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
基本信息
- 批准号:10617062
- 负责人:
- 金额:$ 30.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease testAmyloid beta-ProteinAttenuatedBiologicalBiological MarkersCCL2 geneClinicalClinical ResearchClinical TrialsCognitionCognitiveCyclizationDementiaDevelopmentDiseaseDisease ProgressionDoseEarly treatmentElectroencephalographyEnzymesEquipment and supply inventoriesFutilityGlutamatesGlutamineGoalsIsoenzymesLinkMeasurementMeasuresMonitorNeuropsychological TestsOutcome MeasurePathway interactionsPatientsPersonsPharmaceutical PreparationsPhasePre-Clinical ModelProteinsQuestionnairesRandomizedResistanceSafetySeveritiesSumTestingToxic effectValidationbasecytokinedesigndouble-blind placebo controlled trialeffective therapyefficacy evaluationefficacy outcomesefficacy studyimprovedneuroimagingneuroinflammationneuropsychiatrynoveloverexpressionparticipant safetypre-clinicalprogramssafety studysecondary endpointsecondary outcomesmall moleculesynaptic function
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Howard Feldman其他文献
Howard Feldman的其他文献
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{{ truncateString('Howard Feldman', 18)}}的其他基金
Phase II randomized controlled trial of benfotiamine in early Alzheimer's Disease
苯磷硫胺治疗早期阿尔茨海默病的 II 期随机对照试验
- 批准号:
10420686 - 财政年份:2022
- 资助金额:
$ 30.95万 - 项目类别:
Phase II randomized controlled trial of benfotiamine in early Alzheimer's Disease
苯磷硫胺治疗早期阿尔茨海默病的 II 期随机对照试验
- 批准号:
10661607 - 财政年份:2022
- 资助金额:
$ 30.95万 - 项目类别:
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:
10549805 - 财政年份:2019
- 资助金额:
$ 30.95万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 30.95万 - 项目类别:
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:
10356791 - 财政年份:2019
- 资助金额:
$ 30.95万 - 项目类别:
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