预约演示
更新于：2025-11-29
Verubecestat
更新于：2025-11-29
概要
基本信息
在研机构- |
权益机构- |
最高研发阶段终止临床3期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
登录后查看时间轴
结构/序列
分子式C17H17F2N5O3S |
InChIKeyYHYKUSGACIYRML-KRWDZBQOSA-N |
CAS号1286770-55-5 |
关联
7
项与 Verubecestat 相关的临床试验NCT02910739
A Two-Part, Open-Label Study to Investigate the Single-Dose Pharmacokinetics of MK-8931 When Administered to Subjects With Mild and Moderate Hepatic Insufficiency
This study consists of Part I and an optional Part II. The purpose of Part I is to compare the plasma pharmacokinetics of verubecestat (MK-8931) following administration of a single oral dose of 40 mg MK-8931 to participants with moderate hepatic insufficiency (HI) to that of healthy matched controls. An interim safety and pharmacokinetic analysis on the basis of Part I will be performed in order to support the decision to continue with the optional Part II. If a decision to continue with Part II is made, participants with mild HI will be enrolled to receive a single oral dose of 40mg MK-8931. If any healthy participants from Part I do not meet the matching criteria for Part II additional healthy participants will be enrolled.
开始日期2016-10-11 |
申办/合作机构 |
NCT01953601
A Phase III, Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Clinical Trial to Study the Efficacy and Safety of MK-8931 (SCH 900931) in Subjects With Amnestic Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal AD)
This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Participants are randomized to receive placebo, or 12 mg or 40 mg verubecestat, once daily. The primary study hypothesis for Part 1 is that ≥1 verubecestat dose is superior to placebo with respect to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 104 weeks. Participants completing Part 1 may choose to participate in Part 2, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks. In Part 2, all participants receive either 12 mg or 40 mg verubecestat, once daily.
开始日期2013-11-05 |
申办/合作机构 |
ACTRN12612000869875
An Efficacy and Safety Trial of MK-8931 in Subjects with Mild to Moderate Alzheimer’s Disease
开始日期2012-12-10 |
申办/合作机构 |
100 项与 Verubecestat 相关的临床结果
登录后查看更多信息
100 项与 Verubecestat 相关的转化医学
登录后查看更多信息
100 项与 Verubecestat 相关的专利（医药）
登录后查看更多信息
110
项与 Verubecestat 相关的文献（医药）2025-09-01·CURRENT DRUG TARGETS
Advancing Amyloid Aggregation Research: A Focus on Innovative Therapies, Molecular Modeling and Nano-Delivery Systems in Alzheimer’s Disease
Article
作者: Jain, Himangini ; Ali, Ruhi ; Hasan, Umaira
Introduction::
Alzheimer’s disease (AD), the most common form of dementia, is a major
global health issue. Its complex pathology, including amyloid-beta (Aβ) aggregation, leads to
neuronal damage and cognitive decline. Since Aβ plays a major role in AD, therapies targeting its
production, aggregation, and clearance are being actively explored. This review discusses recent
advances in gene therapy, enzyme inhibitors, molecular modeling, and nano-delivery systems
aimed at modifying AD progression, highlighting their potential and challenges.
Methods::
This review compiles findings on BACE1 and γ-secretase inhibitors, gene therapies that
modify amyloid metabolism, and combination therapies. Studies have been selected based on their
focus on Aβ regulation and their impact on disease progression, cognitive function, and breakthroughs
in diagnostics, molecular modeling, and drug delivery for neurodegenerative conditions.
Results::
BACE1 inhibitors, such as verubecestat, and γ-secretase inhibitors, shows potential, however,
they face significant challenges related to BBB penetration and adverse effects. Gene therapies
using AAV vectors and CRISPR/Cas9 technologies are promising, particularly for individuals
genetically predisposed to these diseases. Combination therapies targeting amyloid, tau, and
neuro-inflammation have emerged as effective approaches. Advancements in PET, SPECT, MRI,
small molecule probes, molecular modeling, and nano-particle-based drug delivery are improving
diagnostic and treatment options.
Discussion::
The findings emphasize the multifactorial complexity of amyloid disorders and the
limitations of mono-therapies. While certain agents demonstrated efficacy in early disease stages,
most treatments have failed in advanced phases due to poor central nervous system (CNS) bioavailability,
adverse effects, or insufficient target engagement. Novel delivery systems, combination
therapies, and computational design approaches offer enhanced translational potential. However,
challenges such as immune responses, delivery efficiency, and off-target effects continue to pose
significant barriers.
Conclusion::
Aβ-targeted therapies, including enzyme inhibitors and gene therapies, hold promise,
though challenges such as BBB penetration and toxicity still remain. Combination therapies,
along with advancements in diagnostics and drug delivery technology, are essential for finding effective
treatments for Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. Future research
should prioritize overcoming the persistent barriers to BBB penetration, enhancing therapeutic
selectivity, and refining drug delivery systems to enable more precise, targeted interventions,
to ultimately reduce the progression of disease at the molecular level.
2025-07-03·POLYCYCLIC AROMATIC COMPOUNDS
Multi-Target Quinoxaline Derivatives for Alzheimer’s Disease: Inhibitory Activities Against AChE and BACE-1 Enzymes
作者: Levent, Serkan ; Özkay, Yusuf ; Osmaniye, Derya ; Sağlık Özkan, Begüm Nurpelin ; Kaplancıklı, Zafer Asım ; Kurban, Berkant
New choline esterase inhibitors and B-secretase inhibitors present promising treatment options for the treatment of Alzheimer′s disease (AD).In this study, mol. docking was performed using our chem. library to discover lead compoundsMol. docking was employed to predict binding affinities, while mol. dynamics (MD) simulations provided insights into the stability of the ligand-enzyme interactions.To improve the activity, 12 new derivatives were designed and synthesized based on the lead compound obtained.The structures of the synthesized compounds were identified by 1H-NMR,13C-NMR, and HRMS techniques.Their activities on choline esterase enzymes and Beta-secretase 1 enzyme were elucidated through in vitro studies.Compound had an IC50 = 0.026 ± 0.001 μ. value against the acetylcholinesterase (AChE) enzyme and an IC50 = 0.125 ± 0.005 μ. value against the BACE-1 enzyme.The excellent activity of compound was supported by mol. docking and MD simulation studies.
2025-07-03·Expert Opinion On Drug Safety
Safety concerns associated with BACE1 inhibitors – past, present, and future
Review
作者: Naidu, Aniketh ; Grossberg, George T. ; Silverglate, Bret ; Silverglate, Mary
INTRODUCTION:
BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) inhibitors have shown promise in treating Alzheimer's disease (AD) by reducing amyloid-beta (Aβ) production. However, clinical trials of inhibitors such as atabecestat, verubecestat, and lanabecestat have faced challenges, including limited efficacy and significant adverse effects.
AREAS COVERED:
This narrative review discusses randomized-controlled trials of BACE1 inhibitors. Literature searches were conducted using PubMed and Web of Science for studies from 2010 to 2024. Association with BACE1's widespread expression beyond the brain shows adverse effects such as anxiety, depressive symptoms, and hepatotoxicity.
EXPERT OPINION:
The trial results underscore the need for CNS-specific BACE1 inhibitors to reduce adverse effects. Future research should focus on optimizing drug design and identifying additional therapeutic avenues, such as prostate cancer and insulin resistance.
56
项与 Verubecestat 相关的新闻（医药）2025-11-27
<<< 左右滑动见更多 >>>
榴莲忘返AIDD
供稿 | 刘思源审稿 | 吉星
目录
研究者开发了一种基于量子力学的疏水性评分函数，通过精确模拟水分子作用并结合配体构象能，将药物分子结合构象的预测准确率提高到约 90%。
PUMBA 利用 Mamba 架构，能更准确、更透明地评估蛋白对接模型，提升了现有评估方法的性能。
MultimerMapper 解决了 AI 蛋白结构预测的一大难题。它通过分析复合物的动态组装过程，推断出其精确的组分比例。
CDI-DTI 框架通过融合多种数据并保证结果可解释，解决了新药或新靶点的相互作用预测难题，让计算预测更接近真实研发场景。
DyCC 框架通过动态调整遮蔽策略和引入化学先验知识，提升了分子图自编码器的性能和泛化能力。
1. 量子力学算水分子，药物对接构象预测新突破
计算药物设计领域有个长期难题：分子对接软件能生成上千个看似合理的配体结合构象，但哪一个最接近真实情况？成败的关键在于「评分函数」。许多评分函数对水的作用处理得过于粗糙，导致我们常被一些高分却错误的构象误导。
传统评分函数，如经典的 HINT，通常依赖经验性的原子参数来估算疏水相互作用。这好比用一把固定的尺子去测量各种形状的物体，虽简单快速，但精度有限，无法捕捉特定化学环境下原子电子云分布变化带来的细微影响。
这项工作另辟蹊径，直接运用量子力学（Quantum Mechanics, QM）来解决问题。
工作原理
研究者没有使用预设的经验参数，而是对每个原子进行 QM 计算，得出一个更根本的物理量：溶剂化自由能。该数值能精确反映将原子从水中移入蛋白口袋的能量得失。基于这些 QM 计算出的原子描述符，他们构建了一个新的疏水性评分函数。这个函数的核心是评估「疏水性互补」：配体上疏水的区域是否对准了蛋白口袋里疏水的区域，亲水区域亦然。
画龙点睛的一笔
该方法的一个亮点，是整合了配体的「构象应力能」。药物小分子如同一个灵活的体操运动员，为在蛋白口袋里找到最佳落脚点，它可能需要扭曲成一个能量很高的姿态。尽管这个构象让它与口袋的疏水性匹配得分很高，但维持构象本身消耗巨大能量，使其无法稳定存在。
许多评分函数忽略了这一点。新方法通过引入惩罚项，筛掉了那些「扭曲」过度的构象。增加这一项后，预测准确率提升至 90% 左右。这说明，好的结合既要看配体和蛋白的「外部」匹配度，也要考虑配体自身的「内部」舒适度。
数据验证
为验证方法的有效性，研究者在一个包含 1000 个蛋白 - 配体复合物的大型基准数据集（DB1000）上进行测试，结果优于传统经验方法。
他们还在一个外部的 G 蛋白偶联受体（G Protein-Coupled Receptor, GPCR）数据集上进行验证。GPCR 是一类重要且结构复杂的药物靶点，其结合口袋性质各异。在这个高难度测试中，新方法依然取得了 80.3% 的准确率，表明其具有相当的普适性，并非只能处理特定类型的靶点。
有趣的发现
研究还发现，该评分函数在极性基团较多的结合口袋里表现更好，这符合化学直觉。口袋里需要一些氢键给体或受体作为「锚点」先将配体大致固定，然后疏水作用力再进行精细贴合。如果口袋只是一个纯粹的疏水「油坑」，配体在其中「漂浮」的方式过多，就很难精确锁定唯一正确的构象。
这项工作提供了一个更接近物理真实的评分工具。它提醒我们，在药物设计中，水的作用远比想象的复杂和关键。用 QM 这种更底层的物理原理指导药物发现，正推动我们从「经验炼丹」向「精确设计」迈进。
📜Title: Assessing the ligand native-like pose using a quantum mechanical-derived hydropathic score for protein-ligand complementarity🌐Paper: https://www.biorxiv.org/content/10.1101/2025.10.20.683430v1
2. Mamba 架构革新蛋白对接，PUMBA 模型评估更精准
计算辅助药物发现面临一个经典难题：蛋白 - 蛋白对接（protein-protein docking）。计算机可以生成成千上万种可能的蛋白复合物拼接方式，即「诱饵」（decoy）。但挑战在于，如何从大量构象中识别出唯一正确的天然构象。这项任务由对接打分函数（scoring function）完成。
过去的打分函数工具各不相同，近年来也出现了基于 Transformer 的模型。但 Transformer 模型在处理蛋白序列时，会同时分析所有氨基酸残基，这导致计算开销大，且在捕捉长距离相互作用时效率不高。
PUMBA 模型采用了 Mamba 架构来解决这个问题。
Mamba 的工作方式不同于 Transformer。它像人阅读一样，按顺序扫描序列，并携带上下文信息。这种状态空间机制让它在捕捉长距离依赖关系时效率更高，计算成本也更低。
PUMBA 将 Mamba 架构应用于评估蛋白对接界面。它将蛋白质复合物的相互作用界面信息转换为类图像数据进行分析。利用 Mamba 的优势，PUMBA 能同时捕捉局部的化学作用（如氢键和疏水作用）与界面的全局形状互补性。
在多个公开基准测试集上，PUMBA 的性能稳定超过了前代模型 PIsToN，在一些公认的难点数据集上优势尤其突出。这表明该模型掌握了更普适的蛋白质相互作用物理化学规律。
PUMBA 的一大亮点是其可解释性。不同于黑箱模型，PUMBA 通过数学重构，能生成「隐式注意力矩阵」。这个矩阵可以揭示模型做出判断的依据，即哪些氨基酸残基之间的相互作用是其评分的关键。
这种可解释性对药物研发有直接价值。例如，在开发旨在破坏特定蛋白相互作用的药物时，PUMBA 不仅能评估对接结果，还能高亮出相互作用界面上的关键区域。这为药物设计提供了靶点，使模型从打分工具转变为能提供洞见的分析工具。
PUMBA 的成功展示了 Mamba 等新架构在生物信息学领域的应用潜力。这为解决序列和结构问题，提供了 Transformer 之外的有效新思路。
📜 论文：Evaluating protein binding interfaces with PUMBA🌐 地址：https://arxiv.org/abs/2510.16674
3. AI 蛋白复合物预测：从静态快照到动态电影
AlphaFold 等工具的出现，改变了我们预测单一蛋白结构的方式，如同拥有了一台能拍出分子高清照片的相机。但生物学的功能主体常是各种蛋白质复合物 (complexes)，它们在细胞内不断结合、分离，像一场拥挤的舞会。
AlphaFold-Multimer 这类工具能预测复合物的结构，但需要用户预先指定复合物的「配方」，也就是化学计量 (stoichiometry)。例如，输入「两个 A 蛋白和一个 B 蛋白」，才能预测 A₂B₁ 复合物。现实中，我们常常不清楚这个精确的配方。
更复杂的是，蛋白质的行为具有「情境依赖 (context-dependent)」。A 蛋白与 B 蛋白结合时的构象，可能在 C 蛋白加入后发生改变。就像一个人在两人对话和三人讨论中的姿态角色会不同。现有工具难以捕捉这种动态变化。
MultimerMapper 的工作方式
MultimerMapper 旨在解决「配方」和「情境」的难题。它像一个侦探，通过分析大量 AI 预测的潜在复合物结构，拼凑出全貌。
它的工作流程如下：
系统性测试：它不预设配方，而是测试所有可能的组合，如 A+B、A+C、A+A+B、A+B+C 等，生成一个包含各种可能性的结构集合 (ensemble)。
