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

• Published in: Journal of hepatology Vol. 57; no. 1; pp. 24 - 31
• Main Authors: Lawitz, Eric J, Gruener, Daniel, Hill, John M, Marbury, Thomas, Moorehead, Lisa, Mathias, Anita, Cheng, Guofeng, Link, John O, Wong, Kelly A, Mo, Hongmei, McHutchison, John G, Brainard, Diana M
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01-07-2012; Elsevier
• Subjects: Adolescent; Adult; Aged; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Benzimidazoles - pharmacokinetics; Biological and medical sciences; Dose-Response Relationship, Drug; Drug Resistance, Viral - genetics; Female; Fluorenes - administration & dosage; Fluorenes - adverse effects; Fluorenes - pharmacokinetics; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Genotype; Hepacivirus - drug effects; Hepacivirus - genetics; Hepatitis C; Hepatitis C, Chronic - drug therapy; Human viral diseases; Humans; Infectious diseases; Male; Medical sciences; Middle Aged; NS5A protein; Pharmacology. Drug treatments; Placebos; RNA, Viral - metabolism; Treatment Outcome; Viral diseases; Viral hepatitis; Viral non-structural protein; Viral Nonstructural Proteins - antagonists & inhibitors; Young Adult; 90% effective inhibitory concentration; NS5A protein; Antiviral agents; ribavirin; body mass index; RBV; AUC; area under the plasma concentration–time curve; EC 90; Viral non-structural protein; EC 50; 50% effective inhibitory concentration; hepatitis C virus; PEG-IFN; HCV; peginterferon alfa; Hepatitis C; BMI; EC90; EC50; Human; Typing; Hepatic disease; Genotype; Protein; Infection; Microbiological investigation; Viral disease; Gastroenterology; Digestive diseases; Antiviral; Dose; Viral hepatitis C
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2011.12.029

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 log10 IU/ml (1 mg QD) to 3.3 log10 IU/ml (10 mg QD in genotype 1b and 30 mg QD). Emax 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.