The purpose of the study is to determine whether LY3314814 can be safely prescribed in participants with liver impairment without a dose adjustment. Participants will be on study for 11 days with follow-up about 7 days afterward.

开始日期2018-06-01

申办/合作机构

Eli Lilly & Co.

[+1]

NCT03506399

/ Withdrawn临床1期

Effect of Lanabecestat on the Pharmacokinetics of Ethinyl Estradiol and Levonorgestrel in Healthy Female Subjects

The study will evaluate the effect of oral contraceptive (birth control pill) on the blood level of lanabecestat when both are given together. Side effects will be monitored and documented. This study will last up to 27 days for each participant, not including screening. Screening is required within 42 days prior to first dose.

开始日期2018-06-01

申办/合作机构

Eli Lilly & Co.

[+1]

NCT03545087

/ Withdrawn临床1期

Pharmacokinetics of Lanabecestat (LY3314814) in Subjects With Impaired Renal Function

The purpose of the study is to determine whether lanabecestat can be safely prescribed in participants with kidney impairment without a dose adjustment.
Participants will be on study for up to 6 weeks; this includes a 2-week screening and a follow-up about 10 days after final drug administration.

开始日期2018-06-01

申办/合作机构

Eli Lilly & Co.

[+1]

100 项与 Lanabecestat 相关的临床结果

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100 项与 Lanabecestat 相关的转化医学

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100 项与 Lanabecestat 相关的专利（医药）

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项与 Lanabecestat 相关的文献（医药）

2026-02-01·BIOORGANIC CHEMISTRY

Unraveling the metabolic potential of Moringa oleifera derived metabolites in combating Parkinson's and Alzheimer's disease

Article

作者: Nawaz, Muhammad Zohaib ; Sun, Xinxiao ; Alghamdi, Huda Ahmed ; Zhu, Daochen ; Haider, Syed Zeeshan ; Iqbal, Muhammad Waleed ; Yuan, Qipeng

Moringa oleifera is a nutrient-rich medicinal plant recognized for its broad-spectrum therapeutic potential. However, the specific bioactive metabolites and their molecular mechanisms in curing and preventing these diseases remain inadequately explored. The present study unveiled how moringa metabolites interact with specific molecular targets linked to various diseases and explored their potential as natural therapeutic agents against these diseases. The study first constructed a metabolite library based on compounds identified through multiple analytical techniques, including GC-MS, LC-MS, HPLC, UFLC, and NMR, as reported in previous studies. Then utilized a comprehensive computational approach integrating virtual screening, ADMET analysis, molecular docking, and dynamics simulations, and MM-GBSA/MM-PBSA methods to predict and evaluate the binding affinities and stabilities of moringa-derived metabolites against disease-related proteins. In total, 72 metabolites derived from moringa were screened against the ten genes, the overexpression of which was reported in five related disease conditions, including Alzheimer's, Parkinson's, Kidney Stones, Multiple Sclerosis, and Asthma diseases. These metabolites demonstrated strong interactions with genes associated specifically with Alzheimer's and Parkinson's diseases. To enhance the reliability and translational relevance of the computational predictions, experimentally validated inhibitors lanabecestat (APP inhibitor), GNE0877 (LRRK2 inhibitor), and olaparib (PARP1 inhibitor) were included as positive controls to benchmark the binding affinity and interaction stability of moringa metabolites. Our findings revealed that metabolites delta-tocopherol and gamma-tocopherol exhibit potential to inhibit poly (ADP-ribose) polymerase 1 (PARP1), while 1-acetyl-4,4-bis[4-(3-bromopropoxy)-3,5-dimethoxyphenyl] piperidine and 9,9'-bianthracene showed potential in inhibiting leucine-rich repeat kinase 2 (LRRK2); overexpression of both genes is linked to Parkinson's disease. Additionally, the metabolite 1-acetyl-4,4-bis[4-(3-bromopropoxy)-3,5-dimethoxyphenyl] piperidine also demonstrated potential in inhibiting the amyloid precursor protein (APP) associated with Alzheimer's disease. The identified metabolites displayed strong binding affinities, favorable ADMET properties, and stable interactions during molecular dynamics simulations compared to their respective control compound, positioning them as promising natural therapeutic agents against Alzheimer's and Parkinson's diseases. The study underscores the relevance of integrating computational methodologies to explore the therapeutic potential of bioactive plant compounds.

2025-12-01·BIOORGANIC CHEMISTRY

Design, synthesis, and biological evaluation of β-secretase inhibitors: An integrated study of molecular docking, dynamics, pharmacokinetics, quantum chemistry, and in-vitro analysis for Alzheimer's disease

Article

作者: Patel, Yamini ; Sharma, Pratibha ; Kumar, Ashok ; Parmar, Hamendra Singh ; Inwati, Gajendra Kumar

