BACKGROUND & AIMS: Vesatolimod (GS-9620) is an oral agonist of toll-like 
receptor 7, an activator of innate and adaptive immune responses. Herein the 
safety and efficacy of vesatolimod is assessed after once-weekly treatment in 
patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral 
treatment.
METHODS: In a phase II, double-blind, randomized, placebo (PBO)-controlled 
study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and 
serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to 
once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks 
per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at 
the primary endpoint (Week 24). Safety assessments included adverse events (AE) 
and laboratory abnormality monitoring. Pharmacodynamic assessments included 
peripheral cytokine level quantification and interferon-stimulated gene (ISG) 
mRNA expression evaluation.
RESULTS: The majority of patients were male (76%) and HBeAg-negative (79%) at 
baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of 
AEs mild or moderate in severity. No significant declines in HBsAg were observed 
at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 
induction was dose-dependent and consistent after repeat dosing, returning 
closer to baseline by one week after treatment at all dose levels; no patient 
demonstrated significant serum interferon alpha (IFNα) expression at any 
timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction 
is associated with 2- or 4-mg vesatolimod dose and female sex.
CONCLUSIONS: Vesatolimod was safe and well-tolerated in patients with CHB, 
demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 
without significant systemic induction of IFNα expression or related symptoms. 
However, no significant HBsAg declines were observed.
LAY SUMMARY: In a phase II study, vesatolimod, an oral, once-weekly, 
experimental immune-activating drug for the treatment of hepatitis B virus 
(HBV), is safe and well-tolerated in chronic HBV patients who are virally 
suppressed on oral antiviral treatment. Despite demonstrating on-target 
biomarker responses in patients, no significant declines in hepatitis B surface 
antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047.