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.

中文翻译：

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HBV核心蛋白抑制剂ABI-H0731的临床前概况和特征。

第一代乙型肝炎病毒（HBV）核心蛋白抑制剂ABI-H0731在1b期临床试验中已显示出对慢性B型肝炎（CHB）患者有效的抗病毒活性，目前正在2期临床试验中进行进一步评估。在这里，我们报告ABI-H0731的临床前概况。在体外细胞培养系统（HepG2衍生的细胞系HepAD38和HepG2-NTCP和原代人肝细胞[PHHs]）中，ABI-H0731表现出对HBV DNA复制的选择性抑制（50％有效浓度[EC ₅₀ ]从173 nM到307） nM）。最重要的是，ABI-H0731在两种EC _50的从头感染模型中抑制了共价闭合环状DNA（cccDNA）的形成从1.84μM到7.3μM。作用机理研究表明，ABI-H0731是一种直接作用的抗病毒药物，靶向HBV核心蛋白，可防止HBV前基因组RNA（pgRNA）衣壳化和随后的DNA复制。与单独的核苷/核苷酸类似物（NrtI）治疗相比，ABI-H0731与恩替卡韦的组合似乎可以更快更深地减少病毒DNA。此外，ABI-H0731破坏了进入的核衣壳，导致松弛的环状DNA（rcDNA）在释放到核之前过早释放，从而阻止了新的cccDNA的形成。当与NrtI结合使用时，ABI-H0731表现出基因型活性，并具有中等协同作用。除了其强大的作用力和新颖的作用机制外，ABI-H0731具有类似药物的特性，并具有临床前药代动力学特征，可支持CHB患者每天一次给药。综上所述，这些数据支持ABI-H0731作为HBV治疗药物正在进行的临床开发。