Present paper elicits the synthesis of a series of 2,2-dimethyl-2H-[1,3]dioxino[4,5-b]pyrrol-4(7H)-one derivatives as novel selective BACE1 inhibitors for the treatment of Alzheimer's disease (AD). A four-component, solvent-free condensation process, catalyzed by 10 mol% NiCl₂·6H₂O strategy was explored to achieve their synthesis. The structures of the synthesized compounds were ascertained using different spectroscopic techniques, including FT-IR, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. In silico molecular docking and molecular dynamics simulations suggest that these compounds exhibit strong potential as β-secretase (BACE1) inhibitors, demonstrating high interaction and binding energies compared to reference inhibitors AZD3293 and E2602. Notably, compounds 5p displayed significant inhibitory interactions, effectively suppressing the catalytic dyad (Asp A:228 and Asp A:32) of BACE1. To further validate the computational findings, in vitro BACE1 enzymatic inhibition assays were performed on the most interactive molecule 5p. Additionally, ADMET descriptors and density functional theory (DFT) calculations were employed to assess the pharmacokinetics, chemical stability, and binding affinity of the synthesized compounds. The findings from this study pave the way for future in vivo investigations to assess the reversal of Alzheimer's disease phenotypes, along with comprehensive safety and toxicity evaluations.

2025-09-01·NEUROGASTROENTEROLOGY AND MOTILITY

Studying the Role of Myenteric Amyloidosis in Gastrointestinal Dysmotility and Enteric Neural Dysfunction Using APP/PS1 Mice—Is It an Adequate Animal Model?

Article

作者: Srikrishna, Nikitha ; Flood, Emma ; Galligan, James J. ; Xu, Hui ; Lansdell, Theresa A. ; Dorrance, Anne M. ; Fernandes, Roxanne ; Masino, Marlene ; Mui, Ryan

ABSTRACT:

Background:

The Gastrointestinal (GI) microbiome and gut‐brain axis are associated with the progression and pathology of Alzheimer's disease (AD). Amyloid deposition is thought to be a driver of AD, causing synaptic dysfunction and neuronal death in the brain. Chronic constipation is a common gastrointestinal (GI) dysmotility in AD patients, which impacts patient outcomes and quality of life. It is unknown if enteric amyloidosis disrupts myenteric neuron function and causes GI dysmotility.

Methods:

Untreated male and female APP/PS1 (a transgenic murine model of brain amyloidosis) and sex‐matched control mice were followed until 12 months of age. A separate cohort of mice was treated with a vehicle or the beta‐secretase (BACE1) inhibitor, lanabecestat, starting at 5 months of age until 7 months. GI motility was assessed in all mice by measuring whole GI transit in vivo. Propulsive colonic motility and GI smooth muscle contractions were measured ex vivo. At 7 or 12 months old, amyloidosis in the brain and myenteric plexus was determined by immunohistochemistry or ELISA; the myenteric neural density, including the cholinergic and nitrergic neurons, was evaluated by immune staining and RT‐PCR; expression of pro‐inflammatory factors in the GI wall was assessed by RT‐PCR.

Key Results:

By 7 months of age, male and female APP/PS1 mice developed abundant amyloid plaques in the brain. Aged untreated male APP/PS1 mice also demonstrated Aβ deposition in the colonic myenteric ganglia, which was associated with increased fecal output and faster whole GI transit starting at 4–7 months old, but vehicle‐ and lanabecestat‐treated male APP/PS1 mice had similar GI motility to their non‐genetic controls until 7 months old. None of the female APP/PS1 mice showed GI dysmotility or myenteric amyloidosis. Two months of lanabecestat treatment effectively reduced amyloid plaque burden in the brains of female APP/PS1 mice but not in male APP/PS1 mice. Treatment with lanabecestat did not affect myenteric Aβ intensity or GI motility in all APP/PS1 mice. All APP/PS1 mice did not show myenteric neuronal degeneration or inflammation until 12 months old.

Conclusions:

APP/PS1 mice do not recapitulate myenteric amyloidosis persistently and lack the phenotype of constipation observed in human AD patients; these mice should not be considered an adequate murine model for studying the role of myenteric amyloidosis in GI dysmotility. An adequate animal model with myenteric amyloidosis is required for further study.

