IND Enabling Studies for the Development of NASH Therapeutic TB-019

NASH 治疗药物 TB-019 开发的 IND 启用研究

• 批准号: 10693602
• 负责人: MAHMOUD N GHAZZI
• 金额: --
• 依托单位: TAMUROBIO INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2024-03-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10693602
• 关键词: 4 hydroxynonenal; Action Potentials; Adipocytes; Adult; Affect; Aldehydes; Alkaline Single-Cell Gel Electrophoresis Assay; Ames Assay; Animal Model; Animals; Antioxidants; Apoptotic; Authorization documentation; Binding; Binding Proteins; Biological Assay; Blood specimen; Canis familiaris; Cardiac; Cardiovascular system; Cells; Cellular Stress; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Conscious; Development; Diagnosis; Disease; Dose; Etiology; Evaluation; FDA approved; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Formulation; Foundations; Functional disorder; Generations; Goals; Good Manufacturing Process; Health; Hepatic Stellate Cell; Hepatitis C; Histologic; Human; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin; Lead; Length; Lipid Peroxidation; Lipids; Liver; Liver Failure; Liver Fibrosis; Lysine; Medical; Metabolic; Mitochondria; Modification; Monitor; Morbidity - disease rate; Nonesterified Fatty Acids; Oxidants; Oxidative Stress Induction; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology Study; Phase; Phase I Clinical Trials; Physiology; Placebos; Play; Polyunsaturated Fatty Acids; Post-Translational Protein Processing; Primary carcinoma of the liver cells; Process; Production; Property; Publishing; Rattus; Recommendation; Research; Research Contracts; Risk; Rodent Model; Role; Running; Safety; Signal Pathway; Source; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Toxicokinetics; Toxicology; Triglycerides; Validation; Work; animal safety; authority; capsule; cardiovascular effects; cell injury; clinical candidate; design; drug testing; end stage liver disease; experience; first-in-human; genotoxicity; good laboratory practice; improved; in vivo; lipophilicity; liver inflammation; liver injury; liver transplantation; loss of function; manufacture; manufacturing test; micronucleus; mortality; new chemical entity; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel strategies; novel therapeutic intervention; novel therapeutics; peroxidation; programs; research clinical testing; safety practice; sample collection; stability testing; therapeutically effective; treatment arm

SUMMARY Nonalcoholic steatohepatitis (NASH) is a significant, worldwide health problem affecting an estimated 14 million people in the US. It is characterized by hepatic inflammation and injury and fibrosis. Subjects diagnosed with NASH are at significantly increased risk of morbidity and mortality due to cirrhosis, and hepatocellular carcinoma. Without any currently available FDA approved treatments, NASH has become a significant unmet medical need. In NASH patients, lipid accumulation along with generation of lipotoxic intermediates leads to the induction of cell stress triggering apoptotic, inflammatory, and fibrotic signaling pathways. Reactive aldehydes, the product of oxidative modification (i.e. peroxidation) of polyunsaturated fatty acids (PUFA), can bind proteins by indirect or secondary protein modification, resulting in an increased risk for aggregation, loss of function, and cell damage. Published evidence points to the critical role of 4-Hydroxynonenal (4-HNE), the most abundant reactive aldehyde, contributing to the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and NASH. 4-HNE has been implicated as a specific driver of multiple pathways in NASH etiology including: a) loss of insulin inhibition of adipocyte lipolytic activity leading to increased fatty acid flux to the liver and generation of lipotoxic products, b) direct activation of inflammatory pathways, and c) as the direct driver of hepatic stellate cell activation and liver fibrosis. While 4-HNE production results from lipid peroxidation, the ability to control its levels by endogenous or exogenous antioxidants is limited; lipophilic reservoirs can provide a long-lasting discharge of 4- HNE beyond the temporal source of oxidant generation. Therefore, controlling 4-HNE levels represents a unique and novel therapeutic approach for the treatment of NASH. TamuroBio has synthesized a new chemical entity, TB-019, that is able to act as a nucleophilic scavenger. TB- 019 binds to 4-HNE, thereby reducing its levels in cells and has been shown in two rodent models of NASH to be effective in reducing liver fat, inflammation, and fibrosis progression. TB-019 has favorable physicochemical and ADME properties, as well as a preliminary good safety profile. This proposal aims to complete IND-enabling GLP safety and toxicology studies and to produce drug supply for the Phase I first-in human trial. This work will be performed by high quality contract research organizations in the US, overseen by the experienced team at TamuroBio. In summary, the overall goal of TamuroBio is to develop TB-019 as a novel therapeutic for the treatment of NASH and to mitigate the progression of fibrosis.

概括 非酒精性脂肪性肝炎（NASH）是一个重大的，全球的健康问题，影响约1400万 美国的人。它的特征是肝炎，损伤和纤维化。被诊断的受试者 NASH由于肝硬化和肝细胞癌而引起的发病率和死亡率的风险显着增加。 如果没有任何当前可用的FDA批准治疗，NASH已成为巨大的未满足医疗需求。 在NASH患者中，脂质积累以及产生的脂肪毒性中间体导致诱导 细胞应力触发凋亡，炎症和纤维化信号通路。反应性醛，产品 多不饱和脂肪酸（PUFA）的氧化修饰（即过氧化）可以通过间接结合蛋白质 或二级蛋白质修饰，导致聚集，功能丧失和细胞的风险增加 损害。已发表的证据指出了4-羟基烯烯（4-HNE）的关键作用，这是最丰富的反应性 醛，有助于非酒精性脂肪肝病（NAFLD）和NASH的发病机理。 4-hne有 被认为是NASH病因中多个途径的特定驱动因素，包括：a）胰岛素抑制作用丧失 脂肪细胞脂肪性活性导致脂肪酸通量增加到肝脏的产生，脂肪毒性产物的产生， b）炎症途径的直接激活，c）作为肝星状细胞激活的直接驱动器和 肝纤维化。虽然4-HNE的产生是由脂质过氧化导致的，但通过 内源性或外源性抗氧化剂受到限制；亲脂性储层可以提供4-的长期排放 HNE超出了氧化剂产生的时间来源。因此，控制4-HNE水平代表一个独特的 以及用于治疗NASH的新型治疗方法。 Tamurobio合成了一个新的化学实体TB-019，该实体能够充当亲核的清除剂。结核病 019与4-HNE结合，从而降低了细胞的水平，并且已在Nash的两个啮齿动物模型中显示 有效减少肝脏脂肪，炎症和纤维化进展。 TB-019具有有利的物理化学 和Adme属性以及初步的良好安全性。该建议旨在完成索引 GLP的安全性和毒理学研究，并为I期第一阶段的人类试验产生药物供应。这项工作将 由美国高质量合同研究组织执行，由经验丰富的团队负责 Tamurobio。 总之，Tamurobio的总体目标是开发TB-019作为纳什治疗的新型治疗方法 并减轻纤维化的进展。