A Phase 2, Randomized, Double Blind Placebo Controlled Trial To Evaluate The Safety, Tolerability, Pharmacokinetics And Efficacy Of Pf-04360365 (Ponezumab) In Adult Subjects With Probable Cerebral Amyloid Angiopathy

Cerebral Amyloid Angiopathy (CAA) is a condition caused by the build-up of a protein called amyloid, predominantly Aβ40, within the walls of brain blood vessels, especially those blood vessels in the occipital lobe of the brain. Probable CAA may be defined as two or more hemorrhages in the brain cortex in individuals 55 years of age or older. This study will examine the study drug (PF-04360365) vs. placebo (saline) at 10 mg/kg - Day 1 and the maintenance dose of the study drug (PF-04360365) vs. placebo (saline) at 7.5mg/kg on Days 30 and 60. Subjects will be followed for 6 months after receiving the last dose of study medication.

开始日期2013-06-01

申办/合作机构

Pfizer Inc.

NCT01125631

/ Completed临床1期

A Phase 1, Randomized, Placebo-Controlled, Double Blind, Multicenter Study Of The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Multiple Intravenous Doses Of PF-04360365 In Japanese Patients With Mild To Moderate Alzheimer's Disease

The purpose of the study is to examine the safety and tolerability of a multiple dose of PF-04360365 administered over approximately 10 minutes in Japanese patients with mild-to-moderate Alzheimer's disease and to characterize the pharmacokinetics of PF-04360365 following administration of multiple doses in Japanese patients with mild-to-moderate Alzheimer's disease.

开始日期2010-05-01

申办/合作机构

Pfizer Inc.

NCT01005862

/ Completed临床1期

A Randomized, Investigator And Subject-Blind, Sponsor-Open, Placebo-Controlled Study To Examine The Effects Of PF-04360365 On ABETA In Patients With Alzheimer's Disease And Healthy Volunteers

The primary goal of this study is to evaluate the effect of PF-04360365 on the clearance of ABETA from the CSF (cerebrospinal fluid) in patients with mild Alzheimer's disease and healthy volunteers. Additionally, the study will assess the pharmacokinetics of PF-04360365, pharmacokinetic and pharmacodynamic relationships in plasma and CSF and the safety and tolerability of single doses of PF-04360365 administered to patients with Alzheimer's disease and healthy volunteers.

开始日期2010-03-01

申办/合作机构

Pfizer Inc.

100 项与 Ponezumab 相关的临床结果

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100 项与 Ponezumab 相关的专利（医药）

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项与 Ponezumab 相关的文献（医药）

2023-12-31·Drug discoveries & therapeutics

Development of amyloid beta-directed antibodies against Alzheimer's disease: Twists and turns

Article

作者: Lu, Daoran ; Dou, Fangzhou ; Gao, Jianjun

Alzheimer's disease (AD) is a severe and progressive neurodegenerative disease, and the treatment options that are currently available are limited. The amyloid cascade hypothesis has had a significant influence in explaining the pathology underlying AD. Inhibiting the production and aggregation of amyloid-beta (Aβ) and promoting its clearance have been important strategies in the development of anti-AD drugs over the past two decades. Specifically, Aβ directed antibodies have been highly anticipated, but drug development has been fraught with obstacles and challenges. Antibodies targeting the C-terminal or central region of Aβ, such as ponezumab, solanezumab, and crenezumab, primarily bind to Aβ monomers, yet no significant clearance of brain plaques or slowing of disease progression has been observed in clinical trials. Antibodies targeting the N-terminal region of Aβ, including aducanumab, lecanemab, and donanemab, primarily bind to aggregated forms of Aβ, and have shown efficacy in clearing brain plaques and slowing early-stage AD progression in clinical trials. However, clinical trials of gantenerumab, which targets conformational epitopes in the N-terminal and central sequences of Aβ and which selectively binds to aggregated forms, have failed, raising some new questions about the Aβ hypothesis. Advances in research on the pathological mechanisms of AD and advances in early diagnostic techniques may shift the time window for drug intervention and offer a potential pathway for developing effective drugs to delay the onset and progression of AD in the future.

