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更新于：2026-08-29
Elenbecestat
更新于：2026-08-29
概要
基本信息
原研机构 |
在研机构- |
最高研发阶段暂停临床3期 |
首次获批日期- |
最高研发阶段(中国)暂停 |
特殊审评- |
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结构/序列
分子式C19H18F3N5O2S |
InChIKeyAACUJFVOHGRMTR-DPXNYUHVSA-N |
CAS号1388651-30-6 |
关联
13
项与 Elenbecestat 相关的临床试验NCT03055962
A Randomized, Double-blind, Placebo-controlled, Multiple Dose Study to Evaluate the Safety and Tolerability of a Once Daily Dose of 50 mg E2609 in Healthy Japanese Subjects
Study E2609-J081-014 is a single-center, randomized, double-blind, placebo-controlled study conducted to evaluate the safety and tolerability of multiple oral doses of E2609 50 milligrams (mg), administered once daily for 14 days, in healthy Japanese participants aged 50 to 85 years.
开始日期2017-02-14 |
申办/合作机构 |
JPRN-jRCT2080223449
A Randomized, Double-blind, Placebo-controlled, Multiple Dose Study to Evaluate the Safety and Tolerability of a Once Daily Dose of 50 mg E2609 in Healthy Japanese Subjects
开始日期2017-02-04 |
申办/合作机构 |
NCT02956486
A Placebo-Controlled, Double-Blind, Parallel-Group, 24 Month Study With an Open-Label Extension Phase to Evaluate the Efficacy and Safety of Elenbecestat (E2609) in Subjects With Early Alzheimer's Disease
The name of this trial is MissionAD1. This phase 3 study consists of a Core and Open Label Extension (OLE) Phase in participants with Early Alzheimer's Disease (EAD), and will be conducted to evaluate the efficacy and safety of E2609. The Core is a 24-month treatment, multicenter, double blind, placebo controlled parallel group study. The OLE is a 24-month treatment, one group study. The data for the studies E2609-G000-301 (NCT02956486, MissionAD1) and E2609-G000-302 (NCT03036280, MissionAD2) will be pooled.
开始日期2016-10-20 |
申办/合作机构  Eisai Co., Ltd. [+1] |
100 项与 Elenbecestat 相关的临床结果
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100 项与 Elenbecestat 相关的转化医学
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100 项与 Elenbecestat 相关的专利（医药）
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35
项与 Elenbecestat 相关的文献（医药）2026-05-01·JPAD-Journal of Prevention of Alzheimers Disease
Discordance in amyloid positivity between visual reads and Centiloids: Impact of white matter uptake
Article
作者: Devanarayan, Viswanath ; Charil, Arnaud ; Reyderman, Larisa ; Kramer, Lynn D ; Irizarry, Michael C ; Reilhac, Anthonin ; Dhadda, Shobha ; Nelson, Todd M
BACKGROUND:
The visual interpretation of amyloid PET scans, or visual read (VR), is the most common technique used in clinical practice to identify the presence of cerebral amyloid plaques. Amyloid status (positive or negative) determined by VR or using a Centiloid (CL) cut-off shows high overall concordance. However, discordant cases can occur where the VR is positive, but the CL is below the positivity cut-off, or vice versa.
OBJECTIVES:
The objective of this analysis was to evaluate the rate of discordance and explore potential causes, particularly the role of amyloid tracer uptake in the white matter (WM), when determining amyloid status using VR and CL in screening for the elenbecestat phase 3 studies in early Alzheimer's disease (AD).
DESIGN:
Amyloid PET scans using either Florbetapir (Amyvid™), Florbetaben (Neuraceq™) or Flutemetamol (Vizamyl™) from 3,232 participants (1507 VR- and 1725 VR+) with cognitive impairment screened for the elenbecestat phase 3 studies in early AD were visually interpreted at screening by trained neuroradiologists and quantified using CL values.
SETTING:
Academic and clinical centers INTERVENTION/MEASUREMENTS: Quantitatively, amyloid positivity was defined as CL > 32.21. The number of positive cortical regions was determined by counting the number of regions with a standardized uptake value ratio (SUVr) that exceeded 1.17. PET SUVr levels in the cerebral WM were measured using an eroded WM region of interest (ROI). Statistical tests were conducted to detect differences among the four concordance groups, defined by the relationship of VR and CL status (positive or negative). Additionally, tests examined the relationship between uptake in the WM and rates and type of discordance. Receiver operating characteristic (ROC) analysis and DeLong's test were also used to examine the effect of different tracers on the discordant rates.
RESULT:
Discordance was observed in 6.53% of cases (n=211), with VR+/CL- in 4.61% (n=149) and VR-/CL+ in 1.92% (n=62). VR+/CL- discordant cases had significantly fewer amyloid-positive cortical regions compared to both VR+/CL+ and VR-/CL+ cases. VR-/CL+ cases had a significantly higher WM uptake than VR-/CL- and VR+/CL- cases. Our findings revealed a relationship between WM uptake and rates and types of discordance. High WM uptake can erroneously lead to CL+, due to gray matter (GM) contamination from the WM, and VR- status, due to reduced contrast between WM and GM, resulting in VR-/CL+ cases. Conversely, low WM uptake can result in an underestimation of CL values, inaccurately classifying a scan as CL-, and at the same time, the increased contrast may result in a VR+, thereby increasing the occurrence of discordant VR+/CL- cases.
CONCLUSION:
Variations in WM uptake significantly contribute to discordances by introducing positive or negative bias in CL values and altering the GM to WM contrast, which forms the basis of the VR. Nevertheless, the rates of discordant cases are low and VR represents a robust and validated method to determine the presence of amyloid deposition. VR enables enrolling patients with amyloid beta pathology, as seen on amyloid PET scans, whereas CL scaling was developed to provide standardized units that more consistently characterize longitudinal amyloid‑β change. These findings reflect the complementary roles of VR and CL in amyloid PET evaluation, with implications for refining diagnostic accuracy and disease monitoring in AD clinical trials and practice.
2026-01-01·PROTEOMICS
Elenbecestat and Compound 89 Potently Inhibit BACE1 but Not BACE2 When Subchronically Dosed in Non‐Human Primates
Article
作者: Hyakkoku, Kana ; Yoshimura, Akimasa ; Lichtenthaler, Stefan F. ; Schmidt, Andree ; Ito, Mana ; Müller, Stephan A. ; Horiguchi, Naotaka ; Tschirner, Sarah K.
