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: 10357575
• 负责人: John Didsbury
• 金额: $ 152.03万
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357575
• 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; Placebo Control; Placebos; Plasma; Randomized; Research Support; Safety; Senile Plaques; Severities; Signal Transduction; 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.

在研新药T3D-959轻度治疗的探索性人体临床试验结果（2a期研究） 中度阿尔茨海默病患者已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）的进程是该药物开发的下一阶段。 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： 在一项规模更大、时间更长的第二期 2 期人体临床试验中对 T3D-959 进行测试。 项目的目的是在 AD 患者中执行并完成 T3D-959 的 PoC 研究。该临床试验将是一项。 随机、双盲、安慰剂对照、多中心 2 期试验 (RCT)，涉及 120 名轻度至中度患者 AD 患者每天口服一次，连续 24 周，分 2 个平行组（T3D-959 30mg 活性组和安慰剂组） 手臂以 1:1 的比例）。共同主要结果测量将包括 ADAS-cog11 认知测量和全局测量。 次要和探索性结果测量将包括 ADCS-ADL。 基于已完成的 ADAS-cog11 数据测量日常生活活动和 FDG-PET 神经影像。 探索性研究，该 RCT 的显着性为 80%，假设有 4 点差异的影响； 24 周时与安慰剂相比，标准差为 7.8 分。 T3D-959 正在被开发为一种潜在的疾病缓解剂，用于治疗认知障碍和 AD 患者的功能衰退除了针对轻度至轻度的探索性/可行性 2a 期临床研究外。 中度 AD 受试者，T3D-959 已在正常个体中成功完成 I 期研究 在 34 项非安慰剂对照、剂量范围的 2a 期试验中，具有出色的安全性和耐受性。 轻度至中度 AD 患者每天口服一次不同剂量的 T3D-959，持续两周，有 观察到，具有显着 ApoE 基因型的 ADAS-cog11 出现快速、大幅度、持久的改善； 与反应的关联，(b) DSST（数字符号替换测试）的改进，这是第二个衡量指标 执行功能和 (c) FDG-PET 神经影像显示 (i) T3D-959 穿透大脑以产生变化； 在葡萄糖代谢中，(ii) T3D-959 增加大脑中的葡萄糖代谢，(iii) 剂量依赖性 FDG-PET 结果，(iv) T3D-959 可能会增加所有 AD 易感区域的相对葡萄糖代谢 大脑原型葡萄糖代谢低下，(v) ApoE 基因型对 T3D-959 的影响 没有观察到相对葡萄糖代谢的安全性或耐受性问题。 T3D-959是一种小分子新化学实体，口服给药，双核受体激动剂和 第一种用于治疗 AD 的 PPAR δ 激活化合物。 激活 PPAR γ（效力低 15 倍），这可能在以下方面提供潜在的累加或协同效应： 调节 AD 中 PPAR δ 和 PPAR γ 功能失调的大脑葡萄糖能量和脂质代谢。 葡萄糖能量和脂质稳态的中枢调节剂。