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Research ArticleDrug Discovery and Translational Medicine

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

Abigail Fosdick, Jim Zheng, Stefan Pflanz, Christian R. Frey, Joseph Hesselgesser, Randall L. Halcomb, Grushenka Wolfgang and Daniel B. Tumas
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 96-105; DOI: https://doi.org/10.1124/jpet.113.207878
Abigail Fosdick
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
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Jim Zheng
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
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Stefan Pflanz
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
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Christian R. Frey
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
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Joseph Hesselgesser
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
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Randall L. Halcomb
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
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Grushenka Wolfgang
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
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Daniel B. Tumas
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
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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.

Footnotes

    • Received July 16, 2013.
    • Accepted October 16, 2013.
  • This work was supported by Gilead Sciences, Inc., Foster City, CA.

  • This work was presented previously, in part, at two meetings: Tumas D, Zheng X, Lu B, Rhodes G, Duatschek P, Hesselgesser J, Frey C, Henne I, Fosdick A, Halcomb R, and Wolfgang G (2011) Preclinical characterization of GS-9620, a potent and selective oral TLR7 agonist (Abstract 1776). 46th Annual Meeting of the European Association for the Study of the Liver; 2011 March 30–April 3; Berlin, Germany; and Tumas D, Fosdick A, Zheng X, Lanford R, Hesselgesser J, Frey C, Wolfgang G, Halcomb R, and Lopatin U (2012) GS-9620, induces a presystemic innate immune response in the absence of serum interferon or adverse effects in both non-clinical species and humans (Abstract 18640). 47th Annual Meeting of the European Association for the Study of the Liver; 2012 April 18–22; Barcelona, Spain.

  • dx.doi.org/10.1124/jpet.113.207878.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 1
1 Jan 2014
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Research ArticleDrug Discovery and Translational Medicine

PK and PD of the TLR7 Agonist GS-9620

Abigail Fosdick, Jim Zheng, Stefan Pflanz, Christian R. Frey, Joseph Hesselgesser, Randall L. Halcomb, Grushenka Wolfgang and Daniel B. Tumas
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 96-105; DOI: https://doi.org/10.1124/jpet.113.207878

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Research ArticleDrug Discovery and Translational Medicine

PK and PD of the TLR7 Agonist GS-9620

Abigail Fosdick, Jim Zheng, Stefan Pflanz, Christian R. Frey, Joseph Hesselgesser, Randall L. Halcomb, Grushenka Wolfgang and Daniel B. Tumas
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 96-105; DOI: https://doi.org/10.1124/jpet.113.207878
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