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: 9034522
• 负责人: SUZANNE M. DE LA MONTE
• 金额: $ 68.69万
• 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/9034522
• 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; Health; Healthcare Systems; Hippocampus (Brain); Image; 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; fluorodeoxyglucose positron emission tomography; functional decline; glucose metabolism; imaging modality; improved; insulin sensitizing drugs; mild cognitive impairment; neuroimaging; novel; phase 1 study; 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 期机械临床概念验证研究，该药物正在开发用于治疗阿尔茨海默病患者的认知和功能衰退。 T3D-959 已成功完成 I 期研究，数据表明在大鼠药代动力学研究中能够强劲进入大脑。 T3D-959 是一种新型口服小分子双核受体激动剂，以前的目标是 2 型糖尿病治疗，现在被重新定位为阿尔茨海默病 (AD) 和轻度认知障碍 (MCI) 的潜在疾病缓解疗法。该项目的目标是检验这样的假设：T3D-959 可以在 AD 患者的大脑中发挥作用，从而在葡萄糖代谢（通过 FDG-PET 测量）和脑功能（通过 BOLD fMRI 测量）产生所需的变化。这些成像方式目前被用作治疗 AD 潜在疗效的替代指标。如果 T3D-959 治疗在葡萄糖代谢和脑功能方面产生所需的变化，则该药物可能具有治疗疾病的潜力，并且本研究可以提供支持性临床数据，证明对 T3D-959 减缓、停止或逆转 AD 患者认知和功能衰退的潜力进行长期临床研究是合理的。该临床试验是一项适应性、序贯入组设计，涉及 24-36 名轻度至中度 AD 患者，每天口服一次，持续两周。该项目有 3 个关键目标：确定 T3D-959 改善脑葡萄糖代谢 (CMRgl) 的潜力。低 CMRgl 是 AD 的一个标志，并且比淀粉样蛋白斑或 tau 束负载更能预测未来的认知障碍。 二.确定 T3D-959 改善记忆相关海马功能连接（静息状态默认模式网络活动）的潜力。 三.确定未来临床研究的适当剂量（寻找剂量范围）。待测试的治疗方法基于两个假设： (A) 通过单一疗法改善疾病的多种病理可能比针对单一病理（例如 β 淀粉样斑块）的治疗方法提供更好的临床益处，以及 (B) 纠正大脑中的胰岛素抵抗，（ AD 病理生理学的关键驱动因素）可能是疾病治疗。