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Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B
Author(s) -
Daffis Stephane,
Balsitis Scott,
Chamberlain Jason,
Zheng Jim,
Santos Rex,
Rowe William,
Ramakrishnan Dhivya,
Pattabiraman Divya,
Spurlock Sandra,
Chu Ruth,
Kang Don,
Mish Michael,
Ramirez Ricardo,
Li Li,
Li Bei,
Ma Sarina,
Hung Magdeleine,
Voitenleitner Christian,
Yon Changsuek,
Suresh Manasa,
Menne Stephan,
Cote Paul,
Delaney William E.,
Mackman Richard,
Fletcher Simon P.
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31255
Subject(s) - woodchuck hepatitis virus , medicine , peripheral blood mononuclear cell , immunology , agonist , pharmacology , hepatitis b virus , virus , virology , receptor , biology , hepadnaviridae , biochemistry , in vitro
Background and Aims GS‐9688 (selgantolimod) is an oral selective small molecule agonist of toll‐like receptor 8 in clinical development for the treatment of chronic hepatitis B. In this study, we evaluated the antiviral efficacy of GS‐9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus. Approach and Results WHV‐infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS‐9688, or 3 mg/kg GS‐9688. Vehicle and 1 mg/kg GS‐9688 had no antiviral effect, whereas 3 mg/kg GS‐9688 induced a >5 log 10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (>5 months after the end of treatment). GS‐9688 treatment reduced intrahepatic WHV RNA and DNA levels by >95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti‐WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS‐9688 was confirmed in a second woodchuck study. The antiviral response to GS‐9688 did not correlate with systemic GS‐9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells and various other immune cell subsets may play a role in the antiviral response to GS‐9688. Conclusions Finite, short‐duration treatment with a clinically relevant dose of GS‐9688 is well tolerated and can induce a sustained antiviral response in WHV‐infected woodchucks; the identification of a baseline intrahepatic transcriptional signature associated with response to GS‐9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect.