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

> **NIH NIH UG3** · BAYLOR COLLEGE OF MEDICINE · 2022 · $569,965

## Abstract

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 ultim...

## Key facts

- **NIH application ID:** 10476619
- **Project number:** 5UG3TR003908-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Lisa Forbes
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $569,965
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476619

## Citation

> US National Institutes of Health, RePORTER application 10476619, Safety and Efficacy of Itacitinib in treatment of JAK/STAT pathway disorders with activating mutations (5UG3TR003908-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10476619. Licensed CC0.

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