Preclinical Profile and Characterization of the HBV Core Protein Inhibitor ABI-H0731 Qi Huang
1, Dawei Cai
1, Ran Yan
1, Lichun Li
1, Yuhua Zong
1, Lida Guo
1, Alexandre Mercier
1, Yi Zhou
1, Ariel Tang
1, Kirk Henne
1, Richard Colonno
1
Affiliations
Affiliation - 1 Current or former employees of Assembly Biosciences, South San Francisco, CA.
Abstract ABI-H0731, a first-generation Hepatitis B Virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a Phase 1b clinical trial and is currently being further evaluated in Phase 2 clinical trials. Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2 derived cell lines: HepAD38 and HepG2-NTCP and Primary Human Hepatocyte (PHH)), ABI-H0731 exhibited selective inhibition of HBV DNA replication (EC50 from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed cccDNA formation in two de novo infection models with EC50s from 1.84 μM to 7.3 μM. Mechanism of action (MOA) studies indicated ABI-H0731 is a direct-acting antiviral that targets HBV core protein, preventing HBV pregenomic RNA (pgRNA) encapsidation and subsequent DNA replication. The combination of ABI-H0731 with entecavir (ETV) appears to decrease viral DNA faster and deeper than nucleoside/nucleotide analogues (NrtI) therapy alone. In addition, ABI-H0731 disrupts incoming nucleocapsids, causing premature release of rcDNA before delivery to the nucleus and thus prevents new cccDNA formation. ABI-H0731 exhibits pan-genotypic activity and is additive to moderately synergistic when combined with a NrtI. In addition to potency and novel mechanism of action, ABI-H0731 possess drug-like properties and a preclinical pharmacokinetic profile supportive of once daily dosing in patients with CHB. Taken together, these data support the ongoing clinical development of ABI-H0731 as a treatment for HBV.
Copyright © 2020 Huang et al. | 
发表于 2020-9-3 20:57