ABSTRACT:
The β‐secretase BACE1 (β‐site amyloid precursor (APP) cleaving enzyme 1) is a major drug target for Alzheimer's disease (AD), as it catalyzes the first step in amyloid β (Aβ) generation, but has additional substrates and functions, in particular in the brain. Several advanced clinical trials with BACE1 inhibitors were stopped because of an adverse event, a mild cognitive worsening. The underlying mechanism is not yet known but may result from co‐inhibition of the BACE1‐homolog BACE2. While a cerebrospinal fluid (CSF) biomarker for measuring BACE2 activity is not yet established, VCAM‐1 has been suggested as such a biomarker, but has not yet been tested upon prolonged dosing in vivo. Using CSF pharmacoproteomics and a subchronic dosing paradigm in non‐human primates, we demonstrate that compound 89, a BACE inhibitor not yet tested in humans, and the clinically tested drug elenbecestat inhibit BACE1 in vivo, with little or no effect on BACE2, as seen with a reduction of substrates of BACE1, but not of the BACE2 substrate VCAM‐1. As a control, verubecestat, which inhibits both BACE2 and BACE1, reduced CSF abundance of BACE1 substrates as well as of VCAM‐1. This study demonstrates the suitability of VCAM‐1 as a pharmacodynamic biomarker for measuring BACE2 target engagement in CSF.
2025-12-01·Alzheimers & Dementia
Alzheimer’s disease molecular subtypes in a clinical trial cohort
Article
作者: Berven, Frode Steingrimsen ; Tijms, Betty M. ; Saxena, Satya ; Teunissen, Charlotte E. ; Visser, Pieter Jelle ; Sachdev, Pallavi ; Mjaavatten, Olav
Abstract:
Background:
Alzheimer’s disease (AD) exhibits significant molecular heterogeneity, which poses challenges for treatment development. Understanding this heterogeneity is essential for creating more effective therapies and improving patient outcomes. Our recent research identified five distinct AD subtypes based on protein level alterations: hyperplasticity (s1), innate immune activation (s2), RNA dysregulation (s3), choroid plexus dysfunction (s4), and blood‐brain barrier dysfunction (s5). This study aims to determine if these subtypes can be identified in an independent cohort of early AD patients from a clinical trial.
Method:
Baseline cerebrospinal fluid (CSF) samples from 101 amyloid‐positive and 101 amyloid‐negative individuals (based on PET visual read) were collected from a Phase 3 program for elenbecestat in subjects with mild cognitive impairment (MCI) or mild dementia due to AD (NCT02956486). These samples were analyzed using 16‐plex tandem mass tag (TMT) mass spectrometry. Each individual was classified into an AD molecular subtype using a random forest classifier trained on our previous discovery cohort, utilizing 1249 overlapping proteins between the studies. We then compared CSF protein levels across the new sample for each subtype and against the amyloid‐negative group to assess amyloid specificity using linear regression models.
Result:
Amyloid‐positive individuals exhibited SMOC1 levels one standard deviation higher than amyloid PET‐negative individuals, confirming previous associations of SMOC1 with amyloid status (p < 0.01x10^‐10) (see figures a‐b). All five AD subtypes were identified in the amyloid‐positive group: 45 (44%) were classified as hyperplasticity s1; 20 (20%) as innate immune activation s2; 1 (1%) as RNA dysregulation s3; 18 (18%) as choroid plexus s4; and 17 (17%) as blood‐brain barrier dysfunction s5. Protein level comparisons across subtypes largely replicated our previous findings (see figures c‐f for example subtype‐specific proteins).
Conclusion:
The replication of the five AD molecular subtypes in an independent clinical trial cohort further supports the robustness of these subtypes and paves the way for personalized medicine and novel combination therapy approaches in AD.Reference
1. Tijms, B. M.
et al
. Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles.
Nat. Aging
33–47 (2024) doi:
10.1038/s43587‐023‐00550‐7
.
24
项与 Elenbecestat 相关的新闻（医药）2026-06-26
·生物通
阿尔茨海默病（Alzheimer’s disease, AD）是一种以认知功能下降、记忆丧失及行为改变为特征的进行性神经退行性疾病，其核心病理特征包括细胞外β-淀粉样蛋白（amyloid-β, Aβ）斑块沉积、细胞内神经纤维缠结（neurofibrillary tangles, NFTs）、突触丢失、神经炎症、线粒体功能障碍及脑代谢异常。AD临床分为早发性与晚发性两类，仅少数早发性病例为家族性，由淀粉样前体蛋白（amyloid precursor protein, APP）、早老素1（presenilin 1, PSEN1）及早老素2（PSEN2）基因突变所致；绝大多数早发与晚发AD均为散发性，受复杂遗传、环境及年龄相关因素共同影响。当前临床常规治疗以胆碱酯酶抑制剂（cholinesterase inhibitors, ChEIs）与N-甲基-D-天冬氨酸（N-Methyl-D-Aspartate, NMDA）受体拮抗剂为主，仅可缓解临床症状，无法延缓疾病进展。靶向Aβ42的单克隆抗体可降低患者脑内淀粉样蛋白负荷，但其临床疗效有限，在学术界仍存在争议。基因治疗、干细胞治疗、纳米技术、精准医疗及人工智能（Artificial Intelligence, AI）驱动的诊断与治疗等新型策略尚处于研发阶段。基于生物标志物的早期诊断联合多模式治疗策略，有望推动AD管理从症状干预向疾病修饰（disease-modifying）方向转变。本综述旨在系统评价AD现有及新兴治疗策略，综合分析新兴疗法临床试验的成功与失败结果，探讨相关挑战并展望未来发展前景。1 引言
1.1 AD概述
AD是最常见的痴呆类型，1906年由Alois Alzheimer首次描述，病理特征为记忆丧失、定向障碍及死后脑组织可见Aβ斑块与神经原纤维缠结。临床进程起始于记忆与执行功能缺损，逐渐进展至语言、识别能力受损及日常生活能力下降。核心致病机制包括Aβ蓄积、tau蛋白过度磷酸化、突触与神经元丢失、胶质增生及小胶质细胞活化，主要累及海马与皮质。AD分为家族性（占比<5%，由APP、PSEN1、PSEN2突变导致）与散发性（占比>95%，受年龄、环境及载脂蛋白E ε4等位基因（APOE ε4）影响）两类。关键病理生理过程还包括线粒体功能障碍、氧化应激、钙稳态失衡、慢性神经炎症及葡萄糖低代谢，共同介导突触损伤与神经退行性变。全球范围内2021年痴呆患病人数达5500万，预计2050年将增至1.39亿，伴随医疗与社会经济负担持续上升。
1.2 AD治疗策略演进的必要性
当前治疗仅能提供症状缓解，无法阻止或逆转疾病进展。传统药物如ChEIs与谷氨酸靶向药物仅可实现有限的认知改善，未触及核心病理过程。近年获批的Aducanumab与Lecanemab等免疫疗法靶向Aβ，但受限于临床获益有限及安全性顾虑：Aducanumab虽可减少淀粉样斑块，但未显示出显著认知获益，已于2024年撤市；Lecanemab可在18个月Ⅲ期试验中轻度降低认知衰退速率。单一靶向Aβ的单克隆抗体虽能降低斑块负荷，但未能充分阻断疾病进展，提示AD是由多通路交互驱动的复杂疾病。现有研究多孤立分析单一靶点，缺乏对成功与失败干预的整合性转化视角，常忽略临床试验失败原因、疾病分期与异质性对疗效的影响，以及新疗法与传统方案的联合策略。本综述通过整合现有与新兴疗法证据，明确转化挑战、最佳干预时机及分期特异性联合治疗的需求。
2 AD病理生理学
胆碱能假说认为基底前脑胆碱能神经元（尤其是Meynert基底核）变性导致乙酰胆碱缺乏，引起海马与皮质突触传递障碍，最终引发记忆与注意力缺损。尸检研究显示AD患者存在显著胆碱能神经元丢失，ChEIs仅可带来症状性认知改善，不影响疾病进展。淀粉样级联假说由Hardy与Higgins于1992年提出，认为Aβ蓄积是神经退行性变的核心驱动因素，尤其在APP与早老素基因突变导致的家族性AD中更为显著。Aβ经分泌酶切割后形成Aβ42，可损伤神经元并促进脑萎缩。tau假说指出tau蛋白过度磷酸化破坏其微管稳定功能，导致细胞骨架失稳、轴突运输缺陷及神经原纤维缠结蓄积，最终介导突触功能障碍与神经元丢失。神经炎症与小胶质细胞、星形胶质细胞持续活化促进促炎介质释放，加重氧化应激并损害Aβ清除，小胶质细胞同时表现出促炎与抗炎表型转换特征。脑葡萄糖低代谢通过降低葡萄糖转运体表达与胰岛素信号传导，限制能量供应，导致ATP耗竭、线粒体功能障碍、氧化应激及突触损伤。线粒体功能障碍被认为是AD早期关键事件，Aβ与tau病理进一步加重线粒体损伤，形成代谢应激恶性循环，使线粒体成为潜在疾病修饰靶点。血管功能障碍则通过减少脑灌注、破坏血脑屏障及损害Aβ清除，加剧神经炎症与神经元易损性。此外，蛋白质稳态失衡（尤其是溶酶体-自噬活性缺陷）驱动Aβ与tau蓄积，钙稳态失衡、金属离子失调、朊病毒样病理播散及潜在感染触发因素共同加速神经元变性。上述多尺度病理过程协同作用，解释了晚期AD中单一靶点疗法疗效有限的原因。
3 传统治疗方法
胆碱能神经元丢失是ChEIs的治疗基础，通过提升乙酰胆碱水平部分代偿海马与皮质胆碱能缺陷。多奈哌齐适用于轻、中、重度AD，卡巴拉汀同时抑制乙酰胆碱酯酶与丁酰胆碱酯酶，有口服与透皮贴剂两种剂型，加兰他敏还可调节烟碱型乙酰胆碱受体，三者均可带来轻度认知与功能获益，但常见胃肠道不适、头晕或失眠等不良反应，无法改变疾病进程。美金刚是NMDA受体拮抗剂，通过减少谷氨酸介导的兴奋性毒性（慢性NMDA受体过度激活、钙内流超载、线粒体功能障碍及神经元损伤）保护生理性突触信号传导，半衰期长、口服给药，可与ChEIs联用以增强疗效，同样不延缓疾病进展。抑郁、焦虑、激越、幻觉及睡眠障碍等行为精神症状可采用选择性5-羟色胺再摄取抑制剂（SSRIs）、5-羟色胺-去甲肾上腺素再摄取抑制剂（SNRIs）、非典型抗精神病药或心境稳定剂治疗，但受限于不良反应。传统AD疗法基于胆碱能与谷氨酸能假说，针对神经递质功能障碍而非核心神经退行性机制，仅能通过增强神经传递实现短期症状改善，反映了神经递质缺损是神经元丢失的下游结果，明确了症状改善机制与疾病根本驱动机制的差异。
4 AD治疗的新兴创新
4.1 淀粉样蛋白靶向免疫疗法
包括主动免疫（疫苗）与被动免疫（单克隆抗体）。主动免疫通过接种抗原联合佐剂诱导内源性抗体反应，可产生持久免疫应答。早期疫苗多采用全长Aβ42抗原，新型策略聚焦于短肽序列、DNA疫苗或初免-加强策略以提升免疫原性。AN1792、CAD106、UB-311等候选疫苗旨在诱导抗Aβ免疫反应，但AN1792因T细胞介导的脑膜脑炎被终止，其余候选药物因长期疗效有限尚未获批。被动免疫直接使用预成型抗体，包括人源化单克隆抗体与静脉注射免疫球蛋白（IVIG）。Aducanumab曾获FDA加速批准，后因疗效与安全性争议于2024年撤市；Lecanemab靶向可溶性及不溶性Aβ，2023年获FDA批准用于早期AD，18个月Ⅲ期试验显示可显著降低淀粉样蛋白负荷并减缓认知衰退，皮下制剂随后获批用于静脉给药后的维持治疗；Donanemab在TRAILBLAZER-ALZⅡ期试验中显示可为早期症状性AD患者带来认知与功能获益，2024年获FDA批准，2025年在欧盟获批，成为25年来首个获许可的淀粉样蛋白靶向疗法。MK-2214等tau靶向抗体已进入早期临床试验，体现双靶点免疫治疗趋势。此类疗法的主要安全性风险为淀粉样蛋白相关影像学异常（amyloid-related imaging abnormalities, ARIA），包括血管源性水肿（ARIA-E）与出血事件（ARIA-H），在APOE ε4携带者中发生率更高，需强化MRI监测与剂量调整，限制了临床推广。Solanezumab、Crenezumab与Gantenerumab等药物的失败进一步凸显AD异质性对疗效的影响，Aβ清除与临床改善的解离提示单一靶向Aβ不足以改变疾病进程，未来需结合患者分层、多靶点策略及tau病理、神经炎症通路联合干预。
