| Reference | 1. Antimicrob Agents Chemother. 2018 May 25;62(6). pii: e00082-18. doi:
10.1128/AAC.00082-18. Print 2018 Jun.
<br>
Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA
Encapsidation.
<br>
Mani N(1), Cole AG(2), Phelps JR(2), Ardzinski A(2), Cobarrubias KD(2), Cuconati
A(2), Dorsey BD(2), Evangelista E(2), Fan K(2), Guo F(2), Guo H(3), Guo JT(4),
Harasym TO(2), Kadhim S(2), Kultgen SG(2), Lee ACH(2), Li AHL(2), Long Q(3),
Majeski SA(2), Mao R(3), McClintock KD(2), Reid SP(2), Rijnbrand R(2), Snead
NM(2), Micolochick Steuer HM(2), Stever K(2), Tang S(2), Wang X(2), Zhao Q(4),
Sofia MJ(2).<br>
Author information: <br>
(1)Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British
Columbia, Canada [email protected].
(2)Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British
Columbia, Canada.
(3)Indiana University, Indianapolis, Indiana, USA.
(4)Baruch S. Blumberg Institute, Doylestown, Pennsylvania, USA.
<br>
AB-423 is a member of the sulfamoylbenzamide (SBA) class of hepatitis B virus
(HBV) capsid inhibitors in phase 1 clinical trials. In cell culture models,
AB-423 showed potent inhibition of HBV replication (50% effective concentration
[EC50] = 0.08 to 0.27 μM; EC90 = 0.33 to 1.32 μM) with no significant
cytotoxicity (50% cytotoxic concentration > 10 μM). Addition of 40% human serum
resulted in a 5-fold increase in the EC50s. AB-423 inhibited HBV genotypes A
through D and nucleos(t)ide-resistant variants in vitro Treatment of HepDES19
cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic
RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid
inhibitor. In a de novo infection model, AB-423 prevented the conversion of
encapsidated rcDNA to covalently closed circular DNA, presumably by interfering
with the capsid uncoating process. Molecular docking of AB-423 into crystal
structures of heteroaryldihydropyrimidines and an SBA and biochemical studies
suggest that AB-423 likely also binds to the dimer-dimer interface of core
protein. In vitro dual combination studies with AB-423 and anti-HBV agents, such
as nucleos(t)ide analogs, RNA interference agents, or interferon alpha, resulted
in additive to synergistic antiviral activity. Pharmacokinetic studies with
AB-423 in CD-1 mice showed significant systemic exposures and higher levels of
accumulation in the liver. A 7-day twice-daily administration of AB-423 in a
hydrodynamic injection mouse model of HBV infection resulted in a dose-dependent
reduction in serum HBV DNA levels, and combination with entecavir or ARB-1467
resulted in a trend toward antiviral activity greater than that of either agent
alone, consistent with the results of the in vitro combination studies. The
overall preclinical profile of AB-423 supports its further evaluation for safety,
pharmacokinetics, and antiviral activity in patients with chronic hepatitis B.
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