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

正在研究的新药T3D-959在轻度患者中的探索性人体临床试验结果(2a期研究) 到中等严重程度的阿尔茨海默病患者已经显示出多种疗效信号，表明有可能 延缓、阻止或逆转阿尔茨海默病(AD)的病程。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)，通过以下方式验证这些观察到的疗效信号 在规模更大、时间更长的第二阶段人体临床试验中测试T3D-959。建议的目标是 项目是在AD患者中执行和完成这项关于T3D-959的PoC研究。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例轻度至中度 AD患者在两个平行的手臂(T3D-959 30 mg主动手臂和安慰剂)中每天口服一次，持续24周 手臂的比例为1：1)。共同主要成果衡量标准将包括ADAS-cog11认知衡量标准和全球 函数CDR-SB度量。次级和探索性结果衡量标准将包括ADCS-ADL 日常生活能力和FDG-PET神经成像的测量。基于已完成的ADAS-cog11数据 探索性研究，这项随机对照试验有80%的意义；α=0.05，假设影响为4分之差 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改良剂，用于治疗认知障碍和 阿尔茨海默病患者功能下降。除探索性/可行性阶段2a临床研究外， 中度AD受试者，T3D-959已成功完成对患有AD的正常人的I期研究 极佳的安全性和耐受性。在34例非安慰剂对照的2a期剂量范围发现试验中 轻至中度AD患者服用不同剂量的T3D-959，每天一次，连续两周，有 观察到；(A)具有显著ApoE基因的ADAS-cog11快速、高幅度、持久的改善 与响应的关联，(B)数字符号替换测试(DSST)的改进，这是 执行功能和(C)FDG-PET神经成像显示；(I)T3D-959穿透大脑以影响变化 在葡萄糖代谢方面，(Ii)T3D-959增加了大脑中的葡萄糖代谢，(Iii)剂量依赖于 FDG-PET结果，(Iv)T3D-959可能增加所有AD易感区域的相对糖代谢 (V)载脂蛋白E基因对T3D-959作用的影响 相对葡萄糖代谢。没有观察到安全性或耐受性问题。 T3D-959是一种小分子新化学实体，口服，双核受体激动剂和 第一个PPAR增量激活化合物将被开发用于治疗AD。独一无二的是，这种药物还 激活PPAR伽马(效力降低15倍)，这可能会在 调节阿尔茨海默病患者脑内糖、能量、脂代谢紊乱。PPAR增量和PPAR伽马是 葡萄糖能量和脂质动态平衡的中央调节器。

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.