THU-198
IN VITROAND IN VIVOANTIVIRAL ACTIVITIES OFAB-423 A POTENT
SMALL MOLECULE INHIBITOR OF HEPATITIS B VIRUS CAPSID
ASSEMBLY
N. Mani1, A. Cole2, J. Phelps3, A. Ardzinski1, K. Cobarrubias3,
A. Cuconati1, B. Dorsey2, E. Evangelista4, T. Harasym4, S. Kadhim4,
A. Lee3, H. Liang5, A. Li3, K. McClintock4, S. Majeski4, S. Reid3,
R. Rijnbrand6, S. Tang4, X. Wang1, M. Sofia2,6. 1Virology; 2Chemistry,
Arbutus Biopharma, Doylestown, United States; 3In Vivo Pharmacology
and Macro-Molecular Discovery; 4Drug Metabolism and
Pharmacokinetics, Arbutus Biopharma, Burnaby, Canada; 5Baruch S.
Blumberg Institute; 6Biology, Arbutus Biopharma, Doylestown, United
States
E-mail: [email protected]
Background and Aims: Hepatitis B virus replication is strictly
dependent upon capsid assembly around pregenomic RNA, which
is essential for viral genome (rcDNA) synthesis, infectious virion
production and maintenance of the nuclear cccDNA pool. The capsid
assembly process thus represents a bona fide antiviral target, and
constitutes a novel mechanism that is distinct from the nucleos(t)ide
analogues currently available for clinical use. Here we characterised
the in vitro and in vivo antiviral activities of AB-423, a potent small
molecule inhibitor of capsid assembly.
Methods: Antiviral potency, cytotoxicity and in vitro combination
studies of AB-423were performed using HBV cell culture models and
quantified using dot blot, branched DNA or quantitative PCR assays.
The in vivo antiviral activity of AB-423 alone and in combination with
entecavir and TKM-HBV, an RNAi treatment under development for
chronic hepatitis B, was assessed in a hydrodynamic injection HBV
mouse model.
Results: AB-423 showed potent inhibition of HBV rcDNA production
in a mouse cell line with an average EC50 of 275 nM and CC50 of
>10 μM. In a human hepatoma cell line in which inducible cccDNA
formation is dependent upon capsid assembly and rcDNA
synthesis, similar potency was observed in the inhibition of cccDNA
formation. In primary human hepatocytes isolated from uPA/SCID
chimeric mice and infected in vitro, AB-423 at 1.0 μM concentration
exhibited a ∼1-log reduction in the extracellular HBV DNA pool.
AB-423 inhibited HBV capsid assembly in a biochemical assay
confirming its mechanism of action. In vitro combination studies of
AB-423 with entecavir in the cccDNA formation cell culture system
showed additive/synergistic effects.
AB-423 showed favourable pharmacokinetic properties when dosed
orally in mice and was tested for efficacy in SCID mice that were
hydrodynamically injected with HBV plasmid DNA. AB-423 showed
rapid and strong dose-dependent reduction in serum HBV DNA with
a maximum reduction of ∼2 logs at 200 mg/kg on day 4 that was
maintained through day 7 of the daily b.i.d. dosing period. When
tested in combination with entecavir or TKM-HBV, no antagonism
was detected
Conclusions: AB-423 is a promising antiviral agent that exhibited
potent inhibition of HBV replication in cell culture systems and in
an HBV mouse model both singly as well as in combination with
entecavir or with TKM-HBV. AB-423 is being evaluated for
advancement into clinical development. 作者: StephenW 时间: 2016-3-31 15:22
LBO6
NVR 3-778, A FIRST-IN-CLASS HBVCORE INHIBITOR, ALONE AND IN
COMBINATION WITH PEG-INTERFERON (PEGIFN), IN TREATMENTNAIVE
HBEAG-POSITIVE PATIENTS: EARLY REDUCTIONS IN HBV
DNA AND HBEAG
M.-F. Yuen1, D.J. Kim2, F. Weilert3, H.L.-Y. Chan4, J.P. Lalezari5,
S.G. Hwang6, T. Nguyen7, S. Liaw8, N. Brown8, K. Klumpp8, O. Flores8,
G. Hartman8, E. Gane9. 1Queen Mary Hospital, University of Hong Kong,
Pok Fu Lam, Hong Kong, China; 2 Chuncheon Sacred Heart Hospital,
Hallym University, Gangwon-do, South Korea; 3Waikato Hospital,
Hamilton, New Zealand; 4Prince ofWales Hospital, Chinese University of
Hong Kong, Shatin, Hong Kong, China; 5Quest Clinical Research,
San Francisco, United States; 6Cha Bundang Medical Center, Gyeonggido,
South Korea; 7Research and Education, Inc., San Diego; 8Novira
Therapeutics, Doylestown, United States; 9Auckland Clinical Studies,
Auckland, New Zealand
E-mail: [email protected]
Abstract LBO6 is under embargo until Saturday, 16 April 2016,
07:00 CET. This abstract has been selected to be highlighted during
official EASL Press Office activities or in official EASL Press Office
materials that will be made publicly available on the congresswebsite
at 07:00 (CET) on the day of their presentation at the congress.
LBO6
NVR 3-778，创一流HBVCORE抑制剂，单独和
用PEG干扰素（PEGIFN），IN TREATMENTNAIVE组合
HBeAg阳性患者：早期削减HBV
DNA和HBeAg
M.-F. Yuen1，D.J Kim2，F. Weilert3，H.L.-Y. 4chan的，J.P Lalezari 5，
S.G.黄某6，T Nguyen7，S. Liaw8，N. Brown8，K Klumpp8，O. Flores8，
G. Hartman8，E Gane9。 1Queen玛丽医院，香港大学，
薄扶林，香港，中国; 2春川圣心医院，
翰林大学，江原道，韩国; 3Waikato医院
汉密尔顿，新西兰; 4Prince ofWales医院的中国大学
香港沙田，香港，中国; 5Quest临床研究，
旧金山，美国; 6Cha盆唐医疗中心，京畿道，
韩国; 7Research和教育公司，圣地亚哥; 8Novira
治疗，Doylestown的，美国; 9Auckland临床研究，
新西兰奥克兰
电子信箱：[email protected]
摘要LBO6正在禁运，直到周六，2016年4月16日，
07:00 CET。这个抽象已被选择时被突出
官方EASL新闻办公室的活动或官方EASL新闻办公室
将公开提供的材料congresswebsite
07:00（CET)在他们的演讲在大会当天07:00（CET）。作者: 齐欢畅2 时间: 2016-4-2 14:41
