JNJ-73763989 药代动力学和安全性：针对乙型肝炎病毒的肝脏靶

StephenW

JNJ-73763989 药代动力学和安全性：针对乙型肝炎病毒的肝脏靶向 siRNA，用于日本和非日本健康成人，并与 JNJ-56136379 和一种核苷（酸）类似物联合用于慢性乙型肝炎患者
Ed Gane 1 , Man-Fung Yuen 2 , Thomas N Kakuda 3 , Tetsuro Ogawa 4 , Yasushi Takahashi 4 , Nele Goeyvaerts 5 , Isabelle Lonjon-Domanec 6 , Tamisha Vaughan 7 , Thomas Schluep 7 , James Hamilton 7 , Emmanuel Njumbe Ediage 5 ,维拉·希勒瓦特 5 ，扬·斯诺伊斯 5 ，奥利弗·伦茨 5 ，威廉·塔伦 5 ，迈克尔·比尔默 5
隶属关系

    PMID：35695169 DOI：10.1177/13596535221093856

抽象的

背景：JNJ-73763989 包含两种乙型肝炎病毒 (HBV) 特异性、肝脏靶向的 N-半乳糖胺偶联短干扰 RNA 触发器，JNJ-73763976 和 JNJ-73763924。 JNJ-73763989 的药代动力学、安全性和耐受性在两项 1 期研究中进行了评估：日本 (NCT04002752) 和非日本健康参与者和慢性乙型肝炎 (CHB) 患者也接受了 HBV 衣壳组装调节剂 JNJ-56136379 和核苷 (t )ide 类似物 (NA) (NCT03365947)。

方法：健康参与者队列是双盲的，随机接受单次皮下 JNJ-73763989 剂量（非日本参与者，35、100、200、300 或 400 毫克；日本参与者，25、100 或 200 毫克）或安慰剂。在 48 小时内评估 JNJ-73763976 和 JNJ-73763924 血浆浓度。 CHB 患者每 4 周接受一次 JNJ-73763989 200 mg 加上每日口服 JNJ-56136379 250 mg 和 NA 以开放标签方式。通过第 28 天（健康参与者）或第 112 天（患者）评估安全性和耐受性。

结果：30 名非日本人（n = 4/剂量；安慰剂，n = 10）和 24 名日本健康参与者（n = 6/剂量；安慰剂，n = 6）被随机分配。 JNJ-73763976 和 JNJ-73763924 的暴露量通常以剂量成比例的方式增加。平均血浆半衰期为 4-9 小时。非日本和日本健康参与者之间的药代动力学参数没有明显差异。在 12 名 CHB 患者中，第 29 天给药后 2 小时的平均 JNJ-73763976、JNJ-73763924 和 JNJ-56136379 血浆浓度分别为 663、269 和 14,718 ng/mL。在这两项研究中，所有不良事件均为轻度/中度。

结论：JNJ-73763976和JNJ-73763924血浆半衰期短，暴露量普遍呈剂量比例增加；日本和非日本健康成人之间没有药代动力学差异。 JNJ-73763989 有或没有 JNJ-56136379 和 NA 通常是安全的并且耐受性良好。
相关数据

    ClinicalTrials.gov/NCT03365947

StephenW

JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B
Ed Gane  1 , Man-Fung Yuen  2 , Thomas N Kakuda  3 , Tetsuro Ogawa  4 , Yasushi Takahashi  4 , Nele Goeyvaerts  5 , Isabelle Lonjon-Domanec  6 , Tamisha Vaughan  7 , Thomas Schluep  7 , James Hamilton  7 , Emmanuel Njumbe Ediage  5 , Vera Hillewaert  5 , Jan Snoeys  5 , Oliver Lenz  5 , Willem Talloen  5 , Michael Biermer  5
Affiliations

    PMID: 35695169 DOI: 10.1177/13596535221093856

Abstract

Background: JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947).

Methods: Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients).

Results: Thirty non-Japanese (n = 4/dose; placebo, n = 10) and 24 Japanese healthy participants (n = 6/dose; placebo, n = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4-9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate.

Conclusion: JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.
Associated data

    ClinicalTrials.gov/NCT03365947

乙肝人1949

日本人