2. Academic Validation
  3. Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein

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

Affiliations

  • 1 Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA. Electronic address: nmani@arbutusbio.com.
  • 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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