TY - JOUR
T1 - The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection
AU - Gane, Edward J.
AU - Lim, Young Suk
AU - Gordon, Stuart C.
AU - Visvanathan, Kumar
AU - Sicard, Eric
AU - Fedorak, Richard N.
AU - Roberts, Stuart
AU - Massetto, Benedetta
AU - Ye, Zhishen
AU - Pflanz, Stefan
AU - Garrison, Kimberly L.
AU - Gaggar, Anuj
AU - Subramanian, G. Mani
AU - McHutchison, John G.
AU - Kottilil, Shyamasundaran
AU - Freilich, Bradley
AU - Coffin, Carla S.
AU - Cheng, Wendy
AU - Kim, Yoon Jun
N1 - Publisher Copyright:
© 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - HBsAg
KW - Hepatitis B virus
KW - Immune response
KW - TLR
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U2 - 10.1016/j.jhep.2015.02.037
DO - 10.1016/j.jhep.2015.02.037
M3 - Article
C2 - 25733157
AN - SCOPUS:84935451137
SN - 0168-8278
VL - 63
SP - 320
EP - 328
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 2
ER -