The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection.
OBJECTIVE
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 0.3mg, 1mg, 2mg, 4mg) 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.
New Zealand Liver Transplant Unit, Auckland City Hospital and University of Auckland, Auckland, New Zealand. Electronic address: edgane@adhb.govt.nz.
Edward J
EJ
Gane
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Young-Suk
YS
Lim
Henry Ford Health Systems, Detroit, MI, USA.
Stuart C
SC
Gordon
The University of Melbourne, Parkville, Victoria, Australia.
Kumar
K
Visvanathan
Algorithme Pharma, Montréal, Canada.
Eric
E
Sicard
University of Alberta, Edmonton, Alberta, Canada.
Richard N
RN
Fedorak
Alfred Health, Victoria, Australia.
Stuart
S
Roberts
Gilead Sciences, Inc., Foster City, CA, USA.
Benedetta
B
Massetto
Gilead Sciences, Inc., Foster City, CA, USA.
Zhishen
Z
Ye
Gilead Sciences, Inc., Foster City, CA, USA.
Stefan
S
Pflanz
Gilead Sciences, Inc., Foster City, CA, USA.
Kimberly L
KL
Garrison
Gilead Sciences, Inc., Foster City, CA, USA.
Anuj
A
Gaggar
Gilead Sciences, Inc., Foster City, CA, USA.
G
G
Mani Subramanian
Gilead Sciences, Inc., Foster City, CA, USA.
John G
JG
McHutchison
National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
Shyamasundaran
S
Kottilil
Kansas City Gastroenterology and Hepatology, Kansas City, MO, USA.
Bradley
B
Freilich
University of Calgary, Calgary, Albert, Canada.
Carla S
CS
Coffin
Royal Perth Hospital, Perth, Australia.
Wendy
W
Cheng
Seoul National University College of Medicine, Seoul, Republic of Korea.
Yoon Jun
YJ
Kim
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D004279:DNA, Viral / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006514:Hepatitis B Surface Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011621:Pteridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012189:Retrospective Studies; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D016896:Treatment Outcome; D055815:Young Adult
D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D011621:Pteridines; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; C582524:vesatolimod
HBsAg; Hepatitis B virus; Immune response; TLR