2020-11-02·Current molecular pharmacology4区 · 生物学

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

4区 · 生物学

Review

作者: Zarini-Gakiye, Elahe ; Parivar, Kazem ; Vaezi, Gholamhassan ; Amini, Javad ; Sanadgol, Nima

Background::

Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated.

Objective::

Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators.

Methods::

We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations.

Results::

Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions.

Conclusion::

The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

2019-04-01·Annals of clinical and translational neurology

Immunotherapy with ponezumab for probable cerebral amyloid angiopathy

Article

作者: Frattura, Linda ; Smith, Eric E. ; Viswanathan, Anand ; Greenberg, Steven M. ; He, Ping ; Goodman, James A. ; Sohur, Usharbudh Shivraj ; Leurent, Claire ; Polimeni, Jonathan R. ; Lindsay, Monica ; Bednar, Martin M. ; Gurol, Mahmut Edip ; Zhang, Yao

Abstract:

Objective:

Cerebral amyloid angiopathy (CAA) is caused by cerebrovascular deposition of β‐amyloid fragments leading to cerebrovascular dysfunction and other brain injuries. This phase 2, randomized, double–blind trial in patients with probable CAA assessed the efficacy and safety of ponezumab, a novel monoclonal antibody against Aβ1–40.

Methods:

Thirty‐six participants aged 55–80 years with probable CAA received intravenous placebo (n = 12) or ponezumab (n = 24). The change from baseline to Days 2 and 90 in cerebrovascular reactivity (CVR) was measured in the visual cortex as the natural log of the rising slope of the BOLD fMRI response to a visual stimulus. Safety and tolerability were also assessed.

Results:

The mean change from baseline to Day 90 was 0.817 (ponezumab) and 0.958 (placebo): a mean ratio of 0.852 (90% CI 0.735–0.989) representing a trend towards reduced CVR in the ponezumab group. This trend was not present at Day 2. There was one asymptomatic occurrence of amyloid–related imaging abnormality–edema in the ponezumab group. The total number of new cerebral microbleeds from baseline to day 90 did not differ between groups. The ponezumab group had a participant with nonfatal new cerebral hemorrhage with aphasia and a participant with subdural hemorrhage that site investigators deemed to be nondrug related. In the placebo group one participant had a fatal intracerebral hemorrhage and one participant had migraine with aura.

Interpretation:

Ponezumab was safe and well‐tolerated. The ponezumab group showed a trend towards treatment effect at Day 90 that was opposite to the hypothesized direction. The prespecified efficacy criteria were thus not met.

项与 Ponezumab 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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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）

2023-07-07

·E药经理人

揭秘！谁成就了阿尔茨海默新药Lecanemab？一场医生、科学家、投资者30余年的接力赛

当卫材/渤健的阿尔茨海默病新药Lecanemab获FDA全面批准的消息传来，除了对其光辉一幕的赞美，更不能忘记登上这座高山的那群幕后英雄。7月6日，等待数月的好消息终于传来，卫材/渤健联合开发的Lecanemab（以下简称“L药”）用于治疗阿尔茨海默病（AD）的加速批准已成功转为完全批准。二十年来，这是首款获FDA完全批准的阿尔茨海默新疗法。攻克阿尔茨海默病领域这块骨头有多难啃，曾经罗氏的折戟，礼来和卫材的屡次落败，阿斯利康、GSK和BMS曾在这方面的“退却”，足以见得。但败和难，是胜的起点，至少已经有L药在极力证明。站在AD治疗的领域这无疑是一款里程碑式的新药。但在见证历史的时刻，不要忘记了是谁成就了这款药。在L药研发接力赛上，如果错失一个坚持者，或者一个机会，也就不可能有它引领阿尔茨海默病药物走到台前的今天。而不管是L药还是曾经的Aducanumab，从早期研究到成药，到上市，都是众人拾柴的结果。没有Lars Lannfelt，也就没有LecanemabLecanemab的前三个英文字母，来源于Lannfelt-Eisai（卫材）-Collaboration的三个首字母。如果没有这位名叫Lars Lannfelt的内科医生，没有他与瑞典生物化学家 Pär Gellerfors 创立的BioArctic公司，那便没有L药，更不用提如今这振奋人心的一幕。上个世纪80年代初，在瑞士斯德哥尔摩某医院的地下实验室里，Pär Gellerfors第一次见到了Lars Lannfelt。Pär刚从美国做了两年客座研究员回来，并带回了一本《分子克隆:实验室手册》。这本书现在已成为分子生物学的经典著作，但在当时，里面提到的“克隆基因”和“发现突变”等概念，几乎是全新的。虽然常年在医院工作，Lannfelt却对这些一无所知。对此，他感到震撼，也是从那时候开始，他与Pär试图一起绘制间歇性卟啉症(一种遗传性疾病)背后的遗传学和生物化学图谱，并决定深扎实验室，研究罕见早发性疾病。他们探索的开始，为后面合作创立Bioarctic和研发L药的故事，书写了序言。在实验室里一起工作了多年之后，Pär进入制药行业，而Lannfelt开始在卡罗林斯卡医学院的本特·温布莱德实验室工作，该实验室以研究阿尔茨海默病而出名。不久之后，Lannfelt得知在瑞典北部，有许多人在较年轻的时候便患有该疾病。其中一个含11个成员的家庭，他们在平均年龄57岁时便患病。基于在实验室多年对疾病背后突变的钻研，他决定对此展开调查研究。1992年，Lannfelt先是发现了“瑞典突变”，这种突变使淀粉样β蛋白聚集形成聚集体（即斑块），这在患者身上被清楚地观察到，当时瑞典很多一流的科学出版物均刊登了这项发现，但彼时的Lannfelt错失了申请专利的机会。不过，这并不是L药的开端，真正的开始，源自1999年，Lannfel研究小组发现并命名的一种“北极突变”。这种突变导致淀粉样β蛋白错误折叠并呈现出不同的形式，后也会发生聚集。彼时科学家的注意力都在“斑块”这一原因上，但淀粉样蛋白有多种形式，如从微小的可溶蛋白质碎片到患者大脑中杂乱的大斑块。Lannfelt则坚持认为，大脑中可溶性形式淀粉样β蛋白的堆积是真正的病因，Lannfelt团队将其称为“原纤维”。随后，Lannfelt欲对其进行专利申请。不过，由于经验尚缺，Lannfelt花了数月的精力去修改专利申请。所幸在同期，原伙伴Pär离开了HemeBiotech公司，并同样看好Lannfelt发现的靶分子潜力，两者新的伙伴关系正式开始，后找到了专业的专利顾问，解决了申请专利的问题。