Toll-like receptor (TLR) 8 recognizes pathogen-derived single-stranded RNA to trigger innate and adaptive immune responses. Published data suggest that TLR8 activation may augment hepatitis B virus (HBV)-specific T cell responses, activate natural killer cells and mucosal-associated invariant T cells, and suppress HBV via induction of antiviral cytokines. Therefore a selective TLR8 agonist has the potential to be a new treatment option for CHB.<br/><br/>GS-9688 is an oral, selective small-molecule agonist of TLR8 currently in clinical development for the treatment of chronic hepatitis B (CHB). Starting from a weakly active dual TLR7/8 agonist lead, potency and selectivity for TLR8 were optimized using a high throughput peripheral blood mononuclear cells (PBMC) assay measuring IL-12p40 production. The TLR8-ectodomain:GS-9688 complex X-ray structure was solved to confirm direct TLR8 binding. In HBV infected primary human hepatocytes, cytokines in the media of human PBMCs activated by GS-9688 reduced viral replication in HBV-infected primary human hepatocytes. The desired oral profile was high intestinal absorption leading to activation of TLR8 in the gut but also sufficient compound activating TLR8 in intrahepatic immune cells, combined with high first pass hepatic clearance, to minimize potential side effects resulting from systemic TLR8 agonism. GS-9688 demonstrated good absorption and high first pass clearance in multiple preclinical species, and stimulated a dose-dependent serum IL-12p40 response in monkeys. GS-9688 is therefore a promising, novel oral agent for the treatment of CHB.

Discovery of the selective TLR8 agonist GS-9688 for HBV cure

2019 Fall National Meeting

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