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 3 期研究的部分支持的提交。这 临床试验使用一种新方法治疗痴呆症高危患者的阿尔茨海默病。它将 测试 SV2a 拮抗剂左乙拉西坦 (AGB101) 低剂量制剂减缓 阿尔茨海默病导致的遗忘性轻度认知障碍 (aMCI) 患者的疾病进展 疾病（AD）。整个第 3 阶段计划将包括 830 名患者，随机分配到 AGB101 或安慰剂，并使用临床痴呆评级框的总和进行 78 周的随访 (CDRsb) 作为第 2 阶段结束时与 FDA 商定的唯一主要疗效指标 会议。作为对公私合作伙伴关系下试验的部分支持，本次请求的资金 应用程序支持 160 名患者（总共 830 名）的亚研究，他们将遵循完整的第 3 阶段 在基线和终点添加 tau PET 成像以评估 AGB101 效果的方案 关于 tau 病理学的传播。大量的临床和临床前数据支持以下假设： 神经过度活动是导致早期 AD 和神经元死亡的神经病理学的关键驱动因素 强烈支持海马过度活跃是 tau 蛋白传播驱动因素的假设 病理。这种过度活动在临床 MCI 和沉积淀粉样蛋白的患者中最为突出 通过淀粉样蛋白 PET 成像（AD 引起的 aMCI）确定。正如申请中所描述的，广泛 临床前数据还表明，抗癫痫药物左乙拉西坦的给药剂量较低，但幅度不大。 较高剂量用于治疗癫痫，使海马活动恢复到正常水平并预防 神经变性；其他非 SV2a 拮抗剂的抗癫痫药不具有此功能 神经生物学效应。测量模式分离期间海马活动的第二阶段研究 aMCI 患者的记忆测试发现 AGB101 使海马活动正常化并改善 在这项用于评估海马功能的高度特异性记忆测试中的表现。最多 重要的是，拟议的子研究将为 AGB101 恢复正常的能力提供强有力的测试 长期给予时的海马活动以及这种正常化与传播的关系 通过 tau PET 成像和纵向系列 3T MRI 结构评估 tau 病理学 针对内侧颞叶回路优化的成像定义了早期 Braak 分期。因此，旁边 部分支持 3 期试验，可能在 2021 年注册新疗法，支持 该奖项将通过测试以下假设，为生物标志物的开发做出潜在贡献： 过度的神经活动会导致疾病进展，特别是 tau 蛋白病理学的传播。