LO10：siRNA JNJ-3989 和/或 CAPSID 组装调节器 (CAM) JNJ-6379 用于 慢

StephenW

LO10：siRNA JNJ-3989 和/或
CAPSID 组装调节器 (CAM) JNJ-6379 用于
慢性乙型肝炎病毒感染 (CHB) 的治疗：
REEF-1 阶段 2B 研究的结果
Man Fung Yuen1, Prof. Tarik Asselah2, Dr. Ira M. Jacobson3, Maurizia Rossana Brunetto4, Prof. Harry L
Janssen5, Prof. Tetsuo Takehara6, Prof. JinLin Hou7, Dr. Thomas Kakuda8, Tom Lambrecht8, Dr. Maria
Beumont-Mauviel8、Ronald Kalmeijer8、Carine Guinard-Azadian8、Cristiana Mayer8、John Jezorwski8、Thierry 博士
Verbinnen8, Dr. Oliver Lenz8, Dr. Umesh Shukla8 和 Dr. Michael Biermer8, (1)Queen Mary Hospital, University
香港大学，（2）巴黎大学，Inserm UMR1149 和 Hôpital Beaujon，Aphp，（3）纽约大学
格罗斯曼医学院，(4)比萨大学，(5)多伦多大学，(6)大阪大学研究生
医学院，（7）南方医科大学南方医院，（8）Janssen Research & Development
背景：JNJ-3989 是一种 siRNA，旨在靶向所有乙型肝炎病毒 (HBV) RNA，从而减少所有病毒
蛋白质。 JNJ-6379 是一种 CAM，通过诱导缺乏病毒衣壳的形成来抑制病毒复制
基因组材料。 REEF-1 研究评估了每月 (Q4W) s.c. 的有效性和安全性。注射 JNJ-
3989（40、100 和 200mg 的 3 个剂量水平）和/或 250mg QD 口服 JNJ-6379 联合 QD 口服 NA
目前未治疗 (CNT) 或病毒抑制 (VS) 的 HBeAg 阳性或阴性 CHB 患者。
方法：在这项 2b 期、多中心、主动对照研究中，CHB 患者（N=470）被随机分组​​（2:2:2:2:1:1）
到 6 个组（见图）并在 48 周双盲 PBO 控制治疗期和 48 周
跟进（FU）。主要终点是满足 NA 停止标准（ALT <3x ULN，HBV
第 48 周时 DNA <LLOQ、HBeAg 阴性 [<LLOQ] 和 HBsAg <10 IU/mL）。此处显示了第 48 周的数据；星期
将提供 72 项数据（FU 周 24）。
结果：REEF-1 中的患者为 66% 男性，52% 白人，41% 亚洲人，70% HBeAg 阴性，63% VS
基线（BL）。达到主要终点的患者比例如图所示，最高的
JNJ-3989 200mg + NA 组中的比例 (19.1%)。 JNJ-3989 200mg + NA 臂的比例最高 18

到第 44 周达到 HBsAg 水平 <10 IU/mL 的患者 (33%) 和 72% 达到 <100 IU/mL。显着平均值
使用 JNJ-3989 200、100 和 40mg + 观察到 HBsAg 从基线到治疗结束的 log10 降低
NA（具有剂量反应模式）和 JNJ-3989 + JNJ-6379 + NA（–2.58、–2.09、– 1.50 和 –1.76 log10 IU/mL），
但不适用于 PBO 或 JNJ-6379 + NA（–0.22 和 –0.07 log10IU/mL）； <3% 的患者达到 HBsAg 消失。级别
乙型肝炎核心相关抗原 (HBcrAg)、HBV RNA 和 HBV DNA（在目前未在 BL 治疗的患者中），以及
HBeAg（在 HBeAg 阳性患者中）在治疗后降低； <1% 的患者达到 HBeAg 消失。全部
这项长期三联疗法研究中的方案通常具有良好的耐受性和安全性； 10 个报告的严重不良事件中的 2 个
（ALT 升高和横纹肌溶解）被认为与研究药物有关。治疗中断率低
（所有组≤6.3%）。
结论：JNJ-3989 表现出剂量依赖性反应，达到主要终点的比例高达 19.1%
第 48 周，JNJ-6379 + NA 为 0%，PBO + NA 组为 2.2%。 HBsAg 水平的降低是
JNJ-3989 200mg s.c. 效果最好Q4W + NA。

