Affiliation:
1. Rega Institute for Medical Research, KULeuven, Leuven 3000, Belgium
2. Debiopharm, Lausanne CP211, Switzerland
Abstract
ABSTRACT
Debio 025 is a potent inhibitor of hepatitis C virus (HCV) replication (J. Paeshuyse et al., Hepatology 43:761-770, 2006). In phase I clinical studies, monotherapy (a Debio 025 dose of 1,200 mg twice a day) resulted in a mean maximal decrease in the viral load of 3.6 log
10
units (R. Flisiak et al., Hepatology 47:817-826, 2008), whereas a reduction of 4.6 log
10
units was obtained in phase II studies when Debio 025 was combined with interferon (R. Flisiak et al., J. Hepatol., 48:S62, 2008). We here report on the particular characteristics of the in vitro anti-HCV activities of Debio 025. The combination of Debio 025 with either ribavirin or specifically targeted antiviral therapy for HCV (STAT-C) inhibitors (NS3 protease or NS5B [nucleoside and nonnucleoside] polymerase inhibitors) resulted in additive antiviral activity in short-term antiviral assays. Debio 025 has the unique ability to clear hepatoma cells from their HCV replicon when it is used alone or in combination with interferon and STAT-C inhibitors. Debio 025, when it was used at concentrations that have been observed in human plasma (0.1 or 0.5 μM), was able to delay or prevent the development of resistance to HCV protease inhibitors as well as to nucleoside and nonnucleoside polymerase inhibitors. Debio 025 forms an attractive drug candidate for the treatment of HCV infections in combination with standard interferon-based treatment and treatments that directly target the HCV polymerase and/or protease.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference64 articles.
1. Pharmasset announces R7128 achieves 85% rapid virologic response in a 4-week combination study for the treatment of chronic hepatitis. 2008
2. InterMune announces continuing progress on ITMN-191 (R7227). 2008
3. Initial results of phase II study with HCV protease inhibitor boceprevir in treatment-naive hepatitis C patients show a high rate of early virologic response. 2007
4. Ribavirin antagonizes inhibitory effects of pyrimidine 2',3'-dideoxynucleosides but enhances inhibitory effects of purine 2',3'-dideoxynucleosides on replication of human immunodeficiency virus in vitro
5. Highly Permissive Cell Lines for Subgenomic and Genomic Hepatitis C Virus RNA Replication
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