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

Eric J. Lawitz, John M. Hill, Thomas Marbury, Michael P. DeMicco, William Delaney, Jenny Yang, Lisa Moorehead, Anita Mathias, Hongmei Mo, John G. McHutchison, Maribel Rodriguez-Torres, Stuart C. Gordon

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)311-319
Number of pages9
JournalAntiviral Therapy
Volume18
Issue number3
DOIs
StatePublished - May 28 2013
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Lawitz, E. J., Hill, J. M., Marbury, T., DeMicco, M. P., Delaney, W., Yang, J., Moorehead, L., Mathias, A., Mo, H., McHutchison, J. G., Rodriguez-Torres, M., & Gordon, S. C. (2013). 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. Antiviral Therapy, 18(3), 311-319. https://doi.org/10.3851/IMP2415