项与 Lanabecestat 相关的新闻（医药）

2025-11-25

·阿尔茨海默病研究

阿尔茨海默病的药物治疗:现状与未来

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. 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Biomarker confirmation requirement. Alzheimers Dement. 2018. https://doi.org/10.1016/j.jalz.2018.02.018 [491] Salloway S, et al. ARIA monitoring protocol. J Prev Alzheimers Dis. 2022. https://doi.org/10.14283/jpad.2022.21 [492] Atri A, et al. Combination with ChEIs. Alzheimer Dis Assoc Disord. 2008. https://doi.org/10.1097/WAD.0b013e31816653bc [493] Grill JD, Karlawish J. Clinical trial participation benefits. Alzheimers Res Ther. 2010. https://doi.org/10.1186/alzrt55 [494] Long JM, Holtzman DM. 30-year journey review. Cell. 2019. https://doi.org/10.1016/j.cell.2019.09.001 [495] Karran E, De Strooper B. Amyloid hypothesis validation. Neuron. 2022. https://doi.org/10.1016/j.neuron.2022.03.015 [496] Jack CR Jr, et al. Earliest intervention window. Lancet Neurol. 2020. https://doi.org/10.1016/S1474-4422(19)30457-4 [497] Hampel H, et al. Personalized medicine future. Alzheimers Dement. 2023. https://doi.org/10.1002/alz.13245 [498] Gao Y, et al. Multi-target future strategies. Pharmacol Ther. 2024. https://doi.org/10.1016/j.pharmthera.2024.108567 [499] Patient convenience innovations review. Synthesis. 2024. [500] Biosimilars potential. Market analysis. Generics Bulletin. 2024. https://www.generics-bulletin.com/alzheimers-biosimilars-2024 [501] Cummings J, et al. Collaborative ecosystem. Nat Rev Drug Discov. 2024. https://doi.org/10.1038/s41573-024-00923-4 [502] Alzheimer's Association. Research progress report 2024. https://www.alz.org/research/for_researchers/partnerships/global-pipeline-report [503] Roche. Trontinemab program announcement. 2023. https://www.roche.com/media/releases/med-cor-2023-11-14 [504] Bohrmann B, et al. Next-generation anti-Aβ design. Alzheimers Res Ther. 2024. https://doi.org/10.1186/s13195-024-01389-6 [505] Ostrowitzki S, et al. Trontinemab Phase 1 safety. Neurology. 2023. https://doi.org/10.1212/WNL.0000000000207891 [506] Salloway S, et al. ARIA comparison across antibodies. Lancet Neurol. 2024. https://doi.org/10.1016/S1474-4422(24)00089-3 [507] ClinicalTrials.gov. SKYLINE-1 Study. NCT06049329. https://clinicaltrials.gov/study/NCT06049329 [508] Roche. SKYLINE program design. Investor presentation. 2024. https://www.roche.com/investors/skyline-ad-program [509] Bateman RJ, et al. Monthly dosing feasibility. Ann Neurol. 2024. https://doi.org/10.1002/ana.26923 [510] Market analysis. Anti-amyloid competitive landscape 2024. Evaluate Pharma. https://www.evaluate.com/vantage/articles/analysis/anti-amyloid-competition-2024 附录:术语表与缩写缩写全称中文 AD Alzheimer's Disease 阿尔茨海默病 Aβ Amyloid-beta β-淀粉样蛋白 ADAS-Cog Alzheimer's Disease Assessment Scale-Cognitive subscale 阿尔茨海默病评估量表-认知部分 APOE Apolipoprotein E 载脂蛋白E ARIA Amyloid-Related Imaging Abnormalities 淀粉样蛋白相关影像异常 ARIA-E ARIA-Edema 淀粉样蛋白相关水肿 ARIA-H ARIA-Hemosiderin deposition 淀粉样蛋白相关微出血/含铁血黄素沉积 ASO Antisense Oligonucleotide 反义寡核苷酸 BACE β-site APP Cleaving Enzyme β分泌酶 BBB Blood-Brain Barrier 血脑屏障 CAA Cerebral Amyloid Angiopathy 脑淀粉样血管病 CDR-SB Clinical Dementia Rating-Sum of Boxes 临床痴呆评定量表-总和评分 ChEI Cholinesterase Inhibitor 胆碱酯酶抑制剂 CSF Cerebrospinal Fluid 脑脊液 EMA European Medicines Agency 欧洲药品管理局 FDA Food and Drug Administration 美国食品药品监督管理局 FDG-PET Fluorodeoxyglucose Positron Emission Tomography 氟脱氧葡萄糖正电子发射断层扫描 MCI Mild Cognitive Impairment 轻度认知障碍 MMSE Mini-Mental State Examination 简易精神状态检查 MRI Magnetic Resonance Imaging 磁共振成像 MTBR Microtubule-Binding Region 微管结合区 NFT Neurofibrillary Tangles 神经原纤维缠结 NMDA N-methyl-D-aspartate N-甲基-D-天冬氨酸 PET Positron Emission Tomography 正电子发射断层扫描 p-tau Phosphorylated tau 磷酸化tau蛋白 TREM2 Triggering Receptor Expressed on Myeloid cells 2 髓系细胞触发受体2 本文内容来自公开信息及研究文献，不代表临床建议。如需投稿、转载、商务合作后台留言，回复有一定延迟敬请谅解。辅助编辑：腾讯元宝or（GPT、Gemini、Claude等）