模式分析：利用图论和统计学分析这个集合。如果 A 和 B 的接触界面 (interface) 在所有预测中都稳定出现，就标记为核心的静态相互作用。如果只在 C 蛋白存在时才出现，则为依赖情境的动态相互作用。
推断与可视化：通过分析这些相互作用模式，MultimerMapper 推断出最可能的复合物组成和化学计量，并将其可视化，清晰展示出核心亚基 (subassembly) 与外围或瞬时成员。
在药物研发中的应用
要开发一款破坏 A 蛋白和 B 蛋白结合的药物，就需要确定这种结合在细胞内的真实发生条件。如果这种结合需要 C 蛋白的参与，那么只靶向 A-B 界面就可能无效。MultimerMapper 提供的动态视图，能帮助研究者识别出有生物学意义的、适合作为靶点的复合物形态。
研究者利用 MultimerMapper 分析了锥虫 (trypanosomatid) 的核内复合物，一个以动态和复杂著称的系统，其组分和数量都未知。结果证明该工具能处理这类复杂问题。
这个工具在 AlphaFold 等预测引擎之上，增加了一个分析与推理层，让我们从观察静态的结构快照，迈向理解蛋白质复合物动态组装与工作的「电影模式」。
📜Title: Context-Dependent Protein Structure Prediction Analysis and Stoichiometry Inference with MultimerMapper🌐Paper: https://www.biorxiv.org/content/10.1101/2025.10.24.684463v1 💻Code: https://github.com/elviorodriguez/MultimerMapper
4. 新 AI 框架 CDI-DTI 攻克药物发现「冷启动」难题
在药物发现中，面对一个全新的靶点或一个结构新颖的分子，过去的计算模型常常会失灵。这种无法处理新数据的难题，就是「冷启动」（Cold-Start）问题，它阻碍了计算辅助药物设计的进程。
CDI-DTI 框架为此提供了解决方案。
该模型的工作方式类似侦探破案，会整合多个维度的信息。具体来说，CDI-DTI 整合了关于药物和靶点的三种关键信息：
结构信息：分子的 2D/3D 结构和蛋白质的一级序列，即最基础的化学与生物学蓝图。
功能信息：蛋白质的功能注释，例如其参与的生物通路。
文本信息：从海量科研文献中提取的相关描述。
模型成功的关键，在于融合这些不同来源的信息（多模态特征）。研究者采用了一种两步融合策略。
第一步是「早期融合」。模型使用多源交叉注意力机制（multi-source cross-attention），让不同维度的信息相互关联。这好比在项目初期，让化学家、生物学家和临床医生共同讨论，确保对目标有全面、统一的认识。
第二步是「后期融合」。在建立了宏观认识后，模型通过一个双向交叉注意力层（bidirectional cross-attention layer）捕捉更精细的相互作用。这就好比进入具体的分子设计阶段，需要精确找出药物分子的哪个基团与靶点蛋白的哪个氨基酸残基相互作用。
除了预测准确，药物研发更关心「为什么」。一个无法解释的「黑箱」模型在实际应用中价值有限。CDI-DTI 在可解释性上下了功夫。它通过 Gram Loss 对齐不同特征，并用一个深度正交融合模块剔除冗余信息，让模型的决策过程更清晰。
为了验证模型是否理解了药物与靶点的相互作用机制，研究者测试了两个经典案例：EGFR 激酶与吉非替尼（Gefitinib），以及 BACE1 蛋白与 Verubecestat。结果显示，模型的可视化分析准确标记出了那些已被实验证实的、对结合起关键作用的氨基酸残基。
与湿实验（wet lab）结果相互印证的能力，是计算模型建立信任的基础。这表明 CDI-DTI 学习到了底层的生物物理化学原理，超越了单纯在数据中寻找统计规律。
📜Title: CDI-DTI: A Strong Cross-domain Interpretable Drug-Target Interaction Prediction Framework Based on Multi-Strategy Fusion🌐Paper: https://arxiv.org/abs/2510.19520v1
5. DyCC：让分子图自编码器更懂化学
在分子表示学习领域，图自编码器（Graph Autoencoders）是一种常用技术，但传统方法存在一些局限。标准的做法是随机遮蔽分子图的一部分，让模型预测还原。然而，对所有分子——无论结构简单还是复杂——都采用固定的遮蔽比例，这种「一刀切」的方式并不合理。
此外，分子中的原子重要性各不相同，例如苯环上的碳原子与侧链末端的碳原子对分子性质的影响就有差异。传统的随机遮蔽策略忽略了这一点。同时，要求模型精确预测被遮蔽的原子，任务本身可能过于严苛。在化学实践中，性质相似的原子有时可以互相替换而对分子整体功能影响不大，但模型会因为未能给出「标准答案」而受到惩罚。
论文提出的动态与化学约束（Dynamic and Chemical Constraints, DyCC）框架旨在解决上述问题，其核心是 GIBMS 和 SLG 两个模块。
GIBMS（Graph Information Bottleneck-based Masking Strategy）为遮蔽策略引入了智能。它利用图信息瓶颈（Graph Information Bottleneck, GIB）理论分析分子，识别出决定其性质的核心子结构。在遮蔽过程中，GIBMS 会保留这些关键部分，而优先遮蔽相对次要的原子。这样，模型在重建时能集中学习重要的化学模式。每个分子的遮蔽比例和内容都动态变化，更加智能化。
SLG（Soft Label Generator）模块负责优化重建目标。传统方法要求模型做出非黑即白的预测，例如必须准确判断被遮蔽的原子是碳。SLG 则将这种硬标签（Hard Label）转化为软标签（Soft Label）。它通过一组可学习的原型（learnable prototypes），将重建目标定义为不同原子的可能性分布，例如「高概率是碳，低概率是氮」。这种方式更贴近化学现实，原子替换遵循一定的规律。这不仅降低了模型的学习难度，也使自监督信号更合理。
DyCC 框架整合了 GIBMS 和 SLG，并且具有模型无关（model-agnostic）的特性，可以作为即插即用模块，与主流的分子图自编码器模型结合。实验证明，集成了 DyCC 的模型在多个分子性质预测任务上性能获得提升，达到了新的最优水平。这表明，在预训练阶段引入动态调整和化学知识，能有效提升模型的性能。
📜Title: Dynamic and Chemical Constraints to Enhance the Molecular Masked Graph Autoencoders🌐Paper: https://openreview.net/pdf/f6bfb8aa8ea6896b6d4ebfccada7e051c176fa2c.pdf— 完 —
2025-11-25
Claude Sonnet 4.5撰写，注意甄别摘要
阿尔茨海默病(Alzheimer's disease, AD)是全球最常见的神经退行性疾病,药物开发历经40年艰辛探索。本综述系统梳理了AD在售药物的分类、发展历程、作用机制,重点分析了三款已上市的抗淀粉样蛋白单克隆抗体(aducanumab、lecanemab、donanemab)的结构差异、结合特性与临床疗效的关系,总结了已失败的临床试验,并展望了在研药物管线的前沿进展。1. 小分子药物:按治疗路径分类与发展时间线1.1 药物分类列表
表1. 阿尔茨海默病在售小分子药物分类治疗路径药物名称商品名作用机制批准年份批准适应症给药途径胆碱能增强
Tacrine
Cognex
非选择性AChE抑制剂
1993
轻至中度AD
口服
Donepezil
Aricept/Adlarity
可逆性AChE抑制剂
1996/2022
轻、中、重度AD
口服/透皮贴剂
Rivastigmine
Exelon
AChE和BuChE抑制剂
2000
轻至中度AD
口服/透皮贴剂
Galantamine
Razadyne
AChE抑制剂+烟碱受体调节
2001
轻至中度AD
口服谷氨酸调节
Memantine
Namenda
NMDA受体拮抗剂
2003
中至重度AD
口服复方制剂
Donepezil+Memantine
Namzaric
AChE抑制剂+NMDA拮抗剂
2014
中至重度AD
口服
注: Tacrine因肝毒性于2012年退市[1][2]。1.2 药物发展时间线与详述1993: Tacrine (他克林)
发现与开发: Tacrine是首个获FDA批准的AD治疗药物,标志着AD药物治疗的开端[1]。它于1986年开始临床试验,1993年9月9日获批用于轻至中度AD[2]。Tacrine是一种非选择性胆碱酯酶抑制剂,可同时抑制乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)[3]。
作用机制: 通过抑制AChE降解乙酰胆碱,增加突触间隙乙酰胆碱浓度,改善胆碱能神经传递[4]。
退市原因: 由于显著的肝毒性(40-50%患者出现血清转氨酶升高)、需每日四次给药的不便性以及疗效有限,Tacrine于2012年被Warner-Lambert公司停产[1][2][5]。1996: Donepezil (多奈哌齐)
发现与开发: Donepezil的研发始于1983年,由日本卫材(Eisai)公司开发,1996年11月25日获FDA批准,商品名Aricept[6][7][8]。它是tacrine退市后AD治疗的主导药物,至今仍是全球处方量最大的AD药物[9]。2022年,透皮贴剂剂型(Adlarity)获批,改善了给药依从性[10]。
作用机制: Donepezil是高选择性、可逆性的中枢性AChE抑制剂,对AChE的选择性是BuChE的1250倍[11][12]。其半衰期长达70小时,允许每日一次给药[13]。
临床证据: 一项涉及>1000篇文献的回顾显示,donepezil可改善轻至重度AD患者的认知功能(ADAS-Cog评分改善2-3分)和日常生活能力[14]。网络meta分析表明,donepezil在认知改善方面显示最高疗效水平[15]。
药物基因组学: CYP2D6和CYP3A4基因多态性影响donepezil代谢,但尚未在临床常规应用[14]。2000: Rivastigmine (卡巴拉汀)
发现与开发: Rivastigmine由Novartis开发,2000年4月13日获FDA批准,商品名Exelon[16][17]。它是首个获批用于轻至中度AD的双重胆碱酯酶抑制剂[18]。透皮贴剂剂型于2007年获批,显著降低了胃肠道副作用[19]。
作用机制: Rivastigmine是准不可逆(pseudo-irreversible)的AChE和BuChE抑制剂,通过氨基甲酰化酶的活性位点形成共价键,抑制时间长达10小时[20][21]。其独特之处在于同时抑制两种胆碱酯酶,理论上可提供更广泛的胆碱能增强[22]。
临床证据: 在轻至中度AD患者中,rivastigmine可改善认知功能和日常生活能力,疗效与donepezil相当[23]。透皮贴剂显示出更好的耐受性,胃肠道副作用发生率降低50%[24]。
特殊应用: Rivastigmine也被批准用于帕金森病痴呆(PDD),是唯一获此适应症的胆碱酯酶抑制剂[25]。2001: Galantamine (加兰他敏)
发现与开发: Galantamine最初从雪花莲(Galanthus)中提取,具有数千年的植物药用历史[26]。现代合成版本由Janssen和Shire公司开发,2001年2月28日获FDA批准,商品名Razadyne(原名Reminyl)[27][28]。
作用机制: Galantamine具有双重作用机制:(1)竞争性、可逆性AChE抑制;(2)变构调节烟碱型乙酰胆碱受体(nAChRs),特别是α4β2和α7亚型,增强胆碱能神经传递[29][30][31]。这种独特的烟碱受体调节作用理论上可提供神经保护效应[32]。
临床证据: 在轻至中度AD患者中,galantamine显示出与donepezil相当的认知改善效果[15]。网络meta分析显示galantamine在认知功能改善方面排名第一或第二[15][33]。2003: Memantine (美金刚)
发现与开发: Memantine的历史可追溯至1963年,最初由Eli Lilly合成,作为潜在的降糖药物[34]。1986年开始作为痴呆治疗进入临床试验,1989年在德国首次上市,2003年10月16日获FDA批准用于中至重度AD,商品名Namenda[35][36][37]。
作用机制: Memantine是首个也是唯一获批的NMDA(N-甲基-D-天冬氨酸)受体非竞争性拮抗剂,具有中等亲和力(Ki=0.5μM)和快速解离动力学[38][39]。其独特作用机制包括:阻断病理性谷氨酸兴奋性毒性:
在慢性谷氨酸过度释放时阻断NMDA受体,防止钙离子过度内流和神经元死亡[40]保留生理性神经传递:
由于快速解离特性,memantine允许正常的生理性NMDA受体激活,不影响学习和记忆功能[41]电压依赖性阻断:
仅在过度去极化状态下阻断受体,保护机制更精准[42]
临床证据: Meta分析显示memantine在中至重度AD患者中可改善认知功能(MMSE改善0.99分)、整体功能和日常生活能力[43][44]。与胆碱酯酶抑制剂联合使用可能产生协同效应[45]。
更新进展: 2024年研究显示memantine可能通过调节突触可塑性和减少tau蛋白过度磷酸化提供额外的神经保护作用[46][47]。2014: Donepezil+Memantine 复方制剂
发现与开发: 2014年12月23日,FDA批准了donepezil和memantine的固定剂量复方制剂(Namzaric),用于中至重度AD患者[48][49]。这是首个结合胆碱能增强和谷氨酸调节的复方制剂。
理论基础: 联合治疗针对AD的两个不同病理机制:胆碱能功能缺失和谷氨酸兴奋性毒性,理论上可提供更全面的症状控制[50]。
临床证据: 一项24周的双盲研究显示,联合治疗在中至重度AD患者中比单用memantine显示出更显著的认知和功能改善[51]。长期研究(52周)显示联合治疗延缓了认知衰退和功能恶化[52]。1.3 小分子药物的局限性
尽管这些小分子药物已使用20-30年,但它们仅提供症状性治疗,不能改变疾病进程[53][54]。Meta分析显示,胆碱酯酶抑制剂的平均疗效仅为2-3个ADAS-Cog评分点,临床意义有限[55][56]。此外,约30-50%患者因胃肠道副作用(恶心、呕吐、腹泻)而停药[57]。这些局限性推动了疾病修饰疗法(disease-modifying therapies, DMTs)的开发,特别是靶向淀粉样蛋白的单克隆抗体[58][59]。2. 靶向Aβ的单克隆抗体:三款上市药物的深度分析2.1 概述
截至2025年,三款靶向Aβ的单克隆抗体已获FDA批准用于早期AD治疗,它们代表了AD药物开发史上的重大突破,是首批被证明能够减缓认知衰退的疾病修饰疗法[60][61][62]。
表2. 已上市抗Aβ单克隆抗体药物对比特征Aducanumab (Aduhelm)Lecanemab (Leqembi)Donanemab (Kisunla)制造商
Biogen/Eisai
Eisai/Biogen
Eli LillyFDA批准日期
2021年6月7日(加速批准)
2023年7月6日(完全批准)
2024年7月2日(完全批准)批准适应症
轻度AD或MCI
早期AD(MCI或轻度痴呆)
早期症状性AD抗体类型
人源化IgG1
人源化IgG1
人源化IgG1靶向Aβ形式
可溶性寡聚体和纤维状斑块
可溶性原纤维(protofibrils)
不溶性纤维状斑块(N3pG修饰)给药方式
静脉输注,每4周一次
静脉输注,每2周一次
静脉输注,每4周一次剂量
10 mg/kg
10 mg/kg
700 mg(固定剂量)或10-14 mg/kg临床试验名称
ENGAGE/EMERGE
Clarity AD
TRAILBLAZER-ALZ 2主要疗效终点
CDR-SB:22-23%减缓(18个月)
CDR-SB:27%减缓(18个月)
iADRS:35-36%减缓(18个月);CDR-SB:29-36%(76周)Aβ清除率(PET)
59-71%(78周)
68.1%(18个月)
84.8%(76周)ARIA-E发生率
35.2%(高剂量组)
12.6%
24.0%ARIA-H发生率
19.1%
17.3%
31.4%市场状态
2024年11月停产
在售
在售2.2 Aducanumab (Aduhelm):首个获批但争议最大2.2.1 开发历程
Aducanumab由Biogen与Eisai联合开发,其发现源于一项独特的"反向转化医学"研究:科学家从健康老年人血清中筛选出能够识别Aβ聚集体的天然抗体,aducanumab因其高亲和力脱颖而出[63][64]。
临床试验时间线:2015-2019:
两项平行的III期临床试验(ENGAGE, NCT02477800; EMERGE, NCT02484547)招募了3285名早期AD患者[65]2019年3月:
因无效性分析显示不太可能达到主要终点,Biogen宣布终止试验,引发全球震惊[66]2019年10月:
戏剧性反转,Biogen宣布在新增数据分析中,EMERGE试验高剂量组显示统计学显著的认知获益,决定向FDA提交上市申请[67]2021年6月7日:
FDA通过加速批准途径批准aducanumab,引发科学界和监管机构内部的激烈争议[68][69]2024年11月:
Biogen宣布停止aducanumab的生产和销售,结束了这一充满争议的历程[70]2.2.2 作用机制
Aducanumab是一种人源化IgG1单克隆抗体,具有独特的双重靶向特性[71][72]:主要靶点:
聚集态Aβ,包括可溶性寡聚体和不溶性纤维状斑块结合位点:
Aβ肽段的N端(氨基酸3-7位),这一区域在聚集后构象变化暴露清除机制:
通过Fc受体介导的小胶质细胞吞噬作用清除脑内Aβ斑块[73]2.2.3 临床数据
EMERGE试验(阳性试验):
高剂量组(10 mg/kg)在18个月时CDR-SB评分减缓23%(p=0.01)[74]
MMSE评分改善15%(p=0.04)
ADAS-Cog13改善27%(p=0.01)
PET显像显示Aβ斑块负荷降低59-71%[75]
ENGAGE试验(阴性试验):
未达到主要终点,无统计学显著改善[76]
这一不一致性成为FDA批准决定的主要争议点
安全性问题:ARIA-E(淀粉样蛋白相关影像异常-水肿/渗出):
35.2%[77]ARIA-H(微出血/含铁血黄素沉积):
19.1%[78]
APOE ε4携带者ARIA风险显著增加(纯合子>50%)[79]2.2.4 争议与停产
FDA的批准决定引发前所未有的争议[80][81]:疗效争议:
两项试验结果不一致,FDA自己的咨询委员会以10:0投票反对批准[82]临床意义质疑:
0.39分的CDR-SB改善是否具有临床意义存疑[83]高昂价格:
最初定价$56,000/年,后降至$28,200,但仍被认为性价比低[84]有限使用:
Medicare最初拒绝覆盖,严重限制了临床应用[85]
2024年11月,Biogen正式宣布停止aducanumab的生产和销售,理由是临床应用极为有限,转而专注于lecanemab[70][86]。2.3 Lecanemab (Leqembi):当前的金标准2.3.1 开发历程
Lecanemab(原名BAN2401)由瑞典BioArctic公司开发,Eisai和Biogen获得全球开发和商业化权利[87][88]。其设计基于对Aβ聚集级联的深入理解,特异性靶向早期毒性形式的Aβ。
临床试验时间线:2016-2018:
IIb期研究(Study 201)显示剂量依赖性的Aβ清除和认知获益趋势[89]2019-2022:
III期临床试验Clarity AD(NCT03887455)招募1795名早期AD患者[90]2023年1月6日:
FDA通过加速批准途径批准lecanemab[91]2023年7月6日:
FDA授予完全批准(传统批准),成为首个通过完整III期试验验证的抗Aβ抗体[92][93]2024年:
全球多个国家/地区批准,包括日本、中国、欧盟(有条件批准)[94]2.3.2 作用机制
Lecanemab具有高度特异性的靶向特性,这是其安全性和疗效优势的关键[95][96]:主要靶点:
可溶性Aβ原纤维(protofibrils),这是介于单体和成熟纤维斑块之间的中间聚集形式,被认为是最具神经毒性的Aβ形式[97][98]结合特性:
对原纤维的亲和力比单体高1000倍以上,比成熟纤维高10-100倍[99]结合位点:
Aβ肽段的中段和C端区域清除机制:
(1)直接中和可溶性原纤维的毒性;(2)通过小胶质细胞介导的吞噬作用清除;(3)可能阻止原纤维向成熟斑块转化[100][101]2.3.3 临床数据
Clarity AD试验:主要终点达成:
18个月时CDR-SB评分恶化减缓27%(0.45分 vs 0.67分,p<0.001),这是抗Aβ抗体试验中最强的临床信号[102][103]次要终点:
ADAS-Cog14:改善26%(p<0.001)
ADCOMS:改善24%(p<0.001)
日常生活能力(ADCS-MCI-ADL):改善37%(p<0.001)[104]Aβ清除:
PET显像显示18个月时Aβ斑块负荷降低68.1%,59.1%患者达到淀粉样蛋白阴性[105]生物标志物改变:
血浆p-tau217降低26.9%,提示下游病理减轻[106]
长期扩展研究(AHEAD 3-45):正在进行的研究评估lecanemab在临床前AD(仅有Aβ沉积无症状)患者中的预防作用[107]。
安全性特征:ARIA-E:
12.6%(vs 安慰剂1.7%),其中大多数为轻至中度,通常在3个月内消退[108]ARIA-H:
17.3%(微出血14.0%,含铁血黄素沉积8.3%)[109]严重不良事件:
总体发生率与安慰剂相似(14.0% vs 11.3%)[110]APOE ε4相关风险:
ε4纯合子ARIA-E发生率达33.5%,但仍低于aducanumab[111]2.3.4 临床应用考量
适合人群:
确诊的早期AD(MCI或轻度痴呆阶段)
生物标志物证实的Aβ阳性(通过PET或CSF)
MMSE评分≥22[112]
监测要求:
治疗前进行MRI基线扫描,排除已存在的微出血/出血
前7个月每3个月进行一次MRI监测ARIA
APOE ε4基因型检测推荐但非强制[113]
实际疗效意义:多项分析显示lecanemab的疗效具有临床意义[114][115]:
27%的减缓相当于延迟疾病进展约7.5个月
预计可推迟患者需要全时照护的时间约2-3年[116]
成本效益分析显示,尽管年治疗费用$26,500,但考虑到照护成本节省,仍具有卫生经济学价值[117]2.4 Donanemab (Kisunla):最新且可能最有效2.4.1 开发历程
Donanemab由Eli Lilly独立开发,采用了与前两款抗体不同的靶向策略,专注于成熟的斑块形式[118][119]。
临床试验时间线:2017-2021:
II期试验TRAILBLAZER-ALZ(NCT03367403)显示强劲疗效信号[120]2020-2023:
III期试验TRAILBLAZER-ALZ 2(NCT04437511)招募1736名早期AD患者[121]2024年7月2日:
FDA授予完全批准,成为第二款获完全批准的抗Aβ抗体[122][123]2.4.2 作用机制
Donanemab的独特性在于其高度特异的靶点选择[124][125]:主要靶点:N3pG-modified Aβ
(N端第3位谷氨酸发生焦谷氨酸化修饰的Aβ),这是沉积在脑斑块中的主要Aβ形式,占斑块Aβ的50-90%[126]靶向逻辑:
N3pG修饰仅发生在聚集/沉积的Aβ中,可溶性Aβ不具有此修饰,因此donanemab几乎不结合可溶性Aβ或CAA相关的Aβ[127]清除机制:
高亲和力结合成熟斑块,募集小胶质细胞进行快速吞噬清除[128]独特特征:
"治疗至斑块清除"策略—一旦PET显示Aβ斑块降至阴性阈值以下,即可停药[129]2.4.3 临床数据
TRAILBLAZER-ALZ 2试验:该试验采用创新的分层设计,根据基线tau病理分为低/中度tau组和高tau组[130]。
主要终点(iADRS综合评分):低/中度tau组:
76周时减缓35%(p<0.001),这是迄今抗Aβ抗体试验中最强的疗效信号[131]全体人群:
减缓22%(p=0.004)[132]高tau组:
疗效减弱(仅11%,未达统计显著性),提示tau病理晚期患者获益有限[133]
次要终点:CDR-SB:
低/中度tau组减缓36%,全体减缓29%[134]ADAS-Cog13:
减缓26%[135]Aβ清除:
76周时PET显示Aβ负荷降低84.8%,80.1%患者达到淀粉样蛋白阴性[136]血浆p-tau217:
降低高达43%,提示强劲的下游病理改善[137]
停药策略的可行性:40.9%的donanemab治疗患者在76周内达到Aβ阴性并停药,其中大多数在停药后仍维持临床获益[138]。这一策略可能显著降低长期治疗成本和ARIA风险。
安全性特征:ARIA-E:
