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

项目总结 尽管有安全有效的疫苗可用，但仍有超过2.57亿人患有慢性病 在世界范围内感染了乙肝病毒(乙肝)。慢性乙肝病毒感染者有可能患上 因肝病和肝癌引起的并发症。慢性乙肝目前用核素(T)来管理。 逆转录酶抑制剂(NRTI)部分抑制HBVDNA复制，使丙氨酸正常化 转氨酶水平(ALT)和延缓疾病进展。然而，一线治疗并不能治愈 慢性乙肝患者表现出较差的停药反应，需要终身治疗。新型抗病毒药物 因此，需要免疫调节方法来进一步抑制病毒复制，并提供 免疫控制所需的条件被称为“功能治愈”。其中最有希望的是 研究中的一类化合物是阻断乙肝病毒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，我们报告了一种同类中最好的CPAM，它展示了强大的 泛基因型抗病毒活性。在这个项目中，我们建议将我们的主导CPAM推进到确凿的非禁用研究中，为该化合物在健康志愿者和慢性乙肝患者中进行第一阶段临床试验做准备。 病人。包括CPAM的联合方案，具有不同作用机制的抗病毒药物 和/或新的免疫调节剂将在乙肝病毒感染的小鼠模型中进行评估，以准备 慢性乙肝患者的第二阶段进展。

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.