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Genotypic and Phenotypic Characterization of HCV Resistance From a Multiple Dose Clinical Trial of GS-9451, a Novel NS3 Protease Inhibitor
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Reported by Jules Levin EASL 2011 Berlin March 31-Apr 2
KA Wong, H Dvory-Sobol, A Bae, K Ku, J Waters, MD Miller, H Mo
Gilead Sciences, Inc., Foster City, CA USA
Summary
· NS3 protease resistance mutations were detected by population sequencing in 17/32 (53%) GS-9451 treated patients in this study
- GS-9451 resistance mutations were not detected by population sequencing in patients dosed at 60 mg
- R155K did not persist in 6/8 patients at Week 24
- D168 substitutions were not detected beyond Day 4 in all four patients
· Phenotypic analysis of clinical isolates with mutations at positions R155 or D168 showed reduced susceptibility to GS-9451 and some other PIs
- R155K showed the broadest cross-resistance among PIs tested
· GS-9451 NS3 resistance mutations are fully susceptible to other HCV inhibitor classes, including tegobuvir, GS-9669, and GS-6620 targeting NS5B; GS-5885 targeting NS5A; and
interferon-α, and ribavirin
References
1. A Corsa, M Robinson, H Yang, et al. Preclinical Properties of the Novel HCV NS3 Protease Inhibitor GS-9451, Poster No. 778, EASL 2011, Berlin, Germany
2. E Lawitz, JM Hill, TC Marbury, et al. Three-Day Dose-Ranging Study of the HCV NS3 Protease Inhibitor GS-9451, Poster No. 820, AASLD 2010, Boston, MA, USA
3. H Yang, C Yang, Y Wang, et al. Preclinical Properties of the Novel HCV NS3 Protease Inhibitor GS-9256, Poster No. 779, EASL 2011, Berlin, Germany
4. M Fenaux, Y Tian, M Matles, et al. Nonclinical and Cross-Genotypic Profi le of GS-9669, a Novel HCV NS5B Non-Nucleoside Thumb Site II Inhibitor, Poster No. 1206, EASL 2011, Berlin, Germany
5. A Ray, J Feng, T Wang, et al. GS-6620, A Liver Targeted Nucleotide Prodrug with Potent Pan-Genotype Anti-Hepatitis C Virus Activity In Vitro, Poster No. 1233, EASL 2011, Berlin, Germany
6. JO Link, R Bannister, LD Beilke, et al. Nonclinical Profi le and Phase I Results in Healthy Volunteers for the Novel and Potent HCV NS5A Inhibitor GS-5885, Poster No. 1883, AASLD 2010, Boston, MA, USA
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