Research Article| Volume 63, ISSUE 2, P320-328, August 2015

The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection

Published:February 28, 2015DOI:

      Background & Aims

      GS-9620 is an oral agonist of toll-like receptor 7, a pattern-recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B.


      In two double-blind, phase 1b trials of identical design, 49 treatment-naïve and 51 virologically suppressed patients were randomized 5:1 to receive GS-9620 (at doses of 0.3 mg, 1 mg, 2 mg, 4 mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha.


      Overall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced ⩾1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point.


      Oral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms.


      CHB (Chronic hepatitis B), AUC (Area under the curve), DMC (Data monitoring committee), GALT (Gut-associated lymphoid tissue), HBV (Hepatitis B virus), HCV (Hepatitis C virus), HCC (Hepatocellular carcinoma), ISG (Interferon-stimulated genes), MAD (Multiple-ascending dose), SAD (Single ascending dose), WHV (Woodchuck hepatitis virus), IFN-alpha (serum interferon (IFN)-alpha)


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        • Ott J.J.
        • Stevens G.A.
        • Groeger J.
        • et al.
        Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity.
        Vaccine. 2012; 30: 2212-2219
        • Kwon H.
        • Lok A.S.
        Hepatitis B therapy.
        Nat Rev Gastroenterol Hepatol. 2011; 8: 275-284
        • Bertoletti A.
        • Ferrari C.
        Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection.
        Gut. 2012; 61: 1754-1764
        • Maini M.L.
        • Schurich A.
        The molecular basis of the failed immune response in chronic HBV: therapeutic implications.
        J Hepatol. 2010; 52: 616-619
        • Kawai T.
        • Akira S.
        Innate immune recognition of viral infection.
        Nat Immunol. 2006; 7: 131-137
        • Sadler A.J.
        Interferon-inducible antiviral effectors.
        Nat Rev Immunol. 2008; 8: 559-568
        • Belloni L.
        • Allweiss L.
        • Guerrieri F.
        • et al.
        IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome.
        J Clin Invest. 2012; 122: 529-537
        • Tel J.
        • Sittig S.P.
        • Blom R.A.M.
        • et al.
        Targeting uptake receptors on human plasmacytoid dendritic cells triggers antigen cross-presentation and robust type I IFN secretion.
        J Immunol. 2013; 191: 5005-5012
        • Bekeredjian-Ding I.B.
        • Wagner M.
        • Hornung V.
        • et al.
        Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN.
        J Immunol. 2005; 174: 4043-4050
        • Fosdick A.
        • Zheng J.
        • Pflanz S.
        • et al.
        Pharmacokinetic and pharmacodynamic properties of GS-9620, a novel TLR7 agonist, demonstrates ISG induction without detectable serum interferon at low oral doses.
        J Pharmacol Exp Ther. 2014; 348: 96-105
        • Lopatin U.
        • Wolfgang G.
        • Tumas D.
        • et al.
        Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral toll-like receptor 7 agonist.
        Antivir Ther. 2013; 18: 409-418
        • Lanford R.E.
        • Guerra B.
        • Chavez D.
        • et al.
        GS-9620, an oral agonist of toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees.
        Gastroenterology. 2013; 144: 1508-1517
      1. Menne S, Tennant BC, Liu KH, et al. Antiviral efficacy and induction of an antibody response against surface antigen with the TLR7 agonist GS-9620 in the woodchuck model of chronic HBV infection. In: 46th annual meeting of the European Association for the Study of the Liver; March 30-April 3, 2011; Berlin, Germany; poster 170.

