Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B

JOURNAL OF HEPATOLOGY

卷:62

Article

Menne, Stephan¹  Tumas, Daniel B.²  Liu, Katherine H.³  Thampi, Linta¹  AlDeghaither, Dalal¹  Baldwin, Betty H.³  Bellezza, Christine A.³  Cote, Paul J.¹  Zheng, Jim⁴  Halcomb, Randall⁵  Fosdick, Abigail⁶  Fletcher, Simon P.²  Daffis, Stephane²  Li, Li⁷  Yue, Peng⁷  Wolfgang, Grushenka H. I.⁶  Tennant, Bud C.³ 

[1] Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20057 USA

[2] Gilead Sci Inc, Dept Biol, Foster City, CA 94404 USA

[3] Cornell Univ, Coll Vet Med, Gastrointestinal Unit, Dept Clin Sci, Ithaca, NY 14853 USA

[4] Gilead Sci Inc, Dept Drug Metab, Foster City, CA 94404 USA

[5] Gilead Sci Inc, Dept Chem, Foster City, CA 94404 USA

[6] Gilead Sci Inc, Dept Drug Safety Evaluat, Foster City, CA 94404 USA

[7] Gilead Sci Inc, Dept Biomarkers, Foster City, CA 94404 USA

关键词: TLR7;    Hepatitis B virus;    Hepatocellular carcinoma;    Immunomodulation;    Seroconversion;    Woodchuck animal model;   

DOI  :  10.1016/j.jhep.2014.12.026

来源: Elsevier

【 摘 要 】

Background & Aims: 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 6.2 log10 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. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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