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

基本信息

批准号：
10408826
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
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-24 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408826
关键词：
Acute Adult Alanine Transaminase Antibodies Antiviral Agents Back 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 study Genotype Goals HBV Genotype Hepatitis Hepatitis B Infection Hepatitis B Surface Antigens Hepatitis B Virus Hepatocyte Histologic Human Immune Immunomodulators In Vitro Individual Infection Interferon-alpha Investigation Investigational Drugs Investigational New Drug Application Lead Life Life Cycle Stages Liver Cirrhosis Liver diseases Macaca fascicularis Malignant neoplasm of liver Maximum Tolerated Dose Mus Patients 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 Disease Transmission Viral Virus Diseases Virus Replication analog base early childhood entecavir experience first-in-human healthy volunteer immunomodulatory therapies immunoregulation mouse model novel pre-clinical preclinical development prevent programs research clinical testing safety study scale up screening seroconversion success treatment response viral DNA

项目摘要

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.

项目摘要尽管有安全有效的疫苗，但长期仍有超过2.57亿人全球感染了丙型肝炎病毒（HBV）。患有慢性HBV感染的人有可能由于肝病和肝癌引起的并发症。慢性HBV目前由核（T）IDE管理逆转录酶抑制剂（NRTI）部分抑制HBV DNA复制，正常化丙氨酸氨基转移酶水平（ALT）和疾病进展缓慢。但是，前线疗法无法治愈慢性HBV患者表现出不良治疗的反应，需要终身治疗。新抗病毒药因此，需要采用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称为“功能治愈”。最有前途的正在研究的化合物类别是阻断HBV的核心蛋白质变构调节剂（CPAM）在病毒生命周期的多个阶段复制。在这里，我们报告了一流的CPAM，该CPAM表现出强大泛基因型抗病毒活性。在这个项目中，我们建议将铅CPAM推向确定的IND，从而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的组合方案和/或新型免疫调节剂将在HBV感染的小鼠模型中进行评估，以准备慢性HBV Patienst的2阶段发展。