GS-9620 is a potent, orally bioavailable small molecule agonist of Toll-like receptor 7 (TLR7) being developed for finite treatment of chronic hepatitis B viral (HBV) infection with the goal of inducing a liver-targeted antiviral effect without inducing the adverse effects associated with current systemic IFN-α therapies. We characterized the pharmacodynamic response of GS-9620 in CD-1 mice and cynomolgus monkeys following intravenous or oral administration and showed that GS-9620 induces the production of select chemokines and cytokines, including interferon-α (IFN-α) and interferon-stimulated genes (ISGs). Importantly, we also demonstrate in animals and healthy human volunteers that oral administration GS-9620 can induce a type I interferon-dependent antiviral innate immune response, as measured by whole blood mRNA of the ISGs 2'5'-oligoadenylate synthetase 1 (OAS1) and Myxovirus resistance 1 (MX1), without the induction of detectable systemic IFN-α i.e. a presystemic response. Additionally, presystemic induction of hepatic OAS1 and MX1 mRNA was observed in CD-1 mice in the absence of detectable systemic IFN-α. We propose that the mechanism of this presystemic response is likely its high intestinal absorption, which facilitates localized activation of TLR7, likely in plasmacytoid dendritic cells at the level of gut associated lymphoid tissue and/or the liver. This localized response is further supported by data that indicate only minimal contributions of systemic immune stimulation to the overall pharmacodynamic response to orally administered GS-9620. These data demonstrate that GS-9620 can induce an antiviral innate immune response without inducing a systemic IFN-α response and thus suggest the therapeutic potential of this approach in the treatment of chronic HBV infection.
- The American Society for Pharmacology and Experimental Therapeutics