1. A double-blind, randomized, placebo-controlled study to assess the safety, antiviral activity and pharmacokinetics of GSK2336805 when given as monotherapy and in combination with peginterferon alfa-2a and ribavirin in hepatitis C virus genotype 1-infected treatment-naive subjects.
- Author
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Gardner S, Cutrell A, Elko-Simms C, Adkison K, Hamatake R, Walker J, Rodriguez-Torres M, and Hong Z
- Subjects
- Adult, Aged, Antiviral Agents adverse effects, Biomarkers blood, Carbamates adverse effects, Double-Blind Method, Drug Administration Schedule, Drug Interactions, Drug Therapy, Combination, Female, Genotype, Hepacivirus enzymology, Hepacivirus genetics, Hepatitis C, Chronic diagnosis, Hepatitis C, Chronic virology, Humans, Interferon-alpha adverse effects, Male, Middle Aged, Phenotype, Polyethylene Glycols adverse effects, Puerto Rico, RNA, Viral blood, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Ribavirin adverse effects, Treatment Outcome, United States, Valine administration & dosage, Valine adverse effects, Valine pharmacokinetics, Viral Load, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins metabolism, Antiviral Agents administration & dosage, Antiviral Agents pharmacokinetics, Carbamates administration & dosage, Carbamates pharmacokinetics, Hepacivirus drug effects, Hepatitis C, Chronic drug therapy, Interferon-alpha administration & dosage, Polyethylene Glycols administration & dosage, Ribavirin administration & dosage, Valine analogs & derivatives
- Abstract
Background & Aims: GSK2336805 is a HCV NS5A inhibitor for chronic hepatitis C (CHC). In a prior Phase I study, GSK2336805 was well tolerated and had an antiviral and pharmacokinetic profile suitable for once-daily administration. This 28-day, double-blind, randomized, placebo-controlled study evaluated once daily GSK2336805 60 mg alone or in combination with peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) (PEG/RIBA) in treatment-naive genotype 1 CHC subjects., Methods: Five centres enrolled 16 subjects in the USA and Puerto Rico who received GSK2336805 + PEG/RIBA or placebo + PEG/RIBA., Results: Following a single monotherapy dose of GSK2336805 on day 1, median reduction from baseline in HCV RNA was -2.96 log10 (N = 11) vs. -0.13 log10 (N = 4) for placebo. With the addition of PEG/RIBA on day 2, subjects receiving GSK2336805 exhibited greater decreases in viral load over the 28-day treatment period as compared with placebo. At day 28, median reduction from baseline was -4.86 log10 (N = 9) in the GSK2336805 + PEG/RIBA group as compared with -1.98 log10 (N = 4) in the placebo + PEG/RIBA group. At day 28, rapid virological response (RVR) occurred in 8/11 (73%) of the GSK2336805 + PEG/RIBA subjects as compared with 1/4 (25%) of the placebo + PEG/RIBA subjects. Adverse events were consistent with those reported in clinical trials of peginterferon and ribavirin, and no unique adverse events appeared to be associated with GSK2336805., Conclusions: GSK2336805 is a potent NS5A inhibitor that showed a substantial antiviral effect as a monotherapy and in combination with peginterferon and ribavirin. ClinicalTrials.gov Identifier: NCT01439373., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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