Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial of T3D-959 in Mild to Moderate Alzheimer's Disease Subjects

T3D-959 在轻度至中度阿尔茨海默病受试者中的 2 期随机、双盲、安慰剂对照临床试验

• 批准号: 9918832
• 负责人: John Didsbury
• 金额: $ 310.25万
• 依托单位: T3D THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918832
• 关键词: Activities of Daily Living; Advanced Development; Agonist; Alzheimer' s Disease; Alzheimer' s disease patient; Apolipoprotein E; Area; Brain; Brain region; CD3D gene; Cerebrum; Chemicals; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Controlled Clinical Trials; Data; Dependence; Digit structure; Disease; Dose; Double-Blind Method; Drug Kinetics; Effectiveness; Energy Metabolism; Event; Exposure to; Genotype; Glucose; Goals; Health; Health Care Costs; Homeostasis; Human; Impaired cognition; Individual; Inflammation; Investigational Drugs; Lipids; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolic dysfunction; Monitor; Nuclear Receptors; Oral; Outcome; Outcome Measure; Oxidative Stress; PPAR alpha; PPAR gamma; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phase II Clinical Trials; Placebos; Plasma; Randomized; Research Support; Safety; Senile Plaques; Severities; Signal Transduction; Structure; Test Result; Testing; Therapeutic; Time; arm; base; biological adaptation to stress; blood-brain barrier penetration; brain dysfunction; catalyst; clinical development; cognitive testing; design; disability; double-blind placebo controlled trial; drug development; executive function; fluorodeoxyglucose positron emission tomography; functional decline; glucose metabolism; glucose uptake; improved; indexing; insulin sensitizing drugs; lipid metabolism; metabolomics; neuroimaging; open label; phase 1 study; phase 2 study; phase II trial; primary outcome; research clinical testing; response; small molecule; tau aggregation

Exploratory human clinical test results (Phase 2a study) of the investigational new drug T3D-959 in mild to moderate severity Alzheimer's disease patients have shown multiple efficacy signals indicating a potential to slow, stop or reverse the course of Alzheimer's disease (AD). The next stage in the development of this drug to eventual market is establishing clinical proof of concept (PoC) to validate these observed efficacy signals by testing in T3D-959 in a larger and longer second Phase 2 human clinical trial. The objective of the proposed project is to execute and complete this PoC study of T3D-959 in AD patients. The clinical trial will be a randomized, double-blind, placebo-controlled, multi-center Phase 2 trial (RCT) involving 120 mild to moderate AD patients dosed orally once-a-day for 24-weeks in 2 parallel arms (T3D-959 30mg active arm and a placebo arm in a 1:1 ratio). Co-primary outcome measures will include the ADAS-cog11 cognition measure and global function CDR-SB measure. Secondary and exploratory outcome measures will include the ADCS-ADL measure of activities of daily living and FDG-PET neuroimaging. Based on ADAS-cog11 data in the completed exploratory study, this RCT is 80% powered for significance; α=0.05, assuming an effect of a 4-point difference vs. placebo at 24-weeks, and a standard deviation of 7.8 pts. T3D-959 is being developed as a potential disease-modifying agent for the treatment of cognitive and functional decline in AD patients. In addition to the exploratory/feasibility Phase 2a clinical study in mild to moderate AD subjects, T3D-959 has successfully completed Phase I studies in normal individuals with an excellent safety and tolerability profile. In the non-placebo-controlled, dose range finding Phase 2a trial in 34 mild to moderate AD patients dosed orally once-a-day for 2-weeks with varying doses of T3D-959, there was observed; (a) rapid, high magnitude, durable improvement in ADAS-cog11 with a significant ApoE genotype association to response, (b) improvement in DSST (Digit Symbol Substitution Test), a second measure of executive function and (c) FDG-PET neuroimaging showing; (i) T3D-959 penetrated the brain to effect changes in glucose metabolism, (ii) T3D-959 increased glucose metabolism in the brain, (iii) a dose dependency to FDG-PET outcomes, (iv) T3D-959 may increase relative glucose metabolism in all AD-vulnerable regions of the brain prototypically glucose hypometabolic, (v) ApoE genotype influence on the effect of T3D-959 on relative glucose metabolism. There were no observed safety or tolerability issues. T3D-959 is a small molecule new chemical entity, orally delivered, dual nuclear receptor agonist and the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma (at 15-fold lower potency) which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD. PPAR delta and PPAR gamma are central regulators of glucose energy and lipid homeostasis.

试验用新药T3 D-959在轻度 中度阿尔茨海默病患者已经显示出多种功效信号，表明有可能 减缓、停止或逆转阿尔茨海默病（AD）的进程。这种药物开发的下一个阶段是 最终市场正在建立临床概念验证（PoC），以通过以下方式验证这些观察到的功效信号 在T3 D-959中进行更大和更长的第二次2期人体临床试验。建议的目标 项目是执行并完成T3 D-959在AD患者中的临床研究。临床试验将是一个 一项随机、双盲、安慰剂对照、多中心II期试验（RCT），纳入120例轻度至中度 AD患者在2个平行组（T3 D-959 30 mg活性组和安慰剂组）中每日一次口服给药24周 1：1的比例）。共同主要结局指标将包括ADAS-cog 11认知指标和总体 功能CDR-SB测量。次要和探索性结局指标将包括ADCS-ADL 日常生活活动和FDG-PET神经成像的测量。基于已完成的ADAS-cog 11数据， 探索性研究，该RCT的显著性把握度为80%; α=0.05，假设效应为4分差异 vs.安慰剂组24周，标准差为7.8例患者。 T3 D-959正在开发作为一种潜在的疾病修饰剂，用于治疗认知和 AD患者的功能下降。除了在轻度至重度糖尿病患者中进行的探索性/可行性2a期临床研究外， 在中度AD受试者中，T3 D-959已成功完成了在正常个体中的I期研究， 良好的安全性和耐受性。在34例非安慰剂对照、剂量范围探索的2a期试验中， 轻度至中度AD患者口服不同剂量的T3 D-959，每天一次，持续2周， 观察到：（a）ADAS-cog 11快速、高幅度、持久改善，具有显著ApoE基因型 与反应的关联，（B）DSST（数字符号替代测试）的改善，DSST是第二种测量 执行功能和（c）FDG-PET神经成像显示;（i）T3 D-959穿透大脑以实现变化 在葡萄糖代谢中，（ii）T3 D-959增加脑中的葡萄糖代谢，（iii）T3 D-959对葡萄糖代谢的剂量依赖性。 FDG-PET结果，（iv）T3 D-959可能会增加所有AD易感区域的相对葡萄糖代谢， （v）ApoE基因型对T3 D-959对脑原型葡萄糖代谢低下的影响， 相对葡萄糖代谢未观察到安全性或耐受性问题。 T3 D-959是一种小分子新化学实体，口服递送，双重核受体激动剂， 这是第一个开发用于治疗AD的PPAR δ激活化合物。独特的是，这种药物还 激活过氧化物酶体增殖物激活受体γ（以15倍的低效力），这可能提供潜在的累加或协同效应， 调节AD中功能失调的脑葡萄糖能量和脂质代谢。PPAR-delta和PPAR-gamma是 葡萄糖能量和脂质稳态的中枢调节器。