4.2 基因治疗与CRISPR-Cas9基因编辑
基因治疗通过腺相关病毒（adeno-associated viruses, AAVs，如AAV2、AAV9）递送神经营养因子或功能基因，在动物模型中可实现基底前脑胆碱能神经元保护、恢复γ-分泌酶活性、降低Aβ负荷、减轻炎症及提升神经元存活率。AAV2介导的神经生长因子（nerve growth factor, NGF）递送、AAV9介导的功能性PSEN1递送及APOE2基因递送均显示出病理改善效应。聚合物介导的脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）mRNA递送可维持BDNF释放、降低兴奋性毒性并改善记忆。神经营养因子α1（neurotrophic factor-α1, NF-α1）可减少AD模型中的Aβ与tau病理。目前尚无基因疗法获批用于AD，主要挑战包括血脑屏障穿透效率低、脱靶编辑风险、转基因长期表达稳定性不足、病毒载体免疫原性及散发性AD的多因素致病机制。CRISPR-Cas9技术可通过精确编辑APP、PSEN1/PSEN2、APOE等AD相关基因，降低Aβ生成、纠正Aβ42/Aβ40比值、改善神经元表型并调节APOE4模型的脂质代谢。PSEN2突变校正或PSEN1敲除可减少γ-分泌酶活性与Aβ负荷，硫氧还蛋白相互作用蛋白（thioredoxin-interacting protein, TXNIP）下调可降低氧化应激。CRISPR技术还可构建精准AD小鼠与类器官模型，如Plcγ2-P522R敲入可改善小胶质细胞功能并减缓神经退行性变。但不可逆基因组改变带来监管与伦理顾虑，需长期安全性监测，目前主要用于机制验证与靶点确证，尚不具备近期临床应用条件。
4.3 干细胞治疗
干细胞治疗主要通过神经保护与网络稳定发挥作用，而非完全替代神经元，在早期阶段（显著神经元丢失前）获益更明显，目前仅显示短期安全性与轻度认知改善，无长期疗效证据。按细胞来源可分为四类：胚胎干细胞（embryonic stem cells, ESCs）来源于囊胚内细胞团，可分化为胆碱能、GABA能等神经元亚型，在AD小鼠模型中可部分恢复胆碱能信号、减轻神经炎症并改善认知，但存在致畸瘤风险、免疫排斥及伦理争议，尚未进入临床试验。间充质干细胞（mesenchymal stem cells, MSCs）来源于骨髓、脂肪组织、脐带等，伦理接受度高、致瘤风险低，主要通过旁分泌神经营养因子（BDNF、NGF）、上调降解酶（脑啡肽酶NEP、胰岛素降解酶IDE）、促进抗炎小胶质细胞极化、增强Aβ降解及改善脑葡萄糖代谢发挥治疗作用，其来源的外泌体也可通过抗炎与Aβ清除途径保护突触功能。诱导多能干细胞（induced pluripotent stem cells, iPSCs）通过重编程成年体细胞获得，可避免伦理问题并实现患者特异性建模，移植后可形成功能性突触、分泌神经营养因子、减轻Aβ与tau病理，但存在致畸瘤风险、重编程效率不稳定及基因组不稳定性等局限。神经干细胞（neural stem cells, NSCs）可分化为神经元、星形胶质细胞与少突胶质细胞，可降低致瘤风险，在动物模型中可恢复胆碱能神经元、提升突触密度并分泌神经营养因子。目前多项临床试验正在评估脐带血、海马或丘脑NSC移植的安全性，尚无干细胞疗法获批，主要障碍包括供体差异、移植后存活与整合率低、免疫排斥、致瘤性及分化技术难题。
4.4 小分子抑制剂
靶向淀粉样生成通路的小分子包括β-位点APP切割酶1（beta-site amyloid precursor protein cleaving enzyme 1, BACE1）抑制剂、γ-分泌酶抑制剂（γ-secretase inhibitors, GSIs）及γ-分泌酶调节剂/稳定剂（γ-secretase modulators/stabilizers, GSMs/GSSs）。BACE1是I型β-分泌酶，负责将APP切割为C99，进而经γ-分泌酶生成Aβ；BACE2在脑内表达较低，可能具有保护作用。BACE1抑制剂通过减少Aβ42生成降低斑块负荷，但Verubecestat、Lanabecestat、Atabecestat、LY3202626、Elenbecestat等多款候选药物因安全性问题或疗效不足在临床试验中失败，目前仍在开发更具选择性的新一代抑制剂。GSIs通过抑制由PS1/PS2、Nicastrin、APH-1、PEN-2组成的γ-分泌酶复合物阻断Aβ生成，但会干扰Notch信号传导，Semagacestat、Avagacestat等临床研究显示可导致Notch相关毒性与认知恶化，未获临床获益。Nirogacestat作为GSIs最初为AD开发，2023年获FDA批准用于治疗硬纤维瘤。GSMs/GSSs通过将γ-分泌酶活性向生成短链、低聚集倾向的Aβ38偏移，避免Notch信号抑制，EVP-0015962、BIIB042、E2012、E2212等化合物在动物模型中可降低斑块负荷，但因毒性与脱靶效应未进入后期临床。Tarenflurbil、RG6289等第一代GSMs及RAGE抑制剂Azeliragon已进入临床试验，但尚未有GSMs或GSSs获批。单一分泌酶靶向治疗的失败提示AD病理复杂性，非选择性分泌酶调节与晚期干预难以取得疗效，未来需聚焦早期干预、选择性通路保留策略、生物标志物指导的患者分层及多靶点联合治疗。
4.5 神经炎症调控
慢性神经炎症是AD核心病理机制，小胶质细胞在疾病早期可通过Aβ清除发挥保护作用，但持续活化会释放促炎细胞因子与活性氧（reactive oxygen species, ROS），加重神经元损伤。因此广谱免疫抑制疗效有限，需选择性调控小胶质细胞信号。NOD样受体家族pyrin结构域包含蛋白3（NOD-like receptor family pyrin domain containing 3, NLRP3）炎性小体与髓系细胞触发受体2（triggering receptor expressed on myeloid cells 2, TREM2）是当前最具潜力的靶点：NLRP3抑制可减轻神经炎症、降低Aβ负荷并改善认知，TREM2信号激活可支持小胶质细胞存活、代谢适应及吞噬功能，与AD遗传风险直接相关。流行病学研究显示长期使用非甾体抗炎药（nonsteroidal anti-inflammatory drugs, NSAIDs）可轻度降低AD风险，但保护程度因药物种类而异。Masitinib、NE3107、Baricitinib、Dasatinib-Quercetin、L-丝氨酸、Lenalidomide、Montelukast及Senicapoc、Salsalate、Emtricitabine等抗炎药物正处于临床试验阶段，但受限于小胶质细胞双重角色、脑内药物渗透不足及通路特异性生物标志物缺乏，尚未实现临床转化。
4.6 纳米药物递送技术
纳米技术并非独立治疗手段，而是通过纳米载体跨越血脑屏障，提升治疗药物脑内生物利用度、靶向精度与安全性，为小分子、生物制剂及核酸药物提供递送平台。脂质体、聚合物纳米粒、树状大分子、纳米凝胶、胶束及硒纳米粒等在AD模型中已显示出疗效：负载利凡斯的明的壳聚糖纳米粒可改善AD模型大鼠记忆，多奈哌齐联合虾青素的纳米结构脂质载体可增强血脑屏障穿透并减少Aβ沉积，负载姜黄素的聚合物纳米粒可降低Aβ与tau病理、减轻氧化应激与神经炎症，转铁蛋白偶联的蜂毒肽负载氧化铁纳米粒可有效靶向海马Aβ斑块。但临床转化仍受限于长期安全性（纳米材料脑内与外周蓄积、慢性毒性与免疫原性数据不足）、规模化生产与批次一致性难题
2026-03-09
关键词： 卫材，渤健，BioArctic，仑卡奈单抗，lecanemab，Leqembi，乐意保，Aricept，多奈哌齐，aducanumab，Aduhelm，elenbecestat，CLARITY AD，BAN2401，E2609，AHEAD 3-45，皮下注射，AD疾病修饰治疗，抗Aβ原纤维单抗
「开拓性文章信息：
期刊：New England Journal of Medicine，影响因子（IF）：158.5，JCR Q1
标题： Lecanemab in Early Alzheimer's Disease（中文：仑卡奈单抗在早期阿尔茨海默病中的研究）
第一作者及单位： Christopher H. van Dyck，美国耶鲁大学医学院（Yale School of Medicine）神经病学系
