title: 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-α (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 IFN-α 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 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, 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-α response and thus suggest the therapeutic potential of this approach in the treatment of chronic HBV infection.
authors.affiliation: Departments of Drug Safety Evaluation (A.F., G.W.), Drug Metabolism (J.Z.), Biology (S.P., C.R.F., D.B.T.), Clinical Virology (J.H.), and Medicinal Chemistry (R.L.H.), Gilead Sciences, Inc., Foster City, California.
authors.forename: Abigail
authors.initials: A
authors.lastname: Fosdick
authors.forename: Jim
authors.initials: J
authors.lastname: Zheng
authors.forename: Stefan
authors.initials: S
authors.lastname: Pflanz
authors.forename: Christian R
authors.initials: CR
authors.lastname: Frey
authors.forename: Joseph
authors.initials: J
authors.lastname: Hesselgesser
authors.forename: Randall L
authors.initials: RL
authors.lastname: Halcomb
authors.forename: Grushenka
authors.initials: G
authors.lastname: Wolfgang
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Tumas
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000097:blood / Q000502:physiology*; D008252:Macaca fascicularis; D051379:Mice; D011621:Pteridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016898:Interferon-alpha; D011621:Pteridines; D051199:Toll-Like Receptor 7; C582524:vesatolimod