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

Liver International

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

Stephen Gardner^1,*, Amy Cutrell¹, Cindy Elko-Simms², Kimberly Adkison¹, Robert Hamatake¹, Jill Walker¹, Maribel Rodriguez-Torres³, Zhi Hong¹

DOI: 10.1111/liv.12334

This article is protected by copyright. All rights reserved.

Publication History

Accepted manuscript online: 25 SEP 2013 06:46AM EST
Manuscript Accepted: 6 SEP 2013
Manuscript Revised: 22 AUG 2013
Manuscript Received: 10 JUN 2013

Keywords: GSK2336805; Peginterferon alfa-2a; Ribavirin; Hepatitis C; direct acting antiviral

Abstract

Background

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.

Aims

The current 28-day, double-blind, randomized, placebo-controlled study evaluated once daily GSK2336805 60mg 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

5 centers 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) versus -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 virologic 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.

Source