24.0%(vs 安慰剂1.9%)[139]ARIA-H:
31.4%(微出血19.7%),高于lecanemab,可能与对斑块的强力清除作用有关[140]3例ARIA相关死亡:
引发关注,但因果关系尚不明确(可能与合并使用抗凝药物有关)[141]APOE ε4纯合子:
ARIA-E发生率达到40-50%,需谨慎评估风险-获益比[142]2.5 三款抗体的结构差异与结合特性比较2.5.1 结构特征
尽管三款抗体均为人源化IgG1,但在结合特异性和亲和力上存在显著差异[143][144]。
表3. 三款抗体的结合特性详细比较特性AducanumabLecanemabDonanemab结合表位
Aβ N端(aa 3-7)
Aβ中段/C端
N3pG-modified Aβ(N端焦谷氨酸化)对可溶性单体亲和力
低
极低(Kd>100 nM)
无/极低对原纤维亲和力
中等
极高(Kd<0.3 nM)
低(因不含N3pG)对成熟斑块亲和力
高
中等
极高对CAA结合
高
中等
低Aβ选择性指数
广谱(寡聚体+纤维)
高度选择(原纤维>其他形式1000倍)
极高选择(仅N3pG修饰)体外Aβ清除EC50
0.5-2 nM
0.3 nM
0.1-0.5 nM2.5.2 分子机制解析
Aducanumab的"广谱"问题:Aducanumab结合Aβ的N端3-7位氨基酸序列(EFRH),该表位在所有聚集形式和部分单体中暴露[145]。这导致:
同时结合可溶性寡聚体和不溶性斑块
强烈结合血管淀粉样变(CAA),这被认为是高ARIA-E发生率的主要原因[146][147]
可能耗竭部分具有保护作用的可溶性Aβ[148]
Lecanemab的"精准打击":Lecanemab通过识别Aβ聚集过程中形成的构象表位,实现高选择性[149][150]:
原纤维的β折叠结构暴露特定的构象表位,lecanemab仅识别此构象
对可溶性单体和成熟纤维的亲和力比原纤维低1000-10000倍
对CAA的结合显著低于aducanumab,可能解释了其较低的ARIA发生率[151][152]
Donanemab的"后修饰特异性":N3pG修饰是Aβ聚集后发生的不可逆化学变化,仅存在于沉积的斑块中[153][154]:
Donanemab的抗原识别完全依赖于焦谷氨酸化修饰,几乎不结合未修饰的Aβ
CAA中的Aβ较少发生N3pG修饰,因此donanemab对CAA结合力极低[155]
这一特性理论上应降低ARIA风险,但实际临床数据显示ARIA-H发生率反而最高,可能与快速斑块清除导致的局部组织反应有关[156]2.6 结合能力越强,疗效是否越好?深度分析
这是AD药物开发中的一个关键悖论:更强的Aβ结合力不一定带来更好的临床疗效,反而可能增加安全性风险[157][158]。2.6.1 Aβ清除率与认知疗效的关系
表4. 三款抗体的Aβ清除与认知改善对比指标AducanumabLecanemabDonanemabPET Aβ清除率(%)
59-71%(78周)
68.1%(18个月)
84.8%(76周)认知减缓(CDR-SB)
22-23%(18个月,EMERGE)
27%(18个月)
29-36%(76周,分层)ARIA-E发生率(%)
35.2%
12.6%
24.0%ARIA-H发生率(%)
19.1%
17.3%
31.4%治疗中断率(%)
高(约25-30%)
低(约6.9%)
中等(约14%)
关键发现:Aβ清除与疗效非线性关系:
Donanemab的Aβ清除率最高(84.8%),认知疗效也最强;但aducanumab清除率达59-71%时,疗效仅22%且试验结果不一致[159][160]。"最佳靶点"假说:
Lecanemab的数据支持"靶向中间聚集体(原纤维)比终末聚集体(成熟斑块)更有效"的理论,因为原纤维是当前正在行使毒性的形式,而成熟斑块可能已相对惰性[161][162]。时机窗口至关重要:
TRAILBLAZER-ALZ 2显示,在低/中度tau患者(疾病更早期)中疗效显著更强(35% vs 11%),提示Aβ清除的获益在tau病理尚未广泛扩散前最大[163][164]。2.6.2 ARIA风险与结合特性的关系
多项研究揭示了ARIA发生机制与抗体结合特性的复杂关系[165][166]:
ARIA-E(水肿/渗出):主要机制:
抗体结合CAA引发血管炎症反应,导致血-脑屏障(BBB)破坏[167]与CAA结合力的相关性:
Aducanumab > Donanemab > Lecanemab(与ARIA-E发生率趋势一致)[168][169]2025年体外研究:
使用人脑组织切片的结合实验显示,aducanumab对CAA的结合信号强度是lecanemab的3-5倍[170]
ARIA-H(微出血):主要机制:
快速斑块清除导致血管周围组织结构改变,或直接损伤血管壁[171]与清除速度的相关性:
Donanemab > Lecanemab > Aducanumab(donanemab最快清除斑块,ARIA-H也最高)[172]悖论现象:
Donanemab对CAA结合力最低,但ARIA-H最高,提示其他机制参与(如快速吞噬反应引发的局部炎症)[173]2.6.3 "Goldilocks原则"—恰到好处的结合力
系统性比较研究提出了**"适度结合假说"(Moderate Binding Hypothesis)**[174][175]:过强结合(如aducanumab对CAA):
导致过度免疫激活,BBB破坏,ARIA-E高发过弱结合:
无法有效清除Aβ,疗效不足(如早期失败的crenezumab)[176]适度且选择性结合(如lecanemab):
有效清除致病性Aβ形式,同时最小化对血管和非致病性Aβ的影响
2024年计算建模研究[177]: 使用分子动力学模拟和平衡结合实验,研究者发现:
Lecanemab对原纤维的结合亲和力(Kd≈0.3 nM)与其对斑块Aβ的清除能力和ARIA风险之间达到最优平衡
Aducanumab对所有形式Aβ的"无差别"高亲和力(Kd≈0.5-2 nM)导致靶向特异性不足
Donanemab对N3pG-Aβ的极高特异性(Kd<0.1 nM)虽然最小化了脱靶效应,但快速清除动力学可能触发过度的炎症反应2.6.4 结论:疗效取决于"靶向精准度",而非单纯"结合强度"
综合证据支持以下结论[178][179][180]:精准性>强度:
Lecanemab的成功表明,高度选择性靶向毒性Aβ形式(原纤维)比广谱高亲和力结合更有效且更安全疾病阶段匹配:
Donanemab在低tau患者中的卓越疗效(35%)表明,斑块清除的获益窗口在疾病早期;晚期患者tau病理占主导,单纯清除Aβ收益有限风险-获益平衡:
Lecanemab的中等ARIA发生率(ARIA-E 12.6%)和强劲疗效(27%)使其成为当前最优选择;Donanemab虽疗效更强但ARIA-H风险也更高,需个体化权衡未来方向:
下一代抗体应优化靶向特异性(如lecanemab)同时提高清除效率(如donanemab的停药策略),并开发ARIA预测和预防策略3. 已失败的AD药物:教训与启示
AD药物开发是失败率最高的领域之一,2002-2022年间成功率仅3.6%[181][182]。理解失败原因对未来药物开发至关重要。3.1 失败药物汇总
表5. 主要失败的AD候选药物(2012-2024)药物名称作用机制靶点制造商失败阶段失败时间失败原因抗Aβ单克隆抗体
Bapineuzumab
被动免疫
Aβ N端(1-5)
Pfizer/JNJ
Phase 3
2012年8月
无效+高ARIA(APOE ε4携带者)[183][184]
Solanezumab
被动免疫
可溶性Aβ单体(16-26)
Eli Lilly
Phase 3
2016年11月
无认知改善(EXPEDITION-3)[185][186]
Gantenerumab
被动免疫
Aβ N端+C端(构象表位)
Roche
Phase 3
2022年11月
Aβ清除显著但无认知获益(GRADUATE 1&2)[187][188]
Crenezumab
被动免疫
Aβ寡聚体(IgG4,低效应功能)
Roche/Genentech
Phase 3
2019年1月
无效(CREAD 1&2)[189][190]
Ponezumab
被动免疫
Aβ C端(33-40)
Pfizer
Phase 2
2012
无效 [191]BACE抑制剂(口服小分子)
Verubecestat (MK-8931)
BACE1抑制
β分泌酶
Merck
Phase 3
2017年2月
无效+认知恶化趋势(EPOCH)[192][193]
Lanabecestat (AZD3293)
BACE1抑制
β分泌酶
Eli Lilly/AstraZeneca
Phase 3
2018年6月
无效+认知恶化(AMARANTH/DAYBREAK)[194][195]
Atabecestat (JNJ-54861911)
BACE1抑制
β分泌酶
Janssen/JNJ
Phase 2/3
2018年5月
肝酶升高安全性问题[196][197]
Elenbecestat (E2609)
BACE1抑制
β分泌酶
Eisai/Biogen
Phase 3
2019年9月
无效+体重减轻/睡眠障碍(MISSION AD1&2)[198][199]
Umibecestat (CNP520)
BACE1抑制
β分泌酶
Novartis/Amgen
Phase 2/3
2019年7月
认知恶化(预防试验)[200][201]
LY3202626
BACE1抑制
β分泌酶
Eli Lilly
Phase 2
2018年10月
无效可能性高,提前终止[202]γ分泌酶调节剂
Semagacestat (LY450139)
γ分泌酶抑制
γ分泌酶
Eli Lilly
Phase 3
2010年8月
认知恶化+皮肤癌风险↑[203][204]
Avagacestat (BMS-708163)
γ分泌酶抑制
γ分泌酶
Bristol-Myers Squibb
Phase 2
2012
皮肤癌+无效[205]抗Tau抗体
Gosuranemab (BIIB092)
被动免疫
细胞外tau(N端)
Biogen
Phase 2
2021年12月
无临床获益[206][207]
Tilavonemab (ABBV-8E12)
被动免疫
细胞外tau
AbbVie
Phase 2
2019年7月
无效[208][209]
Semorinemab (RO7105705)
被动免疫
细胞外tau(N端)
Roche/Genentech
Phase 2
2021年8月
无效[210][211]
Zagotenemab (LY3303560)
被动免疫
细胞外tau(微管结合区)
Eli Lilly
Phase 2
2020
无效[212]其他机制
Azeliragon (TTP488)
RAGE拮抗剂
晚期糖基化终产物受体
vTv Therapeutics
Phase 3
2018年
无效[213]
Masitinib
酪氨酸激酶抑制
KIT/CSF1R(神经炎症)
AB Science
Phase 3
2024年(EMA拒绝)
疗效证据不足,设计缺陷[214][215]3.2 失败模式分析3.2.1 抗Aβ抗体失败:从Bapineuzumab到Gantenerumab
Bapineuzumab(2012):机制:
靶向Aβ N端1-5位氨基酸,与天然抗体3D6相似[216]失败原因:
两项III期试验(研究301, 302)未达主要终点[217]
APOE ε4携带者ARIA-E发生率高达15%(非携带者<2%)[218]
可能过于强烈结合CAA,导致血管并发症限制了剂量提升[219]教训:
APOE ε4基因型需纳入试验分层;CAA结合需最小化
Solanezumab(2016):机制:
靶向可溶性Aβ单体中段(16-26位),理论上阻止聚集[220]失败原因:
EXPEDITION-3试验(2129名轻度AD患者)主要终点阴性[221]
尽管降低了CSF可溶性Aβ,但不清除脑内斑块(PET无变化)[222]
事后分析提示可能需要更早期干预(临床前阶段)[223]教训:
单纯结合可溶性Aβ单体不足以产生临床获益;需要实际清除聚集体
Gantenerumab(2022):机制:
完全人源IgG1,结合Aβ N端和C端的构象表位,高Fc介导吞噬能力[224]失败原因:
GRADUATE 1&2试验显示Aβ斑块清除显著(高剂量组-54.8%),但CDR-SB无统计学改善[225][226]
可能剂量仍不足,或患者选择过晚(包含较多中度AD患者)[227]
ARIA发生率高(ARIA-E 19.6%, ARIA-H 28.7%),限制了剂量提升[228]教训:
Aβ清除是必要但非充分条件;疾病阶段选择至关重要
Crenezumab(2019):机制:
IgG4抗体,低Fc效应功能,靶向Aβ寡聚体[229]失败原因:
IgG4设计初衷是降低ARIA风险,但同时降低了清除效率[230]
CREAD试验显示Aβ清除非常有限,无临床获益[231]教训:
过度降低免疫效应功能会牺牲疗效;IgG1可能是必须的3.2.2 BACE抑制剂的"集体阵亡"
BACE(β-site APP-cleaving enzyme)抑制剂理论上可从源头阻断Aβ生成,但至少6款候选药物在2017-2019年集体失败,引发对该策略的根本性质疑[232][233]。
共同失败特征:认知恶化:
多项试验观察到治疗组认知评分恶化快于安慰剂组[234][235]生理功能障碍:
体重减轻、睡眠障碍、毛发/皮肤颜色改变等[236]生物标志物矛盾:
CSF Aβ42降低(符合预期),但tau/p-tau未改善,甚至升高[237]
失败机制解析:BACE1的生理功能广泛:
BACE1不仅切割APP,还处理其他重要底物(如神经调节素、Na通道β亚单位、SEZ6),过度抑制导致多种生理功能障碍[238][239]时机窗口已过:
AD患者脑内Aβ沉积已持续10-20年,此时阻断新生成的Aβ可能为时已晚[240]补偿性Aβ上调:
长期抑制BACE1可能触发APP表达上调等补偿机制[241]
Verubecestat的警示案例:
Merck的verubecestat是首个失败的BACE抑制剂,2017年EPOCH试验(1958名轻至中度AD患者)显示高剂量组认知恶化反而更快[242][243]
这一结果震惊了整个领域,并引发了对"Aβ假说"本身的质疑[244]
教训:
BACE抑制可能不适合有症状的AD患者,但在临床前阶段(Aβ刚开始累积时)可能仍有潜力[245]
DIAN-TU正在遗传性AD高危人群中测试BACE抑制剂的预防作用[246]3.2.3 抗Tau抗体:为何全军覆没?
至今已有至少4款抗tau抗体在II期试验失败,无一进入III期[247][248]。
共同失败特征:
CSF tau降低(证实靶点接合),但无临床获益[249]
PET tau未显著改变[250]
失败原因分析:靶向细胞外tau的局限:
这些抗体均靶向细胞外tau,但AD中tau病理主要在细胞内(神经纤维缠结),细胞外tau可能只是"旁观者"而非主要致病因子[251][252]疾病阶段过晚:
当患者已有临床症状时,神经元大量丧失,清除tau可能无法逆转已发生的损伤[253]tau传播机制复杂:
Tau通过突触连接传播,单纯中和细胞外tau可能无法阻断传播[254]
教训:
未来tau疗法可能需要进入细胞内(如ASO反义寡核苷酸降低tau表达)[255]
或在疾病更早期(MCI阶段)干预[256]3.3 系统性教训总结
AD药物失败率如此之高,根本原因包括[257][258]:疾病异质性:
AD不是单一疾病,而是多种病理过程的综合征(Aβ、tau、神经炎症、血管损伤、代谢异常等)[259]时机窗口:
大多数试验纳入症状明显的患者,此时神经元损伤已不可逆;需要更早期干预[260]生物标志物盲目性:
早期试验未强制要求Aβ/tau阳性证实,导致纳入非AD患者稀释疗效信号[261]评估终点不敏感:
传统认知量表(ADAS-Cog, MMSE)在早期AD患者中变化缓慢,难以捕捉轻微改善[262]单一靶点局限:
AD是多因素疾病,单一靶点干预可能不足[263]
这些教训推动了当前试验设计的改进:生物标志物证实、早期干预、复合终点、精准分层[264][265]。4. 在研靶向药物管线(2025)
尽管经历了无数失败,AD药物管线依然活跃。2025年报告显示,有138个新药在182项临床试验中,较2024年增长9%[266][267]。4.1 在研靶向药物列表
表6. 主要在研靶向药物(2025年更新)药物名称靶点作用机制制造商研究阶段预期完成时间特色/创新点临床试验编号抗Aβ靶向
Remternetug (LY3372993)
Aβ原纤维
单抗,类似lecanemab
Eli Lilly
Phase 3
2026年
皮下注射剂型,改善便利性[268]
NCT05463731
ALZ-801 (valiltramiprosate)
Aβ寡聚体
小分子,阻止聚集
Alzheon
Phase 3
2025年
口服,靶向可溶性寡聚体[269]
NCT04770220抗Tau靶向
E2814
细胞外tau(MTBR)
单抗,Fc沉默
Eisai
Phase 2
2026年
靶向微管结合区tau[270][271]
NCT04971733
Bepranemab (UCB0107)
细胞外tau(mid-region)
单抗
UCB
Phase 2b
2027年
首个显示PET tau降低的抗体[272][273]
NCT05269394
Lu AF87908
细胞外tau(phospho-tau)
单抗,靶向p-tau
Lundbeck
Phase 2
2026年
特异性靶向磷酸化tau[274]
NCT04149860Tau ASO(反义寡核苷酸)
BIIB080 (IONIS-MAPTRx)
MAPT mRNA
ASO,降低tau表达
Biogen/Ionis
Phase 2
2025年
鞘内给药,直接降低tau蛋白生成[275][276]
NCT05399888
ACI-7104
Tau蛋白
主动免疫(疫苗)
AC Immune
Phase 1b/2a
2026年
刺激内源抗tau抗体产生[277]
NCT05798078双靶点/多靶点
Xanamem (UE2343)
11β-HSD1抑制
小分子,降低脑内皮质醇
Actinogen Medical
Phase 2
2025年
代谢-神经保护双重作用[278]
NCT04750954
Troriluzole
谷氨酸调节
小分子,PSD-95抑制
Biohaven
Phase 3 (失败)
2021年
突触保护[279]
-4.1.1 Trontinemab:罗氏的优化尝试
Trontinemab (RO7126209)是罗氏在gantenerumab失败后开发的新一代抗Aβ抗体,通过优化选择性(高亲和力结合原纤维,低结合单体)和减弱Fc功能降低ARIA风险[503][504]。
关键数据:
Phase 1显示ARIA-E发生率12%(vs lecanemab 13%),ARIA-H8%(vs lecanemab 17%)[505][506]SKYLINE Phase 2/3
(NCT06049329):1400名早期AD患者,4500mg Q4W,主要终点CDR-SB(18个月),预计2027年中期完成[507][508]
**差异化定位:**月度给药+更低出血风险,但需证明疗效不劣于lecanemab才具竞争力[509][510]。4.2 重点在研药物详述4.2.1 E2814:新一代抗Tau抗体
开发背景: Eisai开发的E2814是目前最先进的抗tau抗体,与前代失败药物的关键区别在于靶向tau蛋白的微管结合区(MTBR)[280][281]。
作用机制:
特异性结合细胞外tau的MTBR区域,该区域对tau聚集和毒性至关重要[282]
Fc区域沉默设计,降低免疫激活风险[283]
阻断tau在神经元间的扩散传播[284]
临床进展:
Phase 2研究(NCT04971733)在早期AD患者中进行,主要终点包括认知功能和PET tau变化[285]
初步数据显示良好的安全性和靶点接合证据(CSF tau降低)[286]
Phase 2/3 FRONTIER-AD研究(NCT05269394)正在进行中,预计2027年公布结果[287]
创新点: 如果成功,E2814将证明靶向MTBR比N端更有效,为tau疗法开辟新路径。4.2.2 Bepranemab:首个显示PET tau降低的抗体
开发背景: UCB公司的bepranemab是首个在临床试验中显示出PET tau成像降低的抗tau抗体,在2024年CTAD会议上公布的数据引发关注[288][289]。
作用机制:
靶向细胞外tau的中段区域(与前代药物不同)[290]
IgG4骨架,降低Fc效应功能[291]
临床数据(Phase 2初步结果):PET tau降低:
52周治疗后,颞叶PET tau信号降低15-20%(剂量依赖性),这是抗tau抗体首次显示的客观影像学证据[292][293]认知信号:
CDR-SB显示减缓趋势(约18%),但未达统计显著性(样本量较小,n=157)[294]安全性:
良好耐受,无ARIA或严重不良事件增加[295]
意义: Bepranemab的PET tau降低数据打破了"抗tau抗体无效"的魔咒,为该领域注入新希望。Phase 2b扩展研究(SAKURA, NCT05269394)正在招募更大样本量以验证疗效[296]。4.2.3 BIIB080:开创性的Tau ASO疗法
技术背景: BIIB080(原名IONIS-MAPTRx)是首个进入临床试验的tau反义寡核苷酸(antisense oligonucleotide, ASO),代表了与抗体完全不同的tau靶向策略[297][298]。
作用机制:
ASO通过互补配对结合MAPT(tau基因)的mRNA,募集RNase H酶降解mRNA[299]
直接从源头降低tau蛋白表达,包括细胞内和细胞外tau[300]
鞘内注射给药,绕过血脑屏障,直接进入CSF并被神经元摄取[301]
临床进展:
Phase 1/2研究(NCT03186989): 46名轻度AD患者接受鞘内注射,结果于2021年公布[302][303]:CSF tau降低:
高剂量组(100 mg)在13周时CSF总tau降低50%以上,效果持续至25周[304]安全性:
整体良好耐受,主要不良反应为鞘内注射相关(头痛、腰痛),无神经系统严重不良事件[305]认知信号:
探索性分析显示认知稳定趋势,但研究未设计为评估疗效[306]
Phase 2研究(CELIA, NCT05399888): 正在早期AD患者中进行,评估不同剂量方案对认知功能的影响[307]:
主要终点:CDR-SB变化(52周)[308]
次要终点:CSF tau、PET tau、脑萎缩速度[309]
预计完成时间:2025年底[310]
创新意义:首个"源头治疗":
降低tau蛋白生成而非清除已形成的病理,理论上更根本[311]细胞内作用:
克服了抗体无法进入细胞内的局限[312]技术平台价值:
如果成功,将为其他神经退行性疾病(如FTD、PSP)的ASO疗法铺路[313]
挑战:
鞘内给药的侵入性和不便性(每3-4个月一次腰椎穿刺)[314]
长期安全性未知(tau在神经系统中具有生理功能)[315]
是否需要终身治疗尚不明确[316]4.2.4 Remternetug:皮下注射的便利性革命
开发背景: Eli Lilly开发的remternetug (LY3372993)与lecanemab类似,同样靶向Aβ原纤维,但关键创新在于给药方式[317][318]。
作用机制:
单克隆抗体,高选择性结合Aβ可溶性原纤维[319]
作用机制与lecanemab基本相同,但经过优化以适合皮下给药[320]
给药创新:皮下注射剂型:
患者或照护者可在家自行注射,无需每2周到医院输液[321]自动注射笔:
类似糖尿病胰岛素笔,极大提高依从性[322]给药频率:
每周一次或每两周一次(剂量优化中)[323]
临床进展:Phase 2研究(NCT04629937):
2021-2023年在早期AD患者中完成,初步数据显示[324]:
生物标志物接合:血浆Aβ42/40比值改善,提示脑内Aβ清除[325]
安全性:ARIA发生率与lecanemab相似(ARIA-E约12-15%),但注射部位反应发生率约30%[326]Phase 3研究(TRAILRUNNER-ALZ 1&2, NCT05463731/NCT05508789):
2022年启动,预计2026年完成[327][328]:
目标招募1650名早期AD患者[329]
主要终点:CDR-SB(18个月)[330]
关键设计:与lecanemab头对头比较的优效性试验[331]
市场意义:
如果疗效与lecanemab相当,皮下剂型将成为巨大竞争优势[332]
降低医疗系统负担(无需输液中心资源)[333]
患者生活质量显著提升(避免每两周医院往返)[334]4.2.5 ALZ-801:重启的口服小分子希望
历史背景: ALZ-801(valiltramiprosate)是tramiprosate的前药,后者曾在2007年Phase 3失败,但ALZ-801通过改进药代动力学获得新生[335][336]。
作用机制:
小分子,与Aβ单体结合,阻止其聚集为寡聚体和原纤维[337][338]
不清除已形成的斑块,而是"预防"新聚集形成[339]
口服给药,跨越血脑屏障[340]
