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.

PROJECT NARRATIVE Primary Immunodeficiency Disorders (PIDD), like other rare diseases, have suffered from a lack of clinical trials to study new therapies because of the relatively small number of patients affected with each specific disorder. To address this barrier, we plan to take a new approach to clinical trial design in PIDD, namely the use of a basket clinical trial to study patients with multiple genetic immune disorders that share related mechanistic underpinnings (STAT1 gain of function (STAT1 GOF), STAT3 GOF, STAT5b GOF, and JAK1 GOF) that will be treated with a single, targeted therapy (Itacitinib, a second-generation JAK1 inhibitor) in a phase I/II safety and efficacy trial. Clinical evaluation will be paired with deep profiling of the immune system before and after treatment to judge efficacy in each different disease.