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

摘要 现已鉴定出 400 多种不同的基因缺陷与原发性免疫缺陷相关 疾病。这些都是罕见疾病。患者数量有限，阻碍了其发展 针对这组疾病的经过临床验证的治疗方法。在某些情况下，针对特定的治疗 免疫途径已开发用于其他适应症，并且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，临床试验很少 旨在测试该患者群体的新疗法。因此，大多数靶向治疗都是在“非治疗”状态下使用的。 临床免疫学家的“标签”，几乎没有支持有效性或安全性的具体数据。迫切需要 因此，存在一种更有效、更廉价地进行罕见疾病临床试验的机制。 本申请的目的是使用 I/II 期篮子临床试验方法来研究一种药物 Itacitinib， 治疗四种罕见的免疫疾病，这些疾病是由不同但相关的分子途径缺陷引起的，涉及 Janus 激酶 (JAK) 或信号转导器和转录激活剂 (STAT)。在每种情况下， 杂合性遗传缺陷会导致显性激活“功能获得（GOF）”突变，从而导致早期- 发生自身免疫和免疫失调。轶事证据表明四种疾病（STAT1- GOF、STAT3-GOF、STAT5b-GOF 和 JAK1-GOF）可能都对 Itacitinib 等 JAK 抑制剂有反应。为了满足 为了实现本研究的目标，我们提出以下具体目标： 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，为一篮子 IND 提交做准备 临床试验，2) 实施一项临床试验并获得使用 Itacitinib 治疗 4 种不同的 JAK/STAT-的 IND I/II 期篮子临床试验中的 GOF 疾病，3) 评估 Itacitanib 的安全性和有效性 JAK/STAT-GOF 疾病的治疗，以及 4) 确定 Itacitinib 是否可以纠正潜在的缺陷 JAK/STAT-GOF 患者的免疫表型。由于篮子，拟议的工作具有创新性 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效果的分子特征数量 跨越4种疾病。其意义重大有两个原因：它将提供关键的安全性和有效性数据，以告知 使用 JAK 抑制剂治疗 JAK/STAT-GOF 疾病，更重要的是，可能为治疗提供新模型 罕见疾病领域的临床研究可能会引起更多制药公司探索使用 这些患者的新疗法。所获得的信息预计将减少学习障碍 罕见疾病的靶向精准治疗。因此，拟议的研究与任务高度相关 NIH 的使命、RFA 的目的，以及最终为患有罕见和未充分研究的疾病的患者提供护理。

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.