2001年，“北极突变”这一发现被刊登发表。至此，淀粉样蛋白-β低聚物/原纤维这个治疗阿尔茨海默病的靶点，注定要在史上留名。但起初，推进研究需要钱。21世纪初，IT行业股市的大崩盘波及到生物技术，某段时间里寻求外部资本甚至如天方夜谭。第一批专利发票被塞进Lannfelt和Pär的家庭财务中，由于发票金额太大，只能设法延期付款。“没有人想在我们身上投资一分钱。”Pär曾道出了最初的窘迫，“为了解决问题，我们决定寻找一家可以提供资金帮助的公司。”那时候，Lannfelt和Pär看到了同样在阿尔茨海默领域倾心研究的日本卫材，与其合作之心十分强烈。2003年6月，当在卫材的研究人员面前作出演讲后，Lannfelt和Pär原以为会很久才会收到结果，但谁曾想，就在会面第2天，卫材来电：“您们是否愿意来东京详谈？”也就是在与卫材逐步接洽的那一年，2003年，Lannfelt和Pär共同成了Bioarctic公司，2005与卫材正式开发针对淀粉样蛋白原纤维的抗体。2006年，Pär成为全职CEO，Bioarctic聘请了首批研究人员。一拍即合，“L药”背后的卫材18年2005年，卫材与BioArctic的命运正式交织在了一起。卫材的首席执行官Haruo Naito亦是双方合作中的“关键先生”。他在制药行业工作了几十年，关注阿尔茨海默病的研究时间不亚于BioArctic的两位创始人，并与阿尔茨海默病药物研发做了多年斗争。算起来，卫材从1983年首次进入阿尔茨海默病领域，至今在这条路上已跑了40年。第一次取得突破是于1997年成功开发了Aricept，作为阿尔茨海默病的标准疗法，能够暂时改善认知功能的对症疗法，但其无法从疾病本身成因方面治疗，且可用药期间较短。Haruo Naito并不放弃，曾将为阿尔茨海默病患者提出一种新的治疗方法作为卫材的首要任务。此后多年来，卫材一直致力于研发下一代阿尔茨海默病药物。而BioArctic抛出的橄榄枝迅速吸引了Haruo Naito。“当时BioArctic最吸引我们的便是淀粉样蛋白的发现，特别是原纤维，当时没人知道。”借此，他激动地看到了一种可能性，并由衷感叹“我们可以把这种神奇的药物作为一种治疗阿尔茨海默病的新药物提出来了。”很快，双方一拍即合，BioArctic和卫材在2005年就阿尔茨海默病的疾病修饰治疗进行了研究合作。也是在同一年，BioArctic候选药物mAb158（mAb158是BAN2401/lecanemab的小鼠前体类抗体）在瑞典乌普萨拉大学分离。这只是双方合作的开始。2007年，BioArctic和卫材就抗体BAN2005作为阿尔茨海默病疾病修饰治疗的许可协议签订了许可协议，与此同时提交了关于抗体BAN2401的专利申请；2008年，BioArctic和卫材就BAN2401的后备抗体进行了第二次研究合作；2013年，卫材在美国启动了一项关于候选药物BAN2401的临床2b期研究，并在日本开始了备份临床开发；2014年，BAN2401在阿尔茨海默病中的临床开发在欧洲开始。而卫材和渤健的缘分也始于2014年，双方就BAN2401在阿尔茨海默病中的持续开发和商业化达成协议，这也为三年后加大合作埋下了伏笔。研发仍在紧锣密鼓推进。2015年，BioArctic和卫材加大了合作力度，签订了关于BAN2401备份的许可协议，BAN2401的后续项目，以及关于阿尔茨海默病新疾病修饰疗法的第三项研究合作协议。在卫材的助推下，BAN2401也开始陆续摘得果实。2017年，BAN2401的专利在美国获得授权；2018年，早期阿尔茨海默病的BAN2401 2b期临床研究结果较为优异；2019年BAN2401在早期阿尔茨海默病患者中的3期研究启动，BioArctic与卫材发起了一项进一步研究合作。