title: Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B.
abstract: OBJECTIVE
  New therapies for chronic hepatitis B (CHB) are urgently needed since current treatments rarely lead to cure. We evaluated whether the oral small molecule toll-like receptor (TLR7) agonist GS-9620 could induce durable antiviral efficacy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to human hepatitis B virus (HBV).
  
  
  METHODS
  After evaluating the pharmacokinetics, pharmacodynamics and tolerability of oral GS-9620 in uninfected woodchucks, adult woodchucks chronically infected with WHV (n = 7 per group) were dosed with GS-9620 or placebo for 4 or 8 weeks with different treatment schedules.
  
  
  RESULTS
  GS-9620 treatment induced rapid, marked and sustained reduction in serum viral DNA (mean maximal 6.2log10 reduction), and hepatic WHV DNA replicative intermediates, WHV cccDNA and WHV RNA, as well as loss of detectable serum WHV surface antigen (WHsAg). GS-9620 treatment also induced a sustained antibody response against WHsAg in a subset of animals. Strikingly, treatment reduced the incidence of hepatocellular carcinoma (HCC) from 71% in the placebo group to 8% in GS-9620-treated woodchucks with sustained viral load reduction. GS-9620 treatment was associated with reversible increases in serum liver enzymes and thrombocytopenia, and induced intrahepatic CD8(+) T cell, NK cell, B cell and interferon response transcriptional signatures.
  
  
  CONCLUSIONS
  The data demonstrate that short duration, finite treatment with the oral TLR7 agonist GS-9620 can induce a sustained antiviral response in the woodchuck model of CHB, and support investigation of this compound as a therapeutic approach to attain a functional cure in CHB patients.
authors.affiliation: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States. Electronic address: sm923@georgetown.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Menne
authors.affiliation: Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Tumas
authors.affiliation: Department of Clinical Sciences, Gastrointestinal Unit, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States.
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States.
authors.forename: Linta
authors.initials: L
authors.lastname: Thampi
authors.affiliation: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States.
authors.forename: Dalal
authors.initials: D
authors.lastname: AlDeghaither
authors.affiliation: Department of Clinical Sciences, Gastrointestinal Unit, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States.
authors.forename: Betty H
authors.initials: BH
authors.lastname: Baldwin
authors.affiliation: Department of Clinical Sciences, Gastrointestinal Unit, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Bellezza
authors.affiliation: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cote
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Randall
authors.initials: R
authors.lastname: Halcomb
authors.affiliation: Department of Drug Safety Evaluation, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Abigail
authors.initials: A
authors.lastname: Fosdick
authors.affiliation: Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fletcher
authors.affiliation: Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Stephane
authors.initials: S
authors.lastname: Daffis
authors.affiliation: Department of Biomarkers, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biomarkers, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.affiliation: Department of Drug Safety Evaluation, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Grushenka H I
authors.initials: GH
authors.lastname: Wolfgang
authors.affiliation: Department of Clinical Sciences, Gastrointestinal Unit, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States.
authors.forename: Bud C
authors.initials: BC
authors.lastname: Tennant
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood; D004195:Disease Models, Animal; D006508:Hepatitis Antibodies / Q000097:blood; D018963:Hepatitis Antigens / Q000097:blood; D006509:Hepatitis B / Q000150:complications / Q000188:drug therapy* / Q000276:immunology*; D017919:Hepatitis B Virus, Woodchuck / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000517:prevention & control; D008297:Male; D008392:Marmota; D011621:Pteridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069078:Seroconversion / Q000187:drug effects; D013997:Time Factors; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006508:Hepatitis Antibodies; D018963:Hepatitis Antigens; D011621:Pteridines; D051199:Toll-Like Receptor 7; C582524:vesatolimod
keywords: Hepatitis B virus; Hepatocellular carcinoma; Immunomodulation; Seroconversion; TLR7; Woodchuck animal model