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.

项目概要/摘要 我们提议对 PQ 912 进行无缝 2A-B 阶段概念验证 (POC) 试验，PQ 912 是一种一流的小型药物 具有独特作用机制的针对早期阿尔茨海默病（AD）的分子治疗。 PQ 912 抑制 谷氨酰胺酰环化酶 (QC) 及其同工酶 iso-QC，导致 pGlu-Aβ 水平降低，pGlu-Aβ 是一种后 Aβ 的翻译修饰形式（谷氨酸 3/11 环化），以及 pGlu-CCL2（一种翻译后修饰形式） 细胞因子单核细胞趋化蛋白 1 (CCL2) 的修饰形式（谷氨酰胺环化）。这些蛋白质 在 AD 中显着过度表达，其中 pGlu-Aβ 已被证明具有突触毒性、促炎性、 促进自聚集成寡聚物，并抵抗降解，而 pGlu-CCL2 已与 神经炎症的存在和严重程度。在临床前模型中，这些毒性作用可以减弱 用 PQ 912 处理。 PQ 912已完成广泛的临床前AD测试，这是一项大型第一阶段计划 通过 PK PD 测试和早期 2A 期临床试验探索其剂量范围。它是一个优秀的候选者 进行进一步开发，因为它可以满足一系列严格的 POC 标准，包括目标验证、 用于通过直接 PK PD 测量进行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。定量脑电图 2A 期积极结果对 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。根据这些汇总结果，我们 拟议的临床研究针对早期 AD，旨在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 的双重途径减轻长期疾病进展 912的作用方式。试验的第一阶段，即 2A 期，采用分组序贯剂量设计来寻找 PQ 912 进入 2B 期的最高耐受性和安全剂量，72 周的安全性和有效性 学习。计划在第 52 周进行中期无效性分析。主要疗效结果指标 是临床痴呆评级 – 方框总和，关键的次要结果是一种新颖的认知功能 先前显示复合材料对阿尔茨海默病中 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 抑制的测量和 CSF 中的目标占用率、定量脑电图以及 theta 功率频谱分析、ADAS-Cog 13，已选择 ADNI 神经心理学测试组、功能活动问卷和 神经精神病学调查表。将遵循安全性，包括 SAE、AE、DAE-Is 和其他安全监测 整个过程中，DSMB 对参与者的安全进行监督。总而言之，本次试验将评估一部小说 早期 AD 的治疗具有潜在的症状和疾病缓解作用，同时 同时在试验环境中验证新颖的综合结果测量。