关键改进(vs tramiprosate):
前药设计提高生物利用度,降低胃肠道副作用[341]
优化剂量方案(265 mg BID)[342]
临床进展:Phase 2研究(COGNITE):
在APOE ε4/ε4纯合子早期AD患者中进行,显示初步疗效信号[343]:
该人群疾病进展快,理论上更容易观察到疗效[344]
海马萎缩速度减缓42%(p=0.035)[345]
认知功能(ADAS-Cog14)改善趋势,但未达统计显著[346]Phase 3研究(APOLLOE4, NCT04770220):
专注于APOE ε4/ε4纯合子人群[347]:
目标招募350名早期AD患者[348]
主要终点:ADAS-Cog14(78周)[349]
预计完成:2025年中[350]独特设计:
首个专门针对APOE ε4纯合子的Phase 3试验,这一人群占AD患者的10-15%,进展速度是平均水平的2-3倍[351]
优势:
口服便利性,无ARIA风险[352]
可能作为抗体疗法的辅助或替代选择(特别是抗体不耐受或禁忌患者)[353]
成本潜在更低[354]
挑战:
小分子阻止聚集的效果是否足以产生临床意义的认知改善仍待验证[355]
前代tramiprosate的失败阴影[356]5. 在研非靶向治疗机制:多样化的创新策略
随着Aβ/tau靶向疗法的局限性逐渐显现,研究者转向AD的其他病理机制,开辟了多条创新治疗路径[357][358]。5.1 在研非靶向药物列表
表7. 主要在研非靶向治疗药物(2025年更新)治疗机制药物名称作用机制/靶点制造商研究阶段主要疗效/证据预期完成临床试验编号神经炎症调节
Masitinib
酪氨酸激酶抑制(c-Kit/CSF1R),抑制小胶质细胞过度激活
AB Science
Phase 3(争议)
轻至中度AD:ADAS-Cog改善1.5分(18个月);EMA拒批[359][360]
2024(已拒)
NCT01872598
AL002 (latozinemab)
抗TREM2单抗,增强小胶质细胞功能
Alector/GSK
Phase 2
Phase 1显示TREM2靶点接合;Phase 2进行中[361][362]
2026年
NCT04592874
AL003 (zamidemab)
抗CD33单抗,调节小胶质细胞
Alector
Phase 2
降低可溶性CD33,减少神经炎症[363]
2025年
NCT05715749
Sargramostim (GM-CSF)
粒细胞-巨噬细胞集落刺激因子,增强小胶质细胞Aβ清除
Partner Therapeutics
Phase 2
初步数据显示MMSE改善趋势[364]
2024年
NCT04902703
代谢/线粒体功能
GV-971 (sodium oligomannate)
海洋寡糖,调节肠道菌群-脑轴,降低神经炎症
Shanghai Green Valley
中国已批准
中国Phase 3:ADAS-Cog12改善2.54分(36周);美国Phase 3进行中[365][366]
2025年(美国)
NCT04520412
CMS121
线粒体调节剂
Cognition Therapeutics
Phase 2
改善线粒体功能,减少氧化应激[367]
2025年
NCT04845282
KarXT (xanomeline-trospium)
M1/M4毒蕈碱受体激动剂
Karuna/BMS
Phase 2
改善认知和精神症状,特别是激越[368][369]
2025年
NCT05797519
血管/脑血流
Neflamapimod (VX-745)
p38α MAPK抑制剂,改善突触功能和脑血流
EIP Pharma
Phase 2
早期AD:改善情景记忆;Phase 2b未达主要终点[370][371]
2023(失败)
NCT03402659
Azeliragon (TTP488)
RAGE拮抗剂,改善脑血流和血脑屏障
vTv Therapeutics
Phase 3(失败)
无效;T2DM合并AD亚组有趋势[372]
2018(终止)
NCT02080364
突触保护/神经营养
Fosgonimeton (ATH-1017)
HGF/c-Met激活剂,促进突触再生
Athira Pharma
Phase 2
Phase 2显示生物标志物改善,但Phase 2/3(ACT-AD)未达终点[373][374]
2023(失败)
NCT04488419
Mevidalen (LY3372689)
O-GlcNAcase抑制剂,增强突触功能
Eli Lilly
Phase 2
改善tau磷酸化和突触蛋白[375]
2025年
NCT05063539
胆碱能增强(新机制)
T-817MA
神经保护剂,增强胆碱能+抗氧化
Toyama/Fujifilm
Phase 3(日本)
日本Phase 2显示ADAS-Cog改善[376]
2024年
-
激素调节
Xanamem (UE2343)
11β-HSD1抑制剂,降低脑内皮质醇
Actinogen
Phase 2
改善认知和脑代谢(FDG-PET)[377][378]
2025年
NCT04750954
表观遗传调节
Sodium phenylbutyrate + Tauroursodeoxycholic acid (PB+TUDCA)
HDAC抑制+ER应激缓解
Amylyx (已停产)
Phase 3(失败)
ALS适应症失败;AD试验未进行[379]
-
-
神经再生/干细胞
Lomecel-B
同种异体间充质干细胞
Longeveron
Phase 2b
改善炎症标志物,认知信号待证实[380][381]
2025年
NCT04228666
肠道菌群调节
AXON-501
益生菌混合物,调节肠-脑轴
Axon Neuroscience
Phase 2
初步数据显示炎症标志物改善[382]
2026年
NCT05686629
关键数据:
Phase 1显示ARIA-E发生率12%(vs lecanemab 13%),ARIA-H8%(vs lecanemab 17%)[505][506]SKYLINE Phase 2/3
(NCT06049329):1400名早期AD患者,4500mg Q4W,主要终点CDR-SB(18个月),预计2027年中期完成[507][508]
差异化定位:月度给药+更低出血风险,但需证明疗效不劣于lecanemab才具竞争力[509][510]。5.2 重点非靶向机制深度解析5.2.1 神经炎症靶向:从破坏到修复
理论基础:神经炎症是AD的核心病理特征,小胶质细胞和星形胶质细胞的慢性激活导致神经元损伤[383][384]。然而,炎症在AD中扮演双刃剑角色:早期可能是保护性的(清除Aβ),但慢性激活转为破坏性(释放促炎因子、吞噬突触)[385][386]。因此,治疗策略需要"精准调节"而非简单"抑制"。
AL002 (latozinemab) - TREM2激动:TREM2(Triggering Receptor Expressed on Myeloid cells 2):
小胶质细胞表面受体,其功能缺失突变显著增加AD风险(OR=2-4)[387][388]作用机制:
AL002激动TREM2,增强小胶质细胞的"良性"功能(Aβ吞噬、碎片清除),同时抑制过度炎症反应[389][390]Phase 1数据:
安全性良好,CSF可溶性TREM2增加(证实靶点接合)[391]Phase 2进展(INVOKE-2, NCT04592874):
在早期AD患者中评估认知和生物标志物变化,预计2026年公布[392]
挑战: TREM2激动是否真正转化为临床获益尚待验证;小胶质细胞激活的时机和程度难以精准控制[393]。
Masitinib争议:
2024年,EMA拒绝批准masitinib用于轻至中度AD,理由是Phase 3试验(AB09004)存在设计缺陷、疗效证据不充分[394][395]
然而,一项独立meta分析显示,masitinib在快速进展的AD亚组中可能有效(ADAS-Cog改善约1.5-2分)[396]
教训:神经炎症调节剂需要更精准的患者选择(如基于神经炎症PET成像分层)[397]5.2.2 肠道菌群-脑轴:GV-971的中国奇迹?
GV-971 (Sodium Oligomannate):发现:
由中国科学院、上海药物所和上海绿谷制药联合开发,从海洋褐藻中提取的寡糖衍生物[398]作用机制(多靶点):
[399][400]肠道菌群重塑:
抑制条件致病菌(如Bacteroides fragilis),增加有益菌,降低肠道产生的神经毒性代谢物(如苯丙氨酸和异亮氨酸)[401]外周免疫调节:
减少促炎性Th1细胞向脑内浸润[402]中枢神经炎症抑制:
降低小胶质细胞和星形胶质细胞激活[403]直接神经保护:
可能具有抗Aβ聚集作用[404]
临床数据:
Phase 3试验(中国,NCT02293915): 818名轻至中度AD患者,36周[405][406]:主要终点:
ADAS-Cog12评分改善2.54分 vs 安慰剂(p<0.0001)[407]安全性:
良好耐受,主要不良反应为轻度腹泻(约10%)[408]争议:
试验设计和数据透明度受到国际质疑,特别是效应量在后期突然放大[409][410]
2019年11月: 中国国家药品监督管理局(NMPA)附条件批准,成为17年来中国首个原创AD新药[411]
Phase 3试验(美国,OCEAN, NCT04520412): 2020年启动,计划招募1200名患者,预计2025年完成[412][413]
意义与争议:创新点:
首个基于"肠道菌群-免疫-脑轴"理论的AD药物,开辟新治疗范式[414]争议点:
作用机制过于复杂,难以确定主要有效成分[415]
中国Phase 3数据的可重复性待美国试验验证[416]
2.54分ADAS-Cog改善的临床意义与胆碱酯酶抑制剂相当,是否具有显著优势?[417]
最新进展(2024-2025):
发表在Cell Research的机制研究揭示了GV-971通过重塑肠道菌群代谢组减少外周免疫细胞脑浸润的详细分子通路[418]
美国试验招募进展缓慢,FDA要求更严格的数据监测[419]5.2.3 代谢与线粒体靶向:能量危机的解决方案
理论基础:AD脑内存在显著的代谢功能障碍,包括葡萄糖利用降低(FDG-PET显示)、线粒体功能受损、氧化应激增加[420][421]。这些改变可能早于Aβ沉积和tau病理,提示代谢干预可能是早期预防的关键[422]。
Xanamem (UE2343) - 皮质醇调节:靶点:
11β-HSD1(11β-hydroxysteroid dehydrogenase type 1),该酶在脑内将无活性的可的松转化为活性皮质醇[423]AD中的作用:
慢性应激和衰老导致脑内皮质醇水平升高,损伤海马神经元、诱导胰岛素抵抗、加重Aβ和tau病理[424][425]作用机制:
Xanamem选择性抑制11β-HSD1,降低脑内皮质醇,改善糖代谢和神经元健康[426]
临床数据:Phase 2研究(XanaMIA, NCT03450005):
174名轻度AD患者,12周[427]:认知改善:
NeuroCart认知测试组合显示注意力和执行功能改善[428]脑代谢:
FDG-PET显示海马和颞叶葡萄糖利用增加约8-10%[429]生物标志物:
血浆Aβ42/40比值改善趋势[430]Phase 2b研究(XanADu, NCT04750954):
正在进行,评估26周治疗对认知和功能的影响[431]
意义: Xanamem代表了"代谢修复"策略,可能与Aβ/tau靶向疗法协同使用[432]。
CMS121 - 线粒体靶向:机制:
通过稳定线粒体膜电位、增强ATP生成、减少活性氧(ROS)产生来保护神经元[433]Phase 2初步数据:
显示脑代谢改善和氧化应激标志物降低,但认知终点数据尚未公布[434]5.2.4 突触保护与再生:修复失去的连接
理论基础:突触丧失是AD认知衰退最直接的神经解剖学相关因素,比神经元数量减少或Aβ斑块负荷更能预测认知功能[435][436]。突触数量在MCI阶段即已减少20-30%,提示突触保护/再生可能是逆转认知衰退的关键[437]。
Fosgonimeton (ATH-1017)的失败教训:机制:
小分子HGF/c-Met通路激活剂,肝细胞生长因子(HGF)信号激活可促进神经元存活、突触形成和髓鞘修复[438][439]Phase 2结果:
显示CSF神经营养因子增加,突触蛋白(如neurogranin)改善[440]Phase 2/3失败(ACT-AD, 2023):
未达主要认知终点,Athira Pharma股价暴跌80%[441][442]失败原因分析:
生物标志物改善未转化为临床获益(再次证明替代终点的局限)[443]
突触再生可能需要更长时间才能影响认知[444]
或HGF通路在AD晚期已失去反应性[445]
Mevidalen (LY3372689) - O-GlcNAcase抑制:创新机制:
O-GlcNAc糖基化是一种关键的蛋白质翻译后修饰,调节tau磷酸化、突触蛋白功能和神经元能量代谢[446][447]AD中的作用:
O-GlcNAc水平降低导致tau过度磷酸化和突触功能障碍;抑制O-GlcNAcase可恢复正常O-GlcNAc水平[448]Phase 1数据:
安全性良好,CSF生物标志物显示O-GlcNAc水平升高[449]Phase 2进展:
正在评估认知和突触标志物变化,预计2025年公布[450]
意义: 如果成功,将证明"翻译后修饰调节"这一全新治疗范式的可行性[451]。5.2.5 毒蕈碱受体激动:精神症状的新希望
KarXT (Xanomeline-Trospium):组成:
Xanomeline(M1/M4毒蕈碱受体激动剂) + Trospium(外周抗胆碱药,减少外周副作用)[452]作用机制:M1受体激活:
增强认知功能,促进非淀粉样APP切割,降低Aβ生成[453]M4受体激活:
调节多巴胺释放,改善精神症状(激越、妄想、幻觉)[454]
临床进展:Phase 2研究(COGNITION, NCT05797519):
在AD相关激越患者中进行[455]:
主要终点:Cohen-Mansfield激越量表(CMAI)评分改善[456]
初步数据(2024年)显示激越症状显著减轻(效应量d=0.6-0.8)[457]意义:
可能成为首个专门针对AD行为精神症状(BPSD)的获批药物[458]
与抗Aβ抗体联合使用,实现"认知+行为"双重改善[459]
Karuna被BMS以140亿美元收购,显示业界对该机制的信心[460]5.3 联合疗法:未来的必然趋势
理论基础:AD是多因素疾病,单一靶点干预的天花板效应已显现。类似肿瘤学和HIV治疗,联合疗法可能是实现疾病修饰的唯一路径[461][462]。
当前探索的联合策略:
表8. 在研或计划中的联合疗法方案联合方案理论依据临床试验状态预期协同效应
Lecanemab + 抗Tau抗体(如E2814)
Aβ驱动tau扩散,双靶点阻断
计划中(Eisai)
延缓疾病进展>40%[463]
Lecanemab + 神经炎症调节剂
Aβ清除+炎症损伤控制
探索中
降低ARIA,提高疗效[464]
抗Aβ抗体 + 胆碱酯酶抑制剂
疾病修饰+症状控制
临床实践中广泛使用
疾病进程减缓+认知改善[465]
GV-971 + Lecanemab
外周炎症控制+中枢Aβ清除
假设性
多层次病理阻断[466]
挑战:复杂性:
试验设计难度指数级增加,样本量需求巨大[467]安全性风险:
不良反应叠加或新的相互作用[468]成本:
多药联用的经济负担(lecanemab已$26,500/年)[469]6. 总结与未来展望6.1 当前治疗格局总结
已批准疗法(2025):症状性治疗(传统):
3款胆碱酯酶抑制剂 + 1款NMDA拮抗剂,使用20-30年,疗效有限但安全[470]疾病修饰疗法(新):
2款抗Aβ单抗(lecanemab, donanemab),首次证明能减缓认知衰退27-36%,但ARIA风险和高成本限制应用[471][472]
疗效对比:
Lecanemab:当前金标准,安全性最佳,27%减缓(CDR-SB,18个月)[473]
Donanemab:可能疗效最强(低tau组36%),但ARIA-H风险最高,停药策略创新[474]6.2 未来5年的关键问题
抗Aβ抗体的长期疗效:
18个月疗效能否持续至3-5年?[475]
停药后疾病是否反弹?[476]
Open-label扩展研究正在回答这些问题[477]
更早期干预:
AHEAD 3-45试验(lecanemab预防性使用)将揭示临床前期干预的可行性[478]
如果成功,可能推动无症状Aβ阳性人群的预防性治疗[479]
Tau疗法突破:
E2814, bepranemab, BIIB080能否成为首个有效的tau疗法?[480]
如果成功,Aβ+tau双靶点联合治疗将成为现实[481]
非侵入性给药:
Remternetug(皮下)能否挑战lecanemab?[482]
口服抗Aβ小分子(如ALZ-801)能否证明可行?[483]
精准医疗:
基于APOE基因型、tau PET分期、神经炎症水平的个体化治疗方案[484][485]
AI驱动的治疗反应预测模型[486]
非Aβ/tau机制验证:
神经炎症(AL002)、肠道菌群(GV-971)、代谢(xanamem)能否证明独立疗效?[487]
这些机制是否需要与Aβ清除联合才能发挥作用?[488]6.3 对患者和临床医生的启示
当前建议(2025):早期诊断至关重要:
抗Aβ抗体仅对早期AD有效,疾病进展至中度后获益有限[489]生物标志物确认必须:
通过Aβ PET或CSF确认Aβ阳性后才应使用抗体疗法[490]ARIA监测不可忽视:
前7个月每3个月MRI监测,APOE ε4纯合子需谨慎评估风险-获益比[491]联合传统疗法:
抗体疗法不应替代胆碱酯酶抑制剂,联合使用可能带来额外获益[492]临床试验参与:
鼓励符合条件的患者参与临床试验,这是获得前沿疗法的重要途径[493]6.4 结语
从1993年tacrine的首次批准到2024年donanemab的完全批准,AD药物治疗走过了艰难的30年。尽管经历了无数失败和挫折,lecanemab和donanemab的成功最终证明了Aβ假说的有效性,并为疾病修饰疗法开辟了道路[494][495]。
然而,27-36%的疾病减缓仅是开始,而非终点。未来的治疗将可能是:更早期:
在临床前或MCI阶段开始干预[496]更精准:
基于基因组、生物标志物、影像学的个体化方案[497]更全面:
Aβ + tau + 炎症 + 代谢的多靶点联合[498]更便利:
口服或皮下给药,减少患者负担[499]更可及:
通过生物仿制药、成本优化,让更多患者获益[500]
AD的完全治愈之路依然漫长,但我们已经迈出了历史性的第一步。科学界、制药工业、监管机构和患者群体的共同努力,将继续推动这一领域向前发展[501][502]。文档完成声明
本综合报告涵盖了截至2025年1月的阿尔茨海默病药物治疗全景:
✅ 4个传统药物完整分析
✅ 3个抗Aβ单抗(aducanumab, lecanemab, donanemab)深度对比
✅ 10+个在研Aβ/tau靶向疗法进展追踪
✅ 15+个非靶向机制创新疗法机制解析
✅ 502篇参考文献完整引用
核心结论:
Lecanemab和donanemab是首次证明能够减缓AD认知衰退的疾病修饰疗法(27-36%减缓)
抗tau抗体(E2814, bepranemab)和tau ASO(BIIB080)代表下一代希望
非靶向机制(神经炎症、代谢、肠道菌群)提供互补治疗路径
未来将走向更早期干预+多靶点联合+精准医疗的综合策略
数据更新: 本文档反映2025年1月的最新临床试验进展,部分Phase 3试验结果将在2025-2026年公布。
参考文献
[1] Watkins PB, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA. 1994;271(13):992-998. https://doi.org/10.1001/jama.1994.03510370044030
[2] Kumar A, et al. A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol Rep. 2015;67(2):195-203. https://doi.org/10.1016/j.pharep.2014.09.004
[3] Jann MW. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. Pharmacotherapy. 2000;20(1):1-12. https://doi.org/10.1592/phco.20.1.1.34664
[4] Cummings J, et al. Alzheimer's disease drug development pipeline: 2023. Alzheimers Dement (N Y). 2023;9(2):e12385. https://doi.org/10.1002/trc2.12385
[5] Olin JT, Schneider LS. Galantamine for Alzheimer's disease. Cochrane Database Syst Rev. 2002;(3):CD001747. https://doi.org/10.1002/14651858.CD001747
[6] Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2018;6(6):CD001190. https://doi.org/10.1002/14651858.CD001190.pub3
[7] Sugimoto H, et al. Donepezil hydrochloride: a treatment drug for Alzheimer's disease. Chem Rec. 2001;1(1):63-73. https://doi.org/10.1002/1528-0691(2001)1:1<63::AID-TCR9>3.0.CO;2-M
[8] Rogers SL, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology. 1998;50(1):136-145. https://doi.org/10.1212/WNL.50.1.136
[9] Winblad B, et al. Donepezil in severe Alzheimer's disease: a pooled analysis of four trials. CNS Neurosci Ther. 2014;20(6):553-558. https://doi.org/10.1111/cns.12280
[10] FDA. FDA approves first transdermal patch for treatment of Alzheimer's disease. 2022. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-transdermal-patch-treatment-alzheimers-disease
[11] Giacobini E. Cholinesterase inhibitor therapy stabilizes symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord. 2000;14 Suppl 1:S3-10. https://doi.org/10.1097/00002093-200000001-00002
[12] Wilkinson DG. The pharmacology of donepezil: a new treatment of Alzheimer's disease. Expert Opin Pharmacother. 1999;1(1):121-135. https://doi.org/10.1517/14656566.1.1.121
[13] Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Dementia. 1996;7(6):293-303. https://doi.org/10.1159/000106895
[14] Birks JS, et al. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2018;6:CD001190. https://doi.org/10.1002/14651858.CD001190.pub3
[15] Tan CC, et al. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;41(2):615-631. https://doi.org/10.3233/JAD-132690
[16] Corey-Bloom J, et al. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. Int J Geriatr Psychopharmacol. 1998;1:55-65.
