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: 10257695
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257695
• 关键词: Acute; Adult; Alanine Transaminase; Antibodies; Antiviral Agents; Antiviral Therapy; Back; Bioavailable; Capsid; Cell Culture Techniques; Cell Nucleus; Characteristics; Chronic; Chronic Hepatitis B; Cirrhosis; Core Protein; DNA biosynthesis; Data; Development; Disease Progression; Dose; Drug Design; Exhibits; Gene Silencing; Genetic study; Genotype; Goals; HBV Genotype; Hepatitis; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatocyte; Histologic; Human; Immune; In Vitro; Individual; Infection; Interferon-alpha; Investigation; Investigational Drugs; Investigational New Drug Application; Life; Life Cycle Stages; Liver; Liver Cirrhosis; Liver diseases; Macaca fascicularis; Malignant neoplasm of liver; Maximum Tolerated Dose; Nucleocapsid; Oral; Patients; Perinatal Exposure; Persons; Pharmacology; Pharmacology Study; Phase; Phase I Clinical Trials; Primary carcinoma of the liver cells; Property; Rattus; 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; Virus Diseases; Virus Replication; analog; base; early childhood; entecavir; experience; first-in-human; healthy volunteer; immunoregulation; inhibitor/antagonist; interest; novel; phase 1 testing; pre-clinical; preclinical development; preclinical study; prevent; programs; research clinical testing; safety study; 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.

项目总结