Conference Reports for NATAP

Presented at the 22nd Conference of the Asian Pacific Association for the Study of the Liver (APASL) Taipei, Taiwan February 16-19, 2012 Back

Antiviral Activity of GS-9451, an HCV Specific NS3 Protease Inhibitor, in a Three-Day, Dose-Ranging, Monotherapy Study in Patients with Genotype 1 Hepatitis C Infection       Reported by Jules Levin 22nd Conference of the Asian Pacific Association for the Study of the Liver (APASL) February 16-19, 2012 Taipei, Taiwan J. Yang1, H. Mo1, H. Dvory-Sobol1, E. Lawitz2, L. Moorehead1, A. Mathias1, W. Delaney IV1, J. McHutchison1 1Gilead Sciences, Inc, Foster City, CA, USA; 2Alamo Medical Research, San Antonio, TX, USA Background · GS-9451 is a novel, reversible, non-covalent inhibitor of HCV NS3 serine protease with in vitro equipotent antiviral activity against genotype 1a and 1b - In vitro EC50 ranging from 7-10 nM in HCV 1a or 1b replicon assays - In vitro, GS-9451 selected resistance mutations at positions 168 and 156 in NS3 protease Objectives · Determine safety, tolerability, and pharmacokinetics of multiple ascending doses of GS-9451 in treatment-naïve, HCV-infected patients · Characterize the antiviral activity of multiple ascending doses of GS-9451 monotherapy - Identify mutations in the HCV NS3 gene from HCV patient isolates that are potentially associated with virologic resistance to GS-9451 monotherapy - Investigate the emergence of resistant quasispecies not detected by population sequencing through deep sequencing · Determine the persistence of resistance mutations following termination of treatment Methods · Randomized, double-blind, placebo-controlled, dose-escalation study conducted in treatment-naïve patients with genotype 1 chronic HCV infection - Three days of once-daily GS-9451 monotherapy, dosed under fed conditions (active to placebo ratio of 4:1): · 60 mg GS-9451 or placebo (N=10, GT1a) · 200 mg GS-9451 or placebo (N=10, GT1a) · 200 mg GS-9451 or placebo (N=10, GT1b) · 400 mg GS-9451 or placebo (N=11, GT1a) · Serial PK (Days 1 & 3) - Resistance testing - Population sequencing of the entire NS3/4A coding region at Baseline, Day 4, Day 14, Week 12 and Week 24 - The NS3 protease region (1-181) was analyzed using 454 deep pyrosequencing in 33 longitudinal samples from 7 patients - Plasmid control was processed in parallel with patient samples to establish the background derived from PCR pre-amplifi cation and 454 sequencing - Software was developed to accurately analyze deep sequencing results with an assay cut-off of 0.25%