Safety and Efficacy of Itacitinib in treatment of JAK/STAT pathway disorders with activating mutations

伊他替尼治疗具有激活突变的 JAK/STAT 通路疾病的安全性和有效性

基本信息

  • 批准号:
    10302165
  • 负责人:
  • 金额:
    $ 64.76万
  • 依托单位:
  • 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:
    2021-09-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Over 400 different gene defects have now been identified in association with primary immunodeficiency diseases. Each of these is a rare disease. The limited number of patients has hindered the development of clinically validated therapeutics in this group of disorders. In some cases, therapeutics that target specific immune pathways have been developed for other indications and may have clinical utility in patients with molecular defects in those immune pathways. Because of limited patient numbers, few clinical trials have been performed to test novel therapies in this patient population. As a result, most targeted therapies are used “off- label” by clinical immunologists with little concrete data supporting either efficacy or safety. A critical need therefore exists for a mechanism to more efficiently and inexpensively perform clinical trials for rare diseases. The objective of this application is to use a phase I/II basket clinical trial approach to study one drug, Itacitinib, to treat four rare immune disorders caused by defects in different but related molecular pathways involving Janus Kinases (JAK) or Signal Transducers and Activators of Transcription (STAT). In each case, heterozygous genetic defects cause dominant activating, “gain-of-function (GOF)” mutations that lead to early- onset autoimmunity and immune dysregulation. Anecdotal evidence suggests that the four disorders (STAT1- GOF, STAT3-GOF, STAT5b-GOF and JAK1-GOF) may all respond to JAK-inhibitors like Itacitinib. To meet the objectives of this study, we propose the following specific aims: 1) Define key clinical and biologic endpoints that can be used to assess therapeutic response and toxicity in preparation for IND submission for a basket clinical trial, 2) Operationalize a clinica trial and obtain IND for use of Itacitinib to treat 4 different JAK/STAT- GOF disorders in a Phase I/II basket clinical trial, 3) Evaluate the safety and efficacy of Itacitanib for the treatment of JAK/STAT-GOF disorders, and 4) Determine whether Itacitinib corrects the underlying defects in immune phenotype of JAK/STAT-GOF patients. The proposed work is innovative because of the basket clinical trial approach to rare disease therapeutic trials and the use of deep immune profiling to increase the number of molecular signatures that can be paired with clinical assessments to judge efficacy of the therapy across the 4 diseases. It is significant for two reasons; It will provide key safety and efficacy data to inform the use of JAK inhibitor therapy in JAK/STAT-GOF disorders and more importantly, may provide a new model for clinical studies in the rare disease space that could interest more pharmaceutical companies to explore use of new therapies in these patients. The information gained is anticipated to decrease the barriers to studying targeted precision therapies in rare disease. The proposed research is therefore highly relevant to the mission of the NIH, the purpose of the RFA, and ultimately to the care of patients with rare and understudied diseases.
摘要 目前已发现400多种与原发性免疫缺陷相关的基因缺陷 疾病每一种都是一种罕见的疾病。有限的患者数量阻碍了 在这组疾病中临床有效的治疗方法。在某些情况下,靶向特异性靶向的治疗剂可以是药物。 免疫途径已开发用于其他适应症,并可能对患有以下疾病的患者具有临床实用性 这些免疫途径中的分子缺陷。由于患者数量有限,很少有临床试验 用于在该患者人群中测试新疗法。因此,大多数靶向治疗都是在“关闭”状态下使用的。 临床免疫学家对“标签”的使用几乎没有具体的数据支持疗效或安全性。迫切需要 因此,存在一种机制,以更有效和更便宜地进行罕见疾病的临床试验。 本申请的目的是使用I/II期篮式临床试验方法研究一种药物Itacitinib, 治疗由不同但相关的分子途径缺陷引起的四种罕见的免疫疾病, Janus激酶(JAK)或信号转导和转录激活因子(STAT)。在每一种情况下, 杂合子遗传缺陷导致显性激活,“功能获得性(GOF)”突变,导致早期- 发病自身免疫和免疫失调。传闻证据表明,这四种疾病(STAT 1- G 0 F、STAT 3-G 0 F、STAT 5 b-G 0 F和JAK 1-G 0 F)都可能对JAK抑制剂如Itacitinib有反应。满足 本研究的目的,我们提出了以下具体目标:1)定义关键的临床和生物学终点 可用于评估治疗反应和毒性,以准备IND申报 临床试验,2)开展临床试验并获得使用Itacitinib治疗4种不同JAK/STAT的IND- I/II期篮式临床试验中的GOF病症,3)评价伊他他替尼用于治疗GOF病症的安全性和有效性。 JAK/STAT-GOF疾病的治疗,以及4)确定Itacitinib是否纠正JAK/STAT-GOF疾病的潜在缺陷。 JAK/STAT-GOF患者的免疫表型。建议的工作是创新的,因为篮子 罕见疾病治疗试验的临床试验方法以及使用深度免疫分析来增加 可与临床评估配对以判断治疗疗效的分子特征数量 四种疾病。它的重要性有两个原因:它将提供关键的安全性和有效性数据, 在JAK/STAT-GOF疾病中使用JAK抑制剂治疗,更重要的是,可以提供一种新的模型, 罕见疾病领域的临床研究可能会引起更多制药公司的兴趣, 这些患者的新疗法。预计获得的信息将减少学习的障碍 针对罕见疾病的精准治疗。因此,拟议的研究与使命高度相关 美国国立卫生研究院,RFA的目的,并最终照顾罕见和未充分研究的疾病患者。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Lisa Forbes其他文献

Lisa Forbes的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Lisa Forbes', 18)}}的其他基金

Novel Primary Immunodeficiency Disease Due to IL27RA Deficiency
IL27RA 缺乏导致的新型原发性免疫缺陷病
  • 批准号:
    10311550
  • 财政年份:
    2020
  • 资助金额:
    $ 64.76万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 64.76万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了