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.
Abbreviations:
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)Keywords
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Article info
Publication history
Published online: February 28, 2015
Accepted:
February 19,
2015
Received in revised form:
February 4,
2015
Received:
December 5,
2014
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
