Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Open-Label Extension Study

摘要：这是一个支持NIH的应用程序，用于启用反标签的开放标签扩展(OLE) 淀粉样蛋白治疗无症状阿尔茨海默病(A4)研究。A4研究于2014年启动，是为了 首次在临床正常(CN)老年人中进行的此类二级预防试验 筛查正电子发射计算机断层扫描显示淀粉样β蛋白(Aβ)积聚增加。A4符合条件的参与者处于临床前阶段 (无症状的)阿尔茨海默病的各个阶段，认知功能衰退的风险很高。A4研究的总体目标是测试 以Aβ为靶点的免疫治疗可预防认知功能下降的假说 早期AD病理，如果足够早开始的话。A4研究筛选了6700多名参与者(年龄在65-85岁之间， 14%的少数族裔)，并超过了我们的注册目标，随机抽取了1169名参与者。我们最初的预测是 30%的“淀粉样阳性”被证明是正确的，29.5%的参与者进行了PET会议筛查 “淀粉样蛋白升高”的标准。我们还推出了淀粉样蛋白风险的配套纵向评估和 2015年“淀粉样蛋白阴性”CN(n=541)的神经退行性变(学习)观察研究。基于Sola 试验结果在AD痴呆患者中，我们将剂量增加了四倍，并将双盲(DB)方案延长到4.5年。 第一名A4学员将于2019年初完成DB方案，最后一名学员将于年中完成 2022年保持最初治疗任务的盲目性，A4 OLE将使我们能够继续评估 这些参与者在完成DB后，并调查SOLA暴露对 临床前阿尔茨海默病的认知和功能衰退。此外，我们还将探索最优的“关键窗口” 使用在OLE开始时获得的淀粉样PET、磁共振成像和tau PET(在一个子集中)进行抗Aβ治疗的反应。 A4研究是一个公私慈善合作伙伴关系，资金来自NIA，礼来公司，阿尔茨海默氏症协会， 富达生物科学、GHR基金会和加速药物伙伴关系(AMP)。我们在这里寻找 NIH为A4 OLE提供了部分资金，礼来公司提供了剩余的资金和实物支持。 这笔资金将使我们能够为所有非常敬业的A4参与者提供在OLE中研究药物的机会，以及 继续收集关于最大可用CN队列的极其有价值的纵向数据，其特征为 淀粉样蛋白状态，直到2022年底完成初步疗效分析。我们已经开始分享 将制作来自A4筛查数据的数据和生物样本，以及A4/学习纵向数据 在完成A4研究的初步疗效分析后一年内公开提供。A4研究 处于有利地位，可以用更高剂量的solane zumab和 疾病的适当阶段，在估计Aβ积聚早15年的人群中 比之前的阿尔茨海默病试验更具临床应用价值。来自A4研究的其他纵向数据， 与在学习中获得的类似数据相结合，有可能从根本上改变检测和 治疗阿尔茨海默病，并使我们更接近到2025年找到成功的预防疗法的国家适应行动方案的目标。

SUMMARY: This is an application for NIH support to enable an Open Label Extension (OLE) of the Anti- Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study. The A4 Study was launched in 2014 as the first of its kind secondary prevention trial in clinically normal (CN) older individuals with evidence of elevated amyloid-beta (Aβ) accumulation on screening PET scan. A4 eligible participants are in the preclinical (asymptomatic) stages of AD and at high risk for cognitive decline. The overall goal of the A4 study is to test the hypothesis that immunotherapy targeting Aβ (solanezumab) can prevent the cognitive decline associated with early AD pathology, if initiated early enough. The A4 Study screened over 6700 participants (age 65-85, 14% minority) and exceeded our enrollment target with 1169 participants randomized. Our initial prediction of 30% “amyloid positivity” was proven correct with 29.5% of the participants with screening PET meeting “elevated amyloid” criteria. We also launched the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) observational study in “amyloid negative” CN (n=541) in 2015. Based on the sola trial results in AD dementia, we quadrupled the dose and extended the double-blind (DB) protocol to 4.5 years. The first A4 participant will complete the DB protocol in early 2019, with the last participant completing in mid- 2022. Maintaining the blind of the initial treatment assignment, the A4 OLE will enable us to continue to assess these participants after they complete the DB, and to investigate the long-term effects of sola exposure on cognitive and functional decline in preclinical AD. In addition, we will explore the “critical window” for optimal response to anti-Aβ therapy utilizing amyloid PET, MRI, and tau PET (in a subset) acquired at start of OLE. The A4 Study is a public-private-philanthropic partnership with funding from NIA, Lilly, Alzheimer’s Association, Fidelity Biosciences, GHR Foundation, and the Accelerating Medicines Partnership (AMP). Here we seek partial funding from the NIH for the A4 OLE with Lilly providing the remainder of funding and in-kind support. This funding will allow us to offer all of the very dedicated A4 participants access to study drug in the OLE, and continue to collect extremely valuable longitudinal data on the largest available cohort of CN characterized by amyloid status, until the primary efficacy analyses are completed in late 2022. We have already begun to share the data and biosamples from the A4 screening data, and the A4/LEARN longitudinal data will be made publicly available within one year of completion of the primary efficacy analyses of the A4 Study. The A4 Study is well positioned to rigorously test the amyloid hypothesis with a higher dose of solanezumab and at the appropriate stage of disease, in a population estimated to be up to 15 years earlier in the Aβ accumulation process than the previous AD dementia trials. The additional longitudinal data from the A4 Study, in combination with similar data acquired in LEARN, has the potential to fundamentally alter the detection and treatment of AD, and move us closer to the NAPA goal of finding a successful prevention therapy by 2025.