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Article(id=1241022579071308619, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241022576185634950, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.09.04, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1679932800000, receivedDateStr=2023-03-28, revisedDate=null, revisedDateStr=null, acceptedDate=1723392000000, acceptedDateStr=2024-08-12, onlineDate=1773812439935, onlineDateStr=2026-03-18, pubDate=1727193600000, pubDateStr=2024-09-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773812439935, onlineIssueDateStr=2026-03-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773812439935, creator=13701087609, updateTime=1773812439935, updator=13701087609, issue=Issue{id=1241022576185634950, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='9', pageStart='641', pageEnd='720', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773812439247, creator=13701087609, updateTime=1773813972032, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241029005206417725, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241022576185634950, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241029005206417726, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1241022576185634950, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=657, endPage=660, ext={EN=ArticleExt(id=1241022580451234645, articleId=1241022579071308619, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=A new drug for Alzheimer’s disease: lecanemab, columnId=1239174991388930543, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=New Drug Introduction, runingTitle=null, highlight=null, articleAbstract=

Alzheimer’s disease (AD) is a progressive degenerative disease of the central nervous system. Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble amyloid β-protein aggregates and can slow down the progression of AD. In January 2023, the U.S. Food and Drug Administration approved lecanemab to treat AD patients with mild cognitive impairment or mild dementia stage of disease. The common adverse drug reactions of lecanemab were infusion-related reactions, headache, and amyloid-related imaging abnormalities with edema. The mechanism of action, pharmacokinetics, clinical research, economic evaluation, and safety evaluation of lecanemab were reviewed in this article, so as to provide reference for rational clinical drug use.

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阿尔茨海默病（AD）是一种进行性发展的中枢神经系统退行性疾病。lecanemab是一种人源化IgG1单克隆抗体，优先靶向可溶性β-淀粉样蛋白聚集体，减缓AD的进展。2023年1月，美国食品和药物管理局批准lecanemab用于治疗有轻度认知障碍或轻度痴呆的早期AD。lecanemab常见不良反应为输液相关反应、头痛和淀粉样蛋白相关影像学异常水肿。本文对lecanemab的作用机制、药动学、临床研究、经济学评价、安全性评价等进行综述，为临床合理用药提供参考。

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杨建伟，女，主管药师，硕士，主要从事临床药学的研究，E-mail：

, authorsList=杨建伟)}, authors=[Author(id=1241029119048208501, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1241022579071308619, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=yangjianwei_happy@126.com, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1241029119127900281, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1241022579071308619, authorId=1241029119048208501, language=EN, stringName=Jian-wei YANG, firstName=Jian-wei, middleName=null, lastName=YANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Certification Center for Licensed Pharmacist of National Medical Products Administration, BEIJING 100061, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1241029119346004098, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1241022579071308619, authorId=1241029119048208501, language=CN, stringName=杨建伟, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=国家药品监督管理局执业药师资格认证中心，北京　100061, bio={"content":"

杨建伟，女，主管药师，硕士，主要从事临床药学的研究，E-mail：

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杨建伟，女，主管药师，硕士，主要从事临床药学的研究，E-mail：

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阿尔茨海默病治疗新药lecanemab
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杨建伟
中国新药与临床杂志 | 新药介绍 2024,43(9): 657-660
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中国新药与临床杂志 | 新药介绍 2024, 43(9): 657-660
阿尔茨海默病治疗新药lecanemab
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杨建伟
作者信息
  • 国家药品监督管理局执业药师资格认证中心，北京　100061

    • 杨建伟，女，主管药师，硕士，主要从事临床药学的研究，E-mail：

A new drug for Alzheimer’s disease: lecanemab
Jian-wei YANG
Affiliations
  • Certification Center for Licensed Pharmacist of National Medical Products Administration, BEIJING 100061, China
出版时间: 2024-09-25 doi: 10.14109/j.cnki.xyylc.2024.09.04
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摘要
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阿尔茨海默病（AD）是一种进行性发展的中枢神经系统退行性疾病。lecanemab是一种人源化IgG1单克隆抗体，优先靶向可溶性β-淀粉样蛋白聚集体，减缓AD的进展。2023年1月，美国食品和药物管理局批准lecanemab用于治疗有轻度认知障碍或轻度痴呆的早期AD。lecanemab常见不良反应为输液相关反应、头痛和淀粉样蛋白相关影像学异常水肿。本文对lecanemab的作用机制、药动学、临床研究、经济学评价、安全性评价等进行综述，为临床合理用药提供参考。

lecanemab  /  阿尔茨海默病  /  临床研究  /  β淀粉样蛋白

Alzheimer’s disease (AD) is a progressive degenerative disease of the central nervous system. Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble amyloid β-protein aggregates and can slow down the progression of AD. In January 2023, the U.S. Food and Drug Administration approved lecanemab to treat AD patients with mild cognitive impairment or mild dementia stage of disease. The common adverse drug reactions of lecanemab were infusion-related reactions, headache, and amyloid-related imaging abnormalities with edema. The mechanism of action, pharmacokinetics, clinical research, economic evaluation, and safety evaluation of lecanemab were reviewed in this article, so as to provide reference for rational clinical drug use.

