A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C

Background & Aims: GS-5885 is an inhibitor of the hepatitis C virus (HCV) NS5A protein and exhibits potent suppression of genotype 1 HCV replicons. The safety, tolerability, pharmacokinetics, antiviral activity, and resistance profile of once-daily GS-5885 doses of 1-90 mg were evaluated in patients with chronic genotype 1 HCV. Methods: Genotype 1 HCV-infected patients were randomized to 3 days of once-daily (QD) dosing with placebo (n = 12) or GS-5885 1 mg (n = 10), 3 mg (n = 10), 10 mg (n = 20), 30 mg (n = 10), or 90 mg (n = 10). Plasma samples for pharmacokinetics, HCV RNA, and NS5A sequencing were collected through day 14. Results: GS-5885 was well tolerated and resulted in median maximal reductions in HCV RNA ranging from 2.3 log ₁₀ IU/ml (1 mg QD) to 3.3 log ₁₀ IU/ml (10 mg QD in genotype 1b and 30 mg QD). E _max modeling indicated GS-5885 30 mg was associated with >95% of maximal antiviral response to HCV genotype 1a. HCV RNA reductions were generally more sustained among patients with genotype 1b vs. 1a. Three of 60 patients had a reduced response and harbored NS5A-resistant virus at baseline. NS5A sequencing identified residues 30 and 31 in genotype 1a, and 93 in genotype 1b as the predominant sites of mutation following GS-5885 dosing. Plasma pharmacokinetics was consistent with QD dosing. Conclusions: During 3 days of monotherapy, low doses of GS-5885 demonstrated significant antiviral activity in genotype 1a and 1b HCV-infected patients. GS-5885 is currently being evaluated in combination with direct antiviral regimens with and without peginterferon.