Journal
ANTIVIRAL THERAPY
Volume 18, Issue 3, Pages 311-319Publisher
INT MEDICAL PRESS LTD
DOI: 10.3851/IMP2415
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Funding
- Gilead Sciences
- Abbott Laboratories
- Achillion Pharmaceuticals
- Anadys Pharmaceuticals
- Biolex Therapeutics
- Boehringer Ingelheim
- Bristol-Myers Squibb
- GlaxoSmithKline
- GlobeImmune
- Idenix Pharmaceuticals
- Idera Pharmaceuticals
- Inhibitex Inhibitex Pharmaceuticals
- Medarex
- Medtronic
- Merck Co.
- Novartis
- Pharmasset
- Roche
- Sanofi-Aventis
- Schering-Plough
- Santaris Pharmaceuticals
- Scynexis Pharmaceuticals
- Tibotec Pharmaceuticals
- Vertex Pharmaceuticals
- ViroChem Pharma
- ZymoGenetics
- Conatus Pharmaceuticals
- Eiger Biopharmaceuticals
- Exalenz Bioscience
- Intercept Pharmaceuticals
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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) log(10) IU/ml in genotype 1a patients receiving 60, 200 and 400 mg/day GS-9451, respectively, and -3.48 (-3.54--3.03) log(10) 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-alpha.
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