Pharmacokinetic and Pharmacodynamic Properties of GS-9620, a Novel Toll-Like Receptor 7 Agonist, Demonstrate Interferon-Stimulated Gene Induction without Detectable Serum Interferon at Low Oral Doses

Abstract

GS -9620 [8-(3-(pyrrolidin-1-ylmethyl)benzyl)-4-amino-2-butoxy-7,8-dihydropteridin-6(5H)-one] is a potent, orally bioavailable small-molecule agonist of Toll-like receptor 7 (TLR7) 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 interferon-a (IFN-a) 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 IFN-a and interferon-stimulated genes (ISGs). It is noteworthy that we also demonstrated that, in animals and healthy human volunteers, oral administration of GS-9620 can induce a type I interferon-dependent antiviral innate immune response, as measured by whole-blood mRNA of the ISGs 2959-oligoadenylate synthetase 1 (OAS1) and myxovirus resistance 1 (MX1), without the induction of detectable systemic IFN-a, 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-a. We propose that the mechanism of this presystemic response is likely its high intestinal absorption, which facilitates localized activation of TLR7, probably 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-a response and thus suggest the therapeutic potential of this approach in the treatment of chronic HBV infection.

Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver

“…In this respect it is important to note that the recent demonstration of therapeutic efficacy in HBV-infected chimpanzees of a novel synthetic TLR agonist (GS-9620; labeled as a TLR7 agonist) was not only associated with serum detection of IFN-α, but also of increased IL-12 and CXCL10 levels [18]. Such a cytokine/chemokine profile is also consistent with a TLR8-mediated response and can be explained by the TLR7/TLR8 degeneracy of this synthetic compound at high doses [31].…”

TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy

“…Specifically, formulated TLR7 agonist absorption and its effects are expected to be proportionally higher in the gut, because both agonist compounds have high absorption properties in the gastrointestinal (GI) tract and show only moderate clearance rates during the first phase of hepatic metabolism. Although these properties limit systemic exposure of TLR7 agonists after oral administration, they enhance drug exposure in the GI tract and the liver (18, 19, 24). Therefore, it is not surprising that the effects of these agonists appeared to be enhanced in the gut, as observed in the reduction of SIV DNA in CD4 + T cells from GMMCs.…”

Host-targeting agents for treatment of hepatitis B virus infection

“…This includes clinical trials evaluating the antiviral efficacy of IFN-l, that appears to have less side effects than IFN-a, as well as TLR7 agonists and therapeutic vaccines [53,54]. Furthermore, a recent study reported the potential of antibodies directed against the lymphotoxin-b receptor (LTbR) for HBV cure [55 ].…”