直到2020年，BAN2401有了一个新名字，被赋予国际非专利名称lecanemab，前三个字母便取自于BioArctic创始人Lannfelt -卫材（Eisai）- Collaboration首字母。更大的进展则来自于2021年，FDA授予L药在阿尔茨海默病中的突破性疗法和快速通道指定。卫材开始向FDA提交申请，以加速途径批准L药在早期阿尔茨海默病中的市场批准。卫材较为丰富的经验助力了L药在后续开发和商业化。Thomas D. Fagan Jr.于2022年7月任命为美国阿尔茨海默病商业化副总裁，负责领导公司阿尔茨海默病业务在美国商业化战略的制定和实施，同时加速团队的成长和扩张。卫材副总裁Alex Scott也是一个关键人物。其父母因患上阿尔茨海默病而离世，他长期关注于阿尔茨海默病药物的研发，并致力于将药物推上市。而今，L药正式上市，成为了20年来首款获得FDA完全批准的阿尔茨海默病新药。不过，关于阿尔茨海默病新药的研发还远未结束。即使淀粉样蛋白的堆积是阿尔茨海默病的第一个迹象，也有其他目标需要解决，比如在患者大脑中堆积的被称为tau的蛋白纠结。而今，卫材已在测试将L药与一种针对tau的药物相结合。A药背后“关键先生”们除了L药，渤健和卫材还合作推出了AD领域的里程碑新药Aducanumab（以下简称“A药”）。尽管该药有争议，但不可否认它曾是自2003年以来FDA批准的首个治疗AD的新疗法，也是首个针对该疾病明确病理机制，减少AD患者大脑中的淀粉样蛋白斑块的治疗方法。A药的研发历程比L药更加曲折，因而涉及的关键人物更多。Roger M. Nitsch、Christoph Hock和Jan Grimm共同创办了Neurimmune Therapeutics，确定了研究思路和技术路线，最终成功筛选出抗体NI-101，这便是A药的“雏形”。在Neurimmune创立初期，最需要资金的时候，Karsten Henco投了500万美元的种子基金。而能将A药推向临床及之后的关键源于一起与渤健的合作，给合作牵线搭桥的是渤健当时的首席医疗官以及主管神经病学研发部门的高级副总裁Alfred Sandrock。在抗体NI-101更早前，还有Dale Schenk对AD免疫治疗的研究，他启动了AN-1792的研究，这一研究是A药的“源头”。故事最早要追溯到1995年。第一个出场的人是Dale Schenk，他当时正在美国加州的Athena Neurosciences公司当神经生物学部的主任。当时AD新药开发的主流方向是寻找抑制淀粉样蛋白产生的化合物。Schenk提出了相反的研究思路：激发患者清除多余淀粉样蛋白的抗体。这个想法一提出便被大家认为不可能，在Schenk的坚持下，被放到了待做试验清单的最后一项——第30项。后来随着该实验的成功，AD免疫治疗的研究时代也开启了。2000年前后，Elan Pharmaceuticals（1996年了收购Athena）启动了AN-1792的临床试验。并在次年9月开始AN-1792的2期临床试验。在此期间，Schenk还因此获得了2001年的Potamkin奖（由美国神经病学学会颁发，授予在脑退行性疾病研究领域中做出卓越贡献的学者）。之后因安全性时间激增，Elan于2002年3月宣布永久暂停AN-1792的临床试验。研发的企业放弃了，但承接AN-1792临床的PI们却坚持了下来。故事的主角也随之变成了Roger M. Nitsch和Christoph Hock，他们两人当时在瑞士苏黎世大学精神科医院分别担任精神病学研究部主任、主任医师，而该医院承接了AN-1792多中心临床的部分。