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

用于治疗慢性乙型肝炎病毒感染的衣壳组装调节剂的临床前开发

• 批准号: 10612081
• 负责人: Glen Andrew Coburn
• 金额: $ 100万
• 依托单位: VENATORX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-24 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612081
• 关键词: Acceleration; Acute; Adult; Alanine Transaminase; Antibodies; Antiviral Agents; Capsid; Cell Culture Techniques; Characteristics; Chronic; Chronic Hepatitis B; Cirrhosis; Core Protein; DNA biosynthesis; Data; Development; Disease Progression; Dose; Drug Design; Drug Kinetics; Evaluation; Exhibits; Gene Silencing; Genetic; Genotype; Goals; HBV Genotype; Hepatitis; Hepatitis B Infection; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatocyte; Histologic; Human; Immune; In Vitro; Individual; Infection; Investigation; Investigational Drugs; Investigational New Drug Application; Lead; Life Cycle Stages; Liver Cirrhosis; Liver diseases; Macaca fascicularis; Malignant neoplasm of liver; Maximum Tolerated Dose; Mus; Patients; Pegylated Interferon Alfa; Perinatal Exposure; Persons; Pharmacodynamics; Pharmacology; Pharmacology Study; Phase; Phase I Clinical Trials; Polymerase; Preparation; Primary carcinoma of the liver cells; Property; Public Health; Rattus; Regimen; Reporting; Resistance profile; Reverse Transcriptase Inhibitors; Risk; Rodent; Safety; Series; Small Business Innovation Research Grant; Structure; Tenofovir; Testing; Toxic effect; Toxicokinetics; Toxicology; Vaccines; Vertical Transmission; Viral; Viral Physiology; Virus Diseases; Virus Replication; analog; early childhood; entecavir; experience; first-in-human; healthy volunteer; immune modulating agents; immunomodulatory therapies; immunoregulation; improved; mouse model; novel; pre-clinical; preclinical development; prevent; programs; progression risk; research clinical testing; scale up; screening; seroconversion; success; treatment response; viral DNA

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.

项目概要 尽管已经有了安全有效的疫苗，但仍有超过 2.57 亿人长期处于慢性病状态。 全世界范围内都感染了乙型肝炎病毒（HBV）。慢性乙型肝炎病毒感染者面临以下风险： 肝病和肝癌引起的并发症。慢性乙型肝炎目前采用核（酸）苷治疗 逆转录酶抑制剂 (NrtI) 部分抑制 HBV DNA 复制，使丙氨酸正常化 转氨酶水平 (ALT) 和减缓疾病进展。然而，一线疗法并不能治愈 慢性乙型肝炎患者的治疗后反应较差，需要终生治疗。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并提供 免疫控制所需的条件被称为“功能性治愈”。最有前途的之一 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进行复制。在这里，我们报告了一款一流的 CpAM，它具有强大的 泛基因型抗病毒活性。在这个项目中，我们建议将我们的先导 CpAM 推进到最终的 IND 阶段，使研究能够为该化合物在健康志愿者和慢性 HBV 中进行 1 期临床试验做好准备 患者。包含 CpAM 和具有不同作用机制的抗病毒药物的联合治疗方案 和/或新型免疫调节剂将在 HBV 感染小鼠模型中进行评估，为 慢性乙型肝炎患者的第 2 期开发。