EASL2020[LBP05] 第二代抗病毒活性，藥代動力學和安全性 乙肝核

StephenW

LBP05
Antiviral activity, pharmacokinetics and safety of the second generation
hepatitis B core inhibitor ABI-H2158 in Phase 1b study
of patients with HBeAg-positive chronic hepatitis B infection
Kosh Agarwal1, Junqi Niu2, Yanhua Ding2, Edward Gane3,
Tuan Nguyen4, Katia Alves5, Marc Evanchick5, Hany Zayed5,
Qi Huang5, Steven Knox5, Luisa Stamm5, Richard Colonno5,
Tarek Hassanein6, Dong Joon Kim7, Young-Suk Lim8, Man-Fung Yuen9
. 1Institute of Liver Studies, King’s College Hospital, London, United
Kingdom; 2The First Hospital of Jilin University, Changchun, China;
3Auckland Clinical Studies Limited, Auckland, New Zealand; 4T. Nguyen
Research and Education, San Diego, United States; 5Assembly Biosciences,
South San Francisco, United States; 6Southern California Research
Center, Coronado, United States; 7Hallym University Chuncheon Sacred
Heart Hospital, Chuncheon, Korea, Rep. of South; 8Asan Medical Center,
University of Ulsan College of Medicine, Seoul, Korea, Rep. of South;
9University of Hong Kong, Hong Kong, China
Email: [email protected].
Background and aims: The HBV core protein plays an integral role in
multiple steps of the HBV lifecycle. ABI-H2158 is a second-generation
HBV core inhibitor in development for the treatment of chronic
hepatitis B infection. Here we report the antiviral activity, pharmacokinetics
(PK) and safety from a Phase 1b study in which patients
(pts) were treated with ABI-H2158.
Method: In each cohort, 9 pts (7 active, 2 placebo [Pbo]) were
randomized in a blinded manner to receive either ABI-H2158 100,
300 or 500 mg or Pbo once daily for 14 days. Eligible pts were males
or females aged ≥18 and ≤65 years, HBV treatment naive, HBeAg
positive with HBV DNA ≥2 × 105 IU/mL and Metavir F0-F2. HBV DNA,
pgRNA, HBeAg, HBsAg and HBcrAg were measured on Days 1, 8 and
15. PK was assessed on Days 1 and 14. Safety was evaluated by
treatment-emergent adverse events (AEs) and laboratory
parameters.
Results: Across the cohorts, the mean (range) age of pts was 36 (19–
51) years, with the majority being male (59%), Asian (96%) and HBV
genotype C (59%). At baseline, the mean (range) HBV DNA was 8.0
log10 (4.7–9.1) IU/mL, pgRNA was 6.8 log10 (5.2–7.9) U/mL and ALT
was 40 (14–124) U/L. Change in HBV DNA and pgRNA from baseline to
Day 15 and PK data are shown in the Table 1. AEs were reported for
38% (8/21) of pts receiving ABI-H2158 and 50% (3/6) receiving PBO.
The majority of AEs were Grade 1; none were Grade 3 or 4, serious or
led to treatment discontinuation. Headache was the only AE reported
by more than 1 pt receiving ABI-H2158 (2 pts). Graded laboratory
abnormalities were observed in 71% (15/21) of pts receiving
ABI-H2158 and 50% (3/6) receiving Pbo, the majority of which were
Grade 1. Transient increases in were observed in 24% (5/21) of pts
receiving ABI-H2158 (all Grade 1) and in 33% (2/6) receiving Pbo
(1 Grade 1; 1 Grade 3).
ABI-H2158
Placebo
(n = 6)
100 mg
(n = 7)
300 mg
(n = 7)
500 mg
(n = 7)
HBV DNA change from
Baseline (log10 IU/
mL), mean (range)
−2.3
(−3.0 to −1.7)
−2.5
(−3.3 to −0.8)
−2.7
(−3.2 to −1.7)
−0.1
(−0.3 to 0.1)
pgRNA change from
Baseline (log10 U/
mL), mean (range)
−2.1
(−2.7 to −1.5)
−2.2
(−2.6 to −1.4)
−2.0
(−3.5 to −1.3)a
−0.1
(−0.2 to −0.1)
Cmax, ng/mL 3,390 8,400 9,890a
–
AUC0−24, hr*ng/mL 46,100 112,000 133,000a
–
an = 6.
Conclusion: Results from this Phase 1b study demonstrate that ABIH2158
has potent antiviral activity and a favourable safety profile
when administered once daily for 14 days supporting further
evaluation in combination with nucleos(t)ide analogues in