Nitsch和Hock在患者免疫AN-1792一年后又进行了下一步研究，结果显著。2003年Nitsch在神经科学顶级期刊《Neuron》上发表相关文章，重燃起大家对AD抗体的研发热情，Nitsch也因而获得了2004年的Potamkin奖。文章发表后Schenk的团队重返，先进一步明确了免疫AN-1792后产生的靶向Aβ抗体的抗原表位。Nitsch选择了独辟蹊径。并找到当时在美国Rinat Neuroscience当AD研发主管的Jan Grimm帮忙，他在AD的单抗研发方面很有经验，辉瑞后来AD研发管线里的Ponezumab就是在他手下开发出来的。最终他们有了在当时还是“非主流”但成熟的技术实现路线，并且筛选出了初步看着理想的抗体。之后三人在Karsten Henco的建议下，创立了Neurimmune Therapeutics。Henco是EVOTEC BioSystems的创始人，在Neurimmune创立初期提供了种子资金。Nitsch与Henco的缘分在于，之前Nitsch与后者的公司合作注册了一家叫EVOTEC Neurosciences Gmbh的公司，这家公司主要致力于寻找AD的诊治方法，并寻求与制药公司的合作。Nitsch对药物开发有清晰的认识，他认为开发药物并不简单，必须寻找制药公司的合作。而此时A药的关键人物也跟随一个人、一笔交易发生了变化。当时渤健正在为近乎“枯竭”的研发管线而焦急，2004年Biogen Idec为了拓展合作在苏黎世成立了全球总部，地点正好在Nitsch他们所在的小城。天时地利有了，只欠牵线搭桥的人。现今被行业尊称为全球神经科学领域思想领袖的Alfred Sandrock就是这个关键人物，他当时是渤健的首席医疗官以及主管神经病学研发部门的高级副总裁。而他与Nitsch是“老相识”，当时两人都还在学术界，Nitsch在哈佛大学麻省总医院和MIT当博士，而Sandrock在哈佛大学麻省总医院当助理教授。2007年11月，Nitsch和渤健达成最终合作，由Sandrock监督治疗A药的开发。之后的故事便不再赘述。值得关注的是，A药背后的“关键先生”们如今也在自己的征程上继续发光发热。Sandrock在渤健工作了20多年后，去了一家叫Voyager Therapeutics的公司，并被任命为首席执行官。Voyager专注于开发神经系统疾病AAV疗法。而Roger M. Nitsch、Christoph Hock和Jan Grimm三人分别担任Neurimmune公司的CEO、CMO、CSO。登记邮箱信息订阅E药经理人信息服务扫描二维码精彩推荐CM10 | 集采 | 国谈 | 医保动态 | 药审 | 人才 | 薪资 | 榜单 | CAR-T | PD-1 | mRNA | 单抗 | 商业化 | 国际化｜猎药人系列专题启思会 | 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 | 医药界·E药经理人 | 中国医药手册创新100强榜单 | 恒瑞 | 中国生物制药 | 百济 | 石药 | 信达 | 君实 | 复宏汉霖｜翰森 | 康方生物 | 上海医药 | 和黄医药 | 东阳光药 | 荣昌 | 亚盛医药 | 齐鲁制药 | 康宁杰瑞 | 贝达药业 | 微芯生物 | 复星医药｜再鼎医药跨国药企50强榜单 | 辉瑞 | 艾伯维 | 诺华 | 强生 | 罗氏 | BMS | 默克 | 赛诺菲 | AZ | GSK | 武田 | 吉利德科学 | 礼来 | 安进 | 诺和诺德 | 拜耳 | 莫德纳 | BI | 晖致 | 再生元