lecanemab  /  Alzheimer’s disease  /  clinical study  /  amyloid β-protein
杨建伟. 阿尔茨海默病治疗新药lecanemab. 中国新药与临床杂志, 2024 , 43 (9) : 657 -660 . DOI: 10.14109/j.cnki.xyylc.2024.09.04
Jian-wei YANG. A new drug for Alzheimer’s disease: lecanemab[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (9) : 657 -660 . DOI: 10.14109/j.cnki.xyylc.2024.09.04
正文
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阿尔茨海默病（Alzheimer’s disease, AD）是一种起病隐匿的进行性发展的中枢神经系统退行性疾病[1]。世界卫生组织（WHO）预计2030年痴呆症患者总数将达到8 200万，2050年将达到1.52亿；我国AD患者已经超过600万人，预计到2050年患病人口将超过2 000万[2]。AD临床表现有记忆障碍、失语、失用、失认、视空间技能损害、执行功能障碍以及人格和行为改变等，最终导致患者痴呆或死亡[3]。主要病理特征包括β-淀粉样蛋白（amyloid β-protein，Aβ）斑块沉积和神经原纤维缠结（neuro fibrillary tangles，NFTs）[4,5]。传统的治疗药物，如乙酰胆碱酯酶抑制剂和非竞争性N-甲基-D-天冬氨酸受体拮抗剂等，仅限于部分缓解AD患者的症状，不能改变AD患者潜在的大脑变化，无法改变疾病的进程。2023年1月，美国食品和药物管理局（FDA）批准抗Aβ原纤维抗体lecanemab用于治疗早期AD患者。本文对lecanemab的作用机制、药动学、临床研究、经济学评价、安全性评价等进行介绍。
作用机制
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AD的发病机制有多种假说，包括Aβ级联假说、胆碱能神经元假说、Tau蛋白异常磷酸化假说等，其中最重要的是Aβ级联假说[6]。该假说认为Aβ是导致脑细胞死亡的关键因素，从而会导致记忆和思维缺陷。研究证明，Aβ通过介导持续性连锁反应对神经细胞产生毒性作用，这与AD病理特征直接存在重要联系。因此，通过与原纤维结合治疗可以防止Aβ在大脑中的异常积累，减缓或者停止AD的进展[7]。Aβ存在于各种构象状态，包括可溶性单体、体积逐渐增大的可溶性聚集体（如低聚物、原纤维）以及不溶性原纤维和斑块[8]。可溶性Aβ聚集物已被证明比单体或不溶性纤维具有更大的毒性[9]。lecanemab是一种人源化免疫球蛋白γ1（IgG）单克隆抗体，优先靶向可溶性Aβ聚集体（低聚物和原纤维）。研究表明，lecanemab可降低AD动物模型中致病性Aβ斑块数量，防止Aβ聚集，选择性减少脑和脑脊液中的Aβ原纤维[5]。
药动学
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Ⅰ期临床研究比较了单次腹部皮下注射lecanemab 700 mg和静脉输注10 mg·kg-1的药动学、生物利用度和安全性[10]。59名健康受试者参与了该研究，结果显示单次腹部皮下注射后，lecanemab的绝对生物利用度为49.7%，72 h达到峰浓度（cmax），平均cmax为59.8 µg·mL-1，比静脉输注的平均cmax 262 µg·mL-1降低了4倍，吸收相相对延迟。两种给药方式的半衰期类似，lecanemab耐受性良好，免疫原性低。
lecanemab说明书[11]推荐给药剂量为10 mg·kg-1，稀释后静脉输注约1 h，每2周给药1次，6周后可达稳态。单次输注给药时，在0.3~15 mg·kg-1剂量范围内，lecanemab的cmax和血药浓度-时间曲线下面积（AUC）呈比例增加。稳态时，中央室分布容积为3.22 L。lecanemab在体内被蛋白水解酶降解消除，清除率为0.434 L·d-1。终末半衰期为5~7 d。性别、体重和白蛋白会影响lecanemab的体内暴露量，但无临床意义。lecanemab不会被肾脏清除或被肝酶代谢。
一项关于lecanemab的群体药动学和药效学研究[12]显示，lecanemab具有良好的线性二室模型特征。最终模型中，抗药物抗体阳性状态、性别、体重和白蛋白对药物清除率有影响。PK/PD模拟显示，与10 mg·kg-1每月给药1次相比，10 mg·kg-1每2周给药1次可使标准摄入比值（standard uptake value ratio, SUVr）和AD特异性的生物标志物p-tau181的下降幅度更大，下降速度更快，也可增加Aβ 42/40的比值。此外，治疗中断后，脑淀粉样蛋白重新积聚到基线水平的速度较慢，恢复半衰期约为4年，而血浆Aβ 42/40比值和p-tau181恢复到基线水平的速度比淀粉样蛋白快。
