A phase 1, randomized, dose-ranging study of GS-5816, a once-daily NS5A inhibitor, in patients with genotype 1-4 hepatitis C virus

作者：Lawitz E^*; Freilich B; Link J; German P; Mo H; Han L; Brainard D M; McNally J; Marbury T; Rodriguez Torres M

来源：Journal of Viral Hepatitis, 2015, 22(12): 1011-1019.

DOI：10.1111/jvh.12435

• GS-5816
• hepatitis C virus
• NS5A inhibitor

GS-5816 is an inhibitor of the hepatitis C virus (HCV) NS5A protein that has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. The aim of this study was to evaluate the safety, antiviral activity and pharmacokinetics of once-daily doses of GS-5816 in patients with genotype 1-4 HCV infection. Patients with genotype 1-4 HCV infection were randomized to 3days of GS-5816 at doses ranging from 5 to 150mg or placebo. Adverse events were recorded, and plasma samples obtained for analysis of pharmacokinetics, HCV RNA and NS5A sequencing studies. GS-5816 5-150mg for 3days was well tolerated and resulted in rapid declines in HCV RNA that were sustained over the dosing period. In patients treated with the 150mg dose of GS-5816, the mean maximal HCV RNA declines were 4.0, 4.0, 4.4, 3.3 and 3.5 log(10) IU/mL in patients with genotype 1a, 1b, 2, 3 and 4 HCV infection, respectively. Pretreatment NS5A resistance-associated polymorphisms were detected in 31% (22/70) of patients. Genotype 1 and 3 HCV-infected patients without pretreatment NS5A resistance-associated polymorphisms had greater declines in HCV RNA than patients with resistance-associated polymorphisms. Plasma pharmacokinetics were supportive of once-daily dosing. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.

• 出版日期2015-12