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100 项与 Ponezumab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09952	Ponezumab	-	DB15135

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
脑淀粉样血管病	临床2期	美国	Pfizer Inc.	2013-06-01
脑淀粉样血管病	临床2期	加拿大	Pfizer Inc.	2013-06-01
脑淀粉样血管病	临床2期	法国	Pfizer Inc.	2013-06-01
脑淀粉样血管病	临床2期	荷兰	Pfizer Inc.	2013-06-01
脑淀粉样血管病	临床2期	英国	Pfizer Inc.	2013-06-01
阿尔茨海默症	临床2期	美国	Pfizer Inc.	2008-12-05
阿尔茨海默症	临床2期	澳大利亚	Pfizer Inc.	2008-12-05
阿尔茨海默症	临床2期	比利时	Pfizer Inc.	2008-12-05
阿尔茨海默症	临床2期	加拿大	Pfizer Inc.	2008-12-05
阿尔茨海默症	临床2期	英国	Pfizer Inc.	2008-12-05

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临床结果

适应症

分期

评价

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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


NCT00945672 (CTgov)	临床2期	阿尔茨海默症	36	PF-04360365 (PF-04360365 10 mg/kg (Cohort Q))	鑰膚網範夢願選繭醖糧 = 膚廠獵選鏇艱廠廠願夢廠製廠顧襯鬱襯積遞顧 (艱壓夢蓋夢餘窪壓構膚, 鏇簾蓋構積網廠膚齋遞 ~ 衊構鏇衊壓鏇鬱鹹網糧) 更多	-	2024-04-19
				Placebo (Placebo (Cohort Q))	鑰膚網範夢願選繭醖糧 = 蓋構醖襯觸憲顧鏇積窪廠製廠顧襯鬱襯積遞顧 (艱壓夢蓋夢餘窪壓構膚, 窪襯構範襯廠積鹹築鏇 ~ 鬱鏇窪網淵繭鏇願壓網) 更多
NCT00722046 (CTgov)	临床2期	阿尔茨海默症	198	PF-04360365 (PF-04360365 0.1 mg/kg (Part A))	鑰淵憲鑰選衊窪衊網鏇 = 鏇觸醖網遞壓鑰遞鹹膚餘顧範憲觸簾築鏇選鹹 (顧積鏇網築獵衊製壓鹹, 餘鹹衊簾淵齋壓遞餘選 ~ 繭膚淵網糧製壓衊顧淵) 更多	-	2022-11-07
				PF-04360365 (PF-04360365 0.5 mg/kg (Part A))	鑰淵憲鑰選衊窪衊網鏇 = 衊網獵餘製獵簾鏇糧築餘顧範憲觸簾築鏇選鹹 (顧積鏇網築獵衊製壓鹹, 壓遞製網艱齋壓鏇糧齋 ~ 廠糧壓憲艱網製簾醖衊) 更多
NCT01821118 (CTgov)	临床2期	脑淀粉样血管病	36	PF-04360365 (PF-04360365)	夢鑰願鏇鏇簾窪膚築膚(鹹製襯構簾鑰鏇膚繭衊) = 鏇遞鏇顧齋餘鹽觸鹽遞廠蓋齋鏇獵選網鏇壓壓 (網遞鹽夢淵蓋艱餘願窪, 0.085) 更多	-	2016-11-03
				placebo+PF-04360365 (Placebo)	夢鑰願鏇鏇簾窪膚築膚(鹹製襯構簾鑰鏇膚繭衊) = 獵積餘鏇選膚糧膚獵構廠蓋齋鏇獵選網鏇壓壓 (網遞鹽夢淵蓋艱餘願窪, 0.073) 更多
AAIC2012	N/A	阿尔茨海默症 Aβ 1-x \| Aβ 1-40 \| Aβ 1-42 ... 更多	194	Ponezumab 0.1 mg/kg	糧鬱窪製窪憲艱獵鏇獵(觸鑰積製築範積獵淵願) = 獵窪廠顧觸構憲選網窪鹽積簾鏇網繭範構顧餘 (糧遞範築艱夢築衊顧獵 )	-	2012-07-01
				Ponezumab 0.5 mg/kg	鏇夢築網鹹廠窪顧襯鹽(蓋築憲憲淵夢夢獵鏇窪) = 蓋襯齋鑰鹽選糧築鹽鹹築顧築鏇壓憲餘醖鑰蓋 (糧廠簾獵窪窪膚鏇糧選 ) 更多
AAIC2012	N/A	阿尔茨海默症 Aβ 1-40 \| Aβ 1-x	36	Ponezumab 10 mg/kg every 3 months	積顧衊艱顧壓壓糧網築(壓築鹽鑰簾觸鏇窪網鹹) = 範艱網壓醖廠廠夢齋夢繭艱衊淵壓鑰窪願壓簾 (獵鏇繭積艱醖鹽積壓觸 )	-	2012-07-01
				Placebo	積顧衊艱顧壓壓糧網築(壓築鹽鑰簾觸鏇窪網鹹) = 網範簾簾衊鑰憲積獵廠繭艱衊淵壓鑰窪願壓簾 (獵鏇繭積艱醖鹽積壓觸 )
AAIC2010	N/A	阿尔茨海默症	15	Ponezumab 1 mg/kg	壓窪鏇膚餘範簾齋築遞(艱築醖願蓋憲憲獵醖醖) = 鹹廠鏇鹽築繭製簾膚鹽艱廠製獵鹹製獵壓衊夢 (醖窪觸壓餘構衊簾遞醖 )	-	2010-07-01
				Ponezumab 3 mg/kg	壓窪鏇膚餘範簾齋築遞(艱築醖願蓋憲憲獵醖醖) = 繭鬱齋獵壓窪窪蓋構鏇艱廠製獵鹹製獵壓衊夢 (醖窪觸壓餘構衊簾遞醖 )