2016年EASL ARC-520摘要1

StephenW

THU-193
DIFFERENTIAL REDUCTIONS IN VIRAL ANTIGENS EXPRESSED
FROM CCCDNAVS INTEGRATED DNA IN TREATMENT NAÏVE HBEAG
POSITIVE AND NEGATIVE PATIENTS WITH CHRONIC HBVAFTER
RNA INTERFERENCE THERAPY WITH ARC-520
M.-F. Yuen1, H.L.Y. Chan2, K. Liu1, B.D. Given3, T. Schluep3, J. Hamilton3,
C.-L. Lai1, S.A. Locarnini4, J.Y.N. Lau1,5, C. Ferrari6, R.G. Gish7,8. 1The
University of Hong Kong; 2The Chinese University of Hong Kong, Hong
Kong, China; 3Arrowhead Research Corporation, Pasadena, United
States; 4Victorian Infectious Diseases Reference Laboratory, Victoria,
Australia; 5Hong Kong Polytechnic University, Hong Kong, China;
6University of Parma, Parma, Italy; 7Stanford University, Palo Alto;
8Hepatitis B Foundation, Doylestown, United States
E-mail: [email protected]
Background and Aims: ARC-520 (ARC), a RNA interference drug,
targets cccDNA-derived mRNA in chronic hepatitis B patients (CHB);
we previously reported safety and activity of ARC in entecavir (ETV)
experienced CHB and preliminary results in treatment-naïve CHB
enrolled in a single dose phase 2a study; herein we report full safety
and activity against multiple viral antigens and DNA in naïve CHB.
Methods: 58 CHB (48 ARC, 10 placebo) were accrued to 7 cohorts, of
which 46 were ETV experienced and 12 (6 HBeAg-neg, 6 HBeAg-pos)
were treatment naïve. Naïve CHB received a single IV dose of 4 mg/kg
ARC and started daily oral ETV on the same day. Viral DNA and
antigen knockdown (KD) were measured over 85 days [qHBsAg, HB
core-related antigen (qHBcrAg) in all, qHBeAg in HBeAg-pos].
Results: ARCwaswell tolerated – 23% reported a mild or mod adverse
event (AE) with no AE rated serious, severe, drug-related or causing
withdrawal. For naïve CHB, 5 of 6 HBeAg-neg and 1 of 6 HBeAg-pos
achieved HBV DNA BLOQ within a mean of 11 days. HBeAg-pos above
LLOQ had a max DNA reduction of 5.0 log (mean max 4.2). Two
distinct patterns of qHBsAg KD were seen: an immediate, direct ARC
antiviral effect in 5/6 HBeAg-pos and a delayed response several
weeks after treatment in 5/6 HBeAg-neg. One transitional CHB
became HBeAg neg early during therapy and had an intermediate
qHBsAg response. In HBeAg-pos maximum reduction of antigenswas
1.9 log (mean max 1.5) for qHBsAg, 1.8 log (mean max 1.4) for
qHBcrAg, and 2.0 log (mean max 1.6) for qHBeAg. In HBeAg-neg
max reductionwas 0.4 log (mean max 0.3) for qHBsAg. 5 of 6 HBeAgneg
had HBcrAg BLOQ; 1 with measurable levels had a 0.7 log
decline. Duration of qHBsAg decline was >57 days after a single dosein all CHB.
Conclusions: 1) ARC was well tolerated 2) ARC + ETV acted
synergistically to produce rapid DNA suppression 3) ARC effectively
inhibited cccDNA-derived mRNAwith protein KD up to 2.0 logs (99%)
observed 4) In HBeAg-pos naïve CHB all viral antigens were
effectively suppressed, while in HBeAg-neg less KD in qHBsAg was
observed compared to qHBcrAg. 5) These findings are consistent with
more cccDNA-driven antigen production in naïve HBeAg-pos and a
higher fraction of qHBsAg production from integrated DNA in HBeAgneg
6) These variations in viral protein KD are consistent with ARC
data from chimps showing higher fractions of integrated DNAderived
viral mRNA in HBeAg-neg 7) Chronic ARC studies aimed at
producing HBsAg seroclearance are ongoing.