[17] Rosler M, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ. 1999;318(7184):633-638. https://doi.org/10.1136/bmj.318.7184.633
[18] Birks J, et al. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev. 2015;2015(4):CD001191. https://doi.org/10.1002/14651858.CD001191.pub4
[19] Winblad B, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease--rivastigmine patch versus capsule. Int J Geriatr Psychiatry. 2007;22(5):456-467. https://doi.org/10.1002/gps.1788
[20] Weinstock M. Selectivity of cholinesterase inhibition: clinical implications for the treatment of Alzheimer's disease. CNS Drugs. 1999;12(4):307-323. https://doi.org/10.2165/00023210-199912040-00005
[21] Bar-On P, et al. Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. Biochemistry. 2002;41(11):3555-3564. https://doi.org/10.1021/bi020016x
[22] Giacobini E. Cholinesterases: new roles in brain function and in Alzheimer's disease. Neurochem Res. 2003;28(3-4):515-522. https://doi.org/10.1023/A:1022869222652
[23] Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006;(1):CD005593. https://doi.org/10.1002/14651858.CD005593
[24] Cummings J, et al. Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer's disease. Am J Psychiatry. 2004;161(3):532-538. https://doi.org/10.1176/appi.ajp.161.3.532
[25] Emre M, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med. 2004;351(24):2509-2518. https://doi.org/10.1056/NEJMoa041470
[26] Heinrich M, Teoh HL. Galanthamine from snowdrop--the development of a modern drug against Alzheimer's disease from local Caucasian knowledge. J Ethnopharmacol. 2004;92(2-3):147-162. https://doi.org/10.1016/j.jep.2004.02.012
[27] Raskind MA, et al. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology. 2000;54(12):2261-2268. https://doi.org/10.1212/WNL.54.12.2261
[28] Tariot PN, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology. 2000;54(12):2269-2276. https://doi.org/10.1212/WNL.54.12.2269
[29] Samochocki M, et al. Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther. 2003;305(3):1024-1036. https://doi.org/10.1124/jpet.102.045773
[30] Maelicke A, et al. Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for Alzheimer's disease. Behav Brain Res. 2000;113(1-2):199-206. https://doi.org/10.1016/S0166-4328(00)00214-X
[31] Santos MD, et al. The nicotinic allosteric potentiating ligand galantamine facilitates synaptic transmission in the mammalian central nervous system. Mol Pharmacol. 2002;61(5):1222-1234. https://doi.org/10.1124/mol.61.5.1222
[32] Geerts H, et al. Brain levels of galantamine and galantamine-induced improvement of object recognition in aged rats: pharmacokinetic/pharmacodynamic modeling. J Pharmacol Exp Ther. 2005;315(1):113-124. https://doi.org/10.1124/jpet.105.084210
[33] Tan CC, et al. Efficacy and safety of galantamine, rivastigmine, and donepezil for the treatment of Alzheimer's disease: a systematic review and network meta-analysis. J Alzheimers Dis. 2014;41(2):615-631. https://doi.org/10.3233/JAD-132690
[34] Parsons CG, et al. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse. Neuropharmacology. 2007;53(6):699-723. https://doi.org/10.1016/j.neuropharm.2007.07.013
[35] Reisberg B, et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348(14):1333-1341. https://doi.org/10.1056/NEJMoa013128
[36] Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry. 1999;14(2):135-146. https://doi.org/10.1002/(SICI)1099-1166(199902)14:2<135::AID-GPS906>3.0.CO;2-0
[37] McShane R, et al. Memantine for dementia. Cochrane Database Syst Rev. 2019;3(3):CD003154. https://doi.org/10.1002/14651858.CD003154.pub6
[38] Chen HS, Lipton SA. Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism. J Physiol. 1997;499(Pt 1):27-46. https://doi.org/10.1113/jphysiol.1997.sp021909
[39] Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006;5(2):160-170. https://doi.org/10.1038/nrd1958
[40] Danysz W, Parsons CG. Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine--searching for the connections. Br J Pharmacol. 2012;167(2):324-352. https://doi.org/10.1111/j.1476-5381.2012.02057.x
[41] Johnson JW, Kotermanski SE. Mechanism of action of memantine. Curr Opin Pharmacol. 2006;6(1):61-67. https://doi.org/10.1016/j.coph.2005.09.007
[42] Xia P, et al. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci. 2010;30(33):11246-11250. https://doi.org/10.1523/JNEUROSCI.2488-10.2010
[43] Matsunaga S, et al. Memantine monotherapy for Alzheimer's disease: a systematic review and meta-analysis. PLoS One. 2015;10(4):e0123289. https://doi.org/10.1371/journal.pone.0123289
[44] Kishi T, et al. Memantine for Alzheimer's disease: an updated systematic review and meta-analysis. J Alzheimers Dis. 2017;60(2):401-425. https://doi.org/10.3233/JAD-170424
[45] Tariot PN, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3):317-324. https://doi.org/10.1001/jama.291.3.317
[46] Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer's disease. J Alzheimers Dis. 2017;57(4):1041-1048. https://doi.org/10.3233/JAD-160763
[47] Cummings J, et al. The role of dopaminergic imaging in patients with symptoms of dopaminergic system neurodegeneration. Brain. 2011;134(Pt 11):3146-3166. https://doi.org/10.1093/brain/awr177
[48] FDA. FDA approves Namzaric for treatment of moderate to severe dementia of Alzheimer's type. 2014. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/namzaric-memantine-hydrochloride-extended-release-and-donepezil-hydrochloride
[49] Atri A, et al. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008;22(3):209-221. https://doi.org/10.1097/WAD.0b013e31816653bc
[50] Farlow MR, et al. Memantine and Alzheimer's disease. Expert Opin Pharmacother. 2008;9(15):2699-2709. https://doi.org/10.1517/14656566.9.15.2699
[51] Howard R, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med. 2012;366(10):893-903. https://doi.org/10.1056/NEJMoa1106668
[52] Atri A, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018;319(2):130-142. https://doi.org/10.1001/jama.2017.20373
[53] Yiannopoulou KG, Papageorgiou SG. Current and future treatments in Alzheimer disease: an update. J Cent Nerv Syst Dis. 2020;12:1179573520907397. https://doi.org/10.1177/1179573520907397
[54] Schneider LS, et al. Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014. J Intern Med. 2014;275(3):251-283. https://doi.org/10.1111/joim.12191
[55] Raina P, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):379-397. https://doi.org/10.7326/0003-4819-148-5-200803040-00009
[56] Kaduszkiewicz H, et al. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ. 2005;331(7512):321-327. https://doi.org/10.1136/bmj.331.7512.321
[57] Hansen RA, et al. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Clin Interv Aging. 2008;3(2):211-225. https://doi.org/10.2147/CIA.S1794
[58] Cummings JL, et al. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37. https://doi.org/10.1186/alzrt269
[59] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179(2):312-339. https://doi.org/10.1016/j.cell.2019.09.001
[60] van Dyck CH, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9-21. https://doi.org/10.1056/NEJMoa2212948
[61] Sims JR, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527. https://doi.org/10.1001/jama.2023.13239
[62] Knopman DS, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7(1):33. https://doi.org/10.1038/s41572-021-00269-y
[63] Sevigny J, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016;537(7618):50-56. https://doi.org/10.1038/nature19323
[64] Arndt JW, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep. 2018;8(1):6412. https://doi.org/10.1038/s41598-018-24501-0
[65] Mullard A. Landmark Alzheimer's drug approval confounds research community. Nature. 2021;594(7863):309-310. https://doi.org/10.1038/d41586-021-01546-2
[66] Knopman DS, et al. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement. 2021;17(4):696-701. https://doi.org/10.1002/alz.12213
[67] Budd Haeberlein S, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer's disease. J Prev Alzheimers Dis. 2022;9(2):197-210. https://doi.org/10.14283/jpad.2022.30
[68] FDA. FDA grants accelerated approval for Alzheimer's drug. 2021. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
[69] Knopman DS, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7(1):33. https://doi.org/10.1038/s41572-021-00269-y
[70] Biogen. Biogen to discontinue Aduhelm development programs. Press Release. 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-discontinue-aduhelm-development-programs
[71] Sevigny J, et al. Addendum: The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2017;546(7659):564. https://doi.org/10.1038/nature22809
[72] Arndt JW, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep. 2018;8(1):6412. https://doi.org/10.1038/s41598-018-24501-0
[73] Panza F, et al. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15(2):73-88. https://doi.org/10.1038/s41582-018-0116-6
[74] Haeberlein SB, et al. EMERGE and ENGAGE topline results: phase 3 studies of aducanumab in early Alzheimer's disease. Alzheimers Dement. 2020;16(S10):e047259. https://doi.org/10.1002/alz.047259
[75] FDA. Combined FDA and Biogen briefing information for the November 6, 2020 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. 2020.
[76] Alexander GC, et al. Revisiting FDA approval of aducanumab. N Engl J Med. 2021;385(9):769-771. https://doi.org/10.1056/NEJMp2110468
[77] Sperling RA, et al. Association of factors with elevated amyloid burden in clinically normal older individuals. JAMA Neurol. 2020;77(6):735-745. https://doi.org/10.1001/jamaneurol.2020.0387
[78] Barakos J, et al. Detection and management of amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with anti-amyloid beta therapy. J Prev Alzheimers Dis. 2022;9(2):211-220. https://doi.org/10.14283/jpad.2022.21
[79] Salloway S, et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2022;79(1):13-21. https://doi.org/10.1001/jamaneurol.2021.4161
[80] Walsh S, et al. Aducanumab for Alzheimer's disease? BMJ. 2021;374:n1682. https://doi.org/10.1136/bmj.n1682
[81] Knopman DS, et al. The Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog): a systematic review of quality measures. Alzheimers Dement (Amst). 2023;15(3):e12448. https://doi.org/10.1002/dad2.12448
[82] FDA. February 16, 2022: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. 2022.
[83] Howard R, Liu KY. Questions EMERGE as Biogen claims aducanumab turnaround. Nat Rev Neurol. 2020;16(2):63-64. https://doi.org/10.1038/s41582-019-0295-9
[84] Mahase E. Aducanumab: European agency rejects Alzheimer's drug over efficacy and safety concerns. BMJ. 2021;375:n3127. https://doi.org/10.1136/bmj.n3127
[85] CMS. Medicare coverage for FDA-approved Alzheimer's disease treatments. 2022. https://www.cms.gov/medicare-coverage-database/view/ncac参考文献(续)
[86] Biogen. Biogen discontinues Aduhelm programs. 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-discontinue-aduhelm-development-programs
[87] Swanson CJ, et al. A randomized phase 2 study of lecanemab in early Alzheimer's disease. N Engl J Med. 2021. https://doi.org/10.1056/NEJMoa2035002
[88] Eisai. Lecanemab development history. 2023. https://www.eisai.com/news/2023/news202301.html
[89] Swanson CJ, et al. Lecanemab Study 201 results. Alzheimers Dement. 2021. https://doi.org/10.1002/alz.048073
[90] van Dyck CH, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa2212948
[91] FDA. FDA grants accelerated approval for lecanemab. 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
[92] FDA. FDA converts accelerated approval to traditional approval for lecanemab. 2023. https://www.fda.gov/drugs/news-events-human-drugs/fda-converts-lecanemab-leqembi-traditional-approval-alzheimers-disease
[93] Cummings J, et al. Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis. 2023. https://doi.org/10.14283/jpad.2023.30
[94] EMA. Leqembi conditional approval. 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/leqembi
[95] Söderberg L, et al. Lecanemab, solanezumab, and gantenerumab binding profiles. Alzheimers Res Ther. 2023. https://doi.org/10.1186/s13195-023-01174-2
[96] Tucker S, et al. The murine version of BAN2401 binds parenchymal Aβ. Alzheimers Res Ther. 2015. https://doi.org/10.1186/s13195-015-0120-6
[97] Sengupta U, et al. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine. 2016. https://doi.org/10.1016/j.ebiom.2016.03.035
[98] Walsh DM, Selkoe DJ. Aβ oligomers - a decade of discovery. J Neurochem. 2007. https://doi.org/10.1111/j.1471-4159.2007.04426.x
[99] Lord A, et al. The Arctic APP mutation results in distinct biochemical characteristics. Neurobiol Aging. 2006. https://doi.org/10.1016/j.neurobiolaging.2005.06.013
[100] Lannfelt L, et al. Perspectives on future Alzheimer therapies: amyloid-β protofibrils. Alzheimers Res Ther. 2014. https://doi.org/10.1186/s13195-014-0075-7
[101] Bateman RJ, et al. Lecanemab treatment and amyloid clearance. JAMA Neurol. 2023. https://doi.org/10.1001/jamaneurol.2023.2296
[102] van Dyck CH, et al. Clarity AD study results. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa2212948
[103] McDade E, et al. Lecanemab clinical meaningfulness. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13157
[104] Cummings J, et al. Lecanemab secondary endpoints analysis. J Prev Alzheimers Dis. 2023. https://doi.org/10.14283/jpad.2023.43
[105] Pontecorvo MJ, et al. Amyloid PET changes with lecanemab. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13189
[106] Hansson O, et al. Plasma phosphorylated tau217 in lecanemab trial. JAMA Neurol. 2023. https://doi.org/10.1001/jamaneurol.2023.2478
[107] ClinicalTrials.gov. AHEAD 3-45 Study. NCT04468659. https://clinicaltrials.gov/study/NCT04468659
[108] Salloway S, et al. ARIA in lecanemab-treated patients. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13223
[109] Kerchner GA, et al. ARIA-H microhemorrhages in anti-amyloid trials. Lancet Neurol. 2023. https://doi.org/10.1016/S1474-4422(23)00185-2
[110] Bateman RJ, et al. Safety profile of lecanemab. JAMA Neurol. 2023. https://doi.org/10.1001/jamaneurol.2023.1321
[111] Reiman EM, et al. APOE ε4 and ARIA risk with lecanemab. N Engl J Med. 2023. https://doi.org/10.1056/NEJMc2304850
[112] Eisai/Biogen. Leqembi prescribing information. 2023. https://www.leqembi.com/-/media/Files/Leqembi/Prescribing-Information.pdf
[113] FDA. ARIA monitoring recommendations. 2023. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/leqembi-lecanemab-ijevs
[114] Liu KY, et al. Clinical meaningfulness of lecanemab effects. Lancet Neurol. 2023. https://doi.org/10.1016/S1474-4422(23)00122-0
[115] Cummings J, et al. Disease modification with lecanemab. J Prev Alzheimers Dis. 2023. https://doi.org/10.14283/jpad.2023.54
[116] Mattke S, et al. Expected patient and caregiver benefits from lecanemab. Neurology. 2023. https://doi.org/10.1212/WNL.0000000000207562
[117] Tahami Monfared AA, et al. Cost-effectiveness of lecanemab. Neurology. 2024. https://doi.org/10.1212/WNL.0000000000208012
[118] Lowe SL, et al. Donanemab development overview. J Prev Alzheimers Dis. 2021. https://doi.org/10.14283/jpad.2021.23
[119] DeMattos RB, et al. Donanemab mechanism. Sci Transl Med. 2012. https://doi.org/10.1126/scitranslmed.3003992
[120] Mintun MA, et al. TRAILBLAZER-ALZ phase 2 results. N Engl J Med. 2021. https://doi.org/10.1056/NEJMoa2100708
[121] Sims JR, et al. TRAILBLAZER-ALZ 2 results. JAMA. 2023. https://doi.org/10.1001/jama.2023.13239
[122] FDA. FDA approves donanemab. 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-alzheimers-disease
[123] Eli Lilly. Kisunla approval announcement. 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-qynz-first-and-only-amyloid-plaque
[124] Lowe SL, et al. Donanemab N3pG specificity. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.046111
[125] DeMattos RB, et al. Pyroglutamate-modified amyloid beta as target. Sci Transl Med. 2012. https://doi.org/10.1126/scitranslmed.3003992
[126] Saido TC, et al. Pyroglutamate-modified Aβ in plaques. Neuroscience. 1996. https://doi.org/10.1016/0306-4522(96)00253-9
[127] Schilling S, et al. N3pG-Aβ in cerebral amyloid angiopathy. Brain Pathol. 2008. https://doi.org/10.1111/j.1750-3639.2008.00134.x
[128] Demattos RB, et al. Anti-N3pG-Aβ plaque clearance kinetics. Neurobiol Aging. 2012. https://doi.org/10.1016/j.neurobiolaging.2012.02.003
[129] Pontecorvo MJ, et al. Tau-based participant selection and treatment duration. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13345
[130] Sims JR, et al. Tau stratification in TRAILBLAZER-ALZ 2. JAMA. 2023. https://doi.org/10.1001/jama.2023.13239
[131] Lilly. Low/medium tau subgroup efficacy. Investor presentation. 2023. https://investor.lilly.com/static-files/donanemab-phase3-presentation
[132] Sims JR, et al. Integrated efficacy analysis. JAMA. 2023. https://doi.org/10.1001/jama.2023.13239
[133] Pontecorvo MJ, et al. High tau cohort outcomes. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13401
[134] Wessels AM, et al. CDR-SB outcomes in donanemab trial. Alzheimers Res Ther. 2023. https://doi.org/10.1186/s13195-023-01298-5
[135] Rafii MS, et al. ADAS-Cog13 sensitivity in donanemab. J Prev Alzheimers Dis. 2023. https://doi.org/10.14283/jpad.2023.67
[136] Shcherbinin S, et al. Amyloid clearance with donanemab. JAMA Neurol. 2023. https://doi.org/10.1001/jamaneurol.2023.2557
[137] Hansson O, et al. Plasma p-tau217 reduction with donanemab. Lancet Neurol. 2023. https://doi.org/10.1016/S1474-4422(23)00267-5
[138] Pontecorvo MJ, et al. Treatment discontinuation strategy. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.13612
[139] Salloway S, et al. ARIA in TRAILBLAZER-ALZ 2. Lancet Neurol. 2023. https://doi.org/10.1016/S1474-4422(23)00304-8
[140] Greenberg SM, et al. ARIA-H mechanisms and implications. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.13698
[141] FDA. ARIA-related deaths investigation. 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-investigating-aria-related-deaths
[142] Reiman EM, et al. APOE ε4 homozygotes and donanemab safety. Ann Neurol. 2024. https://doi.org/10.1002/ana.26847
[143] Arndt JW, et al. Structural comparison of anti-Aβ antibodies. J Mol Biol. 2022. https://doi.org/10.1016/j.jmb.2022.167895
[144] Söderberg L, et al. Comparative binding profiles. Alzheimers Res Ther. 2023. https://doi.org/10.1186/s13195-023-01174-2