StephenW

LBP05
第二代抗病毒活性，藥代動力學和安全性
乙肝核心抑製劑ABI-H2158在1b期研究中
HBeAg陽性慢性乙型肝炎感染患者
Kosh Agarwal1，Nunqi Niu2，Dinghua Ding，Edward Gane3，
Tuan Nguyen4，Katia Alves5，Marc Evanchick5，Hany Zayed5，
齊煌5，史蒂文·諾克斯5，路易莎·斯塔姆5，理查德·科隆諾5，
Tarek Hassanein6，Dong Joon Kim7，Lim-Suk Lim8，Yuan-Fung Yuen9
。 1聯合王國倫敦國王學院醫院肝臟研究所
王國; 2吉林大學第一醫院，長春
3奧克蘭臨床研究有限公司，新西蘭奧克蘭； 4T。阮
研究和教育，美國聖地亞哥； 5Assembly Biosciences，
美國南舊金山； 6南加州研究
美國科羅納多市中心； 7Hallym大學春川聖地
韓國春川市心臟醫院8阿三醫療中心
蔚山大學醫學院，韓國首爾，韓國
9香港大學，中國香港
電子郵件：[email protected]。
背景與目的：HBV核心蛋白在
HBV生命週期的多個步驟。 ABI-H2158是第二代
HBV核心抑製劑正在開發中以治療慢性
乙肝感染。在這裡我們報告了抗病毒活性，藥代動力學
（PK）和安全性來自1b期患者的研究
（pts）用ABI-H2158處理。
方法：每個隊列中有9分（7份有效藥物，2份安慰劑[Pbo]）
以盲法隨機接受ABI-H2158 100，
每天一次300或500毫克或Pbo，持續14天。符合資格的男性是男性
或≥18歲且≤65歲的女性，未接受過HBV治療，HBeAg
HBV DNA≥2×105 IU / mL和Metavir F0-F2呈陽性。乙肝病毒DNA
在第1、8和8天測量pgRNA，HBeAg，HBsAg和HBcrAg
15.在第1天和第14天評估PK。
緊急治療不良事件（AE）和實驗室
參數。
結果：在整個隊列中，pts的平均（範圍）年齡為36歲（19–
51歲，大多數為男性（59％），亞洲人（96％）和HBV
基因型C（59％）。基線時，HBV DNA平均（範圍）為8.0
log10（4.7–9.1）IU / mL，pgRNA為6.8 log10（5.2–7.9）U / mL和ALT
是40（14–124）U / L。從基線到HBV DNA和pgRNA的變化
第15天和PK數據如表1所示。
38％（8/21）的患者接受ABI-H2158，50％（3/6）的患者接受PBO。
大部分AE屬於1級。沒有一個是3年級或4年級，嚴重的是
導致治療中斷。頭痛是唯一報導的不良事件
超過1分的接收ABI-H2158（2分）。分級實驗室
在接受治療的患者中有71％（15/21）觀察到異常
ABI-H2158和50％（3/6）接受Pbo，其中大多數是
1級。在24％（5/21）的患者中觀察到短暫增加
接收ABI-H2158（所有1級），接受Pbo的佔33％（2/6）
（1年級1； 1年級3）。
ABI-H2158
安慰劑
（n = 6）
100毫克
（n = 7）
300毫克
（n = 7）
500毫克
（n = 7）
HBV DNA從
基線（log10 IU /
mL），平均值（範圍）
−2.3
（−3.0至-1.7）
−2.5
（−3.3至-0.8）
−2.7
（−3.2至-1.7）
−0.1
（−0.3至0.1）
pgRNA從
基準（log10 U /
mL），平均值（範圍）
−2.1
（−2.7至-1.5）
−2.2
（−2.6至−1.4）
−2.0
（-3.5至-1.3）a
−0.1
（-0.2至-0.1）
Cmax，ng / mL 3,390 8,400 9,890a
–
AUC0-24，hr * ng / mL 46,100 112,000 133,000a
–
一個= 6。
結論：1b期研究的結果表明ABIH2158
具有有效的抗病毒活性和良好的安全性
每天給藥一次，持續14天，進一步支持
在階段2中結合核苷酸（t）化物類似物進行評估