2025-11-21

·E药经理人

冲向万亿市值！GLP-1抢位、BD狂飙、AI加速，礼来颠覆药企生存逻辑？

礼来股价狂飙的背后，离不开替尔泊肽的加持，却又不止于此。万亿之后，礼来还能看什么？撰文｜Kathy 王昭媛生物医药史上的第一个万亿帝国，呼之欲出。距离礼来市值首次突破9900亿美元的一年后，11月20日，这家成立了147年的老牌药企再次距离万亿俱乐部只差临门一脚。若说“GLP-1概念”是成就高市值的催化剂，那诺和诺德与司美格鲁肽明显风头更甚，可丹麦巨头如今的市值是礼来的五分之一。若按业绩，霸榜全球制药公司营收头名的强生，市值只有礼来如今的一半。如今的礼来，一家公司的市值相当于辉瑞、默沙东、BMS、GSK、赛诺菲和诺和诺德六家药企的市值总和。华尔街日报也罕见地用“决定性倾斜”来形容GLP-1减重药的全球战局：“礼来仅用了11个月，便让替尔泊肽（Zepbound版）从新生儿变成新增肥胖处方的绝对霸主，并带着9700亿美元市值向万亿美元龙门发起冲刺。” 其实风向的变化并不突兀。2024年时，市场还习惯以“减肥药之争”看待市值飙升最快的两家公司——礼来与诺和诺德。到了今年，礼来一骑绝尘：单季度营收增长拉升至50%以上、替尔泊肽增速125%，累计销售更加逼近司美格鲁肽。但也有分析师认为，礼来几乎脱离了药企股价上涨的传统逻辑，在GLP-1市场极高预期的推动下，其增长率和估值受人工智能驱动更大。当全球资本开始倒数“礼来距离万亿美元还差几个交易日”时，一个更现实的问题浮现出来——为什么率先和美股七大科技巨头并肩的是礼来？市值捅破天的为什么是礼来？如果回到5年前，没人会相信，市值不足强生一半的礼来，如今能成为万亿市值药企。站在2025年的时间节点来说，GLP-1彻底改变了产业的游戏规则与制药公司的座次。 2023年以来，礼来市值健步如飞。从首次突破4000亿美元大关，到冲破7000亿美元市值，仅用了8个月的时间。紧接着，礼来又用了3个多月的时间，实现了7000亿到8000亿美元市值的晋升。此后虽有波动，但礼来数月来站稳了9000亿门槛。而礼来市值飙升的几个时刻，刺激因素离不开两个：一个是GLP-1类药物的关键临床试验的进展与盈利，另一个则是治疗早期症状性阿尔茨海默病(AD)患者的药物多奈单抗。替尔泊肽的狂飙之势已不可挡。仅从今年前三季度来看，替尔泊肽是礼来的绝对增长引擎。前三季度大卖248.37亿美元，不仅占礼来总营收的49%，增速更是达到了可怕的125%。这种狂飙并不是三季度刚刚发生的，半年报时，替尔泊肽就以121.3%的增速实现收入147.34亿美元，彼时与诺和诺德的司美格鲁肽的营收差距缩小到20亿美元。而到了三季报时，二者的差距已不到10亿美元，再次给年底的药王之争打了问号。此外，礼来和诺和诺德在GLP-1类药物美国处方量上的占比也进一步拉开：上半年分别为57.0%和42.5%，第三季度变为57.9%和41.7%。值得一提的是，今年最后一个季度，礼来在GLP-1领域仍有进展值得期待。其口服小分子GLP-1药物orforglipron计划于年内递交肥胖适应证相关申请，有望在2026年上市后迅速抢占市场份额，而CGR/GIPR/GLP-1R三靶点药物Retatrutide也将完成首个III期研究。总体来看，礼来将2025全年收入预期从600亿-620亿美元再次上调至630亿-635亿美元。业界预计，替尔泊肽全年营收有望在年底反超司美格鲁肽。礼来在产品销售与市场占比上猛追诺和诺德，而诺和诺德在市值上，却难以望其项背。2024年3月时，诺和诺德的市值超过5000亿美元，礼来公司的市值超过7000亿美元。此后礼来市值逐渐飙升至9900亿美元，而诺和诺德的市值已跌至约2000亿美元。同为GLP-1双姝，为何两家公司的市值走向愈发背道而驰？其实不同于诺和诺德聚焦于内分泌与代谢的“专“和“精”，礼来还不断在寻找其它领域的业绩增长点。正如其三季报中所述，除心脏代谢健康领域外，肿瘤、免疫、神经也可圈可点。在阿尔茨海默病领域，礼来算是苦尽甘来。据美国药物生产与研发协会数据，全球累计在阿尔茨海默病领域上的研发投入超过6000亿美元，失败的临床药物超过300种，失败率高达99.6%，包括礼来、辉瑞、罗氏、强生、渤健等一众MNC虽积极布局却总是药企无功而返，近20年全球范围内上市的新药寥寥。礼来前后共开发了5款阿尔茨海默病药物，是在同领域投入最多的企业之一，但也吃尽了苦头。2010年，semagacestat研发宣告失败，此药未能延缓阿尔茨海默病的进展，消息一出，礼来股价跌至冰点。接下来两年时间，礼来不得不罕见展开几千名的大规模裁员。8年后，礼来又宣布停止与阿斯利康联合开发lanabecestat的III期临床试验。如今，多奈单抗在全球的大卖也让礼来迎来柳暗花明。可以说，手握“GLP-1+阿尔茨海默”的礼来，其发展空间颇具想象空间。推荐阅读 * 大变天！2030年全球制药TOP10：礼来登顶，辉瑞“垫底”，BMS、GSK掉队！ * 8000亿美元市值再“封神”！代表药界杀入万亿俱乐部，礼来还差啥？礼来不想昙花一现美股七大科技巨头（Magnificent Seven）长期统治着万亿美元市值俱乐部。而礼来将作为科技巨头之外，全球第一家市值达到万亿美元的医药公司，迈过这个门槛也离不开AI巨头们的加持。就在今年10月28日，礼来宣布将与英伟达合作打造制药企业自有并运营的算力最强“超级计算机”。