patients who took repeat daily doses of mifepristone (>4 days). For instance, repeated oral administration of 100 and 200-mg mifepristone daily for 4 days achieved maximum plasma levels of 4.5 and 5.4 μM, respectively (9). ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C Virus Infection
• Virus Diseases

• NCT number: NCT00255177
• Study type: Interventional
• Source: VGX Pharmaceuticals, LLC
• Status: Completed
• Phase: Phase 2
• Start date: November 2005
• Completion date: January 2008