Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation

  • Antimicrob Agents Chemother. 2018 May 25;62(6):e00082-18. doi: 10.1128/AAC.00082-18.
Nagraj Mani  1 ,  Andrew G Cole  2 ,  Janet R Phelps  2 ,  Andrzej Ardzinski  2 ,  Kyle D Cobarrubias  2 ,  Andrea Cuconati  2 ,  Bruce D Dorsey  2 ,  Ellen Evangelista  2 ,  Kristi Fan  2 ,  Fang Guo  2 ,  Haitao Guo  3 ,  Ju-Tao Guo  4 ,  Troy O Harasym  2 ,  Salam Kadhim  2 ,  Steven G Kultgen  2 ,  Amy C H Lee  2 ,  Alice H L Li  2 ,  Quanxin Long  3 ,  Sara A Majeski  2 ,  Richeng Mao  3 ,  Kevin D McClintock  2 ,  Stephen P Reid  2 ,  Rene Rijnbrand  2 ,  Nicholas M Snead  2 ,  Holly M Micolochick Steuer  2 ,  Kim Stever  2 ,  Sunny Tang  2 ,  Xiaohe Wang  2 ,  Qiong Zhao  4 ,  Michael J Sofia  2
Affiliations
  • 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.
PMID: 29555628 DOI: 10.1128/AAC.00082-18
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 [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.

Keywords
AB-423; CHB; HBV; capsid inhibitor; pgRNA encapsidation; sulfamoylbenzamide.
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