该系统基于英伟达DGX SuperPOD架构，整合超过1000块B300图形处理器，并全部采用可再生能源驱动。礼来计划将其作为“AI工厂”的核心基础设施，用于处理海量数据、训练实验模型并生成推断结果，最终在分子发现等关键环节实现突破，大幅缩短药物开发周期。更值得一提的是，仅2025年内，礼来就进行了十次对外的AI制药领域合作。今年以来，礼来完成的最大单笔AI制药合作总价值高达13亿美元，合作方是专注于专注于G蛋白偶联受体的AI制药公司Superluminal Medicines，涉及领域则是礼来最擅长的心血管代谢疾病和肥胖领域。事实上，礼来押注AI，由来已久。早在2023年时，礼来就与国内AI制药头部公司晶泰科技达成2.5亿美元的AI药物合作，再到2024年，设立了首席人工智能官职位，今年6月联手另一美国AI巨头OpenAI开发抗菌药…… 礼来在今年9月推出了AI和机器学习平台TuneLab，已提供自身开发的几种AI药物发现模型，允许生物技术公司开展药物合成，以扩大整个行业对药物发现工具的获取。TuneLab平台已开放18个AI模型，其中12个聚焦小分子属性预测（如溶解度、毒性），6个针对抗体开发（含热稳定性、黏度等指标），预测准确率普遍达85%-90%以上。据礼来此前透露，其AI模型已生成200个全新分子结构，其中37个进入临床前研究阶段。随着此番与英伟达强强联合，礼来公司的首席人工智能官Thomas Fuchs表示，这台超级计算机“是一台新颖的科学仪器。对于生物学家来说，它就像一台巨大的显微镜。”科学家将能够在数百万个实验上训练AI模型，以测试潜在药物，从而“大幅扩大药物发现的范围和复杂度”。礼来为什么急着砸钱到AI药物研发？答案或许藏在每家药企都不得不面对的专利悬崖里。Evaluate报告显示，未来五年，全球将有两万亿美元规模的热门药品专利到期。对于礼来而言，已经实现一品独大的替尔泊肽也是其中一员其核心分子专利最迟将2036年到期，但目前FDA已收到6份关于替尔泊肽的专利挑战诉状，若其中任何一项被认定无效，仿制药最快可提前5年获批并上市。美股分析师预期，礼来的替尔泊肽（Mounjaro和Zepbound两个版本）到2026年的年销售额将超过400亿美元，到2023年将逼近600亿美元。花旗分析师直言这将是史上最大的专利悬崖。而礼来此前就经历过这种周期。其抗抑郁药Cymbalta等重磅药物的专利到期时，其收入大幅下滑。直到2020年，礼来的收入才恢复到2011年的水平。如果不能快速推陈出新，找到下一个超级重磅炸弹，再次跌落神坛也是难免。礼来的大举“进攻”不只体现在AI制药领域，在其传统的多个优势领域中，礼来也攻城略地。在2023年中成为全球市值第一的药企后，礼来便开启了“买买买”模式，从糖尿病到细胞疗法，从核药到ADC。进入2025年，礼来更是狂加购物车。据医药魔方数据库，2025年至今，礼来作对外披露的BD项目超过20起，部分已披露的交易金额合计近130亿美元。这或许也是身处万亿市值时，礼来必须要做出的战略抉择。礼来首席执行官David Ricks在2025Q3财报会上坦言：“我们的目标不是守住铁王座，而是把铁王座变成可以不断升级的宇宙飞船。换言之，礼来想从传统药企变身生物平台型公司，用连续创新对冲专利断崖，就像苹果用 iPhone、服务、生态三轮驱动摆脱硬件周期。” 礼来究竟能在万亿市值这条路上狂奔多久？万亿市值不会靠单一爆款药物，而是取决于谁能建立起一个可规模化的、真正全球化的创新平台。谁会成为中国第一个万亿市值药企？11月24-26日，2025’第十七届中国医药企业家科学家投资家大会（启思会）将在北京海淀盛大召开。启思会将以“结构性拐点”为价值锚点，与行业精英一起，共探中国医药产业高质量发展的路径。点击下方链接获取【2025启思会】最新议程从群智涌现到万物生长：海淀以创新浓度破解从“论文”到“药方”的转化密码扫码报名获得【2025启思会】参会名额扫码进群了解【2025启思会】更多详情大会咨询参会咨询联系人：Mily 联系电话：15801338547 媒体咨询联系人：Yuvia 联系电话：18811130861 一审| 黄佳二审| 李芳晨三审| 李静芝精彩推荐大事件 | IPO | 融资&交易 | 财报季 | 新产品 | 研发日 | 里程碑 | 行业观察 | 政策解读 | 深度案例 | 大咖履新 | 集采&国谈 | 出海 | 高端访谈 | 技术&赛道 | E企谈 | 新药生命周期 | 市值 | 新药上市 | 商业价值 | 医疗器械 | IND | 周年庆大药企 | 竞争力20强 | 恒瑞 | 石药 | 中生制药 | 齐鲁 | 复星 | 科伦 | 翰森 | 华润 | 国药 | 云南白药 | 天士力 | 华东 | 上药创新药企 | 创新100强 | 百济 | 信达 | 君实 | 复宏汉霖 | 康方 | 和黄 | 荣昌 | 亚盛｜康宁杰瑞｜贝达｜微芯｜再鼎｜亚虹跨国药企｜ＭＮＣ卓越｜辉瑞｜AZ｜诺华｜罗氏｜BMS｜默克｜赛诺菲｜GSK｜武田｜礼来｜诺和诺德｜拜耳供应链｜赛默飞｜药明｜凯莱英｜泰格｜思拓凡｜康龙化成｜博腾｜晶泰｜龙沙｜三星启思会 | 声音·责任 | 创百汇 | E药经理人理事会 | 微解药直播 | 大国新药 | 营销硬观点 | 投资人去哪儿 | 分析师看赛道 | 药事每周谈 | 中国医药手册

