Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731.

Qi Huang,Ariel Tang,Kirk Henne,Lichun Li,Yi Zhou,Yuhua Zong,Dawei Cai,Ran Yan,Richard Colonno,Lida Guo,Alexandre Mercier

doi:10.1128/aac.01463-20

Qi Huang, Ariel Tang + Show 9 more

Open Access

https://doi.org/10.1128/aac.01463-20

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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 hepatocytes [PHHs]), ABI-H0731 exhibited selective inhibition of HBV DNA replication (50% effective concentration [EC50] from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed covalently closed circular DNA (cccDNA) formation in two de novo infection models with EC50s from 1.84 μM to 7.3 μM. Mechanism-of-action studies indicated that 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 appears to decrease viral DNA faster and deeper than nucleoside/nucleotide analogue (NrtI) therapy alone. In addition, ABI-H0731 disrupts incoming nucleocapsids, causing the premature release of relaxed circular DNA (rcDNA) before delivery to the nucleus, and thus prevents new cccDNA formation. ABI-H0731 exhibits pangenotypic activity and is additive to moderately synergistic when combined with an NrtI. In addition to its potency and novel mechanism of action, ABI-H0731 possesses 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.

Highlights

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
Some core protein inhibitors (CIs) alter the morphology of HBV capsids, while others can enhance the formation of aberrant capsids or even promote their disassembly [11]
When core protein (Cp) dimers oligomerize into capsids or other oligomeric structures, fluorophores become trapped inside the capsids and self-quench, causing a decline in fluorescence intensity

Summary

Introduction

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. Mechanism-of-action studies indicated that ABI-H0731 is a direct-acting antiviral that targets HBV core protein, preventing HBV pregenomic RNA (pgRNA) encapsidation and subsequent DNA replication. In addition to its potency and novel mechanism of action, ABI-H0731 possesses 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. Current treatment options for CHB include nucleoside/ nucleotide analogues (NrtIs) targeting the HBV polymerase-reverse transcriptase (HBV Pol-RT), and alpha interferon products These therapies are successful in suppressing HBV replication in an appreciable proportion of CHB patients but are associated with low rates of clinical cures, requiring lengthy, if not lifelong, treatment to maintain viral suppression [1, 2]. The potency, selectivity, spectrum, and mechanism of action of ABI-H0731 and its basic drug-like properties were evaluated in this preclinical study

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