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

基本信息

  • 批准号:
    10693602
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
总结 非酒精性脂肪性肝炎(NASH)是一个重要的全球性健康问题,影响约1400万人 美国的人。其特征在于肝脏炎症和损伤以及纤维化。个诊断患有 由于肝硬化和肝细胞癌,NASH的发病率和死亡率风险显著增加。 在没有任何目前可用的FDA批准的治疗的情况下,NASH已经成为一个显著未满足的医疗需求。 在NASH患者中,脂质蓄积沿着脂毒性中间体的产生导致诱导 细胞应激触发凋亡、炎症和纤维化信号通路。反应性醛,产物 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 或二次蛋白质修饰,导致聚集、功能丧失和细胞凋亡的风险增加。 损害已发表的证据表明,4-羟基壬烯醛(4-HNE)(最丰富的反应物)发挥着关键作用 醛,有助于非酒精性脂肪肝疾病(NAFLD)和NASH的发病机制。4-HNE拥有 作为NASH病因学中多种途径的特定驱动因素,包括:a)胰岛素抑制的丧失 脂肪细胞脂解活性导致增加的脂肪酸流向肝脏和脂毒性产物的产生, B)直接激活炎症途径,和c)作为肝星状细胞激活的直接驱动剂,和 肝纤维化虽然4-HNE的产生是由脂质过氧化作用引起的,但通过脂质过氧化作用来控制其水平的能力是有限的。 内源性或外源性抗氧化剂是有限的;亲脂性水库可以提供持久的排放4- HNE超出氧化剂产生的时间来源。因此,控制4-HNE水平代表了一种独特的 和治疗NASH的新的治疗方法。 TamuroBio合成了一种新的化学实体TB-019,能够作为亲核清除剂。结核病- 019与4-HNE结合,从而降低其在细胞中的水平,并已在两种NASH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具有良好的理化性质, 和ADME性质,以及初步良好的安全性。本提案旨在完成IND赋能 GLP安全性和毒理学研究,并为I期首次人体试验生产药物供应。这项工作将 由美国高质量的合同研究机构执行,由经验丰富的团队监督, 田室生物 总之,TamuroBio的总体目标是开发TB-019作为治疗NASH的新型治疗药物 并减轻纤维化的进展。

项目成果

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MAHMOUD N GHAZZI其他文献

MAHMOUD N GHAZZI的其他文献

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{{ truncateString('MAHMOUD N GHAZZI', 18)}}的其他基金

NUTRITIONAL INFLUENCE ON HYPOTHALAMIC CONTROL
营养对下丘脑控制的影响
  • 批准号:
    3087013
  • 财政年份:
    1987
  • 资助金额:
    --
  • 项目类别:
NUTRITIONAL INFLUENCE ON HYPOTHAMALAMIC CONTROL
营养对下丘脑控制的影响
  • 批准号:
    3087012
  • 财政年份:
    1987
  • 资助金额:
    --
  • 项目类别:
NUTRITIONAL INFLUENCE ON HYPOTHALAMIC CONTROL
营养对下丘脑控制的影响
  • 批准号:
    3087014
  • 财政年份:
    1987
  • 资助金额:
    --
  • 项目类别:
NUTRITIONAL INFLUENCE ON HYPOTHAMALAMIC CONTROL
营养对下丘脑控制的影响
  • 批准号:
    3087011
  • 财政年份:
    1987
  • 资助金额:
    --
  • 项目类别:
NUTRITIONAL INFLUENCE ON HYPOTHALAMIC CONTROL
营养对下丘脑控制的影响
  • 批准号:
    3087015
  • 财政年份:
    1987
  • 资助金额:
    --
  • 项目类别:

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