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

这是对响应PAR-18-028的关键阶段3研究的部分支持。这个 临床试验使用了一种新的方法来治疗痴呆症高危患者的阿尔茨海默病。会的 测试低剂量SV2A拮抗剂左乙拉西坦(AGB101)的减慢效果 阿尔茨海默病患者遗忘性轻度认知障碍患者的疾病进展 疾病(AD)。整个第三阶段计划将包括830名患者，随机分配到 AGB101或安慰剂，并使用临床痴呆评定量表进行78周的随访 (CDRsb)作为与FDA在第二阶段结束时商定的唯一主要疗效措施 开会。作为对公私伙伴关系下的试验的部分支持，本文件中要求的资金 应用程序支持对160名患者的子研究(830名患者中)，这些患者将遵循完整的第三阶段 在基线和终点添加tau PET成像以评估AGB101的效果的方案 关于tau病理学的传播。大量的临床和临床前数据支持这一假设 神经过度活动是导致阿尔茨海默病早期和早期神经元死亡的神经病理的关键驱动因素 有力地支持了海马区过度活跃是tau扩散的驱动因素的假设 病理学。这种过度活动在临床MCI和沉积的淀粉样蛋白AS患者中最为突出。 由淀粉样蛋白PET成像(由于AD引起的aMCI)确定。如申请中所述，广泛 临床前数据还显示，抗癫痫药物左乙拉西坦给药少，但用得不多 高剂量用于治疗癫痫，使海马区活动恢复到正常水平，并防止 神经退行性变；其他非SV2A拮抗剂的抗癫痫药物没有这种作用 神经生物学效应。在模式分离过程中测量海马区活动的第二阶段研究 AMCI患者记忆测试发现AGB101使海马区活动正常化并改善 在这项用于评估海马体功能的高度特异的记忆测试中的表现。多数 重要的是，拟议的子研究将为AGB101恢复正常的能力提供一个强有力的测试 慢性给药时的海马区活动以及这种正常化与脑血管紧张素转换酶扩散的关系 在tau PET成像中评估tau病理，并结合纵向系列3T MRI结构 针对内侧颞叶电路进行了优化的成像定义了早期Braak分期。因此，除了 部分支持3期试验，可能在2021年前注册新的治疗方法，支持 在这个奖项下，将通过检验以下假设来潜在地促进生物标记物的开发 过度的神经活动会推动疾病的发展，特别是tau病理的传播。

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.