Clinical Evaluation of T3D-959 as a Potential Disease Remedial Therapeutic for the Treatment of Alzheimer's Disease

T3D-959 作为治疗阿尔茨海默病的潜在疾病治疗药物的临床评价

• 批准号: 8833069
• 负责人: SUZANNE M. DE LA MONTE
• 金额: $ 112.8万
• 依托单位: T3D THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833069
• 关键词: Agonist; Alzheimer' s Disease; American; Amyloid; Biological Markers; Brain; Brain region; CD3D gene; Cerebrum; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cognition; Cognitive; Controlled Study; Data; Defect; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Enrollment; Evaluation; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glucose; Goals; Healthcare Systems; Hippocampus (Brain); Impaired cognition; Insulin Resistance; Investigational Drugs; Marketing; Measures; Memory; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Positioning Attribute; Positron-Emission Tomography; Protocols documentation; Rattus; Rest; Senile Plaques; Severities; Signal Transduction; Symptoms; Synapses; Testing; Therapeutic; Time; Toxicology; Treatment Protocols; adiponectin; base; cingulate cortex; cohort; design; diabetes mellitus therapy; functional decline; glucose metabolism; imaging modality; improved; insulin sensitizing drugs; mild cognitive impairment; neuroimaging; novel; phase 1 study; public health relevance; research clinical testing; response; rosiglitazone; screening; small molecule; tau Proteins

DESCRIPTION (provided by applicant): The purpose of the proposed project is to conduct a Phase 2a mechanistic clinical proof of concept study of an investigational drug, T3D-959 which is being developed for the treatment of cognitive and functional decline in Alzheimer's disease patients. T3D-959 has successfully completed Phase I studies, and with data demonstrating robust entry into the brain in a rat pharmacokinetic study. T3D-959 is a novel, orally delivered, small molecule, dual nuclear receptor agonist, formerly targeted as a type 2 diabetes therapy and now being re-positioned as a potential disease-modifying therapy for Alzheimer's disease (AD) and mild cognitive impairment (MCI). The project goal is to test the hypothesis that T3D- 959 can mechanistically act in the brain of AD patients to produce desired changes in glucose metabolism (as measured by FDG-PET) and brain function (as measured by BOLD fMRI). These imaging modalities are currently being utilized as surrogate measures of potential efficacy in treating AD. If T3D- 959 treatment produces desired changes in glucose metabolism and brain function, the drug could have disease remedial potential and this study could provide supportive clinical data that justifies the pursuit of longer term clinical studies of the potentia of T3D-959 to slow, stop or reverse cognitive and functional decline in AD patients. The clinical trial is an adaptive, sequential enrollment design involving 24-36 mild-to-moderate AD patients dosed orally once-a-day for 2 weeks. The project has 3 key objectives: i. To determine the potential of T3D-959 to improve cerebral glucose metabolism (CMRgl). Low CMRgl is a hallmark of AD and a better predictor of future cognitive impairment than amyloid plaqe or tau bundle load. ii. To determine the potential of T3D-959 to improve memory-related hippocampal functional connectivity (resting state default mode network activity). iii. Determine appropriate doses for future clinical studies (dose range finding). The therapeutic approach to be tested is based on two suppositions; (A) ameliorating multiple pathologies in the disease with a single therapy may provide a superior clinical benefit than therapeutic approaches which target a single pathology (e.g. beta amyloid plaques) and (B) correcting insulin resistance in the brain, (a key driver of AD pathophysiology) may be disease remedial.

描述（由申请人提供）：拟议项目的目的是对研究药物T3D-959进行2A期机械临床证明，该证明是为治疗阿尔茨海默氏病患者的认知和功能下降而开发的。 T3D-959已成功完成了I期研究，并且数据证明了大鼠药代动力学研究中强大的进入大脑。 T3D-959是一种新颖的，口服的小分子，双核受体激动剂，以前是2型糖尿病疗法，现在被重新定位为针对阿尔茨海默氏病（AD）和轻度认知障碍（MCI）的潜在疾病改良治疗（MCI）。项目目标是检验以下假设：T3D-959可以机械地作用于AD患者的大脑，以产生葡萄糖代谢（通过FDG-PET测量）和脑功能（通过BOLD FMRI测量）的预期变化。目前，这些成像方式被用作治疗AD的潜在功效的替代措施。如果T3D-959治疗会导致葡萄糖代谢和脑功能的预期变化，则该药物可能具有疾病补救潜力，这项研究可以提供支持性的临床数据，以证明对T3D-959的长期临床研究的追求是合理的，以减缓，停止或反向认知和功能降低AD患者。该临床试验是一种自适应，连续的入学设计，涉及24-36名轻度至中度的AD患者，每天口服服用一次，持续2周。该项目有3个关键目标：i。确定T3D-959改善脑葡萄糖代谢（CMRGL）的潜力。低CMRGL是AD的标志，并且比淀粉样蛋白PLAQE或TAU捆绑负载更好地预测了未来认知障碍。 ii。确定T3D-959的潜力以改善与内存相关的海马功能连接性（静止状态默认模式网络活动）。 iii。确定适合未来临床研究的适当剂量（剂量范围发现）。要测试的治疗方法基于两个假设。 （a）与单个疗法相比，通过单个治疗方法改善疾病中多种病理可以提供优异的临床益处，该方法针对单个病理学（例如β-淀粉样蛋白斑块）和（b）纠正大脑中的胰岛素抵抗（a）（a） AD病理生理学的主要驱动力可能是疾病补救症。