PMID- 25105516
OWN - NLM
STAT- MEDLINE
DCOM- 20161104
LR  - 20190214
IS  - 2040-2058 (Electronic)
IS  - 1359-6535 (Linking)
VI  - 20
IP  - 7
DP  - 2015
TI  - Safety, pharmacokinetics and pharmacodynamics of the oral toll-like receptor 7 
      agonist GS-9620 in treatment-naive patients with chronic hepatitis C.
PG  - 699-708
LID - 10.3851/IMP2845 [doi]
AB  - 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-alpha 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-alpha and interferon-gamma-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-alpha 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-alpha or systemic AEs in most patients, supporting a 
      pre-systemic mechanism of action. ClinicalTrials.gov identifier: NCT01591668.
FAU - Lawitz, Eric
AU  - Lawitz E
AD  - Texas Liver Institute, University of Texas Health Science Center, San Antonio, 
      TX, USA. lawitz@txliver.com.
FAU - Gruener, Daniel
AU  - Gruener D
FAU - Marbury, Thomas
AU  - Marbury T
FAU - Hill, John
AU  - Hill J
FAU - Webster, Lynn
AU  - Webster L
FAU - Hassman, David
AU  - Hassman D
FAU - Nguyen, Anh-Hoa
AU  - Nguyen AH
FAU - Pflanz, Stefan
AU  - Pflanz S
FAU - Mogalian, Erik
AU  - Mogalian E
FAU - Gaggar, Anuj
AU  - Gaggar A
FAU - Massetto, Benedetta
AU  - Massetto B
FAU - Subramanian, G Mani
AU  - Subramanian GM
FAU - McHutchison, John G
AU  - McHutchison JG
FAU - Jacobson, Ira M
AU  - Jacobson IM
FAU - Freilich, Bradley
AU  - Freilich B
FAU - Rodriguez-Torres, Maribel
AU  - Rodriguez-Torres M
LA  - eng
SI  - ClinicalTrials.gov/NCT01591668
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20140808
PL  - England
TA  - Antivir Ther
JT  - Antiviral therapy
JID - 9815705
RN  - 0 (Antiviral Agents)
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Pteridines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Toll-Like Receptor 7)
RN  - 0 (Ubiquitins)
RN  - 60267-61-0 (ISG15 protein, human)
RN  - O8M467C50G (vesatolimod)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Antiviral Agents/adverse effects/pharmacokinetics/*therapeutic use
MH  - Biomarkers
MH  - Cytokines/genetics
MH  - Female
MH  - Gene Expression
MH  - Genotype
MH  - *Hepacivirus/genetics
MH  - Hepatitis C, Chronic/diagnosis/*drug therapy/metabolism/virology
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Pteridines/adverse effects/pharmacokinetics/*therapeutic use
MH  - RNA, Messenger/genetics/metabolism
MH  - Toll-Like Receptor 7/*agonists/genetics
MH  - Treatment Outcome
MH  - Ubiquitins/genetics
MH  - Viral Load
MH  - Young Adult
EDAT- 2014/08/12 06:00
MHDA- 2016/11/05 06:00
CRDT- 2014/08/09 06:00
PHST- 2014/07/01 00:00 [accepted]
PHST- 2014/08/09 06:00 [entrez]
PHST- 2014/08/12 06:00 [pubmed]
PHST- 2016/11/05 06:00 [medline]
AID - 10.3851/IMP2845 [doi]
PST - ppublish
SO  - Antivir Ther. 2015;20(7):699-708. doi: 10.3851/IMP2845. Epub 2014 Aug 8.