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
基本信息
- 批准号:10302165
- 负责人:
- 金额:$ 64.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAftercareAutoimmunityBindingBiologicalBiological MarkersBone Marrow TransplantationCell NucleusCellsClinicalClinical ResearchClinical TrialsClinical Trials DesignClinical assessmentsClinical trial protocol documentDNADNA BindingDataDefectDiseaseDoseExhibitsFDA approvedFlow CytometryFutureGene ExpressionGenerationsGenesGeneticGrowth FactorHereditary DiseaseHomeostasisImmuneImmune System DiseasesImmune responseImmune signalingImmune systemImmunityImmunologic Deficiency SyndromesImmunologistJAK1 geneJanus kinaseLeadMissionModelingMolecularMolecular ProfilingMutationNatural HistoryOutcomePathway interactionsPatient CarePatientsPharmaceutical PreparationsPharmacologic SubstancePhasePhase I/II Clinical TrialPhenotypePhosphotransferasesPlasma ProteinsPrecision therapeuticsPreparationProteinsProviderPublishingRNARare DiseasesRegulationResearchResearch DesignSTAT proteinSTAT1 geneSTAT3 geneSTAT5B geneSafetyShapesSignal PathwaySignal TransductionSignaling ProteinTYK2TestingTherapeuticTherapeutic TrialsTreatment EfficacyTreatment-related toxicityTyrosineUnited States National Institutes of HealthWorkXCL1 geneatopyautoinflammationbaseclinical developmentcongenital immunodeficiencycytokinedimerearly onseteffective therapyefficacy trialexperiencegain of functiongain of function mutationimmune functioninnovationinterestkinase inhibitormembernovel strategiesnovel therapeuticsoff-label usepatient populationrare genetic disorderrecurrent infectionresearch clinical testingresponsesmall moleculetargeted treatmenttherapeutic targettherapeutically effectivetranscription factortreatment responsetreatment trial
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lisa Forbes其他文献
Lisa Forbes的其他文献
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{{ truncateString('Lisa Forbes', 18)}}的其他基金
Novel Primary Immunodeficiency Disease Due to IL27RA Deficiency
IL27RA 缺乏导致的新型原发性免疫缺陷病
- 批准号:
10311550 - 财政年份:2020
- 资助金额:
$ 64.76万 - 项目类别:
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