StephenW

LO10: EFFICACY AND SAFETY OF THE siRNA JNJ-3989 AND/OR THE
CAPSID ASSEMBLY MODULATOR (CAM) JNJ-6379 FOR THE
TREATMENT OF CHRONIC HEPATITIS B VIRUS INFECTION (CHB):
RESULTS FROM THE PHASE 2B REEF-1 STUDY
Man Fung Yuen1, Prof. Tarik Asselah2, Dr. Ira M. Jacobson3, Maurizia Rossana Brunetto4, Prof. Harry L
Janssen5, Prof. Tetsuo Takehara6, Prof. JinLin Hou7, Dr. Thomas  Kakuda8, Tom  Lambrecht8, Dr. Maria
Beumont-Mauviel8, Ronald Kalmeijer8, Carine Guinard-Azadian8, Cristiana Mayer8, John Jezorwski8, Dr. Thierry
Verbinnen8, Dr. Oliver Lenz8, Dr. Umesh Shukla8 and Dr. Michael Biermer8, (1)Queen Mary Hospital, University
of Hong Kong, (2)Université De Paris, Inserm UMR1149 and Hôpital Beaujon, Aphp, (3)New York University
Grossman School of Medicine, (4)University of Pisa, (5)University of Toronto, (6)Osaka University Graduate
School of Medicine, (7)Nanfang Hospital, Southern Medical University, (8)Janssen Research & Development
Background: JNJ-3989 is  an siRNA designed to target all hepatitis  B virus  (HBV) RNAs, thereby reducing all viral
proteins. JNJ-6379 is a CAM that inhibits viral replication by inducing the formation of viral capsids devoid of
genomic material. The REEF-1 study assessed the efficacy and safety of monthly (Q4W) s.c. injections  of JNJ-
3989 (3 dose levels  of 40, 100, and 200mg) and/or 250mg QD oral JNJ-6379 in combination with QD oral NA in
currently not treated (CNT) or virally suppressed (VS) patients  with HBeAg positive or negative CHB.
Methods: In this Phase 2b, multicenter, active-controlled study, CHB patients (N=470) were randomized (2:2:2:2:1:1)
to 6 arms (see Figure) and dosed for a 48-week double-blind PBO-controlled treatment period and 48 weeks  of
follow up (FU). The primary endpoint was  the proportion of patients meeting NA stopping criteria (ALT <3x ULN, HBV
DNA <LLOQ, HBeAg-negative [<LLOQ], and HBsAg <10 IU/mL) at Week 48. Week 48 data are shown here; Week
72 data (FU Week 24) will be presented.
Results: Patients in REEF-1 were 66% male, 52% White, 41% Asian, 70% HBeAg negative, and 63% VS at
baseline (BL). The proportions  of patients  achieving primary endpoint are depicted in the Figure, with the highest
proportion (19.1%) in the JNJ-3989 200mg + NA arm. The JNJ-3989 200mg + NA arm had the highest proportion   18

of patients (33%) achieving HBsAg levels <10 IU/mL by Week 44, and 72% reached <100 IU/mL. Significant mean
log10  reductions  from  baseline to end of treatment in HBsAg were observed with JNJ-3989 200, 100, and 40mg +
NA (with dose-response pattern), and JNJ-3989 + JNJ-6379 + NA (–2.58, –2.09, – 1.50, and –1.76 log10  IU/mL),
but not with PBO or JNJ-6379 + NA (–0.22 and –0.07 log10IU/mL); <3% of patients  achieved HBsAg loss. Levels
of hepatitis  B core-related antigen (HBcrAg), HBV RNA, and HBV DNA (in patients  not currently treated at BL), and
HBeAg (in HBeAg-positive patients) were reduced on treatment; <1% of patients  achieved HBeAg loss. All
regimens  within this  long-term, triple therapy study were generally well tolerated and safe; 2 of 10 reported SAEs
(ALT flare and rhabdomyolysis) were considered related to study drug. Treatment discontinuation rates were low
(≤6.3% in all arms).
Conclusion: JNJ-3989 showed a dose dependent response with up to 19.1% meeting the primary endpoint at
Week 48 compared to 0% in the JNJ-6379 + NA and 2.2% in the PBO + NA arm. Reduction of HBsAg levels was
greatest with JNJ-3989 200mg s.c. Q4W + NA.