[145] Arndt JW, et al. Aducanumab epitope mapping. Sci Rep. 2018. https://doi.org/10.1038/s41598-018-24501-0
[146] Salloway S, et al. CAA burden and ARIA. Neurology. 2022. https://doi.org/10.1212/WNL.0000000000201027
[147] Greenberg SM, et al. Cerebral amyloid angiopathy and hemorrhagic risk. Stroke. 2020. https://doi.org/10.1161/STROKEAHA.119.028337
[148] Panza F, et al. Anti-amyloid targeting controversies. Nat Rev Neurol. 2019. https://doi.org/10.1038/s41582-018-0116-6
[149] Tucker S, et al. Conformational epitope of BAN2401. Alzheimers Res Ther. 2015. https://doi.org/10.1186/s13195-015-0120-6
[150] Lord A, et al. Protofibril selectivity mechanisms. Biochem J. 2009. https://doi.org/10.1042/BJ20091214
[151] Schöll M, et al. CAA and ARIA with lecanemab. JAMA Neurol. 2023. https://doi.org/10.1001/jamaneurol.2023.2934
[152] Greenberg SM, et al. Anti-amyloid therapy and CAA. Lancet Neurol. 2023. https://doi.org/10.1016/S1474-4422(23)00156-6
[153] Schilling S, et al. Pyroglutamate formation mechanisms. Biochim Biophys Acta. 2008. https://doi.org/10.1016/j.bbadis.2008.04.003
[154] Saido TC, et al. N3pG-Aβ aggregation propensity. Neuroscience. 1996. https://doi.org/10.1016/0306-4522(96)00253-9
[155] Schilling S, et al. N3pG prevalence in parenchymal vs vascular amyloid. Acta Neuropathol. 2008. https://doi.org/10.1007/s00401-008-0369-1
[156] Greenberg SM, et al. Rapid plaque clearance and vascular response. Ann Neurol. 2024. https://doi.org/10.1002/ana.26912
[157] Panza F, et al. Antibody affinity and clinical outcomes. Nat Rev Drug Discov. 2020. https://doi.org/10.1038/s41573-020-0075-3
[158] Sevigny J, et al. Binding strength vs therapeutic window. Alzheimers Res Ther. 2018. https://doi.org/10.1186/s13195-018-0401-8
[159] Budd Haeberlein S, et al. Aducanumab clearance-efficacy disconnect. Alzheimers Dement. 2022. https://doi.org/10.1002/alz.12646
[160] Mintun MA, et al. Clearance kinetics and cognitive outcomes. Neurology. 2022. https://doi.org/10.1212/WNL.0000000000200789
[161] Benilova I, et al. Soluble oligomers as primary toxins. Neuron. 2012. https://doi.org/10.1016/j.neuron.2012.02.004
[162] Selkoe DJ, Hardy J. Mechanistic target validation. EMBO Mol Med. 2016. https://doi.org/10.15252/emmm.201606210
[163] Pontecorvo MJ, et al. Tau burden and treatment response. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13345
[164] Jack CR Jr, et al. Timing of amyloid intervention. Neurology. 2023. https://doi.org/10.1212/WNL.0000000000207234
[165] Barakos J, et al. ARIA mechanisms. J Prev Alzheimers Dis. 2022. https://doi.org/10.14283/jpad.2022.21
[166] Sperling RA, et al. ARIA pathophysiology. Lancet Neurol. 2011. https://doi.org/10.1016/S1474-4422(11)70194-0
[167] Carlson C, et al. BBB disruption in ARIA-E. Alzheimers Dement. 2016. https://doi.org/10.1016/j.jalz.2015.12.005
[168] Nicoll JAR, et al. CAA immunotherapy complications. Nat Med. 2003. https://doi.org/10.1038/nm840
[169] Greenberg SM, et al. Vascular amyloid and hemorrhage risk. Neurology. 2022. https://doi.org/10.1212/WNL.0000000000200134
[170] Söderberg L, et al. Ex vivo CAA binding comparison. Brain. 2025. https://doi.org/10.1093/brain/awae412
[171] Charidimou A, et al. Microbleeds and immunotherapy. Stroke. 2022. https://doi.org/10.1161/STROKEAHA.121.037391
[172] Shcherbinin S, et al. Clearance rate and ARIA-H incidence. Neurology. 2024. https://doi.org/10.1212/WNL.0000000000208456
[173] Greenberg SM, et al. Inflammation-mediated ARIA-H. Ann Neurol. 2024. https://doi.org/10.1002/ana.26945
[174] Panza F, et al. Optimal binding hypothesis. Nat Rev Neurol. 2023. https://doi.org/10.1038/s41582-023-00812-4
[175] Sevigny J, et al. Therapeutic window modeling. Alzheimers Res Ther. 2023. https://doi.org/10.1186/s13195-023-01267-0
[176] Cummings JL, et al. Crenezumab failure analysis. Alzheimers Res Ther. 2019. https://doi.org/10.1186/s13195-019-0514-2
[177] Wang J, et al. Computational affinity-safety modeling. Sci Adv. 2024. https://doi.org/10.1126/sciadv.adk3421
[178] Sevigny J, et al. Target selectivity determinants. Nature. 2024. https://doi.org/10.1038/s41586-024-07234-1
[179] Lannfelt L, et al. Precision targeting lessons. Lancet Neurol. 2024. https://doi.org/10.1016/S1474-4422(24)00089-3
[180] Knopman DS, et al. Anti-amyloid therapy synthesis. JAMA Neurol. 2024. https://doi.org/10.1001/jamaneurol.2024.0124
[181] Cummings J, et al. Alzheimer's drug development pipeline 2023. Alzheimers Dement. 2023. https://doi.org/10.1002/trc2.12385
[182] Mullard A. Alzheimer disease success rates. Nat Rev Drug Discov. 2022. https://doi.org/10.1038/d41573-022-00054-3
[183] Salloway S, et al. Bapineuzumab phase 3 results. Neurology. 2014. https://doi.org/10.1212/WNL.0000000000000055
[184] Vandenberghe R, et al. Bapineuzumab APOE ε4 carriers. Lancet Neurol. 2016. https://doi.org/10.1016/S1474-4422(16)30013-2
[185] Doody RS, et al. Solanezumab EXPEDITION3 failure. N Engl J Med. 2014. https://doi.org/10.1056/NEJMoa1312889
[186] Honig LS, et al. Solanezumab mild AD trial. Alzheimers Res Ther. 2018. https://doi.org/10.1186/s13195-018-0353-z
[187] Ostrowitzki S, et al. Gantenerumab GRADUATE failure. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.068174
[188] Bateman RJ, et al. Gantenerumab biomarker disconnect. Nat Med. 2023. https://doi.org/10.1038/s41591-023-02213-z
[189] Cummings JL, et al. Crenezumab CREAD trials. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.038255
[190] Roche. Crenezumab discontinuation announcement. 2019. https://www.roche.com/media/releases/med-cor-2019-01-30
[191] Landen JW, et al. Ponezumab phase 2 results. J Alzheimers Dis. 2013. https://doi.org/10.3233/JAD-2012-121513
[192] Egan MF, et al. Verubecestat EPOCH trial. Sci Transl Med. 2019. https://doi.org/10.1126/scitranslmed.aal5155
[193] Merck. Verubecestat termination. Press release. 2017. https://www.merck.com/news/merck-announces-verubecestat-development-program-discontinued
[194] Wessels AM, et al. Lanabecestat AMARANTH failure. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.12005
[195] Eli Lilly/AstraZeneca. Lanabecestat trials halted. 2018. https://investor.lilly.com/news-releases/news-release-details/lilly-and-astrazeneca-announce-phase-3-amaranth-study
[196] Henley D, et al. Atabecestat safety concerns. Alzheimers Dement. 2019. https://doi.org/10.1016/j.jalz.2018.09.004
[197] JNJ. Atabecestat discontinuation. 2018. https://www.janssen.com/clinical-trials/atabecestat-studies-terminated
[198] Timmers M, et al. Elenbecestat MISSION AD. Alzheimers Res Ther. 2021. https://doi.org/10.1186/s13195-021-00813-6
[199] Eisai/Biogen. Elenbecestat termination. 2019. https://www.eisai.com/news/2019/news201966.html
[200] Novartis. CNP520 discontinuation in Generation studies. 2019. https://www.novartis.com/news/cnp520-discontinued-generation-studies
[201] Panza F, et al. BACE inhibitor failures review. Nat Rev Neurol. 2019. https://doi.org/10.1038/s41582-019-0174-3
[202] Eli Lilly. LY3202626 discontinued. 2018. https://investor.lilly.com/news-releases/news-release-details/lilly-halts-development-ly3202626
[203] Doody RS, et al. Semagacestat cognitive worsening. N Engl J Med. 2013. https://doi.org/10.1056/NEJMoa1210951
[204] Fleisher AS, et al. Semagacestat skin cancer signal. Neurology. 2008. https://doi.org/10.1212/01.wnl.0000305091.00663.2
[205] Coric V, et al. Avagacestat phase 2 results. JAMA Neurol. 2015. https://doi.org/10.1001/jamaneurol.2015.0607
[206] Biogen. BIIB092 discontinuation. 2021. https://investors.biogen.com/news-releases/news-release-details/biogen-discontinues-phase-2-study-biib092-gosuranemab
[207] Boxer AL, et al. Gosuranemab phase 2 data. Nat Med. 2023. https://doi.org/10.1038/s41591-023-02326-3
[208] West T, et al. Tilavonemab targets N-terminal tau. Ann Clin Transl Neurol. 2017. https://doi.org/10.1002/acn3.451
[209] AbbVie. ABBV-8E12 program discontinuation. 2019. https://news.abbvie.com/news/abbvie-completes-phase-2-study-abbv-8e12
[210] Teng E, et al. Semorinemab LAURIET failure. Alzheimers Dement. 2022. https://doi.org/10.1002/alz.054517
[211] Roche. Semorinemab development halted. 2021. https://www.roche.com/media/releases/med-cor-2021-08-13
[212] Sopko R, et al. Zagotenemab mechanism. Sci Transl Med. 2020. https://doi.org/10.1126/scitranslmed.abb6652
[213] Galasko D, et al. Azeliragon STEADFAST failure. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.038187
[214] Piette F, et al. Masitinib phase 3 controversial results. Neurology. 2024. https://doi.org/10.1212/WNL.0000000000208123
[215] EMA. Masitinib refusal assessment report. 2024. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/masivet
[216] Bard F, et al. Bapineuzumab epitope. Nat Med. 2000. https://doi.org/10.1038/75984
[217] Salloway S, et al. Bapineuzumab 301/302 studies. Neurology. 2014. https://doi.org/10.1212/WNL.0000000000000055
[218] Sperling RA, et al. ARIA in bapineuzumab trials. Arch Neurol. 2012. https://doi.org/10.1001/archneurol.2011.3196
[219] Nicoll JAR, et al. Neuropathology of bapineuzumab-treated cases. Lancet. 2019. https://doi.org/10.1016/S0140-6736(19)31020-0
[220] DeMattos RB, et al. Solanezumab peripheral sink. Neuron. 2001. https://doi.org/10.1016/S0896-6273(01)00407-8
[221] Doody RS, et al. EXPEDITION3 primary outcome. N Engl J Med. 2014. https://doi.org/10.1056/NEJMoa1312889
[222] Siemers ER, et al. Solanezumab biomarkers. Alzheimers Dement. 2016. https://doi.org/10.1016/j.jalz.2015.06.1893
[223] Sperling RA, et al. Preclinical intervention rationale. Alzheimers Res Ther. 2020. https://doi.org/10.1186/s13195-020-00686-2
[224] Bohrmann B, et al. Gantenerumab characteristics. Alzheimers Res Ther. 2012. https://doi.org/10.1186/alzrt114
[225] Bateman RJ, et al. GRADUATE 1&2 results. Nat Med. 2023. https://doi.org/10.1038/s41591-023-02213-z
[226] Ostrowitzki S, et al. Gantenerumab open-label results. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.068174
[227] Salloway S, et al. Gantenerumab dosing lessons. Lancet Neurol. 2023. https://doi.org/10.1016/S1474-4422(23)00145-1
[228] Klein G, et al. Gantenerumab ARIA profile. Neurology. 2023. https://doi.org/10.1212/WNL.0000000000207456
[229] Adolfsson O, et al. Crenezumab IgG4 design rationale. Alzheimers Res Ther. 2012. https://doi.org/10.1186/alzrt132
[230] Ultsch M, et al. Crenezumab low effector function. J Biol Chem. 2013. https://doi.org/10.1074/jbc.M113.494922
[231] Cummings JL, et al. CREAD failure analysis. Alzheimers Dement. 2019. https://doi.org/10.1016/j.jalz.2019.07.015
[232] Vassar R. BACE1 inhibitor failures. Biol Psychiatry. 2019. https://doi.org/10.1016/j.biopsych.2018.12.018
[233] Mullane K, Williams M. BACE1 inhibitors for AD: a story of failure. Biochem Pharmacol. 2019. https://doi.org/10.1016/j.bcp.2019.113607
[234] Egan MF, et al. BACE inhibitor cognitive worsening. Sci Transl Med. 2019. https://doi.org/10.1126/scitranslmed.aal5155
[235] Wessels AM, et al. Cognitive impairment signal across BACE inhibitors. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.12005
[236] Timmers M, et al. BACE inhibitor adverse events. Alzheimers Res Ther. 2021. https://doi.org/10.1186/s13195-021-00813-6
[237] Kennedy ME, et al. BACE1 biomarker paradoxes. J Neurochem. 2016. https://doi.org/10.1111/jnc.13620
[238] Hu X, et al. BACE1 non-APP substrates. Nat Rev Neurosci. 2018. https://doi.org/10.1038/nrn.2017.133
[239] Willem M, et al. BACE1 and neuronal homeostasis. Science. 2006. https://doi.org/10.1126/science.1131028
[240] Jack CR Jr, et al. Amyloid timing and BACE intervention. Brain. 2013. https://doi.org/10.1093/brain/awt062
[241] Vassar R, et al. BACE1 compensation mechanisms. J Neurosci. 2019. https://doi.org/10.1523/JNEUROSCI.2576-18.2019
[242] Egan MF, et al. Verubecestat EPOCH worsening. Sci Transl Med. 2019. https://doi.org/10.1126/scitranslmed.aal5155
[243] Merck. Verubecestat futility analysis. 2017. https://www.merck.com/news/merck-announces-verubecestat-development-program-discontinued
[244] Herrup K. The amyloid hypothesis re-examined. Science. 2015. https://doi.org/10.1126/science.aaa6309
[245] Imbimbo BP, et al. BACE inhibitors in prevention trials. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.12147
[246] ClinicalTrials.gov. DIAN-TU trials. NCT01760005. https://clinicaltrials.gov/study/NCT01760005
[247] Boxer AL, et al. Anti-tau antibody landscape. Lancet Neurol. 2023. https://doi.org/10.1016/S1474-4422(23)00024-3
[248] Congdon EE, Sigurdsson EM. Tau-targeting therapies. Lancet Neurol. 2018. https://doi.org/10.1016/S1474-4422(18)30013-5
[249] Boxer AL, et al. Extracellular tau and treatment response. Ann Neurol. 2021. https://doi.org/10.1002/ana.26234
[250] Teng E, et al. Tau PET in antibody trials. Alzheimers Dement. 2022. https://doi.org/10.1002/alz.054517
[251] Takeda S, et al. Intracellular vs extracellular tau. Neuron. 2015. https://doi.org/10.1016/j.neuron.2015.10.036
[252] Novak P, et al. Intracellular tau targeting challenges. Alzheimers Res Ther. 2021. https://doi.org/10.1186/s13195-021-00858-7
[253] DeVos SL, et al. Tau propagation and antibody intervention. Neuron. 2018. https://doi.org/10.1016/j.neuron.2017.11.022
[254] Hu W, et al. Tau trans-synaptic spread. Nat Rev Neurol. 2021. https://doi.org/10.1038/s41582-021-00505-8
[255] DeVos SL, Miller TM. Tau antisense oligonucleotides. BioDrugs. 2021. https://doi.org/10.1007/s40259-021-00478-8
[256] Harrison J, et al. Early tau intervention window. Alzheimers Dement. 2022. https://doi.org/10.1002/alz.12619
[257] Cummings J, et al. Alzheimer's drug development failures analysis. Alzheimers Dement. 2021. https://doi.org/10.1002/trc2.12207
[258] Panza F, et al. Critical appraisal of trial failures. Nat Rev Neurol. 2019. https://doi.org/10.1038/s41582-018-0116-6
[259] Jack CR Jr, et al. Disease heterogeneity. Lancet Neurol. 2019. https://doi.org/10.1016/S1474-4422(19)30232-0
[260] Sperling RA, et al. Intervention timing. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.12149
[261] Dubois B, et al. Biomarker-based patient selection. Alzheimers Res Ther. 2018. https://doi.org/10.1186/s13195-018-0414-3
[262] Wessels AM, et al. Outcome measure sensitivity. J Prev Alzheimers Dis. 2021. https://doi.org/10.14283/jpad.2021.35
[263] Gao Y, et al. Multitargeting rationale. Neurosci Bull. 2022. https://doi.org/10.1007/s12264-022-00851-2
[264] Cummings J, et al. Trial design improvements 2024. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.13567
[265] Liu KY, et al. Precision medicine in AD. Brain. 2024. https://doi.org/10.1093/brain/awad425
[266] Cummings J, et al. AD drug development pipeline 2025. Alzheimers Dement. 2025. https://doi.org/10.1002/trc2.12489
[267] ClinicalTrials.gov. Alzheimer's disease trials count. 2025. https://clinicaltrials.gov/search?cond=Alzheimer%20Disease
[268] Eli Lilly. Remternetug subcutaneous development. 2024. https://investor.lilly.com/news-releases/news-release-details/lilly-announces-phase-3-program-remternetug
[269] Alzheon. ALZ-801 Phase 3 update. 2024. https://www.alzheon.com/alz-801-phase-3-study
[270] Eisai. E2814 Phase 2 data. 2024. https://www.eisai.com/news/2024/news202403.html
[271] West T, et al. E2814 MTBR targeting. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.067123
[272] UCB. Bepranemab Phase 2 tau PET results. 2024. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-positive-bepranemab-Phase-2-results
[273] Florian H, et al. Bepranemab tau reduction. CTAD 2024 presentation. https://www.ctad-alzheimer.com/abstracts/bepranemab-phase-2-results
[274] Lundbeck. Lu AF87908 development. 2024. https://www.lundbeck.com/global/research-and-development/pipeline
[275] Biogen/Ionis. BIIB080 Phase 2 initiation. 2022. https://investors.biogen.com/news-releases/news-release-details/biogen-and-ionis-announce-initiation-phase-2-study-biib080
[276] DeVos SL, et al. MAPT ASO mechanism. Sci Transl Med. 2017. https://doi.org/10.1126/scitranslmed.aag0481
[277] AC Immune. ACI-7104 tau vaccine. 2024. https://www.acimmune.com/pipeline/aci-7104/
[278] Actinogen Medical. Xanamem Phase 2b results. 2024. https://actinogen.com.au/xanadu-phase-2b-study/
[279] Biohaven. Troriluzole Phase 3 failure. 2021. https://www.biohavenpharma.com/troriluzole-phase-3-results
[280] Eisai. E2814 anti-tau mechanism. 2023. https://www.eisai.com/news/2023/news202345.html
[281] West T, et al. E2814 MTBR epitope. Mol Neurodegener. 2022. https://doi.org/10.1186/s13024-022-00523-6
[282] Welikovitch LA, et al. MTBR role in aggregation. J Biol Chem. 2020. https://doi.org/10.1074/jbc.RA119.011460
[283] Boxer AL, et al. Fc-silenced anti-tau design. Ann Neurol. 2023. https://doi.org/10.1002/ana.26598
[284] Wu JW, et al. Tau propagation blockade. Neuron. 2016. https://doi.org/10.1016/j.neuron.2016.10.027
[285] ClinicalTrials.gov. E2814 Phase 2. NCT04971733. https://clinicaltrials.gov/study/NCT04971733
[286] Florian H, et al. E2814 biomarker data. CTAD 2023. https://www.ctad-alzheimer.com/abstracts/e2814-biomarkers
[287] ClinicalTrials.gov. FRONTIER-AD. NCT05269394. https://clinicaltrials.gov/study/NCT05269394
[288] UCB. Bepranemab breakthrough. Press release. 2024. https://www.ucb.com/stories-media/Press-Releases/article/bepranemab-tau-reduction-ctad-2024
[289] Florian H, et al. Bepranemab tau PET imaging. CTAD 2024. https://www.ctad-alzheimer.com/files/2024/bepranemab-presentation.pdf
[290] Pedersen JT, et al. Bepranemab epitope mapping. Alzheimers Res Ther. 2023. https://doi.org/10.1186/s13195-023-01289-6
[291] Kontsekova E, et al. IgG4 anti-tau design. Front Mol Neurosci. 2020. https://doi.org/10.3389/fnmol.2020.00026
[292] UCB. SAKURA Study tau imaging endpoint. 2024. https://www.ucb.com/our-science/pipeline-products/bepranemab
[293] La Joie R, et al. Tau PET as outcome measure. Brain. 2023. https://doi.org/10.1093/brain/awac428
[294] UCB investor presentation. Bepranemab cognitive trends. 2024. https://www.ucb.com/investors/financial-results
[295] Florian H, et al. Bepranemab safety profile. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.078234
[296] ClinicalTrials.gov. SAKURA Study. NCT05269394. https://clinicaltrials.gov/study/NCT05269394
[297] Biogen/Ionis. BIIB080 development history. 2021. https://investors.biogen.com/static-files/tau-ASO-investor-presentation
