A Seamless Phase 2A-B Randomized Double Blind Placebo Controlled Trial to Evaluate the Efficacy and Safety of PQ 912 in Patients with Early Alzheimer's Disease

一项无缝 2A-B 期随机双盲安慰剂对照试验，旨在评估 PQ 912 对早期阿尔茨海默病患者的疗效和安全性

• 批准号: 9895611
• 负责人: Howard Feldman
• 金额: $ 434.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895611
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease test; Amyloid beta-Protein; Attenuated; Biological; Biological Markers; Blood; CCL2 gene; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical dementia rating scale; Cognition; Cognitive; Cyclization; Data; Dementia; Dependence; Development; Disease; Disease Progression; Dose; Early treatment; Electroencephalography; Enzyme Inhibition; Enzymes; Equipment and supply inventories; Failure; Futility; Future; Glutamates; Glutamine; Goals; Human; Individual; Inflammation; Inflammatory; Isoenzymes; Link; Measurable; Measurement; Measures; Mediator of activation protein; Monitor; Neuropsychological Tests; Outcome Measure; Outcomes Research; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; PrP; Pre-Clinical Model; Proteins; Questionnaires; Randomized; Resistance; Resources; Risk; Safety; Seeds; Senile Plaques; Severities; Sum; Synapses; Synaptic Membranes; Testing; Toxic effect; Translating; Treatment outcome; Validation; abeta oligomer; base; chemokine; clinical effect; clinical efficacy; cytokine; design; double-blind placebo controlled trial; effective therapy; efficacy evaluation; efficacy outcomes; efficacy study; efficacy testing; improved; neurogranin; neuroimaging; neuroinflammation; neuropsychiatry; next generation; novel; overexpression; participant safety; pre-clinical; prion-like; programs; safety study; secondary endpoint; secondary outcome; small molecule; synaptic function; tau Proteins; treatment duration; trial design

PROJECT SUMMARY/ABSTRACT We are proposing a seamless phase 2A-B Proof of Concept (POC) trial of PQ 912, a first-in-class small molecule treatment for early Alzheimer’s disease (AD) with a unique mechanism of action. PQ 912 inhibits the enzyme glutaminyl cyclase (QC) and its isozyme iso-QC, resulting in reduced levels of pGlu-Aβ, a post- translationally modified form of Aβ (Glutamate 3/11 cyclization), as well as pGlu-CCL2, a post-translationally modified form of cytokine monocyte chemoattractant protein 1 (CCL2) (Glutamine cyclisation). These proteins are significantly overexpressed in AD where pGlu-Aβ has been shown to be synaptotoxic, proinflammatory, promoting of self-aggregation into oligomers, and resistant to degradation, while pGlu-CCL2 has been linked to the presence and severity of neuroinflammation. In preclinical models, these toxic effects can be attenuated with PQ 912 treatment. PQ 912 has completed extensive preclinical AD testing, a large phase 1 program exploring its dose range with PK PD testing, and an early phase 2A clinical trial. It is an excellent candidate to take into further development, as it can address a set of stringent POC criteria including target validation, suitable dose range for testing with direct PK PD measurement, with biomarkers that can evaluate relevant downstream biological effects. Phase 2A positive results on quantitative EEG with effects on theta power and on CSF biomarkers including YKL 40 also support further development. Based on these aggregate results, our proposed clinical study targets early AD with the goal of improving cognition and everyday function through improved synaptic function, and attenuating longer term disease progression through its dual pathways of PQ 912’s mode of action. The first phase of the trial, phase 2A, uses a group sequential dose design to find the highest well tolerated and safe dose of PQ 912 to take through to phase 2B, a 72-week safety and efficacy study. A planned interim futility analysis will be conducted at week 52. The primary efficacy outcome measure is Clinical Dementia Rating – Sum of Boxes, and a key secondary outcome is a novel cognitive-functional composite shown previously to be highly sensitive to change in MCI and early AD in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Additional secondary endpoints include measurement of QC inhibition and target occupancy in CSF, quantitative EEG with spectral analysis of theta power, ADAS-Cog 13, selected measures from the ADNI neuropsychological test battery, Functional Activities Questionnaire, and the Neuropsychiatric Inventory. Safety including SAEs, AEs, DAE-Is and other safety monitoring will be followed throughout with oversight of participant safety from the DSMB. In summary, this trial will evaluate a novel treatment for early AD that has potential for both symptomatic and disease-modifying effects while simultaneously validating novel composite outcome measures within a trial setting.

项目摘要/摘要 我们提出了PQ 912的无缝2A-B概念证明（POC）试验，这是一流的小型 具有独特作用机理的早期阿尔茨海默氏病（AD）的分子治疗。 PQ 912抑制 酶谷氨酰胺基环酶（QC）及其同工酶ISO-QC，导致PGLU-Aβ水平降低，这是一种后。 Aβ的翻译形式（谷氨酸3/11环化）以及PGLU-CCL2，一种后翻译 细胞因子单核细胞趋化剂蛋白1（CCL2）（谷氨酰胺循环）的修饰形式。这些蛋白质 在PGLU-Aβ已被证明是突触毒性，促炎性的AD中明显过表达 将自我聚集促进到低聚物中，并且对降解具有抵抗力，而PGLU-CCL2已与 神经炎症的存在和严重程度。在临床前模型中，这些有毒作用可以减弱 使用PQ 912处理。 PQ 912已完成广泛的临床前广告测试，这是一个大型1阶段计划 通过PK PD测试探索其剂量范围，并进行了2A期早期临床试验。这是一个很好的候选人 进一步开发，因为它可以解决一组严格的POC标准，包括目标验证， 可直接PK PD测量测试的合适剂量范围，并具有可以评估相关性的生物标志物 下游生物学效应。第2A阶段对定量脑电图的阳性结果，对theta功率的影响和 在包括YKL 40在内的CSF生物标志物上，还支持进一步的发展。基于这些总结果，我们 拟议的临床研究针对早期AD的目标，其目的是通过 提高突触功能，并通过其PQ的双重途径减弱长期疾病的进展 912的行动方式。试验的第一阶段2a阶段，使用组顺序剂量设计来找到 PQ 912的最高耐受剂量和安全剂量可用于2B期，这是72周的安全性和轻松性 学习。计划的临时分析将在第52周进行。 是临床痴呆评级 - 盒子总和，关键的次要结果是一种新颖的认知功能 以前显示的复合材料对阿尔茨海默氏病的MCI和早期AD的变化高度敏感 神经影像倡议（ADNI）。其他次要终点包括QC抑制和 CSF中的目标占用率，定量脑电图和theta功率的光谱分析，ADAS-COG 13，选定 来自ADNI神经心理测试电池，功能活动问卷和 神经精神库存。安全包括SAE，AE，DAE-IS和其他安全监控 始终监督DSMB的参与安全性。总而言之，该试验将评估小说 早期AD的治疗，具有症状和疾病改良作用的潜力 同样验证了试验环境中的新型综合结果度量。