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

Antivir Ther. 2012 Sep 28. doi: 10.3851/IMP2415. [Epub ahead of print]

Lawitz EJ, Hill JM, Marbury T, Demicco MP, Delaney W, Yang J, Moorehead L, Mathias A, Mo H, McHutchison JG, Rodriguez-Torres M, Gordon SC.

Source

Alamo Medical Research, San Antonio, TX, USA. lawitz@alamomedicalresearch.com.

Abstract

BACKGROUND: GS-9451 is a novel inhibitor of the hepatitis C virus (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 1 study in treatment-naïve, 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 through Day 14 for pharmacokinetic evaluation, serum HCV RNA quantitation, and NS3 sequencing.

RESULTS: No patients interrupted or discontinued dosing due to 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) log(10) IU/mL in genotype 1a patients receiving 60, 200, and 400 mg/d GS-9451, respectively, and -3.48 (-3.54, -3.03) log(10) IU/mL in genotype 1b patients receiving GS-9451 200 mg/d. Median half-life ranged from 14-17 hours. Day 3 mean C(tau) was 5.5- and 17-fold above protein-binding adjusted mean EC(50) in 200- and 400-mg cohorts, respectively. No resistance mutations were detected with GS-9451 60 mg/d. In the 200 mg/d or 400 mg/d 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/d or 400 mg/d 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 peginterferon alfa.

PMID: 23047118 [PubMed - as supplied by publisher]

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