        • Shaffer A.
        • Hubbard J.
        • Townsend K.
        • et al.
        Serum-based assay accurately detects single nucleotide polymorphisms of IL28B and SOCS3 in HIV/hepatitis C virus-coinfected subjects.
        AIDS Res Hum Retroviruses. 2014; 30: 792-795
        • Schott E.
        • Witt H.
        • Neumann K.
        • et al.
        Association of TLR7 single nucleotide polymorphisms with chronic HCV-infection and response to interferon-a-based therapy.
        J Viral Hepat. 2008; 15: 71-78
        • Sawhney R.
        • Visvanathan K.
        Polymorphisms of toll-like receptors and their pathways in viral hepatitis.
        Antivir Ther. 2011; 16: 443-458
        • Howell J.
        • Angus P.
        • Gow P.
        • Visvanathan K.
        Toll-like receptors in hepatitis C infection: implications for pathogenesis and treatment.
        Gastroenterol Hepatol. 2013; 28: 766-776
        • Shen N.
        • Fu Q.
        • Deng Y.
        • et al.
        Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus.
        Proc Natl Acad Sci U S A. 2010; 107: 15838-15843
        • Yue M.
        • Feng L.
        • Tang S.
        • et al.
        Sex-specific association between X-linked toll-like receptor 7 with the outcomes of hepatitis C virus infection.
        Gene. 2014; 548: 244-250
        • Xu H.C.
        • Grusdat M.
        • Pandyra A.A.
        • et al.
        Type I interferon protects antiviral CD8+ T cells from NK cell cytotoxicity.
        Immunity. 2014; 40: 949-960
        • Crouse J.
        • Bedenikovic G.
        • Wiesel M.
        • et al.
        Type I interferons protect T cells against NK cell attack mediated by the activating receptor NCR1.
        Immunity. 2014; 40: 961-973
        • Menne S.
        • Tumas D.B.
        • Liu K.H.
        • et al.
        Sustained efficacy and seroconversion with the toll-like receptor 7 agonist GS-9620 in the woodchuck model of chronic hepatitis B.
        J Hepatol. 2015; 62: 1237-1245
        • Micco L.
        • Peppa D.
        • Loggi E.
        • et al.
        Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B.
        J Hepatol. 2013; 58: 225-233
        • Livak K.J.
        • Schmittgen T.D.
        Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method.
        Methods. 2001; 25: 402-408
        • García-García I.
        • González-Delgado C.A.
        • Valenzuela-Silva C.M.
        • et al.
        Pharmacokinetic and pharmacodynamic comparison of two “pegylated” interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study.
        BMC Pharmacol. 2010; 10: 15
      2. EASL. Clinical practice guidelines: management of chronic hepatitis B virus infection.
        J Hepatol. 2012; 57: 167-185
        • Boni C.
        • Laccabue D.
        • Lampertico P.
        • et al.
        Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues.
        Gastroenterology. 2012; 143: 963-973
        • Birmachu W.
        • Gleason R.M.
        • Bulbulian B.J.
        • Riter C.L.
        • Vasilakos J.P.
        • Lipson K.E.
        • et al.
        Transcriptional networks in plasmacytoid dendritic cells stimulated with synthetic TLR 7 agonists.
        MBC Immunol. 2007; 12: 8-26
        • Jaruga B.
        • Hong F.
        • Kim W.H.
        • Gao B.
        IFN-gamma/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1.
        Am J Physiol Gastrointest Liver Physiol. 2004; 287: G1044-G1052
        • Groom J.R.
        • Luster A.D.
        CXCR3 in T cell function.
        Exp Cell Res. 2011; 317: 620-631
        • Oo Y.H.
        • Shetty S.
        • Adams D.H.
        The role of chemokines in the recruitment of lymphocytes to the liver.
        Dig Dis. 2010; 28: 31-44
        • Jaroszewicz J.
        • Ho H.
        • Markova A.
        • et al.
        Hepatitis B surface antigen (HBsAg) decrease and serum interferon-inducible protein-10 levels as predictive markers for HBsAg loss during treatment with nucleoside/nucleotide analogues.
        Antivir Ther. 2011; 16: 915-924
        • Wang Y.
        • Zhao C.
        • Zhang L.
        • et al.
        Predictive value of interferon-gamma inducible protein 10 kD for hepatitis B e antigen clearance and hepatitis B surface antigen decline during pegylated interferon alpha therapy in chronic hepatitis B patients.
        Antiviral Res. 2014; 103: 51-59
        • Campbell J.A.
        • Lenschow D.J.
        Emerging roles for immunomodulatory functions of free ISG15.
        J Interferon Cytokine Res. 2013; 33: 728-738