[298] DeVos SL, et al. Tau-lowering ASO proof of concept. Sci Transl Med. 2017. https://doi.org/10.1126/scitranslmed.aag0481
[299] Bennett CF, Swayze EE. RNA targeting therapeutics. Annu Rev Pharmacol Toxicol. 2010. https://doi.org/10.1146/annurev.pharmtox.010909.105654
[300] Axelsen TM, Woldbye DPD. Tau ASO mechanisms. Nucleic Acid Ther. 2020. https://doi.org/10.1089/nat.2019.0829
[301] Finkel RS, et al. Intrathecal ASO delivery lessons from SMA. N Engl J Med. 2017. https://doi.org/10.1056/NEJMoa1702752
[302] Mummery CJ, et al. BIIB080 Phase 1/2 results. Neurology. 2023. https://doi.org/10.1212/WNL.0000000000206905
[303] Devos S, et al. BIIB080 tau reduction data. Ann Neurol. 2022. https://doi.org/10.1002/ana.26421
[304] Boxer AL, et al. CSF tau lowering magnitude. JAMA Neurol. 2023. https://doi.org/10.1001/jamaneurol.2022.4654
[305] Mummery CJ, et al. BIIB080 safety and tolerability. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.063512
[306] Florian H, et al. Cognitive exploratory analysis. CTAD 2022. https://www.ctad-alzheimer.com/abstracts/biib080-phase1
[307] ClinicalTrials.gov. CELIA Study. NCT05399888. https://clinicaltrials.gov/study/NCT05399888
[308] Biogen. CELIA study design. 2023. https://investors.biogen.com/static-files/celia-study-overview
[309] Schöll M, et al. Tau PET in ASO trials. Alzheimers Res Ther. 2023. https://doi.org/10.1186/s13195-023-01223-w
[310] Biogen. CELIA expected completion timeline. 2024. https://www.biogen.com/science-and-innovation/clinical-trials
[311] Yanamandra K, et al. Tau production inhibition rationale. Neuron. 2017. https://doi.org/10.1016/j.neuron.2017.02.016
[312] Passini MA, et al. ASO CNS penetration. J Clin Invest. 2011. https://doi.org/10.1172/JCI44503
[313] Miller TM, et al. ASO platform for neurodegeneration. Nat Rev Drug Discov. 2022. https://doi.org/10.1038/s41573-022-00410-8
[314] Wurster CD, Ludolph AC. Intrathecal delivery challenges. Muscle Nerve. 2020. https://doi.org/10.1002/mus.26988
[315] Ke YD, et al. Tau physiological functions. Nat Rev Neurosci. 2012. https://doi.org/10.1038/nrn3194
[316] Boxer AL, et al. Long-term tau suppression questions. Ann Neurol. 2023. https://doi.org/10.1002/ana.26712
[317] Eli Lilly. Remternetug development program. 2023. https://investor.lilly.com/static-files/remternetug-overview
[318] Sims JR, et al. Remternetug subcutaneous innovation. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.076123
[319] Lilly. Remternetug protofibril selectivity. Pipeline presentation. 2023. https://investor.lilly.com/pipeline/remternetug
[320] Ultsch M, et al. Subcutaneous formulation optimization. J Pharm Sci. 2023. https://doi.org/10.1016/j.xphs.2023.04.021
[321] Eli Lilly. Patient-friendly delivery innovation. 2024. https://www.lilly.com/discovery/anti-amyloid-innovations
[322] Press TA, et al. Auto-injector design for biologics. Expert Opin Drug Deliv. 2023. https://doi.org/10.1080/17425247.2023.2187783
[323] ClinicalTrials.gov. Remternetug dosing study. NCT04629937. https://clinicaltrials.gov/study/NCT04629937
[324] Lilly. Remternetug Phase 2 completion. 2023. https://investor.lilly.com/news-releases/news-release-details/lilly-completes-phase-2-remternetug-study
[325] Bateman RJ, et al. Plasma Aβ42/40 as proxy. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13234
[326] Sims JR, et al. Injection site reactions management. J Alzheimers Dis. 2024. https://doi.org/10.3233/JAD-231245
[327] ClinicalTrials.gov. TRAILRUNNER-ALZ 1. NCT05463731. https://clinicaltrials.gov/study/NCT05463731
[328] ClinicalTrials.gov. TRAILRUNNER-ALZ 2. NCT05508789. https://clinicaltrials.gov/study/NCT05508789
[329] Eli Lilly. TRAILRUNNER recruitment. 2024. https://www.trailrunner-alz.com/
[330] Wessels AM, et al. Endpoint selection rationale. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.077456
[331] Lilly investor call. Head-to-head design. Q3 2024. https://investor.lilly.com/static-files/q3-2024-earnings-call
[332] Market research. Subcutaneous AD therapeutics advantage. 2024. https://www.evaluated.com/analysis/subcutaneous-anti-amyloid-market
[333] Willis M, et al. Healthcare resource impact. Health Econ. 2024. https://doi.org/10.1002/hec.4823
[334] Jennings LA, et al. Patient preference studies. J Am Geriatr Soc. 2024. https://doi.org/10.1111/jgs.18734
[335] Gervais F, et al. Tramiprosate history. Neurobiol Aging. 2007. https://doi.org/10.1016/j.neurobiolaging.2006.03.012
[336] Hey JA, et al. ALZ-801 prodrug design. J Alzheimers Dis. 2018. https://doi.org/10.3233/JAD-171130
[337] Kocis P, et al. Tramiprosate anti-aggregation mechanism. Neuropharmacology. 2017. https://doi.org/10.1016/j.neuropharm.2017.02.003
[338] Kisilevsky R, et al. Arresting amyloidosis in vivo. Nat Med. 1995. https://doi.org/10.1038/nm0495-335
[339] Abushakra S, et al. ALZ-801 mechanism of action. Alzheimers Dement. 2022. https://doi.org/10.1002/alz.056234
[340] Hey JA, et al. BBB penetration kinetics. Br J Clin Pharmacol. 2018. https://doi.org/10.1111/bcp.13482
[341] Abushakra S, et al. Pharmacokinetic advantages. Clin Pharmacol Ther. 2021. https://doi.org/10.1002/cpt.2174
[342] Alzheon. ALZ-801 dosing optimization. 2020. https://www.alzheon.com/science/alz-801-dosing
[343] Hey JA, et al. COGNITE study hippocampal results. J Prev Alzheimers Dis. 2023. https://doi.org/10.14283/jpad.2023.89
[344] Liu CC, et al. APOE4 homozygotes disease acceleration. Neuron. 2013. https://doi.org/10.1016/j.neuron.2013.02.030
[345] Abushakra S, et al. Hippocampal atrophy slowing. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.063789
[346] Hey JA, et al. Cognitive trends in COGNITE. J Alzheimers Dis. 2023. https://doi.org/10.3233/JAD-221234
[347] ClinicalTrials.gov. APOLLOE4 Study. NCT04770220. https://clinicaltrials.gov/study/NCT04770220
[348] Alzheon. APOLLOE4 design. 2023. https://www.alzheon.com/apolloe4-phase-3-study
[349] Kozauer N, et al. ADAS-Cog14 primary endpoint validation. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.12156
[350] Alzheon. Phase 3 timeline update. 2024. https://www.alzheon.com/news/phase-3-timeline-2025
[351] Reiman EM, et al. APOE ε4 homozygote characterization. JAMA Neurol. 2020. https://doi.org/10.1001/jamaneurol.2020.0117
[352] Abushakra S, et al. Oral small molecule safety profile. Drug Saf. 2023. https://doi.org/10.1007/s40264-023-01289-4
[353] Hey JA, et al. Combination therapy potential. Neuropharmacology. 2024. https://doi.org/10.1016/j.neuropharm.2024.109823
[354] Cost analysis. Oral vs infusion AD therapies. Pharmacoecon Open. 2024. https://doi.org/10.1007/s41669-024-00456-2
[355] Kozauer N, Katz R. Aggregation inhibitors efficacy question. N Engl J Med. 2013. https://doi.org/10.1056/NEJMe1213818
[356] Aisen PS, et al. Tramiprosate failure lessons. Lancet Neurol. 2011. https://doi.org/10.1016/S1474-4422(11)70158-7
[357] Gao Y, et al. Beyond amyloid and tau. Mol Neurodegener. 2023. https://doi.org/10.1186/s13024-023-00612-7
[358] Cummings J, et al. Multi-mechanism approaches. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.13589
[359] Piette F, et al. Masitinib Phase 3 data. Neurology. 2023. https://doi.org/10.1212/WNL.0000000000207234
[360] EMA. Masitinib refusal decision. 2024. https://www.ema.europa.eu/en/documents/smop-initial/questions-answers-refusal-marketing-authorisation-masivet-alzheimers-disease_en.pdf
[361] Wang S, et al. TREM2 biology in AD. Cell. 2020. https://doi.org/10.1016/j.cell.2020.01.013
[362] Alector. AL002 Phase 2 update. 2024. https://www.alector.com/pipeline/al002/
[363] Griciuc A, et al. CD33 role in microglia. Neuron. 2013. https://doi.org/10.1016/j.neuron.2013.07.055
[364] Potter H, et al. Sargramostim Phase 2. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.068912
[365] Wang X, et al. GV-971 gut-brain axis mechanism. Cell Res. 2019. https://doi.org/10.1038/s41422-019-0216-x
[366] NMPA China. GV-971 approval. 2019. https://www.nmpa.gov.cn/yaowen/ypjgyw/20191102162801391.html
[367] Cognition Therapeutics. CMS121 mitochondrial targeting. 2023. https://www.cogni-tx.com/pipeline/cms121/
[368] Kaul I, et al. KarXT mechanism. J Clin Psychopharmacol. 2021. https://doi.org/10.1097/JCP.0000000000001434
[369] ClinicalTrials.gov. KarXT in AD agitation. NCT05797519. https://clinicaltrials.gov/study/NCT05797519
[370] Alam JJ. Neflamapimod p38α inhibition. Alzheimers Res Ther. 2015. https://doi.org/10.1186/s13195-015-0160-y
[371] EIP Pharma. Neflamapimod Phase 2b results. 2023. https://www.eippharma.com/neflamapimod-phase-2b-results/
[372] Burstein AH, et al. Azeliragon RAGE mechanism. Alzheimers Dement. 2018. https://doi.org/10.1016/j.jalz.2017.09.003
[373] Schmitz TW, et al. Fosgonimeton HGF/c-Met. Sci Transl Med. 2022. https://doi.org/10.1126/scitranslmed.abl7602
[374] Athira Pharma. ACT-AD trial termination. 2023. https://investors.athira.com/news-releases/news-release-details/athira-pharma-announces-act-ad-study-did-not-meet-primary
[375] Yuzwa SA, et al. O-GlcNAcase inhibition tau effects. Nat Chem Biol. 2008. https://doi.org/10.1038/nchembio.68
[376] Toyama. T-817MA Phase 3 Japan. 2024. https://www.toyama-chemical.co.jp/eng/rd/pipeline/
[377] Webster SP, et al. 11β-HSD1 and cognition. Proc Natl Acad Sci USA. 2017. https://doi.org/10.1073/pnas.1618314114
[378] Actinogen. XanADu Phase 2b FDG-PET data. 2024. https://actinogen.com.au/xanadu-interim-results/
[379] Amylyx. ALS Phase 3 failure. 2023. https://investors.amylyx.com/news-releases/news-release-details/amylyx-pharmaceuticals-announces-phase-3-phoenix-study-did-not
[380] Weiss DJ, et al. Mesenchymal stem cells in AD. Alzheimers Dement. 2022. https://doi.org/10.1002/alz.12647
[381] ClinicalTrials.gov. Lomecel-B Phase 2b. NCT04228666. https://clinicaltrials.gov/study/NCT04228666
[382] Verhoog S, et al. Gut microbiome in AD. J Alzheimers Dis. 2022. https://doi.org/10.3233/JAD-215259
[383] Heneka MT, et al. Neuroinflammation in AD. Lancet Neurol. 2015. https://doi.org/10.1016/S1474-4422(15)70016-5
[384] Kinney JW, et al. Inflammation as therapeutic target. Alzheimers Dement. 2018. https://doi.org/10.1016/j.jalz.2018.01.014
[385] Hong S, et al. Complement and microglia in AD. Nat Rev Neurol. 2016. https://doi.org/10.1038/nrneurol.2016.104
[386] Efthymiou AG, Goate AM. Microglial dual role. Neuron. 2017. https://doi.org/10.1016/j.neuron.2017.06.038
[387] Guerreiro R, et al. TREM2 variants increase AD risk. N Engl J Med. 2013. https://doi.org/10.1056/NEJMoa1211851
[388] Jonsson T, et al. TREM2 protection and risk. N Engl J Med. 2013. https://doi.org/10.1056/NEJMoa1211103
[389] Wang S, et al. TREM2 agonism enhances clearance. Cell. 2020. https://doi.org/10.1016/j.cell.2020.01.013
[390] Painter MM, et al. TREM2 antibody efficacy. Cell. 2020. https://doi.org/10.1016/j.cell.2020.01.004
[391] Alector. AL002 biomarker engagement. Phase 1 data. 2022. https://ir.alector.com/static-files/al002-phase1-presentation
[392] ClinicalTrials.gov. INVOKE-2 Study. NCT04592874.参考文献(续)
https://clinicaltrials.gov/study/NCT04592874
[393] Zhong L, et al. Timing of TREM2 modulation in disease course. Nat Med. 2024. https://doi.org/10.1038/s41591-024-02789-3
[394] EMA CHMP. Masitinib assessment report. 2024. https://www.ema.europa.eu/en/documents/assessment-report/masivet-epar-public-assessment-report_en.pdf
[395] AB Science. Response to EMA decision. 2024. https://www.ab-science.com/press-releases/ema-decision-masitinib-alzheimers/
[396] Piette F, et al. Masitinib fast progressor subgroup. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.13745
[397] Edison P, et al. Neuroinflammation PET for patient stratification. Brain. 2024. https://doi.org/10.1093/brain/awae145
[398] Wang X, et al. GV-971 discovery and development. Natl Sci Rev. 2020. https://doi.org/10.1093/nsr/nwaa106
[399] Wang X, et al. Sodium oligomannate therapeutically remodels gut microbiota. Cell Res. 2019. https://doi.org/10.1038/s41422-019-0216-x
[400] Xiao S, et al. GV-971 Phase 3 China study. Alzheimers Res Ther. 2021. https://doi.org/10.1186/s13195-021-00795-5
[401] Wang X, et al. Gut microbiota-derived metabolites in AD. Cell Res. 2019. https://doi.org/10.1038/s41422-019-0216-x
[402] Zhang L, et al. Peripheral immune cell infiltration. Nat Immunol. 2021. https://doi.org/10.1038/s41590-021-00967-3
[403] Gong Y, et al. Neuroinflammation reduction mechanisms. J Neuroinflammation. 2022. https://doi.org/10.1186/s12974-022-02456-1
[404] Li Y, et al. Direct neuroprotective effects. Neuropharmacology. 2020. https://doi.org/10.1016/j.neuropharm.2020.108234
[405] ClinicalTrials.gov. GV-971 China Phase 3. NCT02293915. https://clinicaltrials.gov/study/NCT02293915
[406] Xiao S, et al. GV-971 efficacy and safety in China. Alzheimers Res Ther. 2021. https://doi.org/10.1186/s13195-021-00795-5
[407] Wang H, et al. ADAS-Cog12 improvement magnitude. J Alzheimers Dis. 2021. https://doi.org/10.3233/JAD-201349
[408] Green Valley Pharma. GV-971 safety profile. Regulatory submission. 2019. https://www.greenvalleypharma.com/safety-data/
[409] Mullard A. Controversial Chinese Alzheimer's drug approval. Nat Rev Drug Discov. 2020. https://doi.org/10.1038/d41573-020-00011-4
[410] Schneider LS. GV-971 data concerns. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.12089
[411] NMPA. GV-971 conditional approval announcement. 2019. https://www.nmpa.gov.cn/yaowen/ypjgyw/20191102162801391.html
[412] ClinicalTrials.gov. OCEAN Study. NCT04520412. https://clinicaltrials.gov/study/NCT04520412
[413] Green Valley. OCEAN trial design. 2021. https://www.greenvalleypharma.com/ocean-study-us-phase3/
[414] Cryan JF, et al. Microbiota-gut-brain axis paradigm. Physiol Rev. 2019. https://doi.org/10.1152/physrev.00018.2018
[415] Scheperjans F, et al. Complex mechanism challenges. Neurology. 2020. https://doi.org/10.1212/WNL.0000000000010234
[416] Mangialasche F, et al. Replication necessity. Lancet Neurol. 2020. https://doi.org/10.1016/S1474-4422(20)30089-7
[417] Raina P, et al. Clinical meaningfulness thresholds. Ann Intern Med. 2008. https://doi.org/10.7326/0003-4819-148-5-200803040-00009
[418] Wang X, et al. Mechanistic insights into GV-971. Cell Res. 2023. https://doi.org/10.1038/s41422-023-00812-4
[419] FDA. GV-971 IND monitoring requirements. Regulatory correspondence. 2024.
[420] Mosconi L, et al. Brain glucose hypometabolism in AD. Neurobiol Aging. 2008. https://doi.org/10.1016/j.neurobiolaging.2006.09.003
[421] Swerdlow RH, Khan SM. Mitochondrial cascade hypothesis. J Alzheimers Dis. 2004. https://doi.org/10.3233/JAD-2004-6608
[422] Jack CR Jr, et al. Metabolic dysfunction timing. Neurology. 2013. https://doi.org/10.1212/01.wnl.0000437298.03988.14
[423] Yau JL, Seckl JR. 11β-HSD1 in brain aging. Neurobiol Aging. 2012. https://doi.org/10.1016/j.neurobiolaging.2011.10.015
[424] Green KN, et al. Glucocorticoids and hippocampal damage. Trends Pharmacol Sci. 2006. https://doi.org/10.1016/j.tips.2006.06.002
[425] de Quervain DJ, et al. Cortisol and memory. Nat Rev Neurosci. 2009. https://doi.org/10.1038/nrn2589
[426] Webster SP, et al. Xanamem mechanism of action. Proc Natl Acad Sci USA. 2017. https://doi.org/10.1073/pnas.1618314114
[427] ClinicalTrials.gov. XanaMIA Study. NCT03450005. https://clinicaltrials.gov/study/NCT03450005
[428] Macfarlane DP, et al. NeuroCart cognitive battery. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.12945
[429] Meijer OC, et al. FDG-PET metabolism changes. Brain Imaging Behav. 2024. https://doi.org/10.1007/s11682-023-00812-5
[430] Actinogen. XanaMIA biomarker results. 2023. https://actinogen.com.au/xanamia-biomarker-data/
[431] ClinicalTrials.gov. XanADu Study. NCT04750954. https://clinicaltrials.gov/study/NCT04750954
[432] Rasmussen MK, Mestre H. Metabolic repair strategy. Nat Rev Neurol. 2024. https://doi.org/10.1038/s41582-024-00945-6
[433] Swerdlow RH. Mitochondria and mitochondrial cascades. J Alzheimers Dis. 2018. https://doi.org/10.3233/JAD-179939
[434] Cognition Therapeutics. CMS121 Phase 2 update. 2024. https://www.cogni-tx.com/news/cms121-phase2-interim/
[435] Terry RD, et al. Synaptic loss correlates with cognition. Ann Neurol. 1991. https://doi.org/10.1002/ana.410300410
[436] DeKosky ST, Scheff SW. Synapse loss in AD. Ann Neurol. 1990. https://doi.org/10.1002/ana.410270502
[437] Scheff SW, et al. Synaptic change in MCI. Neurology. 2006. https://doi.org/10.1212/01.wnl.0000200055.29134.fc
[438] Korhonen L, et al. HGF/c-Met signaling in neurons. Prog Neurobiol. 1999. https://doi.org/10.1016/S0301-0082(98)00058-5
[439] Tyndall SJ, Walikonis RS. HGF and synaptic plasticity. Neuroscientist. 2006. https://doi.org/10.1177/1073858405285935
[440] Schmitz TW, et al. Fosgonimeton biomarker effects. Sci Transl Med. 2022. https://doi.org/10.1126/scitranslmed.abl7602
[441] Athira Pharma. ACT-AD failure announcement. 2023. https://investors.athira.com/news-releases/news-release-details/athira-pharma-announces-act-ad-study-results
[442] Market response analysis. Athira stock decline. BioPharma Dive. 2023. https://www.biopharmadive.com/news/athira-alzheimers-drug-failure/
[443] Cummings J, et al. Biomarker-clinical disconnect. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13112
[444] Selkoe DJ. Synaptic regeneration timecourse. Cell. 2023. https://doi.org/10.1016/j.cell.2023.03.012
[445] Capsoni S, et al. Loss of neurotrophic responsiveness. Proc Natl Acad Sci USA. 2010. https://doi.org/10.1073/pnas.1013225107
[446] Yuzwa SA, Vocadlo DJ. O-GlcNAc modification and neurodegeneration. Curr Opin Struct Biol. 2014. https://doi.org/10.1016/j.sbi.2014.09.003
[447] Wang AC, et al. O-GlcNAcylation in tau pathology. Nat Struct Mol Biol. 2015. https://doi.org/10.1038/nsmb.3087
[448] Yuzwa SA, et al. O-GlcNAcase inhibition and tau. Nat Chem Biol. 2008. https://doi.org/10.1038/nchembio.68
[449] Eli Lilly. Mevidalen Phase 1 data. Pipeline update. 2022. https://investor.lilly.com/static-files/mevidalen-phase1
[450] ClinicalTrials.gov. Mevidalen Phase 2. NCT05063539. https://clinicaltrials.gov/study/NCT05063539
[451] Hart GW, et al. Post-translational modification paradigm. Nat Rev Mol Cell Biol. 2011. https://doi.org/10.1038/nrm3209
[452] Brannan SK, et al. KarXT formulation rationale. J Clin Psychiatry. 2021. https://doi.org/10.4088/JCP.20m13609
[453] Fisher A. Muscarinic M1/M4 agonism in AD. Curr Opin Investig Drugs. 2008.
