慢性乙肝病毒感染患者的乙肝病毒衣壳装配调节剂GLS4的抗病

StephenW

Antiviral Activity and Pharmacokinetics of the HBV Capsid Assembly Modulator GLS4 in Patients With Chronic HBV Infection
Hong Zhang  1 , Fengjiao Wang  2 , Xiaoxue Zhu  1 , Yunfu Chen  3 , Hong Chen  1 , Xiaojiao Li  1 , Min Wu  1 , Cuiyun Li  1 , Jingrui Liu  1 , Yingjun Zhang  3 , Yanhua Ding  1 , Junqi Niu  2
Affiliations
Affiliations

    1
    Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China.
    2
    Department of Hepatology, The First Hospital of Jilin University, Jilin, China.
    3
    HEC R&D Center, Sunshine Lake Pharma Co., Ltd.

    PMID: 32649736 DOI: 10.1093/cid/ciaa961

Abstract

Background: GLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator (class I) that can inhibit HBV replication by interfering with the assembly and disassembly of HBV nucleocapsid. Here, we evaluated its antiviral activity, pharmacokinetics (PK), and tolerability in a double-blind, randomized, parallel, entecavir-controlled study.

Methods: Twenty four chronic HBV patients were randomized to receive a 28-day course of GLS4 (120 or 240 mg) and ritonavir (100 mg) combination (cohorts A and B, respectively) or entecavir treatment (cohort C) at a 1:1:1 ratio. Patients were followed-up for 40 days in a phase 1b study.

Results: The GLS4/ritonavir combination was a tolerated combination for the treatment of chronic HBV infection. A total of two, three, and three subjects presented with alanine aminotransferase flare in cohorts A, B and C, respectively. This contributed to the withdrawal of one, two, and one patient from cohorts A, B and C, respectively. The mean Ctrough of GLS4 was 205-218 ng/mL, which was approximately 3.7-3.9 times the EC90 (55.8 ng/mL), with a lower accumulation (accumulation rate: 1.1-2.0). In cohorts A, B and C, the mean declines in HBV DNA after 28 days of treatment were -1.42, -2.13, and -3.5 log10 IU/mL; in hepatitis B surface antigen were -0.06, -0.14, and -0.33 log10 IU/mL; in pregenomic RNA were -0.75, -1.78, and -0.96 log10 copies/mL; and in hepatitis B core antigen (were -0.23, -0.5, and -0.44 log10 U/mL, respectively.

Conclusions: Treatment with 120 mg GLS4 was tolerated and had antiviral activity in patients with chronic HBV infection.

Keywords: Hepatitis B Treatment; capsid assembly modulator; clinical trial; hepatitis B virus; response.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

StephenW

慢性乙肝病毒感染患者的乙肝病毒衣壳装配调节剂GLS4的抗病毒活性和药代动力学
张宏1，王凤娇2，朱小雪1，陈云浮3，陈宏1，李小娇1，吴敏1，李翠云1，刘静瑞1，张英军3，丁艳华1，牛俊奇2
隶属关系
隶属关系

    1个
    吉林大学第一医院临床研究中心一期，吉林
    2
    吉林大学第一医院肝科，吉林
    3
    阳光湖制药股份有限公司HEC研发中心

    PMID：32649736 DOI：10.1093 / cid / ciaa961

抽象

背景：GLS4是一流的乙型肝炎病毒（HBV）衣壳装配调节剂（I类），可通过干扰HBV核衣壳的装配和拆卸来抑制HBV复制。在这里，我们在一项双盲，随机，平行，恩替卡韦对照研究中评估了其抗病毒活性，药代动力学（PK）和耐受性。

方法：将二十四位慢性HBV患者随机分为1组，分别接受28天疗程的GLS4（120或240 mg）和利托那韦（100 mg）联合治疗（A组和B组）或恩替卡韦治疗（C组）。 1：1的比例。在1b期研究中对患者进行了40天的随访。

结果：GLS4 /利托那韦组合是一种可耐受的组合，用于治疗慢性HBV感染。 A，B和C组分别有2、3和3名受试者出现了丙氨酸氨基转移酶耀斑。这导致分别从队列A，B和C中撤出一名，两名和一名患者。 GLS4的平均Ctrough为205-218 ng / mL，约为EC90（55.8 ng / mL）的3.7-3.9倍，并且累积较低（累积速率：1.1-2.0）。在A，B和C组中，治疗28天后HBV DNA的平均下降为-1.42，-2.13和-3.5 log10 IU / mL。乙型肝炎患者的表面抗原分别为-0.06，-0.14和-0.33 log10 IU / mL;基因组前RNA中的-10，-1.78和-0.96 log10个拷贝/ mL;和乙型肝炎核心抗原中的浓度分别为-0.23，-0.5和-0.44 log10 U / mL。

结论：慢性HBV感染患者可以耐受120 mg GLS4治疗并具有抗病毒活性。

关键字：乙型肝炎治疗；衣壳装配调节剂临床试验;乙型肝炎病毒;响应。

©2020作者。牛津大学出版社，美国传染病学会出版。