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: 10617062
• 负责人: Howard Feldman
• 金额: $ 30.95万
• 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/10617062
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease test; Amyloid beta-Protein; Attenuated; Biological; Biological Markers; CCL2 gene; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Cyclization; Dementia; Development; Disease; Disease Progression; Dose; Early treatment; Electroencephalography; Enzymes; Equipment and supply inventories; Futility; Glutamates; Glutamine; Goals; Isoenzymes; Link; Measurement; Measures; Monitor; Neuropsychological Tests; Outcome Measure; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Proteins; Questionnaires; Randomized; Resistance; Safety; Severities; Sum; Testing; Toxic effect; Validation; base; cytokine; design; double-blind placebo controlled trial; effective therapy; efficacy evaluation; efficacy outcomes; efficacy study; improved; neuroimaging; neuroinflammation; neuropsychiatry; novel; overexpression; participant safety; pre-clinical; programs; safety study; secondary endpoint; secondary outcome; small molecule; synaptic function

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.

项目总结/摘要 我们正在提议PQ 912的无缝2A-B阶段概念验证（POC）试验，PQ 912是一流的小型 分子治疗早期阿尔茨海默病（AD）具有独特的作用机制。PQ 912抑制 酶β-氨基环化酶（QC）及其同工酶同工酶QC，导致pGlu-Aβ水平降低， Aβ的构象修饰形式（谷氨酸3/11环化），以及pGlu-CCL 2，一种构象后修饰形式， 细胞因子单核细胞趋化蛋白1（CCL 2）的修饰形式（谷氨酰胺环化）。这些蛋白质 在AD中显著过表达，其中pGlu-Aβ已被证明具有突触毒性，促炎性， 促进自聚集成寡聚体，并抗降解，而pGlu-CCL 2已连接到 神经炎症的存在和严重程度。在临床前模型中，这些毒性作用可以减弱 PQ 912治疗PQ 912已经完成了广泛的临床前AD测试，这是一个大型的I期项目 通过PK PD测试探索其剂量范围，以及早期2A期临床试验。这是一个很好的候选人， 考虑到进一步的发展，因为它可以解决一套严格的POC标准，包括目标验证， 用于直接PK PD测量的测试的合适剂量范围，以及可以评估相关的生物标志物 下游生物效应。定量EEG的2A阶段阳性结果，对θ功率和 包括YKL 40在内的CSF生物标志物也支持进一步的开发。根据这些综合结果， 拟议的临床研究针对早期AD，目标是通过以下方式改善认知和日常功能： 改善突触功能，并通过PQ的双重途径减弱长期疾病进展 912的行动方式试验的第一阶段，即2A期，使用组序贯剂量设计来寻找 PQ 912的最高耐受性良好和安全剂量，以进入2B期，72周的安全性和有效性 study.计划在第52周进行中期无效性分析。主要疗效结局指标 是临床痴呆评分-方框总和，关键的次要结局是一种新的认知功能 先前显示的复合物对阿尔茨海默病中MCI和早期AD的变化高度敏感 神经影像学倡议（ADNI）。其他次要终点包括QC抑制的测量， CSF中的目标占有率，定量EEG和θ功率谱分析，ADAS-Cog 13，选择 从ADNI神经心理测试组合、功能活动问卷和 神经精神量表。将随访安全性，包括SAE、AE、DAE-I和其他安全性监测 在整个过程中，由DSMB监督参与者的安全性。总而言之，这次试验将评估一部小说 治疗早期AD，具有潜在的症状和疾病改善作用， 同时在试验环境中验证新的复合结局指标。