Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein

  • Antiviral Res. 2022 Jan;197:105211. doi: 10.1016/j.antiviral.2021.105211.
Nagraj Mani  1 ,  Andrew G Cole  2 ,  Janet R Phelps  2 ,  Andrzej Ardzinski  2 ,  Robbin Burns  2 ,  Tim Chiu  2 ,  Andrea Cuconati  2 ,  Bruce D Dorsey  2 ,  Ellen Evangelista  2 ,  Kristi Fan  2 ,  Fang Guo  2 ,  Troy O Harasym  2 ,  Salam Kadhim  2 ,  Roseann Kowalski  2 ,  Steven G Kultgen  2 ,  Amy C H Lee  2 ,  Alice H Li  2 ,  Sara A Majeski  2 ,  Angela Miller  2 ,  Chris Pasetka  2 ,  Stephen P Reid  2 ,  Rene Rijnbrand  2 ,  Holly M Micolochick Steuer  2 ,  Kim Stever  2 ,  Sunny Tang  2 ,  Xiaowei Teng  2 ,  Xiaohe Wang  2 ,  Michael J Sofia  2
Affiliations
  • 1. Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA. Electronic address: [email protected].
  • 2. Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA.
PMID: 34826506 DOI: 10.1016/j.antiviral.2021.105211
Abstract

AB-506, a small-molecule inhibitor targeting the HBV core protein, inhibits viral replication in vitro (HepAD38 cells: EC50 of 0.077 μM, CC50 > 25 μM) and in vivo (HBV mouse model: ∼3.0 log10 reductions in serum HBV DNA compared to the vehicle control). Binding of AB-506 to HBV core protein accelerates capsid assembly and inhibits HBV pgRNA encapsidation. Furthermore, AB-506 blocks cccDNA establishment in HBV-infected HepG2-hNTCP-C4 cells and primary human hepatocytes, leading to inhibition of viral RNA, HBsAg, and HBeAg production (EC50 from 0.64 μM to 1.92 μM). AB-506 demonstrated activity across HBV genotypes A-H and maintains Antiviral activity against nucleos(t)IDE analog-resistant variants in vitro. Evaluation of AB-506 against a panel of core variants showed that T33N/Q substitutions results in >200-fold increase in EC50 values, while L30F, L37Q, and I105T substitutions showed an 8 to 20-fold increase in EC50 values in comparison to the wild-type. In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B.

Keywords
AB-506; Aminoindane; CHB; Capsid inhibitor; HBV; pgRNA encapsidation.
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