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

摘要 目前已发现400多种不同的基因缺陷与原发免疫缺陷有关。 疾病。这些都是一种罕见的疾病。有限的病人数量阻碍了疾病的发展。 这组疾病的临床验证的治疗方法。在某些情况下，针对特定目标的治疗学 免疫途径已被开发用于其他适应症，并可能在慢性阻塞性肺疾病患者中具有临床实用价值。 这些免疫途径中的分子缺陷。由于患者数量有限，很少有临床试验被 在这个患者群体中测试新的治疗方法。因此，大多数靶向治疗都是“非”使用的。 临床免疫学家在缺乏支持有效性或安全性的具体数据的情况下做出了“标签”。迫切需要 因此，存在一种机制来更有效、更廉价地进行罕见疾病的临床试验。 本申请的目的是使用I/II期篮子临床试验方法来研究一种药物，伊他替尼， 治疗由不同但相关的分子通路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， 杂合性遗传缺陷会导致显性激活，即“功能增益(GOF)”突变，导致早期... 发病的自身免疫和免疫失调。坊间证据表明，这四种疾病(STAT1- GOF、STAT3-GOF、STAT5b-GOF和JAK1-GOF)均对依他替尼等JAK抑制剂有反应。为了满足 在本研究的目标中，我们提出以下具体目标：1)确定关键的临床和生物学终点 可用于评估治疗反应和毒性，为IND提交篮子做准备 临床试验，2)进行临床试验，获得使用伊他替尼治疗4种不同JAK/STAT的IND。 一项I/II期篮子临床试验中的GOF障碍，3)评估伊他西尼治疗高血压的安全性和有效性 治疗JAK/STAT-GOF疾病，以及4)确定依他替尼是否纠正了 JAK/STAT-GOF患者的免疫表型由于篮子的存在，建议的工作具有创新性 罕见疾病治疗试验的临床试验方法和深度免疫图谱的使用以增加 可与临床评估配对以判断治疗效果的分子标记数量 横跨4种疾病。它的重要意义有两个原因；它将提供关键的安全性和有效性数据，以告知 JAK抑制剂在JAK/STAT-GOF疾病中的应用，更重要的是，可能为 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，以探索其用途 这些患者的新疗法。所获得的信息有望减少学习的障碍 对罕见疾病进行有针对性的精确治疗。因此，拟议的研究与特派团高度相关。 NIH的目标，RFA的目的，最终是为了护理罕见和未被研究的疾病的患者。

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.