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.

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.

• Authors: 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
• Journal: Antiviral therapy (Antivir Ther) Vol. 18 Issue 3 Pg. 311-9 ( 2013) ISSN: 2040-2058 [Electronic] England
• PMID: 23047118 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Carrier Proteins
• GS-9451
• Intracellular Signaling Peptides and Proteins
• NS3 protein, hepatitis C virus
• NS4A cofactor peptide, Hepatitis C virus
• Protease Inhibitors
• Quinolines
• RNA, Viral
• Viral Nonstructural Proteins

Topics

• Adult
• Aged
• Antiviral Agents (pharmacology, therapeutic use)
• Carrier Proteins (antagonists & inhibitors)
• Drug Resistance, Viral
• Female
• Genotype
• Hepacivirus (genetics)
• Hepatitis C (drug therapy, virology)
• Humans
• Intracellular Signaling Peptides and Proteins
• Male
• Middle Aged
• Mutation
• Protease Inhibitors (pharmacology, therapeutic use)
• Quinolines (pharmacology, therapeutic use)
• RNA, Viral (genetics)
• Treatment Outcome
• Viral Load
• Viral Nonstructural Proteins (antagonists & inhibitors)