Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada. Electronic address: firstname.lastname@example.org.
Clinical and Experimental Medicine Department, University of Pisa, Pisa, Italy.
Seoul National University Hospital, Seoul, South Korea.
Università Degli Studi di Parma, Italy.
Gilead Sciences, Inc., Foster City, CA, United States.
The University of British Columbia, Vancouver, Canada.
Yonsei University College of Medicine, Seoul, South Korea.
John A. Burns School of Medicine, University of Hawaii, Manoa, United States.
Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada.
Auckland Clinical Studies Ltd, Auckland, New Zealand.
BACKGROUND & AIMS:
Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Here the safety and efficacy of vesatolimod is assessed after once-weekly treatment in chronic hepatitis B (CHB) infected patients suppressed on oral antiviral treatment.
In a Phase 2, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum 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 and efficacy 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.
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 to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum IFNα expression at any timepoint evaluated. Multivariate analyses showed ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex.
Vesatolimod was safe and well-tolerated in CHB patients, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic IFNα expression induction or related symptoms. However, no significant HBsAg declines were observed.
In a Phase 2 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, however, no significant declines in hepatitis B surface antigen were observed.