AASLD2018[439]单剂量药代动力学（PK），安全性 和JNJ-64530440（JNJ

StephenW

439
Single-Dose Pharmacokinetics (PK), Safety
and Tolerability of JNJ-64530440 (JNJ-0440), a
Novel Hepatitis B Virus (HBV) Capsid Assembly
Modulator (CAM), in Healthy Volunteers (HV)
Thomas Kakuda1, Jeysen Yogaratnam1, Edward J. Gane2,
Christian Schwabe2, Christopher Westland1, Jennifer Vuong1,
Willem Talloen3, Oliver Lenz3, John Fry1, Sushmita Chanda1
and Pieter Van Remoortere4, (1)Alios Biopharma Inc., Part
of the Janssen Pharmaceutical Companies, South San
Francisco, CA, USA, (2)New Zealand Liver Transplant Unit,
University of Auckland, Auckland, New Zealand, (3)Janssen
Research & Development, Janssen Pharmaceutica NV,
Beerse, Belgium, (4)Janssen Research & Development,
Janssen Pharmaceuticals, Titusville, New Jersey, USA
Background: JNJ-0440 is a HBV CAM with improved
potency and dual mechanism of action. In vitro, JNJ-0440
interferes with HBV capsid assembly and cccDNA formation
with a median 50% effective concentration (EC50) of 24
and 136 nM, respectively, in HBV-infected primary human
hepatocytes. The safety, tolerability and PK of JNJ-0440, in
HVs was evaluated in a first in-human study JNJ-440-1301
(NCT03439488). Interim blinded results are described.
Methods: JNJ-440-1301 Part 1 is a double-blind, randomized,
placebo-controlled study of single ascending oral doses of
JNJ-0440 administered as tablets under fasted conditions.
40 HVs have completed dosing, 10 (2 placebo:8 active) per
dosing cohort (50, 150, 300, and 900 mg). JNJ-0440 plasma
concentrations were obtained over 120 hours and assayed
using liquid chromatography with tandem mass spectrometry
(LLOQ 1.00 ng/mL), PK parameters were estimated using noncompartmental
analysis (WinNonlin, Certara, Princeton NJ).
Safety and tolerability was assessed throughout. Results:
There were no withdrawals due to adverse events (AEs),
serious AEs, or dose limiting toxicities. AEs were mostly mild
(grade 1) with 1 case of grade 2 rash starting 3 days post-900
mg dose (doubtfully related; resolved with treatment). 5 AEs
(all grade 1) were identified as possibly or probably related: 1
case of nausea at 900 mg, 2 cases of fatigue at 150 mg, and 1
case each of headache and erythematous rash occurring at 50
mg. No clinically relevant changes in laboratory parameters or
electrocardiograms were observed. After a single dose of 50,
150, 300 or 900 mg, mean maximum plasma concentrations
(Cmax) of JNJ-0440 were 687, 1591, 2335 and 6345 ng/mL,
respectively and were achieved (median) 1.5–3 hours postdose;
mean area under the plasma concentration-time curve
over 24 hours was 7719, 17910, 24187 and 65820 ng.h/mL,
respectively. All subjects dosed 900 mg had 24-hour postdose
concentrations above the EC90 for inhibition of cccDNA
formation (373 nM). PK increased in a dose proportional
manner. The mean terminal elimination half-life was ~10–13
hours supporting once-daily dosing. Conclusion: Singledose
JNJ-0440 up to 900 mg was safe and well tolerated in
HVs. PK was dose proportional, achieved concentrations that
are expected to have antiviral activity, and supports once daily
dosing. Further single- and multiple-dose escalations in HVs,
as well as assessment of antiviral activity in HBV-infected
patients in this study is ongoing or planned.

StephenW

439
单剂量药代动力学（PK），安全性
和JNJ-64530440（JNJ-0440）的耐受性，a
新型乙型肝炎病毒（HBV）衣壳组装
调制器（CAM），健康志愿者（HV）
Thomas Kakuda1，Jeysen Yogaratnam1，Edward J. Gane2，
Christian Schwabe2，Christopher Westland1，Jennifer Vuong1，
Willem Talloen3，Oliver Lenz3，John Fry1，Sushmita Chanda1
和Pieter Van Remoortere4，（1）Alios Biopharma Inc.，Part
南桑山的Janssen制药公司
美国加利福尼亚州旧金山，（2）新西兰肝脏移植科，
奥克兰大学，奥克兰，新西兰，（3）Janssen
研究与开发，Janssen Pharmaceutica NV，
Beerse，比利时，（4）Janssen Research＆Development，
Janssen Pharmaceuticals，Titusville，New Jersey，USA
背景：JNJ-0440是一款经过改进的HBV CAM
效力和双重作用机制。体外，JNJ-0440
干扰HBV衣壳组装和cccDNA形成
中位数50％有效浓度（EC50）为24
在HBV感染的原发性人类中分别为136 nM和136 nM
肝细胞。 JNJ-0440的安全性，耐受性和PK，in
在第一次人体研究JNJ-440-1301中评估HV
（NCT03439488）。描述了临时盲法结果。
方法：JNJ-440-1301第1部分是双盲，随机，
单次上调口服剂量的安慰剂对照研究
JNJ-0440在禁食条件下作为片剂给药。
40个HV已完成给药，10个（2个安慰剂：8个有效）
给药组（50,150,300和900mg）。 JNJ-0440等离子
在120小时内获得浓度并进行测定
使用液相色谱 - 串联质谱
（LLOQ 1.00 ng / mL），使用非房室估计PK参数
分析（WinNonlin，Certara，Princeton NJ）。
始终评估安全性和耐受性。结果：
由于不良事件（AE）没有退出，
严重的AE，或剂量限制毒性。 AE大多是温和的
（1级）1例2级皮疹从900后3天开始
mg剂量（怀疑相关;用治疗解决）。 5个AE
（所有1级）被确定为可能或可能相关：1
在900毫克时出现恶心，在150毫克时出现2例疲劳，1例
每例头痛和红斑性皮疹发生在50岁
毫克。没有临床相关的实验室参数变化或
观察到心电图。单剂量50后，
150,300或900毫克，平均最大血浆浓度
JNJ-0440的（Cmax）分别为687,1591,2335和6345ng / mL，
分别达到（中位数）给药后1.5-3小时;
血浆浓度 - 时间曲线下的平均面积
超过24小时是7719,17910,24187和65820 ng.h / mL，
分别。所有给药900mg的受试者在给药后24小时
浓度高于EC90抑制cccDNA
形成（373 nM）。 PK剂量成比例增加
方式。平均终末消除半衰期为~10-13
小时支持每日一次给药。结论：Singledose
JNJ-0440高达900毫克是安全的，并且耐受性良好
的HV。 PK与剂量成比例，达到浓度即可
预计会有抗病毒活性，并且每天支持一次
剂量。 HV中的进一步单剂量和多剂量递增，
以及评估HBV感染的抗病毒活性
本研究中的患者正在进行或计划中。