API A4 Alzheimer's Prevention Trial

项目总结/摘要 迫切需要找到并加速批准阿尔茨海默病（AD）预防疗法。 Aducanumab是一种选择性结合β淀粉样蛋白（Aβ）寡聚体和原纤维的抗体。在1b期试验中， 临床上患有Aβ斑块的AD患者，它显着减少了Aβ斑块负担，并且似乎减缓了 认知能力下降阿尔茨海默病预防倡议（API）和无症状性阿尔茨海默病患者的抗淀粉样蛋白治疗 阿尔茨海默氏症（A4）试验的领导者们聚集在一起，提出了一个为期24个月的、多中心、双盲、安慰剂- 使用AD生物标志物终点作为主要结局的aducanumab对照预防试验，沿着 认知功能未受损的65-80岁Aβ PET+患者的认知/临床、安全性和耐受性结局 根据APOE 4等位基因的存在或不存在进行分层。我们将继续进行盲态随机治疗， 24个月，直到我们了解正在进行的早期AD患者3期aducanumab项目的结果。如果 3期项目显示出显著的认知和/或临床益处，还显示aducanumab的Aβ PET效应（单独或与下游生物标志物效应联合）与临床获益相关， 我们为期24个月的试验显示了相同的生物标志物效应，这些发现将用于支持aducanumab的 根据这些生物标志物的影响，在未受损的Aβ+患者中“加速批准”;这样做， 推进替代生物标志物终点的潜在用途，以快速测试几乎所有国家的预防治疗。 每个人都有生物标志物或遗传风险。在这一点上，参与者将接受开放标签治疗和Biogen 将按照FDA的指导进行上市后研究，以确认治疗的24个月 根据FDA加速批准的要求，生物标志物与随后的临床获益相关 条文我们雄心勃勃的计划旨在：1）尽早找到一种经批准的预防治疗方法 截至2023年，在国家计划解决AD的目标“到2025年预防AD”之前，以及2）推进使用 替代生物标志物，以快速测试和支持几乎所有人的预防治疗的加速批准 在生物标志物或遗传风险，即使在早期临床前AD阶段，当一些治疗可能具有最大的 效益然而，如果第三阶段计划没有显示出显着的好处， 我们的试验，因为问题仍然是是否有必要在AD临床阶段之前进行干预， 效益我们将通过使用临床前阿尔茨海默综合终点修订版（PACC-R）来修改试验， 主要结局和持续设盲治疗直至末例受试者的48个月访视，澄清是否 治疗的24个月生物标志物效应与随后的认知益处相关，并寻求 到2025年实现我们的目标不管第三阶段的结果如何，拟议中的试验提供了一个前所未有的机会， 尽快发现、批准和支持预防治疗的可用性。它将利用 公私合作伙伴关系，NIH的支持，500万至1000万美元的慈善事业，获得aducanumab和大部分的金融 Biogen的支持，提供数据和样品的公共资源，并具有最大的公共利益。

Project Summary/Abstract There is an urgent need to find and accelerate approval of Alzheimer’s disease (AD) prevention therapies. Aducanumab is an antibody that binds selectively to amyloid-β (Aβ) oligomers and fibrils. In a Phase 1b trial of clinically affected AD patients with Aβ plaques, it dramatically reduced Aβ plaque burden and appeared to slow cognitive decline. Alzheimer’s Prevention Initiative (API) and Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Trials leaders have come together to propose a 24-month, multicenter, double blind, placebo- controlled prevention trial of aducanumab using AD biomarker endpoints as primary outcomes, along with cognitive/clinical, safety, and tolerability outcomes, in cognitively unimpaired 65-80 year-old Aβ PET+ persons stratified for presence or absence of the APOE4 allele. We will continue the blinded, randomized treatment past 24 months until we learn the results of the ongoing Phase 3 aducanumab program in persons with early AD. If the Phase 3 program shows significant cognitive and/or clinical benefit and also shows that aducanumab’s Aβ PET effects, alone or in combination with downstream biomarker effects, are associated with clinical benefit, and our 24-month trial showed identical biomarker effects, the findings would be used to support aducanumab’s “accelerated approval” in unimpaired Aβ+ persons based on those biomarker effects; in doing so, it would advance the potential use of surrogate biomarker endpoints to rapidly test prevention therapies in almost everyone at biomarker or genetic risk. At that point, participants would receive open-label treatment and Biogen would conduct post-marketing studies following FDA’s guidance to confirm that the treatment’s 24-month biomarker are associated with subsequent clinical benefit, as required under the FDA’s accelerated approval provisions. Our deliberately ambitious proposal is intended to 1) find an approved prevention therapy as early as 2023, ahead of the National Plan to Address AD’s goal to “prevent AD by 2025,” and 2) advance the use of surrogate biomarkers to rapidly test and support accelerated approval of prevention therapies in almost everyone at biomarker or genetic risk, even in earlier preclinical AD stages when some treatments may have their greatest benefit. However, if the Phase 3 program does not show significant benefit, the stakes would be even higher for our trial, since the question would remain whether intervention before clinical stages of AD is necessary to attain benefit. We would modify the trial by using the Preclinical Alzheimer Composite Endpoint-Revised (PACC-R) as the primary outcome and continuing blinded treatment until the last participant’s 48-month visit, clarify whether the treatment’s 24 month biomarker effects are associated with subsequent cognitive benefit, and seek to achieve our goals by 2025. Regardless of the Phase 3 results, the proposed trial offers an unprecedented chance to find, approve and support the availability of prevention therapies as soon as possible. It would capitalize on a public-private partnership, NIH support, $5-10M in philanthropy, access to aducanumab and most of the financial support from Biogen, provide a public resource of data and samples, and have the maximum public benefit.