Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B

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 (log(10) 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 (IFN alpha) 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 IFNa expression or related symptoms. However, no significant HBsAg declines were observed. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.