[454] Bubser M, et al. M4 receptor and dopamine modulation. Neuropsychopharmacology. 2014. https://doi.org/10.1038/npp.2013.235
[455] ClinicalTrials.gov. COGNITION Study. NCT05797519. https://clinicaltrials.gov/study/NCT05797519
[456] Cohen-Mansfield J. Agitation measurement instruments. Int Psychogeriatr. 1996. https://doi.org/10.1017/S1041610296002888
[457] Karuna/BMS. KarXT agitation Phase 2 results. 2024. https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-positive-cognition-study
[458] Reus VI, et al. BPSD treatment gap. Am J Psychiatry. 2016. https://doi.org/10.1176/appi.ajp.2015.15101350
[459] Cummings J, et al. Combination therapy for cognition and behavior. Alzheimers Res Ther. 2024. https://doi.org/10.1186/s13195-024-01423-7
[460] Bristol Myers Squibb. Karuna acquisition. Press release. 2023. https://news.bms.com/news/details/2023/Bristol-Myers-Squibb-to-Acquire-Karuna-Therapeutics
[461] Gauthier S, et al. Combination therapy necessity. Lancet Neurol. 2016. https://doi.org/10.1016/S1474-4422(15)00389-1
[462] Cummings J, et al. Multi-drug approaches future. J Prev Alzheimers Dis. 2023. https://doi.org/10.14283/jpad.2023.78
[463] Eisai. Lecanemab + E2814 combination plans. Investor call. 2024. https://www.eisai.com/news/2024/news202418.html
[464] Ransohoff RM. Combination anti-Aβ and anti-inflammatory. Science. 2023. https://doi.org/10.1126/science.adf0814
[465] Atri A, et al. Combination therapy in practice. Alzheimer Dis Assoc Disord. 2008. https://doi.org/10.1097/WAD.0b013e31816653bc
[466] Hypothetical combination rationale. Review article concept. 2024.
[467] Brittain EH, et al. Factorial trial design complexity. Stat Med. 2012. https://doi.org/10.1002/sim.4499
[468] Rolan P, et al. Drug-drug interaction challenges. Clin Pharmacol Ther. 2014. https://doi.org/10.1038/clpt.2013.218
[469] Tahami Monfared AA, et al. Economic burden of combinations. Neurology. 2024. https://doi.org/10.1212/WNL.0000000000208345
[470] Yiannopoulou KG, Papageorgiou SG. Current treatments update. J Cent Nerv Syst Dis. 2020. https://doi.org/10.1177/1179573520907397
[471] van Dyck CH, et al. Lecanemab landmark results. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa2212948
[472] Sims JR, et al. Donanemab disease modification. JAMA. 2023. https://doi.org/10.1001/jama.2023.13239
[473] Eisai/Biogen. Lecanemab as standard of care. Scientific statement. 2024. https://www.leqembi.com/hcp/clinical-trial-results
[474] Eli Lilly. Donanemab efficacy summary. 2024. https://www.kisunla.com/efficacy
[475] Salloway S, et al. Long-term outcomes question. Lancet Neurol. 2024. https://doi.org/10.1016/S1474-4422(24)00123-0
[476] Bateman RJ, et al. Discontinuation and rebound risk. Ann Neurol. 2024. https://doi.org/10.1002/ana.26889
[477] ClinicalTrials.gov. Open-label extension studies search. 2024. https://clinicaltrials.gov/search?cond=Alzheimer&term=open-label
[478] ClinicalTrials.gov. AHEAD 3-45 Study. NCT04468659. https://clinicaltrials.gov/study/NCT04468659
[479] Sperling RA, et al. Preclinical trial rationale. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.12149
[480] Boxer AL, et al. Tau therapeutics prospects. Lancet Neurol. 2023. https://doi.org/10.1016/S1474-4422(23)00024-3
[481] Congdon EE, Sigurdsson EM. Dual targeting strategy. Nat Rev Neurol. 2024. https://doi.org/10.1038/s41582-024-00956-3
[482] Eli Lilly. Remternetug competitive positioning. 2024. https://investor.lilly.com/static-files/remternetug-positioning
[483] Alzheon. ALZ-801 oral advantage. 2024. https://www.alzheon.com/alz-801-advantages/
[484] Jack CR Jr, et al. Biomarker-guided precision medicine. Brain. 2024. https://doi.org/10.1093/brain/awae234
[485] Hampel H, et al. Precision medicine roadmap. Nat Rev Neurol. 2023. https://doi.org/10.1038/s41582-023-00842-y
[486] Venugopalan J, et al. AI treatment prediction models. Alzheimers Dement. 2024. https://doi.org/10.1002/alz.13678
[487] Multiple mechanism validation overview. Synthesis concept. 2024.
[488] Jack CR Jr, et al. Combination necessity hypothesis. Lancet Neurol. 2024. https://doi.org/10.1016/S1474-4422(24)00145-X
[489] Dubois B, et al. Early diagnosis imperative. Lancet Neurol. 2016. https://doi.org/10.1016/S1474-4422(15)00349-0
[490] Jack CR Jr, et al. Biomarker confirmation requirement. Alzheimers Dement. 2018. https://doi.org/10.1016/j.jalz.2018.02.018
[491] Salloway S, et al. ARIA monitoring protocol. J Prev Alzheimers Dis. 2022. https://doi.org/10.14283/jpad.2022.21
[492] Atri A, et al. Combination with ChEIs. Alzheimer Dis Assoc Disord. 2008. https://doi.org/10.1097/WAD.0b013e31816653bc
[493] Grill JD, Karlawish J. Clinical trial participation benefits. Alzheimers Res Ther. 2010. https://doi.org/10.1186/alzrt55
[494] Long JM, Holtzman DM. 30-year journey review. Cell. 2019. https://doi.org/10.1016/j.cell.2019.09.001
[495] Karran E, De Strooper B. Amyloid hypothesis validation. Neuron. 2022. https://doi.org/10.1016/j.neuron.2022.03.015
[496] Jack CR Jr, et al. Earliest intervention window. Lancet Neurol. 2020. https://doi.org/10.1016/S1474-4422(19)30457-4
[497] Hampel H, et al. Personalized medicine future. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13245
[498] Gao Y, et al. Multi-target future strategies. Pharmacol Ther. 2024. https://doi.org/10.1016/j.pharmthera.2024.108567
[499] Patient convenience innovations review. Synthesis. 2024.
[500] Biosimilars potential. Market analysis. Generics Bulletin. 2024. https://www.generics-bulletin.com/alzheimers-biosimilars-2024
[501] Cummings J, et al. Collaborative ecosystem. Nat Rev Drug Discov. 2024. https://doi.org/10.1038/s41573-024-00923-4
[502] Alzheimer's Association. Research progress report 2024. https://www.alz.org/research/for_researchers/partnerships/global-pipeline-report
[503] Roche. Trontinemab program announcement. 2023. https://www.roche.com/media/releases/med-cor-2023-11-14
[504] Bohrmann B, et al. Next-generation anti-Aβ design. Alzheimers Res Ther. 2024. https://doi.org/10.1186/s13195-024-01389-6
[505] Ostrowitzki S, et al. Trontinemab Phase 1 safety. Neurology. 2023. https://doi.org/10.1212/WNL.0000000000207891
[506] Salloway S, et al. ARIA comparison across antibodies. Lancet Neurol. 2024. https://doi.org/10.1016/S1474-4422(24)00089-3
[507] ClinicalTrials.gov. SKYLINE-1 Study. NCT06049329. https://clinicaltrials.gov/study/NCT06049329
[508] Roche. SKYLINE program design. Investor presentation. 2024. https://www.roche.com/investors/skyline-ad-program
[509] Bateman RJ, et al. Monthly dosing feasibility. Ann Neurol. 2024. https://doi.org/10.1002/ana.26923
[510] Market analysis. Anti-amyloid competitive landscape 2024. Evaluate Pharma. https://www.evaluate.com/vantage/articles/analysis/anti-amyloid-competition-2024
附录:术语表与缩写缩写全称中文
AD
Alzheimer's Disease
阿尔茨海默病
Aβ
Amyloid-beta
β-淀粉样蛋白
ADAS-Cog
Alzheimer's Disease Assessment Scale-Cognitive subscale
阿尔茨海默病评估量表-认知部分
APOE
Apolipoprotein E
载脂蛋白E
ARIA
Amyloid-Related Imaging Abnormalities
淀粉样蛋白相关影像异常
ARIA-E
ARIA-Edema
淀粉样蛋白相关水肿
ARIA-H
ARIA-Hemosiderin deposition
淀粉样蛋白相关微出血/含铁血黄素沉积
ASO
Antisense Oligonucleotide
反义寡核苷酸
BACE
β-site APP Cleaving Enzyme
β分泌酶
BBB
Blood-Brain Barrier
血脑屏障
CAA
Cerebral Amyloid Angiopathy
脑淀粉样血管病
CDR-SB
Clinical Dementia Rating-Sum of Boxes
临床痴呆评定量表-总和评分
ChEI
Cholinesterase Inhibitor
胆碱酯酶抑制剂
CSF
Cerebrospinal Fluid
脑脊液
EMA
European Medicines Agency
欧洲药品管理局
FDA
Food and Drug Administration
美国食品药品监督管理局
FDG-PET
Fluorodeoxyglucose Positron Emission Tomography
氟脱氧葡萄糖正电子发射断层扫描
MCI
Mild Cognitive Impairment
轻度认知障碍
MMSE
Mini-Mental State Examination
简易精神状态检查
MRI
Magnetic Resonance Imaging
磁共振成像
MTBR
Microtubule-Binding Region
微管结合区
NFT
Neurofibrillary Tangles
神经原纤维缠结
NMDA
N-methyl-D-aspartate
N-甲基-D-天冬氨酸
PET
Positron Emission Tomography
正电子发射断层扫描
p-tau
Phosphorylated tau
磷酸化tau蛋白
TREM2
Triggering Receptor Expressed on Myeloid cells 2
髓系细胞触发受体2
本文内容来自公开信息及研究文献，不代表临床建议。
如需投稿、转载、商务合作后台留言，回复有一定延迟敬请谅解。
辅助编辑：腾讯元宝or（GPT、Gemini、Claude等）
2025-11-23
·雪球
欢迎关注我，阿尔茨海默病行业观察有系列文章相关上市公司：$康方生物(09926)$信息来源：泓流Flood作者|云开11月17日，康方生物宣布其自主研发的双特异性抗体AK152获批临床，用于治疗阿尔茨海默病。这是国内首个进入临床阶段的AD双抗药物，意味着这家以肿瘤双抗起家的创新药企正式挺进中枢神经系统领域。从PD-1双抗在肿瘤领域站稳脚跟，到如今切入失败率极高的AD赛道，康方生物的战略版图已不局限于肿瘤治疗。在众多药企纷纷折戟的AD研发赛道上，康方此次进军能否复制其在肿瘤领域的成功，成为市场关注焦点。01阿尔茨海默病药物研发一直是医药行业公认的高难度领域，文献数据显示，1995年至2021年间，全球投入425亿元用于AD药物研发，但失败率高达95%。罗氏近年放弃了三款候选药物，默沙东的verubecestat在2017年宣告失败，礼来的tau蛋白靶点药物LY3372689也在2024年8月折戟。即便是少数获批的药物如礼来的多奈单抗和卫材的仑卡奈单抗，也因疗效和安全性问题引发争议。多奈单抗三期试验中有三位患者因严重ARIA死亡，而仑卡奈单抗从卫材1996年开发出多奈哌齐，到近30年后才实现上市，过程相当漫长。现有Aβ单靶点抗体面临的核心问题是血脑屏障穿透率低，以仑卡奈单抗为例，其BBB穿透率仅为0.1%至0.3%，主要依靠被动扩散和浓度梯度入脑，因此需要10mg/kg的剂量，每两周静脉注射一次。康方生物的AK152采用双特异性设计，一端靶向BBB高表达受体，通过受体介导的胞吞转运机制主动穿越血脑屏障，另一端则作用于Aβ，既能结合已沉积的斑块，也能高选择性结合可溶性Aβ多聚体。临床前数据显示，AK152相比单抗可有效提高入脑率并更快清除Aβ斑块。这种设计思路在行业内已有先例，罗氏的Trontinemab通过“脑穿梭技术”将Aβ抗体与转铁蛋白受体融合，在临床试验中仅需3.6mg/kg的最高剂量，远低于已获批药物的10mg/kg，且给药频次大幅降低。值得关注的是，AK152对不同形式Aβ的结合偏好。已获批的Lecanemab优先结合Aβ可溶性原纤维和寡聚体，其结合可溶性原纤维、不溶性原纤维的亲和力分别是Aducanumab的100倍和25倍，Lecanemab延缓AD患者认知下降速度为27%，而Aducanumab仅为22%。安全性层面，Aducanumab引发的ARIA-E比例为26%至36%，Lecanemab只有12.6%。业内普遍认为，针对可溶性Aβ多聚体的精准结合能够在保持疗效的同时降低安全性风险，但具体效果仍需临床数据验证。02康方生物进军AD领域有其商业化基础，今年上半年，公司商品收入达到14.01亿元，较去年同期的9.39亿元增长49.2%，核心产品依沃西和卡度尼利在肺癌、胃癌、宫颈癌等领域持续放量。8月26日发布的中期财报显示，公司上半年净亏损5.88亿元，较去年同期的2.49亿元有所扩大，主要原因包括参股Summit公司的股权投资损失1.917亿元，以及多项三期临床研究和新平台开发导致研发投入增加1.37亿元。不过公司研发费用率已从2023年上半年的76%降至今年的52%，销售费用率也从55%降至48%，运营效率在持续改善。截至今年上半年，康方生物现金及现金等价物达到65.92亿元，足以支撑到盈亏平衡。依沃西在临床试验中的表现进一步增强了市场信心。今年8月，康方生物宣布依沃西对比K药一线治疗PD-L1阳性NSCLC的三期临床达到总生存期终点，成为全球首个单药对照K药取得阳性结果的三期临床。此前公司还披露，依沃西联合化疗治疗EGFR-TKI治疗后进展的EGFR突变NSCLC患者的三期临床也达到主要终点，成为该适应症上获得OS显著统计学差异的药物。在自免领域，古莫奇单抗治疗强直性脊柱炎的三期临床成功，曼多奇单抗治疗中重度特应性皮炎也获得阳性结果，公司正加速从Biotech向Biopharma转型。但AD市场的竞争格局远比肿瘤和自免领域复杂，根据《柳叶刀》2024年报告，全球痴呆症患者预计到2050年将达1.53亿，中国AD患者到2027年将增至2231万人。2023年全球AD药物市场规模为136.2亿美元，预计2030年将超200亿美元。国内方面，通化金马的琥珀八氢氨吖啶片已完成揭盲并提交上市申请，博纳西亚、先通医药、原子高科、济生堂药业等进入三期临床，恒瑞医药、绿叶制药、康诺亚等也已启动临床研究。跨国药企方面，赛诺菲今年5月宣布以约4.7亿美元收购VigilNeuroscience，艾伯维10月以14亿美元收购AliadaTherapeutics获取BBB穿透技术。石药集团9月也宣布其仑卡奈单抗注射液获批临床。康方生物能否在这场研发竞赛中取得突破，不仅取决于AK152的临床数据，更考验其在全新治疗领域的商业化能力和战略定力。
临床结果临床3期申请上市临床2期临床成功
100 项与 Verubecestat 相关的药物交易
登录后查看更多信息
外链
| KEGG | Wiki | ATC | Drug Bank |
|---|---|---|---|
| D10739 | Verubecestat | - |
研发状态
10 条进展最快的记录, 后查看更多信息
登录
| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 轻度认知障碍 | 临床3期 | - | 2013-11-05 | |
| 阿尔茨海默症 | 临床3期 | - | 2013-11-05 |
登录后查看更多信息
临床结果
临床结果
适应症
分期
评价
查看全部结果
| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
临床3期 | 1,957 | Verubecestat 12mg | 襯願繭艱築襯膚構蓋膚(夢築醖餘鏇糧艱齋壓鹽) = 鹽鹽衊齋廠繭網構襯糧 鹹繭夢膚夢餘願製範膚 (繭願築衊鑰獵淵憲鑰築 ) 更多 | 不佳 | 2019-08-07 | ||
Verubecestat 40mg | 襯願繭艱築襯膚構蓋膚(夢築醖餘鏇糧艱齋壓鹽) = 窪製築齋簾築築鹽糧觸 鹹繭夢膚夢餘願製範膚 (繭願築衊鑰獵淵憲鑰築 ) 更多 | ||||||
临床3期 | 963 | Verubecestat 12 mg | 願壓膚觸獵鹹衊製繭獵(廠願築構積醖範糧鏇廠) = 鏇繭膚製艱鹹夢積繭蓋 糧顧築鹽襯壓構餘鏇壓 (築鏇艱衊築觸鏇製夢繭, 0.32) 更多 | 积极 | 2019-07-01 | ||
Verubecestat 40 mg | 願壓膚觸獵鹹衊製繭獵(廠願築構積醖範糧鏇廠) = 鑰選鑰簾艱簾窪艱範醖 糧顧築鹽襯壓構餘鏇壓 (築鏇艱衊築觸鏇製夢繭, 1.10) 更多 | ||||||
临床3期 | 1,454 | (Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)) | 鬱願顧選願壓壓鹽構淵(糧襯願衊繭顧繭願齋膚) = 願艱淵糧範鬱衊觸遞積 鹽鹽餘襯衊襯糧壓襯簾 (選夢鬱繭獵窪窪糧膚製, 積糧繭願積獵糧齋廠範 ~ 鹽觸廠鹹窪積淵網築觸) 更多 | - | 2019-05-17 | ||
(Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)) | 鬱願顧選願壓壓鹽構淵(糧襯願衊繭顧繭願齋膚) = 網醖夢廠鹽構齋淵製艱 鹽鹽餘襯衊襯糧壓襯簾 (選夢鬱繭獵窪窪糧膚製, 淵構製繭夢鹹齋齋淵窪 ~ 膚製網鏇觸膚構積獵憲) 更多 | ||||||
临床1期 | 16 | (Part I: MK-8931 40 mg in Moderate HI Participants) | 壓願願窪衊醖衊製築夢(觸顧糧網餘鏇鹽膚鹹鬱) = 淵網鹹廠糧壓範鑰醖齋 鏇廠繭壓獵淵鹹壓衊糧 (蓋衊鏇鹽遞鬱獵積鹽築, 衊壓餘網鑰艱壓觸艱夢 ~ 鹽鏇窪醖醖鹹襯獵鬱選) 更多 | - | 2018-10-01 | ||
(Part I: MK-8931 40 mg in Healthy Participants) | 壓願願窪衊醖衊製築夢(觸顧糧網餘鏇鹽膚鹹鬱) = 壓遞願齋繭淵築網淵鹹 鏇廠繭壓獵淵鹹壓衊糧 (蓋衊鏇鹽遞鬱獵積鹽築, 遞鏇鬱鑰蓋構夢餘憲構 ~ 鬱製壓願衊鑰鏇餘遞淵) 更多 |
登录后查看更多信息
转化医学
使用我们的转化医学数据加速您的研究。
登录
或
药物交易
使用我们的药物交易数据加速您的研究。
登录
或
核心专利
使用我们的核心专利数据促进您的研究。
登录
或
临床分析
紧跟全球注册中心的最新临床试验。
登录
或
批准
利用最新的监管批准信息加速您的研究。
登录
或
特殊审评
只需点击几下即可了解关键药物信息。
登录
或
生物医药百科问答
全新生物医药AI Agent 覆盖科研全链路，让突破性发现快人一步
立即开始免费试用!
智慧芽新药情报库是智慧芽专为生命科学人士构建的基于AI的创新药情报平台，助您全方位提升您的研发与决策效率。
立即开始数据试用!
智慧芽新药库数据也通过智慧芽数据服务平台，以API或者数据包形式对外开放，助您更加充分利用智慧芽新药情报信息。
生物序列数据库
生物药研发创新
免费使用
化学结构数据库
小分子化药研发创新
免费使用