Q2 · MEDICINE
Article
Author: Cobarrubias, Kyle D. ; Cole, Andrew G. ; Majeski, Sara A. ; Reid, Stephen P. ; Kadhim, Salam ; Guo, Haitao ; Dorsey, Bruce D. ; Phelps, Janet R. ; Cuconati, Andrea ; Rijnbrand, Rene ; Stever, Kim ; Guo, Ju-Tao ; Evangelista, Ellen ; Tang, Sunny ; Sofia, Michael J. ; Kultgen, Steven G. ; McClintock, Kevin D. ; Fan, Kristi ; Guo, Fang ; Micolochick Steuer, Holly M. ; Snead, Nicholas M. ; Wang, Xiaohe ; Mani, Nagraj ; Li, Alice H. L. ; Mao, Richeng ; Harasym, Troy O. ; Long, Quanxin ; Ardzinski, Andrzej ; Zhao, Qiong ; Lee, Amy C. H.
ABSTRACT:
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 [EC
50
] = 0.08 to 0.27 μM; EC
90
= 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 EC
50
s. 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.