Vesatolimod（GS-9620）在慢性乙型肝炎病毒抑制患者中的安全性

StephenW

J Hepatol. 2017 Nov 2. pii: S0168-8278(17)32408-X. doi: 10.1016/j.jhep.2017.10.027. [Epub ahead of print]
Safety, Efficacy and Pharmacodynamics of Vesatolimod (GS-9620) in Virally-Suppressed Patients with Chronic Hepatitis B.Janssen HLA1, Brunetto MR2, Kim YJ3, Ferrari C4, Massetto B5, Nguyen AH5, Joshi A5, Woo J5, Lau AH5, Gaggar A5, Subramanian GM5, Yoshida EM6, Ahn SH7, Tsai NCS8, Fung S9, Gane EJ10.
Author information
1Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada. Electronic address: [email protected].2Clinical and Experimental Medicine Department, University of Pisa, Pisa, Italy.3Seoul National University Hospital, Seoul, South Korea.4Università Degli Studi di Parma, Italy.5Gilead Sciences, Inc., Foster City, CA, United States.6The University of British Columbia, Vancouver, Canada.7Yonsei University College of Medicine, Seoul, South Korea.8John A. Burns School of Medicine, University of Hawaii, Manoa, United States.9Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada.10Auckland Clinical Studies Ltd, Auckland, New Zealand.

AbstractBACKGROUND & 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.
METHODS: 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.
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 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.
CONCLUSIONS: 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.
LAY SUMMARY: 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.

Copyright © 2017. Published by Elsevier B.V.

KEYWORDS: HBsAg; Hepatitis B virus; Immune response; TLR7

PMID:29104121DOI:10.1016/j.jhep.2017.10.027

StephenW

J Hepatol。 2017年11月2日。pii：S0168-8278（17）32408-X。 doi：10.1016 / j.jhep.2017.10.027。 [电子版提前打印]
Vesatolimod（GS-9620）在慢性乙型肝炎病毒抑制患者中的安全性，有效性和药效学
Janssen HLA1，Brunetto MR2，Kim YJ3，Ferrari C4，Massetto B5，Nguyen AH5，Joshi A5，Woo J5，Lau AH5，Gaggar A5，Subramanian GM5，Yoshida EM6，Ahn SH7，Tsai NCS8，Fung S9，Gane EJ10。
作者信息

1
    加拿大安大略省多伦多大学健康网络多伦多肝病中心。电子地址：[email protected]。
2
    比萨大学临床和实验医学系，意大利比萨。
3
    首尔国立大学医院，韩国首尔。
4
    德意志大学帕尔马大学。
五
    吉列德科学公司，美国加州福斯特市。
6
    不列颠哥伦比亚大学，加拿大温哥华。
7
    延世大学医学院，韩国首尔。
8
    美国马诺阿夏威夷大学John A. Burns医学院。
9
    加拿大安大略省多伦多大学健康网络多伦多肝病中心。
10
    奥克兰临床研究有限公司，新西兰奥克兰。

抽象
背景与目的：

Vesatolimod（GS-9620）是Toll样受体7的一种口服激动剂，是先天性和适应性免疫反应的激活剂。在此，在经口服抗病毒治疗抑制的慢性乙型肝炎（CHB）感染患者中每周一次治疗之后评估维沙朵莫的安全性和功效。
方法：

在一项2期双盲随机安慰剂对照研究中，162例按乙肝表面抗原（HBsAg）水平和血清HBeAg状态分层的患者随机分为1：3：3：3和每周一次的口服PBO （1-，2-或4-mg剂量）持续4,8或12周，并且通过在主要终点（第24周）基线HBsAg（log 10 IU / mL）的变化评估疗效。安全性评估包括不良事件（AE）和实验室异常监测。药效学评估包括外周细胞因子水平定量和干扰素刺激的基因（ISG）mRNA表达评估。
结果：

基线时大多数患者是男性（76％）和HBeAg阴性（79％）。在研究期间，大多数（41-80％）的AE发生≥1AE，大部分AE轻度或中度。在初级（第24周）或次级终点（第4,8,12和48周）HBsAg没有显着下降。 ISG15诱导剂量依赖性且在重复给药后一致，在所有剂量水平下治疗后恢复至基线一周;没有患者在评估的任何时间点表现出显着的血清IFNα表达。多变量分析显示≥2倍的ISG15诱导与2-或4-mg的vesatolimod剂量和女性性别相关。
结论：

Vesatolimod在CHB患者中是安全且耐受良好的，证明ISG15的一致的剂量依赖性药效学诱导，没有显着的全身IFNα表达诱导或相关症状。然而，没有观察到显着的HBsAg下降。
总结：

在第二阶段的研究中，口服，一周一次的实验性免疫活化药物--Vacatolimod用于治疗乙型肝炎病毒（HBV），在口服抗病毒治疗病毒性抑制的慢性HBV患者中是安全和耐受良好的。尽管在患者中证实了靶向生物标志物应答，然而，没有观察到乙肝表面抗原的显着下降。

版权所有©2017. Elsevier B.V.
关键词：

乙肝表面抗原;乙型肝炎病毒;免疫反应; TLR7

结论：
    29104121
DOI：
    10.1016 / j.jhep.2017.10.027

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