A Phase I, randomized, placebo-controlled, 3-day, ascending-dose study of GS-9451, an NS3/4A protease inhibitor, in genotype 1 hepatitis C patients.

BACKGROUND GS-9451 is a novel inhibitor of the HCV NS3/4A protease and demonstrates potent in vitro suppression of HCV genotype 1 replicons. METHODS The safety, pharmacokinetics and antiviral efficacy of GS-9451 were evaluated in a Phase I study in treatment-naive, HCV genotype-1-infected patients. Patients were randomized to 3 days of once-daily dosing with placebo (n=8) or GS-9451 60 mg (n=8 genotype 1a), 200 mg (n=8 genotype 1a; n=8 genotype 1b) or 400 mg (n=9 genotype 1a). Plasma samples were collected up to and on day 14 for pharmacokinetic evaluation, serum HCV RNA quantitation and NS3 sequencing. RESULTS No patients interrupted or discontinued dosing because of an adverse event. The median (range) maximal HCV RNA reductions from baseline were -0.88 (-1.24- -0.64), -3.19 (-3.31- -2.94) and -3.64 (-4.08- -3.54) log10 IU/ml in genotype 1a patients receiving 60, 200 and 400 mg/day GS-9451, respectively, and -3.48 (-3.54- -3.03) log10 IU/ml in genotype 1b patients receiving GS-9451 200 mg/day. Median half-life ranged from 14 to 17 h. Day 3 mean concentration at the end of dosing interval was 5.5- and 17-fold above protein-binding adjusted mean 50% effective inhibitory concentration in 200 mg and 400 mg cohorts, respectively. No resistance mutations were detected with GS-9451 60 mg/day. In the 200 mg/day or 400 mg/day groups, predominant mutations were NS3 R155 (R155K) in genotype 1a patients and D168 (D168E, D168V and D168G) in genotype 1b patients. CONCLUSIONS GS-9451 was well-tolerated. During 3 days of monotherapy, GS-9451 200 mg/day or 400 mg/day demonstrated potent antiviral activity in both HCV genotype 1a- and 1b-infected patients. GS-9451 is currently being evaluated in combination regimens with and without pegylated interferon-α.