发表时间： 2023年1月5日
DOI： 10.1056/NEJMoa2212948
主要结论概要： 本文是卫材×渤健×BioArctic三方合作的核心成果——CLARITY AD Phase III研究完整数据的正式发表。n=1795名早期AD患者，18个月治疗后lecanemab使主要终点CDR-SB恶化减缓27%（p<0.001），所有关键次要终点全部达成，淀粉样蛋白PET清除-59.1 Centiloid。这是人类历史上第一篇在NEJM以"早期阿尔茨海默病疾病修饰治疗完整Phase III正面结果"发表的文章，直接推动FDA于2023年7月完全批准Leqembi®，中国NMPA于2024年1月批准乐意保®，标志着卫材历经40年、渤健历经数十亿美元投入后在AD领域的历史性突破[1]。」
一、总论：两家公司的AD战略交汇
卫材株式会社（Eisai Co., Ltd.，东证一部：4523）与渤健公司（Biogen Inc.，NASDAQ：BIIB）是当前AD疾病修饰治疗赛道最具代表性的战略合作伙伴。两家公司在AD领域的合作跨越十余年，历经重大失败与历史性突破，共同构建了迄今全球AD治疗领域最完整的上市产品线[2][3]。
卫材是一家以神经科学为核心战略的日本制药公司，以"hhc（human health care）"理念著称，是全球最早投入AD药物研发的制药公司之一。其1996年上市的多奈哌齐（Aricept®）是迄今全球销售规模最大的AD对症治疗药物，全球累计销售额超200亿美元[4]。
渤健是一家以神经科学为核心的美国生物技术公司，拥有深厚的抗体工程和临床运营能力，aducanumab（Aduhelm®）的开发失败曾使其遭遇严峻的公司信誉危机，而lecanemab（Leqembi®）的成功则成为其战略重生的核心支柱[5]。
BioArctic是一家总部位于瑞典斯德哥尔摩的神经科学生物技术公司，以Lars Lannfelt教授（乌普萨拉大学）发现的"arctic APP突变体产生大量Aβ原纤维"这一科学发现为基础，成为lecanemab原始抗体的发现者和核心科学提供方[6]。
三方合作的完整科学与商业路径，是本综述系统梳理的核心内容。二、卫材AD布局第一阶段：多奈哌齐与AChEI时代（1983—2003）2.1 多奈哌齐的研发与划时代获批
卫材在AD领域的战略布局，最早可追溯至1983年。卫材研发团队受胆碱能假说（cholinergic hypothesis）驱动，启动乙酰胆碱酯酶抑制剂（AChEI）的系统性筛选项目，目标是开发比他克林（tacrine）更安全、更有效的AD对症治疗药物[4]。
经历超过10年的化学合成与临床前优化，卫材最终确定了多奈哌齐（donepezil hydrochloride，研发代号E2020）这一化合物。多奈哌齐具有高选择性AChE抑制活性（对BuChE的选择性远低于tacrine），半衰期约70小时，每日一次给药，肝毒性极低[4]。
1993年，卫材就多奈哌齐与辉瑞（Pfizer）签署全球联合推广协议，由辉瑞负责北美、欧洲等主要市场的商业化推广，卫材负责亚太区及研发，形成强强联合的商业模式[4]。
1996年11月25日，FDA批准Aricept®（donepezil hydrochloride）5mg和10mg剂型，适应症为轻至中度AD，这是全球第二款获批的AChEI类AD药物（他克林于1993年首批），但因其安全性和依从性的优越性，很快成为全球最广泛处方的AD药物[4][7]。
2003年10月，FDA进一步批准Aricept®用于重度AD，使多奈哌齐成为唯一获批覆盖AD**全阶段（轻度、中度、重度）**的处方药[7]。Aricept在其专利保护期内（2001—2010年）的全球年销售额一度突破30亿美元，是卫材公司收入的最重要支柱，也为其后续投入AD疾病修饰治疗研发提供了资金基础[4]。
2010年多奈哌齐专利到期后，仿制药浪潮使Aricept销售额大幅下滑，但其作为"20世纪AD对症治疗奠基性药物"的历史地位无可撼动——迄今发表的多奈哌齐相关论文已超过2000篇[7][8]。三、合作伙伴BioArctic与BAN2401的科学起源（2005—2007）3.1 "北极突变"与Aβ原纤维毒性假说
BioArctic公司的科学基础来自乌普萨拉大学Lars Lannfelt教授团队2001年在Nature Neuroscience发表的研究——"arctic APP突变体（E693G）"揭示了一种特殊的家族性AD突变，其核心特征是该突变导致Aβ前体蛋白产生大量可溶性Aβ原纤维（protofibrils），而这些原纤维比Aβ单体或不溶性斑块对突触的毒性更强[6]。
这一发现促使BioArctic开发了一系列专门针对Aβ原纤维的单克隆抗体，其中BAN2401（后来的lecanemab）是最具临床开发价值的候选抗体。BAN2401是一种人源化IgG1单抗，对Aβ原纤维的亲和力约是Aβ单体的1000倍，提供了高度特异的靶向能力[6][9]。3.2 卫材与BioArctic的许可协议（2007）
2007年12月，卫材与BioArctic签署BAN2401许可协议，卫材获得BAN2401的全球开发权和商业化权，并向BioArctic支付特许权使用费和里程碑款项[10]。BioArctic保留瑞典/北欧地区的共同推广权利，并持续提供科学支持。这一协议是整个lecanemab开发历程的法律与商业起点[10]。
2012年，卫材启动BAN2401的Phase IIb研究（201研究），这是lecanemab首个规模化人体临床试验，为后续的突破奠定基础[9]。四、卫材×渤健战略合作的建立与演进（2012—2014）4.1 2012年aducanumab合作的背景
2012年，渤健从苏黎世大学（Neurimmune公司）获得aducanumab（BIIB037）的全球许可。aducanumab是一种靶向Aβ聚集体（包括可溶性寡聚体和不溶性斑块）的人源化IgG1单抗，来源于长寿健康老年人的记忆B细胞（"逆向翻译医学"策略）[5]。
同年，渤健开始与卫材就aducanumab的临床开发进行合作讨论，两家公司意识到在AD领域各有互补优势——渤健拥有神经科学临床运营能力，卫材拥有日本及亚洲市场准入网络和多奈哌齐的AD临床经验[11]。4.2 2014年联合开发协议：BAN2401与E2609的双线布局
2014年3月，卫材与渤健正式签署联合开发与商业化协议，合作标的包含两项资产[10][11]：
① BAN2401（lecanemab）：卫材将BAN2401的全球共同开发权授予渤健，双方50/50分担开发成本，渤健负责北美及欧洲商业化，卫材负责日本及亚洲区商业化。这是整个lecanemab故事从实验室走向全球的关键协议。
② E2609（elenbecestat）：卫材自主研发的口服BACE1抑制剂，渤健同步纳入联合开发，启动Phase II/III研究。两款药物代表了"清除已有Aβ斑块（BAN2401）"与"从源头减少Aβ生成（E2609）"的双线战略[11]。五、elenbecestat（E2609）：BACE抑制剂的挫折（2014—2019）5.1 临床开发历程
elenbecestat是卫材自主研发的选择性口服BACE1抑制剂，通过抑制BACE1酶（β-位点APP切割酶1）从源头阻断Aβ肽的生成。Phase IIb研究（Study 202）显示elenbecestat可使CSF Aβ显著降低，支持其生物学效应[12]。
2016—2017年，卫材与渤健联合启动两项Phase III研究：MISSION AD1
（NCT02956486）：针对早期AD患者MISSION AD2
（NCT03036280）：针对早期AD患者，与MISSION AD1设计相同，双盲平行进行
两项研究合计入组超过3000名早期AD患者，是当时规模最大的BACE抑制剂Phase III试验之一[12][13]。5.2 2019年安全性终止
2019年9月13日，卫材与渤健发表联合声明：独立数据安全监察委员会（IDMC）审查MISSION AD1和MISSION AD2研究的数据后，建议立即终止两项研究。终止原因为：接受elenbecestat治疗的患者出现不良的风险获益比，具体表现为神经精神相关不良事件（包括焦虑、抑郁、异常梦境等）发生率显著高于安慰剂组[12][13]。
