LBP30
Antiviral activity and safety of the hepatitis B core inhibitor ABIH0731
administered with a nucleos(t)ide reverse transcriptase
inhibitor in patients with HBeAg-positive chronic hepatitis B
infection in a long-term extension study
Man-Fung Yuen1, Kosh Agarwal2, Xiaoli Ma3, Tuan Nguyen4,
Eugene R. Schiff5, Hie-Won Hann6, Douglas Dieterich7,
Ronald Nahass8, James Park9, Sing Chan10, Steven-Huy Han11,
Edward Gane12, Michael Bennett13, Katia Alves14, Hany Zayed14,
Qi Huang14, Richard Colonno14, Steven Knox14, Luisa Stamm14,
Maurizio Bonacini15, Ira Jacobson9, Walid Ayoub16, Frank Weilert17,
Natarajan Ravendhran18, Alnoor Ramji19, Paul Kwo20,
Magdy Elkhashab21, Tarek Hassanein22, Ho Bae23, Jacob Lalezari15,
Scott Fung24, Mark Sulkowski25. 1The University of Hong Kong,
Department of Medicine, Hong Kong, China; 2Institute of Liver Studies,
King’s College Hospital, London, United Kingdom; 3Office of Xiaoli Ma,
Philadelphia, United States; 4T Nguyen Research and Education, Inc., San
Diego, United States; 5Schiff Center for Liver Diseases, University of
Miami School of Medicine, Miami, United States; 6Thomas Jefferson
University Hospital, Philadelphia, United States; 7Icahn School of
Medicine, Mount Sinai Hospital, Department of Medicine, Division of
Liver Diseases, New York, United States; 8Infectious Disease Care,
Hillsborough, United States; 9New York University Langone Medical
Center, New York, United States; 10Sing Chan MD, New York, United
States; 11Pfleger Liver Institute, University of California, Los Angeles,
United States; 12Auckland Clinical Studies Ltd, Auckland, New Zealand;
13Medical Associates Research Group, San Diego, United States;
14Assembly Biosciences Inc., South San Francisco, United States; 15Quest
Clinical Research, San Francisco, United States; 16Cedars-Sinai Medical
Center, Los Angeles, United States; 17Waikato Hospital, Hamilton, NewZealand; 18Digestive Disease Associates, Catonsville, United States;
19Providence Health Care Research Institute, Vancouver, Canada;
20Stanford University Medical Center, Stanford, United States; 21Toronto
Liver Centre, Toronto, Canada; 22Southern California Research Center,
Coronado, United States; 23Asian Pacific Liver Center, Los Angeles, United
States; 24University of Toronto, Toronto, Canada; 25Johns Hopkins
University School of Medicine, Baltimore, United States
Email: [email protected].
Background and aims: ABI-H0731 (731) is a first-generation HBV
core inhibitor in development for the treatment of chronic hepatitis B
infection (CHB). In the Phase 2a studies 202 and 201, treatment naïve
(TN) and virally suppressed (VS) HBeAg-positive patients (pts) with
CHB were randomized 1:1 to 731 or placebo (Pbo) with NrtI in a
blinded manner for 24 weeks. The combination of 731+NrtI was well
tolerated and demonstrated faster and greater reductions in HBV DNA
and pgRNA than NrtI alone. Following study completion, eligible pts
entering an open-label extension study 211 received 731+NrtI for up
to an additional 76 weeks. Here we report the updated data from
study 211 through the current last reported observation.
Method: For TN pts, HBV DNA was measured by COBAS TaqMan 2.0
(LLOQ = 20 IU/mL) and pgRNA by an in-house quantitative PCR assay
(LLOQ = 135 U/mL). For VS pts, HBV DNA was measured by an inhouse
semi-quantitative PCR assay (LLOD = 5 IU/mL) and pgRNA by
an in-house semi-quantitative RT-PCR assay (LLOD = 5 IU/mL). For all
pts, quantitative HBeAg and HBsAg were measured by Abbott
Architect (LLOQ = 0.11 IU/mL and 0.05 IU/mL, respectively) and
HBcrAg by Lumipulse G (LLOD = 1 kU/mL). Safety was assessed by
adverse events (AEs) and laboratory parameters.
Results: Of the 23 TN pts from study 202, median (range) treatment
duration 57 (36–83) weeks, 21 pts have DNA declines to <100 IU/mL
and 6 pts have pgRNA declines to <500 U/mL. Declines of ≥1 log or at
<LLOQ in HBeAg, HBcrAg and HBsAg have been observed in 6, 8 and 3
pts, respectively. Of the 43 VS pts from study 201, median (range)
treatment duration 58 (30–81) weeks, 34 and 21 pts have now
achieved DNA and pgRNA <5 IU/mL, respectively. In addition, 29 pts
have HBeAg <5 IU/mL, 27 pts have HBcrAg <500 kU/mL and 4 pts have
HBsAg <1000 IU/mL. During the first 24weeks of study 211, AEs were
reported by 47% (31/66) pts, most of which were Grade 1 or 2. There
were no SAEs or AEs leading to study drug discontinuation. The only
AE reported by >5% was upper respiratory tract infection (4 pts, 6%).
Most laboratory abnormalities were Grade 1 or 2. Transient or
intermittent Grade 3 elevations in ALT were observed in 2 pts (3%),
both of whom continue on study drug.
