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

Edward J. Gane, Young Suk Lim, Stuart C. Gordon, Kumar Visvanathan, Eric Sicard, Richard N. Fedorak, Stuart Roberts, Benedetta Massetto, Zhishen Ye, Stefan Pflanz, Kimberly L. Garrison, Anuj Gaggar, G. Mani Subramanian, John G. McHutchison, Shyamasundaran Kottilil, Bradley Freilich, Carla S. Coffin, Wendy Cheng, Yoon Jun Kim

Research output: Contribution to journalArticlepeer-review

127 Scopus citations


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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)320-328
Number of pages9
JournalJournal of Hepatology
Issue number2
StatePublished - 2015


  • HBsAg
  • Hepatitis B virus
  • Immune response
  • TLR

ASJC Scopus subject areas

  • Hepatology


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