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

这是一份提交材料，用于部分支持响应PAR-18-028的关键III期研究。的 一项临床试验使用了一种新的方法来治疗老年痴呆症高危患者的阿尔茨海默病。它将 测试SV 2a拮抗剂左乙拉西坦（AGB 101）的低剂量制剂减缓 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3期项目将包括830名患者，随机分配至 AGB 101或安慰剂，并使用临床痴呆评分总和框随访78周 （CDRsb）作为II期结束时与FDA商定的唯一主要疗效指标 会议作为对公私伙伴关系下试验的部分支持， 应用程序支持160例患者（共830例）的子研究，这些患者将遵循完整的III期研究 在基线和终点增加tau PET成像以评估AGB 101的效果的方案 关于tau病理学的传播。广泛的临床和临床前数据支持以下假设： 神经过度活动是导致早期AD中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蛋白扩散的驱动因素的假设 病理这种过度活动在临床MCI和淀粉样蛋白沉积的患者中最为突出， 通过淀粉样蛋白PET成像（由于AD的aMCI）确定。如申请书所述， 临床前数据还表明，抗癫痫药物左乙拉西坦的剂量较低，但不是很高， 更高剂量用于治疗癫痫，恢复海马活动到正常水平， 神经退行性变;其他非SV 2a拮抗剂的抗癫痫药物不具有这种作用。 神经生物学效应一项测量模式分离期间海马活动的II期研究 aMCI患者的记忆测试发现，AGB 101使海马活动正常化，并改善了 这是一项高度特异性的记忆测试，用于评估海马功能。最 重要的是，拟议的子研究将为AGB 101恢复正常的能力提供可靠的测试， 海马活动时，给予慢性和这种正常化的关系， 在tau PET成像中评估的tau病理学与纵向系列3 T MRI结构 针对内侧颞叶回路优化的成像定义了早期Braak分期。因此， 部分支持3期试验，到2021年可能注册一种新的治疗方法，支持 根据该奖项将有可能有助于生物标志物的发展，通过测试的假设， 过度的神经活动驱动疾病进展，特别是tau病理学的传播。

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.