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：
Lisa Forbes
金额：
$ 64.76万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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

来源：
https://reporter.nih.gov/project-details/10302165
关键词：
Address Affect Aftercare Autoimmunity Binding Biological Biological Markers Bone Marrow Transplantation Cell Nucleus Cells Clinical Clinical Research Clinical Trials Clinical Trials Design Clinical assessments Clinical trial protocol document DNA DNA Binding Data Defect Disease Dose Exhibits FDA approved Flow Cytometry Future Gene Expression Generations Genes Genetic Growth Factor Hereditary Disease Homeostasis Immune Immune System Diseases Immune response Immune signaling Immune system Immunity Immunologic Deficiency Syndromes Immunologist JAK1 gene Janus kinase Lead Mission Modeling Molecular Molecular Profiling Mutation Natural History Outcome Pathway interactions Patient Care Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase I/II Clinical Trial Phenotype Phosphotransferases Plasma Proteins Precision therapeutics Preparation Proteins Provider Publishing RNA Rare Diseases Regulation Research Research Design STAT protein STAT1 gene STAT3 gene STAT5B gene Safety Shapes Signal Pathway Signal Transduction Signaling Protein TYK2 Testing Therapeutic Therapeutic Trials Treatment Efficacy Treatment-related toxicity Tyrosine United States National Institutes of Health Work XCL1 gene atopy autoinflammation base clinical development congenital immunodeficiency cytokine dimer early onset effective therapy efficacy trial experience gain of function gain of function mutation immune function innovation interest kinase inhibitor member novel strategies novel therapeutics off-label use patient population rare genetic disorder recurrent infection research clinical testing response small molecule targeted treatment therapeutic target therapeutically effective transcription factor treatment response treatment trial

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.

抽象的现在已经确定了超过400种不同的基因缺陷，与原发性免疫缺陷有关疾病。这些都是一种罕见的疾病。有限的患者阻碍了这组疾病的临床验证疗法。在某些情况下，靶向特定的治疗已经开发了用于其他适应症的免疫途径，并且可能具有这些免疫途径中的分子缺陷。由于患者人数有限，很少有临床试验在该患者人群中测试新疗法进行。结果，大多数靶向疗法都被“非 - 临床免疫学家的标签”，几乎没有具体数据支持有效性或安全性。因此，存在一种机制，可以对罕见疾病进行更有效和廉价地进行临床试验。该应用的目的是使用I/II期篮子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中的缺陷引起的四种罕见免疫疾病 Janus激酶（JAK）或转录的信号换能器和激活因子（STAT）。在每种情况下，杂合遗传缺陷引起显性激活，“功能获得（GOF）”突变，导致早期自身免疫和免疫失调。轶事证据表明这四种疾病（Stat1- GOF，STAT3-GOF，STAT5B-GOF和JAK1-GOF）都可能响应诸如Itacitinib之类的JAK抑制剂。见面这项研究的目标，我们提出以下特定目的：1）定义关键的临床和生物终点可以用来评估治疗反应和毒性，以准备篮子临床试验，2）操作临床试验，并获得使用ITAcitinib的IND来治疗4个不同的JAK/Stat-- I/II期篮子临床试验中的GOF疾病，3）评估Itacitanib的安全性和效率 jak/stat-gof疾病的治疗，4）确定itacitinib是否纠正了基本缺陷 JAK/Stat-GoF患者的免疫表型。拟议的工作是创新的，因为篮子罕见疾病疗法试验的临床试验方法和使用深度免疫分析以增加可以与临床评估配对以判断治疗效率的分子特征数量跨四种疾病。这很重要，原因有两个；它将提供关键的安全性和效率数据，以告知在JAK/Stat-Gof疾病中使用JAK抑制剂疗法，更重要的是，可以为在罕见疾病空间中的临床研究，可能会让更多的制药公司探索使用这些患者的新疗法。预计获得的信息将减少学习的障碍有针对性的稀有疾病精确疗法。因此，拟议的研究与任务高度相关 NIH，RFA的目的，最终是罕见和被理解的疾病患者的护理。