JNJ-56136379是一种HBV衣壳装配调节剂，在慢性感染患者的1期研

StephenW

Gastroenterology. 2020 Apr 25. pii: S0016-5085(20)30519-9. doi: 10.1053/j.gastro.2020.04.036. [Epub ahead of print]
JNJ-56136379, an HBV Capsid Assembly Modulator, is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients with Chronic Infection.
Zoulim F1, Lenz O2, Vandenbossche JJ2, Talloen W2, Verbinnen T2, Moscalu I3, Streinu-Cercel A4, Bourgeois S5, Buti M6, Crespo J7, Pascasio JM8, Sarrazin C9, Vanwolleghem T10, Shukla U11, Fry J12, Yogaratnam JZ12.
Author information

1
    Hepatology Unit, Hospices Civils de Lyon and Lyon University, Lyon, France & INSERM U1052-Cancer Research Institute of Lyon, Lyon, France. Electronic address: [email protected].
2
    Janssen Pharmaceuticals NV, Beerse, Belgium.
3
    Spitalul Clinic Republican, ARENSIA EM, Chișinău, Moldova.
4
    National Institute for Infectious Diseases "Prof. Dr Matei Bals", Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
5
    ZNA Jan Palfijn, CPU, Antwerp, Belgium.
6
    Hospital Universitario Vall d'Hebrón and CIBERHED del Instituto Carlos III, Barcelona, Spain.
7
    Hospital Universitario Marqués de Valdecilla, IDIVAL Santander, Spain.
8
    Hospital Universitario Virgen del Rocio, Seville, Spain.
9
    Medizinische Klinik II, St. Josefs-Hospital, Weisbaden, Germany.
10
    Erasmus MC, University Medical Center, Rotterdam, Netherlands; Antwerp University Hospital, Antwerp, Belgium.
11
    Janssen Pharmaceuticals R&D, Titusville, New Jersey, USA. Electronic address: [email protected].
12
    Janssen Biopharma Inc., South San Francisco, USA.

Abstract
BACKGROUND & AIMS:

JNJ-56136379 (JNJ-6379), a capsid assembly modulator that blocks hepatitis B virus (HBV) replication, was well tolerated and demonstrated dose-proportional pharmacokinetics in healthy participants in part 1 of its first clinical trial. In part 2, we have evaluated the safety, pharmacokinetics, and antiviral activity of multiple doses of JNJ-6379 in patients with chronic HBV infection.
METHODS:

We performed a double-blind study of 57 treatment-naïve patients with HB e antigen-positive or -negative (74%) chronic HBV infection without cirrhosis. Patients were randomly assigned to groups given JNJ-6379 at 25 mg (100 mg loading dose), 75 mg, 150 mg or 250 mg or placebo daily for 4 weeks with an 8-week follow-up period.
RESULTS:

Twenty-three of 41 patients (56%) given JNJ-6379 had at least 1 adverse event (AE) during treatment, compared with 10/16 patients (63%) given placebo. No serious AEs were reported during the treatment period. Three patients (7%) given JNJ-6379 vs none given placebo had grade 3 AEs; of these, 1 patient (150 mg) also had an isolated grade 4 increase in level of alanine aminotransferase that led to treatment discontinuation. JNJ-6379 exposure increased with dose, with time-linear pharmacokinetics. HBV-DNA and HBV-RNA decreased from baseline in patients receiving all doses of JNJ-6379, independently of viral genotype and HB e antigen status. On day 29, 13/41 patients (32%) had levels of HBV DNA below the lower limit of quantification. No clinically significant changes in levels of HB surface antigen were observed.
CONCLUSIONS:

In a phase 1 study of treatment-naïve patients with chronic HBV infection, all doses tested of JNJ-6379 were well tolerated, showed dose-dependent pharmacokinetics, and had potent antiviral activity in patients with CHB. The findings support a phase 2a study to evaluate JNJ-6379±nucleos(t)ide analogs in patients with chronic HBV infection, which is underway. ClinicalTrials.gov identifier: NCT02662712.

Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
KEYWORDS:

HBeAg; HBsAg; drug; liver

PMID:
    32343960
DOI:
    10.1053/j.gastro.2020.04.036

StephenW

肠胃病学。 2020年4月25日。pii：S0016-5085（20）30519-9。 Doi：10.1053 / j.gastro.2020.04.036。 [Epub提前发行]
JNJ-56136379是一种HBV衣壳装配调节剂，在慢性感染患者的1期研究中耐受性良好且具有抗病毒活性。
Zoulim F1，Lenz O2，Vandenbossche JJ2，Talloen W2，Verbinnen T2，Moscalu I3，Streinu-Cercel A4，Bourgeois S5，Buti M6，Crespo J7，Pascasio JM8，Sarrazin C9，Vanwolleghem T10，Shukla U11 F
作者信息

1个
法国里昂市民医院和里昂大学肝病科，法国里昂INSERM U1052-癌症研究所。电子地址：[email protected]。
2
Janssen Pharmaceuticals NV，比利时比尔。
3
Spitalul Clinic共和党人，ARENSIA EM，摩尔多瓦基希讷乌。
4
国立传染病研究所“ Matte Bals教授”，罗马尼亚布加勒斯特卡罗尔·达维拉医药大学。
5
ZNA Jan Palfijn，比利时安特卫普CPU。
6
西班牙巴塞罗那大学瓦莱德赫布隆大学医院和CIBERHED del Instituto Carlos III。
7
西班牙IDIVAL桑坦德大学马尔库斯·瓦尔德迪利亚大学医院。
8
西班牙塞维利亚维尔京德尔罗西奥大学医院。
9
德国威斯巴登圣约瑟夫医院的Medilinische Klinik II。
10
Erasmus MC，荷兰鹿特丹大学医学中心；比利时安特卫普安特卫普大学医院。
11
Janssen Pharmaceuticals R＆D，美国新泽西州蒂图斯维尔。电子地址：[email protected]。
12
美国南旧金山的Janssen Biopharma Inc.。

抽象
背景与目的：

JNJ-56136379（JNJ-6379）是一种可阻断乙型肝炎病毒（HBV）复制的衣壳装配调节剂，在其第一项临床试验的第1部分中，其对健康受试者的耐受性良好，并显示出与剂量成比例的药代动力学。在第2部分中，我们评估了多剂量JNJ-6379在慢性HBV感染患者中的安全性，药代动力学和抗病毒活性。
方法：

我们对57例未经治疗的HBe抗原阳性或阴性（74％）慢性HBV感染而无肝硬化的患者进行了双盲研究。将患者随机分为两组，每天给予25 mg（100 mg负荷剂量），75 mg，150 mg或250 mg JNJ-6379或安慰剂，持续4周，并进行8周的随访。
结果：

接受JNJ-6379治疗的41名患者中有23名（56％）在治疗期间发生了至少1次不良事件（AE），而接受安慰剂的患者中有10/16名患者（63％）。在治疗期间未报告严重的不良事件。 3例（7％）接受JNJ-6379的患者，无3例接受AE。其中，有1名患者（150 mg）的丙氨酸转氨酶水平也升高了4级，导致治疗中断。 JNJ-6379暴露随剂量增加，随时间线性药代动力学。接受所有剂量的JNJ-6379的患者的HBV-DNA和HBV-RNA均较基线水平降低，与病毒基因型和HBe抗原状态无关。在第29天，有13/41名患者（32％）的HBV DNA水平低于定量下限。没有观察到HB表面抗原水平的临床显着变化。
结论：

在一项未经治疗的慢性HBV感染患者的1期研究中，对JNJ-6379的所有测试剂量均耐受良好，显示出剂量依赖性药代动力学，并且对CHB患者具有有效的抗病毒活性。这些发现支持2a期研究，以评估正在进行中的慢性HBV感染患者的JNJ-6379±核苷（t）ide类似物。 ClinicalTrials.gov标识符：NCT02662712。

版权所有©2020 AGA Institute。由Elsevier Inc.出版。保留所有权利。
关键字：

乙肝抗原乙肝表面抗原药品;肝

PMID：
32343960
DOI：
10.1053 / j.gastro.2020.04.036