title: A phase 1, randomized, dose-ranging study of GS-5816, a once-daily NS5A inhibitor, in patients with genotype 1-4 hepatitis C virus.
abstract: GS-5816 is an inhibitor of the hepatitis C virus (HCV) NS5A protein that has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. The aim of this study was to evaluate the safety, antiviral activity and pharmacokinetics of once-daily doses of GS-5816 in patients with genotype 1-4 HCV infection. Patients with genotype 1-4 HCV infection were randomized to 3 days of GS-5816 at doses ranging from 5 to 150 mg or placebo. Adverse events were recorded, and plasma samples obtained for analysis of pharmacokinetics, HCV RNA and NS5A sequencing studies. GS-5816 5-150 mg for 3 days was well tolerated and resulted in rapid declines in HCV RNA that were sustained over the dosing period. In patients treated with the 150 mg dose of GS-5816, the mean maximal HCV RNA declines were 4.0, 4.0, 4.4, 3.3 and 3.5 log10 IU/mL in patients with genotype 1a, 1b, 2, 3 and 4 HCV infection, respectively. Pretreatment NS5A resistance-associated polymorphisms were detected in 31% (22/70) of patients. Genotype 1 and 3 HCV-infected patients without pretreatment NS5A resistance-associated polymorphisms had greater declines in HCV RNA than patients with resistance-associated polymorphisms. Plasma pharmacokinetics were supportive of once-daily dosing. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.
authors.affiliation: Texas Liver Institute, University of Texas Health Sciences Center, San Antonio, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Kansas City Gastroenterology and Hepatology, Kansas City, MO, USA.
authors.forename: B
authors.initials: B
authors.lastname: Freilich
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Link
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: German
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Mo
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Han
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: McNally
authors.affiliation: Orlando Clinical Research Center, Orlando, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Marbury
authors.affiliation: Fundacion De Investigacion, San Juan, Puerto Rico.
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez-Torres
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002219:Carbamates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012367:RNA, Viral / Q000097:blood; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase; D001562:Benzimidazoles; D001578:Benzopyrans
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D006576:Heterocyclic Compounds, 4 or More Rings; D010919:Placebos; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C000604171:velpatasvir; D001562:Benzimidazoles; D001578:Benzopyrans
keywords: GS-5816; NS5A inhibitor; hepatitis C virus