这一结果与同期BACE抑制剂领域的整体失败（默克verubecestat、罗氏umibecestat等均告失败）相互印证，从根本上动摇了"抑制Aβ生成"作为AD治疗策略的近期可行性，并促使整个行业资源向"清除已有Aβ"的抗体策略进一步集中[14]。六、aducanumab：争议性获批与历史性退市（2019—2024）6.1 EMERGE与ENGAGE：戏剧性的Phase III历程
aducanumab的Phase III故事是制药史上最具戏剧性的案例之一。两项Phase III研究（EMERGE，n=1638；ENGAGE，n=1647）在2019年3月被渤健/卫材联合宣布以无效性为由中期终止，震惊业界[5]。
然而，仅数月后，2019年10月，渤健宣布重新分析扩充后的数据集后发现：EMERGE研究高剂量亚组达到主要终点（CDR-SB减缓22%，p=0.01），而ENGAGE研究高剂量亚组呈中性结果。渤健据此向FDA提交BLA申请[5][15]。6.2 争议性加速批准与FDA顾问委员会的反对
2021年6月7日，FDA以"加速批准"路径批准aducanumab（商品名：Aduhelm®），批准依据为淀粉样蛋白清除这一替代终点，而非直接的认知功能改善[15]。
然而，这一批准极具争议：
FDA肿瘤学和神经科学顾问委员会曾以10:0（反对）：0（赞成）：1（不确定）的投票结果明确建议不批准
3名顾问委员因不满FDA无视建议而辞职
美国国会介入调查FDA与渤健的"不寻常互动"
多数医疗中心和保险公司拒绝使用和报销
初始定价每年56,000美元，随后在压力下降至28,200美元，但CMS（美国医疗保险和医疗救助服务中心）最终决定将aducanumab的报销范围限定于参与临床试验的患者[15][16]。6.3 主动退市：2024年1月的战略重组
随着lecanemab的成功使渤健无需aducanumab维持AD产品线，渤健于2024年1月31日宣布：主动终止aducanumab的开发与商业化，将aducanumab的权利归还给原许可方Neurimmune，公司资源全面向lecanemab重新聚焦[16][17]。
现有患者可继续使用至2024年11月1日，临床试验参与者可获得药物直至2024年5月。aducanumab从加速批准到完全退市，仅历时约2年半，成为制药史上最短命的重磅AD药物[17]。七、lecanemab的完整开发历程与历史性突破（2016—2024）7.1 Phase IIb研究（201研究，2016—2020）
卫材于2016年正式启动BAN2401的Phase IIb研究（201研究，NCT01767311），与渤健联合运营。该研究采用贝叶斯自适应设计（Bayesian adaptive randomization），n=856名早期AD患者，探索5个剂量组，主要终点为淀粉样蛋白PET和认知功能评估，研究持续18个月[9][18]。
2018年7月，卫材公布Phase IIb期中分析结果：高剂量lecanemab（10mg/kg双周）使CDR-SB减缓30%（p=0.034，贝叶斯分析），同时显著降低淀粉样蛋白PET负荷和多项血浆生物标志物（pTau181、Aβ42/40等）。FDA于2018年12月授予lecanemab快速通道资格（Fast Track Designation）[18]。
2020年，Phase IIb完整数据在Alzheimer's Research & Therapy发表（Swanson等，2021），结果全面支持进入确证性Phase III[9]。7.2 CLARITY AD Phase III（2021—2022）
设计：n=1795名早期AD患者（MCI至轻度AD痴呆，均经PET或CSF确认淀粉样蛋白阳性），随机1:1分配至lecanemab（10mg/kg，每2周静脉输注）或安慰剂组，治疗持续18个月，在全球约30个国家270个研究中心开展[1]。
2022年9月27日：卫材宣布CLARITY AD达到主要终点，CDR-SB减缓具有高度统计学显著性[19]。
2023年1月5日：van Dyck等在NEJM发表完整结果：CDR-SB减缓27%（p<0.001），iADRS减缓26%，ADAS-Cog14减缓26%，ADCS-MCI-ADL减缓37%，淀粉样蛋白PET -59.1 Centiloid[1]。7.3 FDA批准历程2023年1月6日
：FDA基于Phase IIb生物标志物数据，加速批准lecanemab（商品名：Leqembi®）[19]2023年7月6日
：FDA基于CLARITY AD完整数据，完全批准Leqembi®，成为2003年以来首款获FDA完全批准的AD药物。同日，卫材宣布在美国定价为每年26,500美元[20]2024年1月9日
：中国NMPA批准lecanemab（商品名：乐意保®），成为在中国获批的第一款AD疾病修饰治疗药物[21]7.4 长期OLE数据与皮下注射新剂型（2025）
36个月OLE数据（AAIC 2025发布）：早期治疗组与延迟治疗组（原安慰剂交叉组）相比，CDR-SB减缓51%，证实越早开始治疗长期获益越大[22]。
Leqembi IQLIK（皮下注射维持剂型）：在完成18个月静脉输注初始治疗后，患者可转换为每周一次皮下注射（360mg/mL，SC）维持治疗。2025年8月，FDA正式批准Leqembi IQLIK，这是全球首款获批的皮下注射AD单克隆抗体维持剂型，将使患者可在家自行注射，大幅提升便利性和依从性[22][23]。八、症状前AD预防研究：AHEAD 3-45（2020年至今）
AHEAD 3-45研究是卫材×渤健与美国NIH/ADCS（阿尔茨海默病合作研究）合作开展的全球最大规模症状前AD预防随机对照试验[24]，旨在证明lecanemab能否在无认知症状但已有Aβ积累的中年人群中预防AD进展。
研究包含两个并行亚研究：A45研究
：针对中度Aβ积累人群（55—80岁），接受lecanemab 10mg/kg每2周静脉输注A3研究
：针对轻度Aβ积累人群（55—80岁），接受lecanemab较低剂量方案
主要终点为tau PET变化（A45）和脑淀粉样蛋白积累速率（A3），持续治疗约4年，预计在2026—2028年有初步认知终点数据读出[24][25]。AHEAD 3-45是继A4研究（solanezumab失败）之后，AD症状前预防领域最被寄予期望的大型RCT。九、综合总结表：卫材×渤健AD产品线·合作伙伴·重要节点
序号
产品/项目
类型
靶点/机制
合作方
关键里程碑
时间节点
结局/现状
1Aricept®（多奈哌齐）5/10mg
AChEI对症
AChE抑制
辉瑞（全球推广）
FDA批准，全球首批安全性AChEI
1996年11月
✅持续上市
2Aricept®（多奈哌齐）
AChEI对症
AChE抑制
—
FDA批准重度AD适应症，覆盖全程
2003年10月
✅持续上市
3Aricept 23mg
AChEI高剂量
AChE抑制
辉瑞
FDA批准中重度AD高剂量剂型
2010年
✅上市
4BAN2401许可协议
科学授权
Aβ原纤维单抗BioArctic
（授权方）
卫材获得BAN2401全球开发权
2007年12月
✅协议持续有效
5BAN2401 Phase IIb（201研究）
临床研究
可溶性Aβ原纤维
渤健（联合运营）
贝叶斯自适应设计，CDR-SB减缓30%
2016—2020年
✅支持进入Phase III
6elenbecestat（E2609）
口服小分子
BACE1抑制渤健
（联合开发）
卫材×渤健2014年协议纳入，启动MISSION AD Phase III
2014—2016年
❌终止
7elenbecestat MISSION AD1/2
Phase III
BACE1
渤健
IDMC安全性终止：神经精神不良事件
2019年9月
❌终止
8aducanumab（BIIB037）
抗Aβ聚集体单抗
Aβ寡聚体+斑块渤健
（原研）×卫材（联合商业化）
FDA加速批准（争议性批准）
2021年6月
❌已退市
9Aduhelm® 退市
—
—
渤健×卫材
渤健宣布主动放弃aducanumab，权利归还Neurimmune
2024年1月
❌全面终止
10CLARITY AD Phase III
确证性RCT
可溶性Aβ原纤维
渤健×BioArctic
主要终点CDR-SB减缓27%，n=1795
2021—2022年
✅成功
11Leqembi®（lecanemab）加速批准
抗Aβ原纤维单抗
可溶性Aβ原纤维
渤健×BioArctic
FDA加速批准，全球首款抗Aβ原纤维单抗上市
2023年1月
✅上市
12Leqembi®（lecanemab）完全批准
抗Aβ原纤维单抗
可溶性Aβ原纤维