StephenW

THU-193
在病毒抗原差的减少表示关心
从CCCDNAVS整合的DNA在初次接受治疗大三阳
慢性HBVAFTER正负患者
采用圆弧520 RNA干扰治疗
M.-F. Yuen1，H.L.Y. CHAN2，K. Liu1，B.D. Given3，T. Schluep3，J. Hamilton3，
C.-L. Lai1，S.A Locarnini4，J.Y.N. Lau1,5，C Ferrari6，R.G. Gish7,8。 1The
香港大学;香港，香港的2The中国大学
中国香港; 3Arrowhead研究公司，帕萨迪纳，美国
状态; 4Victorian传染病参考实验室，维多利亚，
澳大利亚; 5Hong香港理工大学，香港，中国;
帕尔马，帕尔马，意大利6University; 7Stanford大学，帕洛阿尔托;
8Hepatitis乙基金会，Doylestown的，美国
电子信箱：[email protected]
背景和目的：ARC-520（ARC），一个RNA干扰药物，
目标cccDNA的衍生慢性乙型肝炎患者的mRNA（CHB）;
我们此前报道的恩替卡韦ARC的安全和活动（ETV）
经历CHB初步结果在治疗初治慢性乙肝
报名参加单剂量2a期研究报告;在此我们报告全面的安全
并针对多种病毒抗原和天真CHB DNA的活性。
方法：58 CHB（48 ARC，10安慰剂）被计入7同伙的
其中46人ETV经验丰富，12（6例HBeAg负，6大三阳-POS）
是初次接受治疗。朴素CHB接收的4毫克/ kg的单IV剂量
ARC和开始于同一天，每天口服ETV。病毒DNA和
85天后测定抗原敲除（KD）[qHBsAg，HB
核心相关抗原（qHBcrAg）所有，qHBeAg对于HBeAg POS]。
结果：ARCwaswell容忍 - 23％报告有轻度或国防部不利
事件（AE），无AE额定严重，严重，与毒品有关的或造成
撤出。对于天真CHB，6例HBeAg负5和6例HBeAg POS 1
11天，平均内达到HBV DNA BLOQ。上述大三阳-POS
LLOQ为5.0日志中的最大DNA降低（平均4.2最大值）。二
qHBsAg KD的不同的模式被视为：立即，直接ARC
在5/6的HBeAg-POS抗病毒效果和延迟响应数
在5/6的HBeAg负治疗后数周。一个过渡CHB
成为大三阳负治疗在早期并有一个中间
qHBsAg响应。对于HBeAg POS最大减少antigenswas的
1.9日志（平均1.5最大值）为qHBsAg，1.8日志（平均1.4最大值）为
qHBcrAg和2.0日志（平均最大1.6）为qHBeAg。对于HBeAg NEG
最大reductionwas 0.4日志（平均最大0.3）为qHBsAg。 5 6 HBeAgneg
有HBcrAg BLOQ; 1可测量的水平有一个0.7日志
下降。的qHBsAg下降时间为一个单一的dosein所有CHB后>57天。
结论：1）ARC的耐受性良好2）ARC + ETV行动
协同有效地产生快速DNA抑制3）ARC
抑制的cccDNA衍生mRNAwith蛋白KD高达2.0日志（99％）
观察4）对于HBeAg-POS天真CHB所有病毒抗原是
有效抑制，而对于HBeAg NEG在qHBsAg KD少了
相比qHBcrAg观察。 5）这些研究结果是一致
更多的cccDNA驱动的抗原生产的天真大三阳-POS和
从在HBeAgneg整合的DNA qHBsAg生产更高分数
6）在病毒蛋白KD这些变化与ARC一致
从黑猩猩显示出综合DNAderived更高的分数数据
对于HBeAg NEG病毒mRNA针对7）慢性ARC的研究
生产的HBsAg血清学清除正在进行中。

齐欢畅2

香港大学和香港理工大学也参与了研究。有香港的战友可以去了解一些情况。呼唤香港的战友。