title: Safety, pharmacokinetics and pharmacodynamics of the oral toll-like receptor 7 agonist GS-9620 in treatment-naive patients with chronic hepatitis C.
abstract: BACKGROUND
  GS-9620 is a potent oral agonist of toll-like receptor 7, a key modulator of the innate immune response. In healthy volunteers, low doses of GS-9620 (2, 4 and 6 mg) induced significant expression of peripheral interferon-stimulated-gene (ISG) mRNA in the absence of detectable serum interferon-α and systemic adverse events (AEs). We evaluated the safety, pharmacokinetics and pharmacodynamics of GS-9620 in treatment-naive patients chronically infected with HCV genotype 1.
  
  
  METHODS
  In this double-blind, placebo-controlled study, 51 patients were randomized 5:1 (active:placebo) to receive either a single dose or two once-weekly doses of GS-9620 at four dose levels (0.3, 1, 2 and 4 mg) or placebo. Pharmacodynamic assessments included peripheral ISG15 mRNA expression, serum interferon-α and interferon-γ-inducible protein (IP)-10 levels and HCV RNA quantification.
  
  
  RESULTS
  GS-9620 was well-tolerated at all doses. Most AEs were mild or moderate in severity. GS-9620 exhibited dose-linear pharmacokinetics with a median half-life in plasma of 18 h. Transient, dose-dependent ISG15 induction was observed at 1, 2 and 4 mg, with peak mean fold change within 48 h followed by a decline to baseline levels within 7 days of dosing. Serum interferon-α induction post-baseline was detected in 16.7% (8/48) of patients. No clinically significant reductions in HCV RNA were observed.
  
  
  CONCLUSIONS
  GS-9620 was safe, well-tolerated and biologically active in patients with HCV infection. Induction of ISG15 occurred in the absence of detectable serum interferon-α or systemic AEs in most patients, supporting a pre-systemic mechanism of action. ClinicalTrials.gov identifier: NCT01591668.
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. lawitz@txliver.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Daniel
authors.initials: D
authors.lastname: Gruener
authors.forename: Thomas
authors.initials: T
authors.lastname: Marbury
authors.forename: John
authors.initials: J
authors.lastname: Hill
authors.forename: Lynn
authors.initials: L
authors.lastname: Webster
authors.forename: David
authors.initials: D
authors.lastname: Hassman
authors.forename: Anh-Hoa
authors.initials: AH
authors.lastname: Nguyen
authors.forename: Stefan
authors.initials: S
authors.lastname: Pflanz
authors.forename: Erik
authors.initials: E
authors.lastname: Mogalian
authors.forename: Anuj
authors.initials: A
authors.lastname: Gaggar
authors.forename: Benedetta
authors.initials: B
authors.lastname: Massetto
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: Bradley
authors.initials: B
authors.lastname: Freilich
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodriguez-Torres
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers; D016207:Cytokines / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011621:Pteridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000235:genetics; D016896:Treatment Outcome; D014452:Ubiquitins / Q000235:genetics; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D016207:Cytokines; D011621:Pteridines; D012333:RNA, Messenger; D051199:Toll-Like Receptor 7; D014452:Ubiquitins; C074034:ISG15 protein, human; C582524:vesatolimod