A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C.

Abstract

BACKGROUND & AIMS:

GS-5885 is an inhibitor of the hepatitis C virus (HCV) NS5A protein and exhibits potent suppression of genotype 1 HCV replicons. The safety, tolerability, pharmacokinetics, antiviral activity, and resistance profile of once-daily GS-5885 doses of 1-90 mg were evaluated in patients with chronic genotype 1 HCV.

METHODS:

Genotype 1 HCV-infected patients were randomized to 3 days of once-daily (QD) dosing with placebo (n=12) or GS-5885 1 mg (n=10), 3 mg (n=10), 10 mg (n=20), 30 mg (n=10), or 90 mg (n=10). Plasma samples for pharmacokinetics, HCV RNA, and NS5A sequencing were collected through day 14.

RESULTS:

GS-5885 was well tolerated and resulted in median maximal reductions in HCV RNA ranging from 2.3 log(10) IU/ml (1 mg QD) to 3.3 log(10) IU/ml (10 mg QD in genotype 1b and 30 mg QD). E(max) modeling indicated GS-5885 30 mg was associated with>95% of maximal antiviral response to HCV genotype 1a. HCV RNA reductions were generally more sustained among patients with genotype 1b vs. 1a. Three of 60 patients had a reduced response and harbored NS5A-resistant virus at baseline. NS5A sequencing identified residues 30 and 31 in genotype 1a, and 93 in genotype 1b as the predominant sites of mutation following GS-5885 dosing. Plasma pharmacokinetics was consistent with QD dosing.

CONCLUSIONS:

During 3 days of monotherapy, low doses of GS-5885 demonstrated significant antiviral activity in genotype 1a and 1b HCV-infected patients. GS-5885 is currently being evaluated in combination with direct antiviral regimens with and without peginterferon.

• Authors: Eric J Lawitz, Daniel Gruener, John M Hill, Thomas Marbury, Lisa Moorehead, Anita Mathias, Guofeng Cheng, John O Link, Kelly A Wong, Hongmei Mo, John G McHutchison, Diana M Brainard
• Journal: Journal of hepatology (J Hepatol) Vol. 57 Issue 1 Pg. 24-31 (Jul 2012) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 22314425 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• Benzimidazoles
• Fluorenes
• Placebos
• RNA, Viral
• Viral Nonstructural Proteins
• ledipasvir
• NS-5 protein, hepatitis C virus

Topics

• Adolescent
• Adult
• Aged
• Antiviral Agents (administration & dosage, adverse effects, pharmacokinetics)
• Benzimidazoles (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Resistance, Viral (genetics)
• Female
• Fluorenes (administration & dosage, adverse effects, pharmacokinetics)
• Genotype
• Hepacivirus (drug effects, genetics)
• Hepatitis C, Chronic (drug therapy)
• Humans
• Male
• Middle Aged
• Placebos
• RNA, Viral (metabolism)
• Treatment Outcome
• Viral Nonstructural Proteins (antagonists & inhibitors)
• Young Adult