Preclinical profile of AB-423, an inhibitor of Hepatitis B virus pgRNA encapsidation [PublishAheadOfPrint]

AB-423 is a sulfamoylbenzamide (SBA) class of HBV capsid inhibitor in Phase 1 clinical trials. In cell culture models AB-423 showed potent inhibition of HBV replication (EC₅₀/EC₉₀ = 0.08-0.27 μM/0.33-1.32 μM) with no significant cytotoxicity (CC₅₀ >10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC₅₀ values. AB-423 inhibited HBV genotypes A through D and nucleos/tide-resistant variants in vitro. Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pgRNA and rcDNA indicating it is a class II capsid inhibitor. In a de novo infection model AB-423 prevented the conversion of encapsidated rcDNA to cccDNA 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/tide analogs, RNAi agents, or interferon-α resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher liver accumulation. A 7-day BID administration of AB-423 in a hydrodynamic injection mouse model of HBV model resulted in a dose-dependent reduction in serum HBV DNA levels and combination with ETV or ARB-1467 resulted in a trend towards greater antiviral activity than either agent alone consistent with the results of the in vitro combination studies. The overall preclinical profile of AB-423 supports further evaluation for safety, pharmacokinetics and antiviral activity in CHB patients.

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