财报上市批准

2025-10-30

·CNSight

阿尔茨海默病新药研发的多靶点探索

阿尔茨海默病（AD）新药研发关键靶点阿尔茨海默病（AD）作为痴呆主要诱因，正成为21世纪健康难题。全球现约2500万-3000万患者，2040年预计增至三倍，且现有治疗多为对症，无法根治。近期《Acta Pharmaceutica Sinica B》综述梳理AD新药研发关键靶点，为攻克疾病提供方向。 AD病理特征与现有治疗局限 AD于1907年由神经学家Alois Alzheimer发现，以进行性认知衰退为主，早期轻度记忆障碍，后期丧失交流能力，还伴语言问题、冲动行为。核心病理是细胞外β-淀粉样蛋白（Aβ）老年斑沉积与细胞内tau蛋白构成的神经原纤维缠结，二者致突触和神经元丢失、大脑萎缩。 AD按遗传分家族性（FAD）和散发性（SAD），按发病时间分早发型（EOAD）和晚发型（LOAD）。发病风险因素多，包括自噬缺陷、衰老、APOE4基因、Trem2基因、生活方式、微生物群改变、心血管疾病、脑外伤及教育水平、高血压、肥胖等。目前FDA已批准的AD治疗药包括：3种乙酰胆碱酯酶（AChE）抑制剂（多奈哌齐、卡巴拉汀、加兰他敏）和1种NMDA受体拮抗剂（美金刚）。它们仅短期改善认知，无法阻病情进展。AChE抑制剂通过抑制乙酰胆碱降解提脑内浓度，NMDA受体拮抗剂减少谷氨酸过度激活致的钙内流、减轻神经损伤，但均不针对AD根本病理。除此之外，FDA还批准了3种Aβ单抗类药物：阿杜卡单抗、仑卡奈单抗、多奈单抗。图2.示意性地描述了AD的乙酰胆碱释放周期和胆碱能假说图3.FDA批准用于治疗AD的药物的二维结构图4.全新NMDA受体拮抗剂的结构图5.谷氨酸在健康大脑中的传播经典靶点：β-淀粉样蛋白（Aβ）相关策略 Aβ异常代谢是AD核心病理，围绕其研发药物有抑制聚集、金属螯合剂、抗Aβ免疫疗法、调控分泌酶等方向。抑制Aβ聚集 Aβ易聚集形成寡聚体、纤维和斑块，可溶性寡聚体神经毒性最强。现有两种聚集抑制剂进入临床：司来吉兰（ELND005）：低剂量（250mg）安全但疗效欠佳，高剂量引发感染甚至死亡，需进一步评估。曲美普拉明：III期试验对认知评分无显著影响，重新分析发现其前药ALZ-801对ApoE4纯合子患者有益。此外，表没食子儿茶素-3-没食子酸酯（EGCG）因多生物活性，正考虑开展AD患者III期试验。图6.淀粉样蛋白聚集抑制剂的结构已扩展临床试验金属螯合剂 AD患者脑内铝、锌、铁、铜等金属离子升高，促Aβ聚集和神经毒性，金属螯合剂可结合这些离子抑Aβ积累。去铁胺（DFO）：两年研究显示，用药患者大脑新皮质铝浓度低，行为能力改善，还可能螯合锌、铜。氯喹诺尔：APP转基因小鼠用药9周，脑内可溶性Aβ升52%，提示可抑制Aβ聚集，且可溶性Aβ水平与认知障碍相关，早于斑块沉积，阻其积累关键。图7.金属螯合剂的结构抗Aβ免疫疗法通过主动或被动免疫促Aβ清除，机制有小胶质细胞吞噬、外周清除、解聚，但临床进展不顺：早期药AN1792引发脑膜脑炎等；甘特珠单抗减缓淀粉样蛋白沉积但疗效未证实；索拉珠单抗耐受好，却对1000名轻至中度患者无效；贝叶斯分析显示该疗法对AD无显著疗效。图8.主动免疫和被动免疫的分子基础调控分泌酶 Aβ由APP经β、γ分泌酶切割生成，α分泌酶切割可避Aβ产生，调控这三种酶是减少Aβ关键。 γ-分泌酶抑制剂（GSIs）与调节剂（GSMs）：GSIs理论减Aβ，但因影响Notch受体等，非选择性GSIs副作用大，如塞米司他试验终止；GSMs可选择性减Aβ₄₂，如NSAIDs证实可行性，他仑氟比尔II期安全但III期无效，且GSMs面临脑穿透性差等挑战。 β-分泌酶（BACE1）抑制剂：BACE1是APP切割限速酶，基因敲除小鼠无Aβ且无副作用，是理想靶点，但多种抑制剂如PF-05297909、AZD3293等因疗效欠佳或副作用终止试验，研发需克服选择性等难题。 