Effects of AFQ056 on Language Learning in Young Children with Fragile X Syndrome (FXS)

AFQ056 对患有脆性 X 综合征 (FXS) 的幼儿语言学习的影响

• 批准号: 9120161
• 负责人: LEONARD J. ABBEDUTO
• 金额: $ 347.35万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120161
• 关键词: Accounting; Adolescent; Adult; Age; Animal Model; Animals; Autistic Disorder; Behavior; Behavioral; Binding Proteins; Biological Assay; Biological Markers; Brain; Cellular Morphology; Child; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; Dendritic Spines; Development; Developmental Course; Disease; Disease model; Dose; Double-Blind Method; Drosophila genus; Drug Targeting; Electrophysiology (science); Equilibrium; Event-Related Potentials; Exposure to; Eye; FMR1; Fragile X Syndrome; Future; Genes; Genetic; Goals; Growth; Human; Individual; Inherited; Intellectual functioning disability; Intervention; Language; Language Development; Lead; Learning; Literature; Maximum Tolerated Dose; Measurement; Measures; Messenger RNA; Modeling; Molecular; Mus; Nature; Neurobiology; Neurodevelopmental Disability; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neurosciences; Neurosciences Research; Outcome; Parents; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Placebo Control; Placebos; Population; Pre-Clinical Model; Process; Proteins; Publications; Randomized; Receptor Activation; Research; Safety; Signal Pathway; Signal Transduction; Synapses; Synaptic plasticity; System; Testing; Time; Titrations; Translations; Work; autism spectrum disorder; behavioral outcome; conditioning; design; developmental disease; drug development; fenobam; flexibility; follow-up; improved; innovation; meetings; open label; overexpression; pre-clinical; preclinical study; public health relevance; skills; small molecule; social; synaptic function; theories; trial design

 DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. Enormous progress in basic and translational FXS research has allowed identification of neuronal pathway targets for treatment of the underlying disorder. The most well-studied of these has been pharmacological (using mGluR5 negative allosteric modulators (NAMs)) and genetic reduction of excessive mGluR5 translational pathway signaling to correct abnormal synaptic plasticity, dendritic morphology, cellular signaling, electrophysiological, cognitive, social, behavioral and even growth phenotypes in FXS models. Human early phase trials of mGluR5 NAMs fenobam (Neuropharm), AFQ056 (Novartis) and RO4917523 (Roche) have suggested possible benefit in FXS, but larger phase IIb studies of AFQ056 and RO4917523 failed to meet primary behavioral outcomes in adolescents/adults. These trials may have failed due to lack of measurement of core FXS phenotypes of cognition and learning in a sufficiently young population over a long enough period of time. The proposed project will seek to determine whether the human mGluR5 NAM trials failed because the animal model is not adequate or because the trials were not conducted in a way that benefit could be seen in a neurodevelopmental disorder (NDD). Indeed it may be that the benefits of translational work from preclinical models of NDDs can never be realized via standard drug development pathways. This NeuroNEXT trial seeks to use an innovative exploratory design to change the paradigm for translation of targeted treatments in FXS and determine whether AFQ056 can improve language learning in 100 very young (age 3-6 years) children with FXS during participation in an intensive language learning intervention (LLI), as a surrogate for enhanced neural plasticity. The trial will use a double blind placebo-controlled parallel flexible- dose forced-titration design with a 4 month placebo-lead-in, randomization to AFQ056 or placebo and titration to maximum tolerated dose (MTD), 6 months treatment with AFQ056/placebo combined with the LLI, an open- label extension with re-titration to MTD followed by 6 months of treatment of all participants with LLI and AFQ056, and follow up off AFQ056 at the end of the trial. The study will seek to assess effects of AFQ056 versus placebo on developmental (language, cognitive, adaptive and maladaptive) functioning in young children with FXS receiving the LLI (Aim 1), evaluate safety and tolerability of long-term exposure to AFQ056 in young children with FXS (Aim 2), validate biomarkers that interrogate neural functioning (event-related potentials and eye tracking) and cellular pathway signaling during treatment with AFQ056 and/or LLI and correlate these with developmental outcomes (Aim 3), validate the LLI by evaluating its effects on trajectories of language, cognitive, adaptiv, and maladaptive functioning (Aim 4). If the design is successful, this trial can serve as a model for future trials of mechanistically-targeted treatments operating on neural plasticity in other NDDs, and can accelerate the process of bringing needed treatments to these disorders with high unmet need.

 描述（由申请人提供）：脆性X综合征（FXS）是智力残疾和自闭症谱系障碍最常见的遗传原因。在基础和翻译FXS研究的巨大进展，允许识别神经元通路的目标，用于治疗潜在的疾病。其中研究最充分的是药理学（使用mGluR 5负变构调节剂（NAM））和过量mGluR 5翻译途径信号传导的遗传减少，以纠正FXS模型中异常的突触可塑性、树突形态、细胞信号传导、电生理学、认知、社会、行为甚至生长表型。mGluR 5 NAM非诺班（Neuropharm）、AFQ 056（Novartis）和RO 4917523（Roche）的人体早期试验表明，FXS可能获益，但AFQ 056和RO 4917523的大型IIb期研究未能满足青少年/成人的主要行为结局。这些试验可能失败，因为缺乏足够长时间内在足够年轻的人群中测量认知和学习的核心FXS表型。拟议的项目将寻求确定人类mGluR 5 NAM试验失败是因为动物模型不充分，还是因为试验没有以神经发育障碍（NDD）中可以看到的方式进行。事实上，NDD临床前模型的转化工作的益处可能永远无法通过标准药物开发途径实现。这项NeuroNEXT试验旨在使用创新的探索性设计来改变FXS靶向治疗的转化模式，并确定AFQ 056是否可以在参与强化语言学习干预（LLI）期间改善100名FXS非常年幼（3-6岁）儿童的语言学习，作为增强神经可塑性的替代品。该试验将使用双盲安慰剂对照平行灵活剂量强制滴定设计，其中4个月安慰剂导入，随机分配至AFQ 056或安慰剂并滴定至最大耐受剂量（MTD），用AFQ 056/安慰剂联合LLI治疗6个月，开放标签扩展，重新滴定至MTD，随后用LLI和AFQ 056治疗所有参与者6个月，并在试验结束时随访AFQ 056。该研究将寻求评估AFQ 056与安慰剂相比对发育的影响。（语言，认知，适应性和适应不良）功能，评估长期暴露于AFQ 056在FXS幼儿中的安全性和耐受性（目标2），验证询问神经功能的生物标志物在用AFQ 056和/或LLI治疗期间，研究了事件相关电位（事件相关电位和眼跟踪）和细胞通路信号传导，并将这些与发育结果相关联（目的3），通过评估LLI对语言、认知、适应和适应不良功能轨迹的影响来验证LLI（目标4）。如果设计成功，这项试验可以作为未来对其他NDD中神经可塑性进行机械靶向治疗的试验模型，并可以加速为这些高度未满足需求的疾病带来所需治疗的过程。