Preclinical Profile and Characterization of the HBV Core Protein Inhibitor ABI-H0731.

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.