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.

项目摘要/摘要 我们提议对PQ 912进行无缝阶段的概念验证(POC)试验，PQ 912是一款一流的小型 早期阿尔茨海默病(AD)的分子治疗具有独特的作用机制。PQ 912抑制小鼠肾上腺皮质激素释放 谷氨酰环酶(QC)及其同工酶QC导致pGlu-Aβ水平降低，这是一种后 翻译修饰形式的Aβ(谷氨酸3/11环化)，以及翻译后的pGlu-CCL2 修饰形式的细胞因子单核细胞趋化蛋白1(CCL2)(谷氨酰胺环化)。这些蛋白质 在AD中显著过度表达，其中pGlu-Aβ已被证明具有突触毒性，促炎， 促进自聚集成低聚物，并抵抗降解，而pGlu-CCL2已连接到 神经炎的存在和严重程度。在临床前模型中，这些毒性效应可以减弱。 用PQ 912治疗。PQ 912已经完成了广泛的临床前AD测试，这是一个大型的第一阶段计划 通过PK PD测试和早期2A期临床试验探索其剂量范围。它是一个很好的候选人 考虑到进一步的发展，因为它可以解决一组严格的PoC标准， 适合用直接PK PD测量进行测试的剂量范围，具有可以评估相关 下游生物效应。定量脑电的2a相阳性结果对theta功率和 包括YKL 40在内的脑脊液生物标志物也支持进一步的发展。基于这些综合结果，我们的 拟议的临床研究针对早期阿尔茨海默病，目的是通过 改善突触功能，并通过其PQ双通路延缓长期疾病进展 912年S的行动模式。试验的第一阶段，即阶段2A，使用成组序贯剂量设计来寻找 最高耐受性和安全剂量的PQ 912可通过2B阶段，72周的安全性和有效性 学习。计划中的临时无效性分析将在第52周进行。主要疗效结果衡量标准 是临床痴呆症评分--方框总和，一个关键的次要结果是新的认知功能 先前显示的复合体对阿尔茨海默病患者MCI和早期AD的变化高度敏感 神经成像倡议(ADNI)。其他次要终点包括QC抑制的测量和 脑脊液中的目标占有率，定量脑电，具有theta功率的频谱分析，ADAS-Cog 13，选择 ADNI神经心理测试组合、功能活动问卷和 神经精神病学清单。将跟踪包括SAE、AES、DAE-IS和其他安全监控在内的安全 在整个过程中，由dsmb监督参与者的安全。总而言之，这场审判将评估一部小说 对早期AD的治疗既有症状又有改善疾病的作用，而 同时在试验环境中验证新的复合结果测量。