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

T3 D-959是一种新的（非淀粉样蛋白/非tau蛋白导向的）新化学实体，旨在改善功能障碍的大脑 阿尔茨海默病（AD）中的葡萄糖能量和脂质代谢。T3 D-959是一种口服给药的小分子 分子双核受体激动剂的工作，以恢复和维持代谢稳态，当 在AD中改变，导致蛋白质错误折叠，导致斑块形成、缠结形成和炎症。 T3 D-959在轻度至中度AD患者中的探索性人体临床试验结果（2a期研究） 已经显示出多个功效信号，表明减缓、停止或逆转疾病进程的潜力。的 该药物临床开发的下一阶段是在更大范围内验证这些观察到的功效信号， 较长的II期临床试验，具有统计学把握度，可测量与安慰剂相比结局的显著差异 认知、功能和疾病生物标志物的测量。II期随机、安慰剂对照 “PIONEER”研究（通过以下途径抑制和克服阿尔茨海默病神经变性的前瞻性治疗） Brain Energetics and Metabolism Restoration）正在评估多种T3 D-959剂量规格与安慰剂的对比 (15mg，30 mg和45 mg QD和安慰剂，比例为1：1：1：1），以确定最安全有效的剂量 用于后续的第三阶段测试。这项多中心试验涉及256名轻度至中度AD患者 (MMSE=14-26）每日一次口服给药，持续24周。共同主要结局指标包括ADAS- cog 11认知和ADCS-CGIC整体功能测量。次要结局指标包括执行 通过DSCT测量的功能和血浆Aβ 42/40比值较基线的变化。先锋开始 2020年2月入学。六周后，在新冠肺炎疫情日益严重的情况下，所有筛查和 停止新受试者的随机化，33例已随机化的受试者继续给药 （“Covid队列”）。4月初，由于COVID-19给研究行为带来了不可逾越的障碍， 在大流行期间，试验停止，所有随机化受试者的研究药物给药停止。经过两 由于流行性疾病激增，PIONEER尝试终止研究，但均失败， 2021年3月1日，根据修订后的方案，针对大流行进行了试验调整（DSMB，NIA， IRB和FDA批准）。已与一家新的CRO签约，并增加了新的美国临床试验中心， 弥补因疫情造成的损失。大流行引起的CA延迟。13个月， 不可预测的“沉没”成本。申请的行政补充资金将用于确保 PIONEER能够在最初提议的时间轴内全部完成，尽管发生了大流行- 相关延迟对该研究进行了与大流行相关的调整，包括新冠病毒检测， 所有受试者，新的入选标准（例如，CDR-MMSE>3.0，MMSE范围从16-26扩展到14-26），所有 电子数据管理（CRIO eSource和eRegulatory），减少患者测试负担，增加 预先计划的盲态中期分析，并纳入额外的生物标志物评估。

T3D-959 is a novel (non-amyloid/non-tau-directed) new chemical entity aimed at improving dysfunctional brain glucose energy and lipid metabolism in Alzheimer’s disease (AD). T3D-959 is an orally delivered small molecule dual nuclear receptor agonist that works to restore and maintain metabolic homeostasis, which when altered in AD, leads to protein misfolding which causes plaque formation, tangle formation and inflammation. Exploratory human clinical test results (Phase 2a study) of T3D-959 in mild to moderate severity AD patients have shown multiple efficacy signals indicating a potential to slow, stop or reverse the course of disease. The next stage in clinical development of this drug is to validate these observed efficacy signals in a larger and longer Phase 2 clinical trial statistically powered to measure significant differences versus placebo in outcome measures of cognition, function, and biomarkers of disease. The Phase 2 randomized, placebo-controlled ‘PIONEER’ Study (Prospective therapy to Inhibit and Overcome Alzheimer’s Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration) is assessing multiple T3D-959 dose strengths vs. placebo (15mg, 30mg & 45mg QD and placebo in a 1:1:1:1 ratio) to identify the most safe and effective dose or doses to use in subsequent Phase 3 testing. The multi-center trial involves 256 mild to moderate AD patients (MMSE=14-26) dosed orally once-a-day for 24-weeks. Co-primary outcome measures include the ADAS- cog11 cognition and ADCS-CGIC global function measures. Secondary outcome measures include executive function as measured by DSCT and change from baseline in plasma Aβ 42/40 ratio. PIONEER began enrollment in February 2020. Six weeks later, amid a growing Covid-19 pandemic, all screening and randomization of new subjects was discontinued with 33 already-randomized subjects continuing their dosing (“Covid Cohort”). In early April, due to the insurmountable barriers to study conduct posed by the COVID-19 pandemic, the trial was halted with cessation of study medication dosing for all randomized subjects. After two attempted resumptions of the study, each thwarted by pandemic surges, PIONEER successfully re-started on March 1, 2021, under an amended protocol with trial adaptations in response to the pandemic (DSMB, NIA, IRB and FDA approved). A new CRO has been contracted and new U.S. clinical trial sites have been added to replace those lost due to the pandemic. The pandemic-elicited delay of ca. 13 months resulted in significant unpredicted ‘sunk’ costs . The requested Administrative Supplement (AS) funding will be utilized to ensure that PIONEER can be completed in its totality and within the original proposed timeline, despite the pandemic- related delay. Pandemic-related adaptations to the study have been implemented including Covid-19 testing of all subjects, new inclusion criteria (e.g., CDR-SOB >3.0 and expanding MMSE range from 16-26 to 14-26), all electronic data management (CRIO eSource and eRegulatory), reducing patient test burdens, addition of a pre-planned, blinded interim analysis, and incorporation of additional biomarker assessments.