Conclusion: Results from the ongoing Phase 2a extension study
demonstrate continued declines in HBV DNA, pgRNA and viral
antigens in pts treated with 731+NrtI. 731 continues to exhibit a
favorable safety and tolerability profile in pts treated for over 1 year.
The data support the continued development of 731.作者: StephenW 时间: 2020-8-26 14:22
LBP30
乙型肝炎核心抑制剂ABIH0731的抗病毒活性和安全性
与核苷酸（t）逆转录酶一起使用
HBeAg阳性慢性乙型肝炎患者体内的抑制剂
长期延伸研究中的感染
袁文峰1，Kosh Agarwal2，小李玛3，阮阮4，
尤金·希夫（Eugene R.
Ronald Nahass8，James Park9，Sing Chan10，Steven-Huy Han11，
Edward Gane12，Michael Bennett13，Katia Alves14，Hany Zayed14，
齐煌14，理查德·科隆诺14，史蒂文·诺克斯14，路易莎·斯塔姆14，
毛里齐奥·博纳西尼15，艾拉·雅各布森9，瓦尔德·阿尤布16，弗兰克·韦勒特17，
Natarajan Ravendhran18，Alnoor Ramji19，Paul Kwo20，
Magdy Elkhashab21，Tarek Hassanein22，Ho Bae23，Jacob Lalezari15，
冯思达（Scott Fung）24，马克·苏尔科夫斯基（Mark Sulkowski）25 1香港大学，
中国香港医学部； 2肝病研究所，
英国伦敦国王学院医院； 3马小莉办公室，
美国费城； 4T Nguyen Research and Education，Inc.，San
美国圣地亚哥； 5 University of Schiff肝病中心
美国迈阿密迈阿密医学院； 6托马斯·杰斐逊
美国费城大学医院； 7伊坎学校
西奈山医院医学部医学科
美国纽约肝病； 8传染病护理，
美国希尔斯伯勒； 9纽约大学Langone Medical
美国纽约中心； 10Sing Chan MD，纽约，美国
状态; 11加州大学洛杉矶分校弗雷格肝脏研究所
美国; 12奥克兰临床研究有限公司，新西兰奥克兰；
13Medical Associates Research Group，美国圣地亚哥；
14Assembly Biosciences Inc.，美国南旧金山； 15任务
临床研究，美国旧金山； 16Cedars-Sinai Medical
美国洛杉矶中心； 17新西兰汉密尔顿威卡托医院； 18美国卡顿斯维尔消化系统疾病协会；
19加拿大温哥华Providence Health Care Research Institute；
20美国斯坦福大学斯坦福大学医学中心； 21多伦多
加拿大多伦多肝中心； 22南加州研究中心，
美国科罗纳多； 23亚洲太平洋肝脏中心，美国洛杉矶
状态; 24多伦多大学，加拿大多伦多; 25约翰·霍普金斯
美国巴尔的摩大学医学院
电邮：[email protected]。
背景和目标：ABI-H0731（731）是第一代HBV
核心抑制剂正在开发中，用于治疗慢性乙型肝炎
感染（CHB）。在2a期研究202和201中，未进行过治疗
（TN）和病毒抑制（VS）的HBeAg阳性患者（pts）
将CHB随机分为1：1至731或NrtI的安慰剂（Pbo）。
盲目地呆了24周。 731 + NrtI的组合很好
耐受并证明HBV DNA更快，更大地减少
和pgRNA比单独的NrtI。完成学习后，符合资格的分数
进入开放标签延伸研究211接受了731 + NrtI的费用
再延长76周。在这里，我们报告来自
研究211通过当前最新报告的观察结果。
方法：对于TN pts，通过COBAS TaqMan 2.0测量HBV DNA
（LLOQ = 20 IU / mL）和pgRNA通过内部定量PCR分析
（LLOQ = 135 U / mL）。对于VS pts，通过内部测量HBV DNA
半定量PCR分析（LLOD = 5 IU / mL）和pgRNA通过
内部半定量RT-PCR分析（LLOD = 5 IU / mL）。对所有人
雅培（Abbott）测量了pts，定量的HBeAg和HBsAg
建筑师（LLOQ = 0.11 IU / mL和0.05 IU / mL）和
Lumipulse G的HBcrAg（LLOD = 1 kU / mL）。安全性由
不良事件（AE）和实验室参数。
结果：研究202的23个TN分中，中位（范围）治疗
持续57（36–83）周，其中21个患者的DNA下降至<100 IU / mL
有6分的pgRNA降至<500 U / mL。下降≥1log或下降
<在6、8和3中观察到HBeAg，HBcrAg和HBsAg中的LLOQ
分。研究201的43个VS点中，中位数（范围）
治疗时间58（30–81）周，现在有34和21分
获得的DNA和pgRNA分别<5 IU / mL。此外，29分
HBeAg <5 IU / mL，27点HBcrAg <500 kU / mL，4点
HBsAg <1000 IU / mL。在研究211的前24周内，不良事件是
报告为47％（31/66）点，其中大多数为1级或2级。
没有SAE或AE导致研究药物停用。唯一的
> 5％报道的AE是上呼吸道感染（4分，6％）。
大多数实验室异常均为1级或2级。
在2分（3％）中观察到间歇性的ALT 3级升高，
他们俩都继续研究药物。
结论：正在进行的2a期扩展研究的结果
证明HBV DNA，pgRNA和病毒的持续下降
731 + NrtI处理的患者中的抗原。 731继续展示
治疗一年以上的患者的安全性和耐受性良好。
数据支持731的持续发展。