渤健×BioArctic
FDA完全批准，2003年以来首款完全批准AD药
2023年7月
✅完全批准
13乐意保®（仑卡奈单抗）中国
抗Aβ原纤维单抗
可溶性Aβ原纤维
渤健×BioArctic
中国NMPA批准，第一款中国AD靶向单抗
2024年1月
✅中国上市
14Leqembi IQLIK（SC皮下注射）
皮下注射维持剂型
可溶性Aβ原纤维
渤健
FDA批准，全球首款皮下注射AD单抗维持剂型
2025年8月
✅上市
15AHEAD 3-45
症状前预防RCT
lecanemab预防
NIH/ADCS×卫材×渤健
全球最大症状前AD预防RCT，tau PET为主要终点
2020—进行中
🔄Phase III进行中
参考文献
[1] van Dyck, C. H. et al. "Lecanemab in Early Alzheimer's Disease." New England Journal of Medicine vol. 388 (2023): 9–21. doi:10.1056/NEJMoa2212948. https://www.nejm.org/doi/full/10.1056/NEJMoa2212948
[2] Cummings, J. et al. "Alzheimer's disease drug development pipeline: 2025." Alzheimer's & Dementia: Translational Research & Clinical Interventions vol. 11 (2025): e70098. doi:10.1002/trc2.70098. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70098
[3] Cummings, J. et al. "Alzheimer's disease drug development pipeline: 2024." Alzheimer's & Dementia: Translational Research & Clinical Interventions vol. 10 (2024): e12465. doi:10.1002/trc2.12465. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.12465
[4] Birks, J. S. & Harvey, R. J. "Donepezil for dementia due to Alzheimer's disease." Cochrane Database of Systematic Reviews Issue 6 (2018): CD001190. doi:10.1002/14651858.CD001190.pub3. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001190.pub3/abstract
[5] Knopman, D. S. et al. "Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019." Alzheimer's & Dementia vol. 17 (2021): 696–701. doi:10.1002/alz.12213. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12213
[6] Lannfelt, L. et al. "Amyloid-β protofibrils as Alzheimer's disease drug target: preclinical and clinical studies with the mAb158 antibody." Alzheimer's Research & Therapy vol. 6 (2014): 16. doi:10.1186/alzrt246. https://alzres.biomedcentral.com/articles/10.1186/alzrt246
[7] Rogers, S. L. et al. "A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease." Neurology vol. 50 (1998): 136–145. doi:10.1212/WNL.50.1.136. https://www.neurology.org/doi/10.1212/WNL.50.1.136
[8] Mohs, R. C. et al. "Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope." Alzheimer Disease and Associated Disorders vol. 11 Suppl 2 (1997): S13–21. doi:10.1097/00002093-199700112-00003. https://pubmed.ncbi.nlm.nih.gov/9236949/
[9] Swanson, C. J. et al. "A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody." Alzheimer's Research & Therapy vol. 13 (2021): 80. doi:10.1186/s13195-021-00813-8. https://alzres.biomedcentral.com/articles/10.1186/s13195-021-00813-8
[10] Eisai Co., Ltd. "The commercialization agreement on the lecanemab antibody was signed in December 2007." Eisai News Release (2022). https://www.eisai.com/news/2022/news202232.html
[11] Eisai Co., Ltd. & Biogen Inc. "Since March 2014, Eisai and Biogen have been jointly developing BAN2401." Eisai News Release (2017). https://www.eisai.com/news/news201773.html
[12] Eisai Co., Ltd. & Biogen Inc. "Eisai and Biogen to Discontinue Phase III Clinical Studies of BACE Inhibitor Elenbecestat in Early Alzheimer's Disease." Eisai News Release, September 13, 2019. https://www.eisai.com/news/2019/news201965.html
[13] Wessels, A. M. et al. "Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials." JAMA Neurology vol. 77 (2020): 199–209. doi:10.1001/jamaneurol.2019.3988. https://jamanetwork.com/journals/jamaneurology/fullarticle/2755347
[14] Egan, M. F. et al. "Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease." New England Journal of Medicine vol. 378 (2018): 1691–1703. doi:10.1056/NEJMoa1706441. https://www.nejm.org/doi/full/10.1056/NEJMoa1706441
[15] Sevigny, J. et al. "The antibody aducanumab reduces Aβ plaques in Alzheimer's disease." Nature vol. 537 (2016): 50–56. doi:10.1038/nature19323. https://www.nature.com/articles/nature19323
