Preclinical development of capsid assembly modulators for the treatment of chronic hepatitis B virus infection

项目摘要 尽管有安全有效的疫苗，但仍有超过2.57亿人长期 感染B型肝炎病毒（HBV）。慢性HBV感染者有以下风险： 肝脏疾病和肝癌引起的并发症。慢性HBV目前用核苷（酸）治疗 逆转录酶抑制剂（NrtI）部分抑制HBV DNA复制，使丙氨酸氨基转移酶正常化， 转氨酶水平（ALT）和缓慢的疾病进展。然而，一线疗法并不能治愈 慢性HBV患者表现出需要终身治疗的不良停药反应。新的抗病毒药物 因此，需要免疫调节方法来进一步抑制病毒复制， 免疫控制所需的条件称为“功能性治愈”。最有前途的 正在研究的一类化合物是阻断HBV的核心蛋白变构调节剂（CpAM 在病毒生命周期的多个阶段复制。在这里，我们报告了一种最好的CpAM， 泛基因型抗病毒活性。在本项目中，我们建议将我们的主要CpAM推进到最终IND使研究能够为健康志愿者和慢性HBV的1期临床试验做好准备 患者包括CpAM、具有不同作用机制的抗病毒药物的联合方案 和/或新型免疫调节剂将在HBV感染的小鼠模型中进行评价， 慢性HBV患者的2期发展。

PROJECT SUMMARY Despite the availability of a safe and effective vaccine, there remains over 257 million people chronically infected with hepatitis B virus (HBV) world-wide. Individuals with chronic HBV infections are at risk for complications due to liver disease and liver cancer. Chronic HBV is currently managed with nucleos(t)ide reverse transcriptase inhibitors (NrtI) which partly suppress HBV DNA replication, normalize alanine aminotransferase levels (ALT) and slow disease progression. Front-line therapies, however, are not curative and patients with chronic HBV exhibit poor off-treatment responses requiring life-long therapy. New antivirals and immunomodulatory approaches are, therefore, needed to further suppress viral replication and provide the conditions that are required for immune control known as a “functional cure”. One of the most promising classes of compounds under investigation are the core protein allosteric modulators (CpAM) that block HBV replication at multiple stages of the viral life-cycle. Here, we report on a best-in-class CpAM that exhibits potent pan-genotypic antiviral activity. In this project, we propose to advance our lead CpAM into definitive INDenabling studies to ready the compound for Phase 1 clinical trials in healthy volunteers and chronic HBV patients. Combination regimens that include a CpAM, antivirals possessing distinct mechanisms of action and/or novel immunomodulatory agents will be evaluated in a mouse model of HBV infection in preparation for Phase 2 development in chronic HBV patienst.