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

• 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
• 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

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。