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

Authors
 Harry L.A. Janssen  ;  Maurizia R. Brunetto  ;  Yoon Jun Kim  ;  Carlo Ferrari  ;  Benedetta Massetto  ;  Anh-Hoa Nguyen  ;  Adarsh Joshi  ;  Jacky Woo  ;  Audrey H. Lau  ;  Anuj Gaggar  ;  G. Mani Subramanian  ;  Eric M. Yoshida  ;  Sang Hoon Ahn  ;  Naoky C.S. Tsai  ;  Scott Fung  ;  Edward J. Gane 
Citation
 JOURNAL OF HEPATOLOGY, Vol.68(3) : 431-440, 2018 
Journal Title
JOURNAL OF HEPATOLOGY
ISSN
 0168-8278 
Issue Date
2018
Keywords
HBsAg ; Hepatitis B virus ; Immune response ; TLR7
Abstract
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.
Full Text
https://www.sciencedirect.com/science/article/pii/S016882781732408X
DOI
10.1016/j.jhep.2017.10.027
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/167604
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