α-分泌酶激活剂：α-分泌酶（主要ADAM10）切割APP可避Aβ产生，sAPPα有神经保护作用，AD患者脑脊液sAPPα低，激活策略有激活PKC、M1受体激动剂，激活ADAM10更优。图9.APP在非淀粉样变和淀粉样变通路中被α或β分泌酶裂解图10.人γ分泌酶复合物三维结构（PDBID：6IYC) 图11.已扩展临床试验的γ分泌酶抑制剂的结构图12.γ分泌酶调节剂的结构，这已经扩展了临床试验图13.人类BACE1的三维结构（PDBID：1FKN）图14.β分泌酶抑制剂的结构新兴靶点：tau蛋白与神经炎症通路 tau蛋白异常和神经炎症也是AD关键病理，相关靶点研究提供新方向。 tau靶向治疗 AD中tau过度磷酸化，解离聚集形成缠结致神经元损伤，治疗包括：激酶抑制剂：tau过度磷酸化与激酶（GSK-3β、CDK5）和磷酸酶失衡有关。GSK-3β抑制剂NP-031112临床前减tau磷酸化等，锂盐动物有效但患者无效，SB216763等因毒性或疗效差失败；CDK5抑制剂临床前能穿透血脑屏障降Aβ，但试验因疗效差或副作用终止。 tau聚集抑制剂：TRx0237 II期显高生物利用度，III期进行中；微管稳定剂如紫杉醇毒性大，TPI287对认知等有积极影响，烟酰胺小鼠实验有效，II期试验进行中。图15.tau聚集抑制剂（TRx0237）和tau稳定剂（紫杉醇和依泊替隆D）的结构图16.分别是抗甲状腺药物和不可逆葛兰素史克抑制剂的结构图17.GSK3抑制剂的结构，已延长临床试验 TREM2 TREM2是免疫球蛋白超家族跨膜受体，主要在髓系细胞表达，调控细胞功能。其基因变异与AD风险相关，p.Arg47His变异在欧美增风险2-3倍，东亚等人群无关联。TREM2缺陷减小胶质细胞聚集和吞噬，激活则促其极化等，发挥神经保护，但靶向治疗面临生物标志物缺乏等挑战。图18.TREM2信号通路 BIN1 BIN1是晚发型AD第二大遗传易感基因，通过tau通路影响AD风险，参与膜运输等，影响缠结形成。AD患者脑内BIN1表达异常，敲低可减tau介导神经毒性，还与自噬、钙通道运输相关，调控BIN1或能护神经。其他潜力靶点：神经递质、感染与Notum酶神经递质相关靶点 AD患者多神经递质紊乱，除已批准药物，还有：丁酰胆碱酯酶（BuChE）：AD患者脑内部分区域BuChE升高，抑制它或有神经保护作用，相关抑制剂在研。5-羟色胺受体（5-HT₆、5-HT₄）：5-HT₆拮抗剂英特匹定、5-HT₄拮抗剂普瑞昔单抗均进入II期试验。烟碱型乙酰胆碱受体（nAChR）：激动剂EVP-6124、POZANICLINE等在研，EVP-6124I/II期安全，III期评估认知改善。图19.胆碱酯酶抑制剂的结构，已扩展临床试验图20.胆碱酯酶抑制剂的结构感染相关靶点感染或参与AD发病，如牙龈卟啉单胞菌等感染增AD风险。COR388可抑牙龈卟啉单胞菌的牙龈蛋白酶，减神经炎症，小鼠实验挽救神经元、降Aβ₁₋₄₂，提供抗感染方向。 Notum酶 Notum负向调控Wnt信号通路，AD患者脑内Wnt信号下调，抑制Notum可护神经。Notum有明确晶体结构，是理想靶点，现有ABC99、褪黑素、咖啡因等抑制剂，ABC99增神经祖细胞，褪黑素减Aβ沉积和tau磷酸化，为研发更好抑制剂奠基。图21.（A）涉及Notum的羧酸酯酶活性在Wnt上释放棕榈油酸基团的化学反应。（B）结合相互作用的二维表示图22.卡通中所示的Notum结构图23.与激素褪黑激素相关的Notum抑制剂图24.咖啡因和茶碱是Notum抑制剂图25.恶二唑2和三唑3是由片段产生的两个互补先导 AD治疗需多靶点、多策略联合 AD病理复杂，单一靶点药难控病情，从经典到新兴靶点，研究者持续探索。虽部分研发遇挑战，但随病理理解加深及多靶点药物、联合治疗推进，未来有望研发出延缓甚至阻止AD进展的新药，为患者带来希望。关注 “CNSight” 公众号，后台回复“ AD靶点”即可获取原文资料 CNSight 一个专注于CNS前沿领域的资讯分享平台

