A Phase 3 Pivotal Trial of AGB101 to Slow Progression in MCI due to Alzheimer's Disease

AGB101 减缓阿尔茨海默病导致的 MCI 进展的 3 期关键试验

• 批准号: 10436755
• 负责人: RICHARD Charles MOHS
• 金额: $ 159.52万
• 依托单位: AGENEBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436755
• 关键词: Address; Alzheimer' s Disease; Amyloid; Antiepileptic Agents; Award; Caregivers; Chronic; Clinical; Clinical Research; Clinical Trials; Data; Dementia; Deposition; Disease Progression; Dose; Epilepsy; Formulation; Funding; Healthcare Systems; Hippocampus (Brain); Image; Levetiracetam; Magnetic Resonance Imaging; Measures; Medial; Memory; Nerve Degeneration; Neurobiology; Pathology; Patients; Pattern; Performance; Pharmaceutical Preparations; Phase; Placebos; Positron-Emission Tomography; Prevention trial; Protocols documentation; Randomized; Safety; Series; Staging; Sum; Temporal Lobe; Testing; amnestic mild cognitive impairment; antagonist; biomarker development; dementia risk; efficacy testing; high risk; improved; meetings; neuron loss; neuropathology; novel strategies; novel therapeutics; phase 2 study; phase 3 study; phase III trial; pre-clinical; prevent; programs; public-private partnership; relating to nervous system; tau Proteins; trial design

This is a submission for partial support of a pivotal Phase 3 study responsive to PAR-18-028. The clinical trial uses a novel approach to Alzheimer's disease in patients at high risk for dementia. It will test the efficacy of a low-dose formulation of the SV2a antagonist levetiracetam (AGB101) to slow disease progression in patients with amnestic Mild Cognitive Impairment (aMCI) due to Alzheimer's disease (AD). The entire Phase 3 program will include 830 patients randomly assigned to either AGB101 or placebo and followed for 78 weeks using the Clinical Dementia Rating sum of boxes (CDRsb) as a sole primary efficacy measure as agreed upon with the FDA at the End of Phase 2 meeting. As partial support for the trial under a public private partnership, the funds requested in this application support a substudy of 160 patients (out of the total 830), who will follow the full phase 3 protocol with the addition of tau PET imaging at baseline and endpoint to assess the effect of AGB101 on the spread of tau pathology. Extensive clinical and preclinical data support the hypothesis that neural overactivity is a critical driver of neuropathology leading to neuronal death in early AD and strongly support the hypothesis that hippocampal overactivity is a driver of the spread of tau pathology. This overactivity is most prominent in patients with clinical MCI and deposited amyloid as determined by amyloid PET imaging (aMCI due to AD). As described in the application, extensive preclinical data also show that the antiepileptic drug levetiracetam given in low, but not at the much higher doses used to treat epilepsy, restores hippocampal activity to normal levels and prevents neurodegeneration; other antiepileptic drugs that are not SV2a antagonists do not have this neurobiological effect. A Phase 2 study measuring hippocampal activity during a pattern separation memory test in patients with aMCI found that AGB101 normalized hippocampal activity and improved performance on this highly specific memory test for assessment of hippocampal function. Most importantly, the proposed substudy will provide a robust test of the ability of AGB101 to restore normal hippocampal activity when given chronically and the relationship of this normalization to the spread of tau pathology as assessed in tau PET imaging together with a longitudinal series of 3T MRI structural imaging optimized for the medial temporal lobe circuits the define early Braak staging. Thus, alongside partial support for the Phase 3 trial, with possible registration of a new therapeutic by 2021, support under this award will potentially contribute to biomarker development by testing the hypothesis that excess neural activity drives disease progression, specifically the spread of tau pathology.

这是对PAR-18-028响应的关键阶段3研究的部分支持。这 临床试验使用一种新的方法来对患有痴呆症的高风险患者进行阿尔茨海默氏病。会 测试SV2A拮抗剂Levetiracetam（AGB101）的低剂量公式的功效 由于阿尔茨海默氏症而导致的羊膜轻度认知障碍（AMCI）患者的疾病进展 疾病（AD）。整个第三阶段计划将包括830名随机分配给任何一个的患者 AGB101或安慰剂，然后使用临床痴呆评级盒子持续78周 （CDRSB）作为第2阶段结束时FDA同意的唯一主要疗效措施 会议。作为对审判的部分支持，根据公共私人合伙企业，此要求的资金 应用程序支持160名患者（在总计830例中）的物质，他们将遵循整个阶段3 协议在基线和端点上添加tau PET成像以评估AGB101的效果 关于tau病理的传播。广泛的临床和临床前数据支持以下假设 神经过度活动是神经病理学的关键驱动力，导致AD早期神经元死亡，并且 强烈支持海马过度活动是tau扩散的驱动力的假设 病理。在临床MCI的患者中，这种过度活动性最为突出，并沉积淀粉样蛋白 由淀粉样蛋白宠物成像（由于AD引起的AMCI）确定。如应用程序中所述，广泛 临床前数据还表明，在低点给出的抗癫痫药左旋核酸 用于治疗癫痫的较高剂量，将海马活性恢复到正常水平，并防止 神经变性；其他不是SV2A拮抗剂的其他抗癫痫药没有 神经生物学效应。在模式分离期间测量海马活性的2期研究 AMCI患者的记忆测试发现AGB101标准化海马活性并改善 在这项高度特定的记忆测试中，用于评估海马功能。最多 重要的是，拟议的子公司将对AGB101恢复正常的能力提供可靠的测试 海马活动慢性化时，这种归一化与扩散的关系 Tau病理学与Tau PET成像一起评估，以及一系列3T MRI结构的纵向系列 对内侧颞叶电路进行了优化的成像，定义的早期braak分期。因此，与旁边 对第三阶段试验的部分支持，可能会在2021年之前注册新的治疗方法 根据该裁决 过多的神经活动驱动疾病进展，特别是tau病理的传播。