[16] Knopman, D. S. et al. "Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019." Alzheimer's & Dementia vol. 17 (2021): 696–701. doi:10.1002/alz.12213. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12213
[17] Biogen Inc. "Biogen to Realign Resources for Alzheimer's Disease Franchise." Investor News Release, January 31, 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-realign-resources-alzheimers-disease-franchise
[18] van Dyck, C. H. et al. "Lecanemab in Early Alzheimer's Disease." New England Journal of Medicine vol. 388 (2023): 9–21. doi:10.1056/NEJMoa2212948. https://www.nejm.org/doi/full/10.1056/NEJMoa2212948
[19] Eisai Co., Ltd. & Biogen Inc. "Eisai and Biogen Announce Positive Topline Results of the Final Analysis for CLARITY AD Study of Lecanemab." Investor News Release, September 27, 2022. https://investors.biogen.com/news-releases/news-release-details/eisai-and-biogen-announce-positive-topline-results-final
[20] U.S. Food and Drug Administration. "FDA Converts Novel Alzheimer's Disease Treatment to Traditional Approval." FDA Press Announcement, July 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
[21] Biogen Inc. & Eisai Co., Ltd. "LEQEMBI® (Lecanemab) Approved for the Treatment of Alzheimer's Disease in China." Investor News Release, January 9, 2024. https://investors.biogen.com/news-releases/news-release-details/leqembir-lecanemab-approved-treatment-alzheimers-disease-china
[22] Eisai Co., Ltd. "FDA Approves LEQEMBI® IQLIK™ (lecanemab-irmb) Subcutaneous Injection for Maintenance Dosing for the Treatment of Early Alzheimer's Disease." Eisai News Release, August 29, 2025. https://media-us.eisai.com/2025-08-29-FDA-Approves-LEQEMBI-R-IQLIK-TM-lecanemab-irmb-Subcutaneous-Injection-for-Maintenance-Dosing-for-the-Treatment-of-Early-Alzheimers-Disease
[23] BioArctic AB. "Latest data presented at AAIC 2025 reinforces lecanemab's clinical effect with consistent safety profile." BioArctic Press Release, 2025. https://www.bioarctic.com/en/latest-data-presented-at-aaic-2025-reinforces-lecanemabs-clinical-effect-with-consistent-safety-profile/
[24] Rafii, M. S. et al. "The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer's disease." Alzheimer's & Dementia vol. 19 (2023): 1227–1233. doi:10.1002/alz.12748. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12748
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临床3期申请上市引进/卖出并购上市批准
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。
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 阿尔茨海默症 | 临床3期 | 美国 | 2016-10-20 | |
| 阿尔茨海默症 | 临床3期 | 美国 | 2016-10-20 | |
| 阿尔茨海默症 | 临床3期 | 日本 | 2016-10-20 | |
| 阿尔茨海默症 | 临床3期 | 日本 | 2016-10-20 | |
| 阿尔茨海默症 | 临床3期 | 阿根廷 | 2016-10-20 | |
| 阿尔茨海默症 | 临床3期 | 阿根廷 | 2016-10-20 | |
| 阿尔茨海默症 | 临床3期 | 澳大利亚 | 2016-10-20 | |
| 阿尔茨海默症 | 临床3期 | 澳大利亚 | 2016-10-20 | |
| 阿尔茨海默症 | 临床3期 | 奥地利 | 2016-10-20 | |
| 阿尔茨海默症 | 临床3期 | 奥地利 | 2016-10-20 |
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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2期 | 70 | placebo+elenbecestat (Core Phase: Placebo) | 憲憲簾選夢艱夢糧範醖 = 製餘壓憲膚餘齋衊鹹膚 蓋鹹艱選餘廠簾願簾襯 (衊醖顧蓋廠鬱夢製顧壓, 鑰築範鬱獵餘網廠膚鑰 ~ 網壓觸壓鹹鹽艱醖蓋艱) 更多 | - | 2021-03-05 | ||
(Core Phase: Elenbecestat 5 mg Then 50 mg) | 憲憲簾選夢艱夢糧範醖 = 廠範觸網簾網簾願醖餘 蓋鹹艱選餘廠簾願簾襯 (衊醖顧蓋廠鬱夢製顧壓, 膚觸積製艱糧淵選夢餘 ~ 鑰積壓鹽鹽觸窪艱範糧) 更多 | ||||||
临床3期 | 2,212 | placebo+elenbecestat (Core Phase: Placebo) | 鏇醖糧淵糧構艱網範鹹(齋醖鬱醖齋餘觸鑰蓋願) = 醖繭觸衊憲壓餘艱簾壓 鏇憲築觸齋淵夢鹽鹽艱 (醖餘艱繭膚糧網鏇築鏇, 0.142) 更多 | - | 2021-02-03 | ||
(Core Phase: Elenbecestat 50 mg) | 鏇醖糧淵糧構艱網範鹹(齋醖鬱醖齋餘觸鑰蓋願) = 鏇齋襯鏇顧繭衊築鬱壓 鏇憲築觸齋淵夢鹽鹽艱 (醖餘艱繭膚糧網鏇築鏇, 0.146) 更多 |
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