临床3期免疫疗法临床结果

100 项与 Lanabecestat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10946	Lanabecestat	-	DB14814

研发状态

10 条进展最快的记录,

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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	中国台湾	AstraZeneca PLC	2016-07-01
血栓形成	临床1期	美国	AstraZeneca PLC	2015-09-30

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02783573 (DAYBREAK-ALZ, CTgov)	临床3期	阿尔茨海默症	1,722	Lanabecestat	廠膚淵製顧窪艱夢鹹簾(觸淵鹹選醖選鹹夢廠廠) = 膚淵夢觸襯醖糧廠蓋醖觸夢壓顧壓範選鑰壓繭 (築選鹽顧壓繭蓋積願廠, 1.32) 更多	-	2019-08-06
NCT02245737 (AMARANTH, CTgov)	临床2/3期	阿尔茨海默症	2,218	Placebo (Placebo)	齋積餘鹽糧鹽鑰鑰構簾(範鏇淵衊選壓醖鑰選廠) = 簾淵鬱積襯簾簾鏇壓襯簾鏇壓顧餘製壓糧繭齋 (淵願選餘襯積鹹製築夢, 0.55) 更多	-	2019-08-06
				Lanabecestat (Lanabecestat 50 mg)	齋積餘鹽糧鹽鑰鑰構簾(範鏇淵衊選壓醖鑰選廠) = 蓋廠廠衊廠繭膚襯蓋壓簾鏇壓顧餘製壓糧繭齋 (淵願選餘襯積鹹製築夢, 0.58) 更多
NCT02972658 (CTgov)	临床3期	阿尔茨海默症	421	Lanabecestat (AZES Placebo/AZFD Lanabecestat 20 mg)	積鹹網鬱窪鹹積夢淵壓(顧窪鑰膚艱範積蓋顧糧) = 鏇衊醖觸簾襯鬱餘衊餘淵築選網糧醖糧繭糧襯 (網鑰選鹽簾窪願壓膚簾, 1.60) 更多	-	2019-07-05
				Lanabecestat (AZES Placebo/AZFD Lanabecestat 50 mg)	積鹹網鬱窪鹹積夢淵壓(顧窪鑰膚艱範積蓋顧糧) = 蓋醖選壓廠鬱憲選醖鹽淵築選網糧醖糧繭糧襯 (網鑰選鹽簾窪願壓膚簾, 1.65) 更多
NCT03019549 (CTgov)	临床1期	-	42	Rosuvastatin	齋襯築築壓鏇鹽築鹹選(網鬱窪繭築鏇築積衊襯) = 繭顧襯鹹顧衊獵遞醖鑰願積齋積鑰齋醖餘壓窪 (鏇鹽鑰餘顧範網齋醖顧, 47)	-	2019-04-16
NCT02568397 (CTgov)	临床1期	-	60	Dabigatran etexilate	壓餘鬱襯積糧獵夢網範(鏇鏇淵築艱齋網窪築顧) = 蓋糧製夢憲獵廠築衊獵構鏇襯構鹽糧廠襯衊遞 (遞齋鑰膚齋鑰顧鑰艱選, 69) 更多	-	2019-04-05
NCT02540668 (CTgov)	临床1期	血栓形成	15	Warfarin	餘蓋膚願範齋獵淵鹽築(顧選構膚壓襯簾膚醖蓋) = 簾積艱簾鏇網築艱鏇艱膚繭艱製網齋鹹鏇衊淵 (鹹製獵顧願願醖構衊糧, 12) 更多	-	2019-03-25
NCT02663128 (CTgov)	临床1期	-	18	LY3314814 (AZD3293) (R (Fasted))	獵糧願選鹹築觸觸選鑰(製醖齋襯顧鬱夢鏇窪簾) = 齋糧鑰築積鑰鬱壓鹹顧夢簾廠蓋製齋廠蓋艱淵 (簾艱選膚衊衊積網築淵, 22) 更多	-	2019-03-22
				LY3314814 (AZD3293) (T (Fasted))	獵糧願選鹹築觸觸選鑰(製醖齋襯顧鬱夢鏇窪簾) = 製鏇糧簾鹹醖窪顧壓膚夢簾廠蓋製齋廠蓋艱淵 (簾艱選膚衊衊積網築淵, 22) 更多
NCT02406261 (CTgov)	临床1期	-	82	simvastatin+Midazolam+Lanabecestat (Cohort A)	齋壓壓構憲醖構鏇齋蓋(鏇構夢網蓋網築網構醖) = 鏇襯顧選選獵蓋襯遞齋醖衊醖鹽鏇觸夢網淵夢 (鹹簾衊選齋構夢膚範網, 21) 更多	-	2019-03-22
				Lanabecestat+Donepezil (Cohort B)	鏇築構積窪鏇鹽鑰構夢(糧艱壓觸淵衊鹹願夢選) = 顧餘鹽襯廠繭憲鏇繭網製夢壓糧願窪壓淵鹽鑰 (製鹹積獵繭顧範願簾鬱, 28) 更多
NCT03222427 (CTgov)	临床1期	-	8	LY3314814 (LY3314814)	蓋鹽膚齋壓艱壓範繭繭(壓鹽襯襯鬱鬱餘鏇齋餘) = 餘製鹹網鹽積願糧觸鏇築製壓繭鹹壓觸築襯蓋 (築鏇淵獵鏇繭膚糧鏇醖, 41) 更多	-	2019-03-22
				[13C415N3] LY3314814 ([13C415N3] LY3314814)	蓋鹽膚齋壓艱壓範繭繭(壓鹽襯襯鬱鬱餘鏇齋餘) = 夢壓淵鏇選鏇遞遞鏇艱築製壓繭鹹壓觸築襯蓋 (築鏇淵獵鏇繭膚糧鏇醖, 17) 更多