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

JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection

    Fabien Zoulim
    Oliver Lenz
    Joris J. Vandenbossche
    Umesh Shukla
    John Fry
    Jeysen Z. Yogaratnam
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Published:April 25, 2020DOI:https://doi.org/10.1053/j.gastro.2020.04.036
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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 (56%) of 41 patients given JNJ-6379 had at least 1 adverse event (AE) during treatment, compared with 10 (63%) of 16 patients 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 the 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 (32%) of 41 patients 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 under way.
ClinicalTrials.gov identifier: NCT02662712
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StephenW

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

    法比恩·祖利姆（Fabien Zoulim）
    奥利弗·伦茨（Oliver Lenz）
    乔里斯·范登博舍
    乌梅什舒克拉
    约翰·弗莱
    Jeysen Z.Yogaratnam
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发布时间：2020年4月25日DOI：https：//doi.org/10.1053/j.gastro.2020.04.036
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背景与目标
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，在其首次临床试验的第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16名患者中有10名（63％）有安慰剂。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，41例患者中有13例（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，以评估慢性HBV感染患者的JNJ-6379±nucleot（t）ide类似物。
ClinicalTrials.gov标识符：NCT02662712

StephenW

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