临床研究
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一项随机、双盲、前瞻性的Ⅱb期临床试验（NCT01767311）[9]探讨了lecanemab不同给药剂量在早期AD、AD引起的轻度认知障碍和轻度AD痴呆患者中的疗效并确定lecanemab 90%有效剂量（ED90）。研究主要终点是治疗12个月时对ED90剂量组AD综合评分（ADCOMS）的临床变化进行贝叶斯分析，要求ED90剂量组ADCOMS与安慰剂组相比，下降≥25%的概率达到80%。次要终点包括18个月时脑淀粉样蛋白的减少，ADCOMS、临床痴呆评分总和量表（CDR-SB）和AD认知功能量表（ADAS-Cog14）评分的临床下降，脑脊液核心生物指标以及海马总体积的变化。研究纳入了854例AD患者，分别随机接受lecanemab（n=609）和安慰剂（n=245）治疗。lecanemab治疗剂量组包括2.5 mg·kg-1每2周1次、5 mg·kg-1每月1次、5 mg·kg-1每2周1次、10 mg·kg-1每月1次和10 mg·kg-1每2周1次。研究确定lecanemab ED90为10 mg·kg-1每2周1次。治疗12个月时，ED90剂量组ADCOMS优于安慰剂组25%的概率为64%，未达到12个月的主要终点指标。在治疗18个月时，根据贝叶斯和频率分析，lecanemab ED90剂量组脑淀粉样蛋白减少，同时ADCOMS、ADAS-Cog14、CDR-SB结果分别降低了27%、56%和33%，优于安慰剂组的概率≥96.4%。脑脊液生物标志物也支持药物的治疗效果。试验表明，研究虽未达到治疗12个月的主要终点，但治疗18个月时，次要终点指标显示脑淀粉样蛋白的减少伴随着临床和生物标志物的持续下降，lecanemab对淀粉样蛋白的清除有剂量和时间依赖性。
MCDADE等[13]在Ⅱ期临床试验基础上开展了一项开放标签的长期研究。Ⅱb期的核心研究进行18个月后没有解盲，所有受试者可继续接受每2周1次的安慰剂或lecanemab治疗，为期24个月，以评估lecanemab的疗效和安全性（OLE研究，NCT01767311）。结果显示，在所有测试剂量中，lecanemab 10 mg·kg-1每2周给药1次对关键生物标志物和临床终点的影响最大，可减少脑淀粉样蛋白。与lecanemab 10 mg·kg-1每月给药1次相比，每2周给药1次的方案中淀粉样蛋白的下降、血浆Aβ 42/40比值的增加以及血浆p-tau181下降都更快。研究表明，lecanemab能显著减少淀粉样蛋白斑块，减缓临床衰退。随着时间的推移，lecanemab组与安慰剂组的差异也越来越大，也提示了lecanemab的治疗潜力并且应持续给药。
一项为期18个月的多中心、双盲、Ⅲ期临床试验（NCT03887455）[14]中，年龄在50~90岁之间的1 795例早期AD患者随机按1∶1的比例分别接受静脉输注lecanemab（10 mg·kg-1每2周1次，n=898）或安慰剂（n=897）治疗。主要终点指标为治疗18个月时CDR-SB较基线的变化。次要终点指标为PET中淀粉样蛋白的变化和ADAS-Cog14、ADCOMS、AD轻度认知障碍日常生活活动量表（ADCS-MCI-ADL）评分。试验结果显示，2组CDR-SB评分基线值均为3.2分；治疗18个月时，lecanemab组和安慰剂组CDR-SB评分较基线变化的校整最小二乘均值分别为1.21和1.66，差异有显著意义（P<0.001）。在698例患者的亚组研究中，lecanemab组较安慰剂组能够显著减少脑淀粉样蛋白（P<0.001）。lecanemab组和安慰剂组ADAS-cog14、ADCOMS、ADCS-MCI-ADL评分较基线变化的平均差异分别为-1.44（P<0.001）、-0.050（P<0.001）、2.0（P<0.001）。研究表明，治疗18个月时，lecanemab组与安慰剂组相比，CDR-SB的临床衰退幅度显著减缓，所有次要终点指标也有显著改善，lecanemab可以降低早期AD患者的淀粉样蛋白标记物，功能与认知指标的下降幅度小于安慰剂组。
在Ⅲ期临床试验后续的开放标签研究中，评估了lecanemab 10 mg·kg-1每2周给药1次在早期AD患者中的长期安全性和耐受性[15]。评估的关键指标是治疗中出现的不良事件以及CDR-SB相较于核心研究基线的变化，试验也将评估lecanemab的长期疗效。该试验结果目前尚未报道。目前，一项针对lecanemab治疗临床前期AD以及伴有淀粉样蛋白升高的临床前期AD患者的疗效和安全性的研究（NCT04468659）[16]正在进行中，其上市后的疗效及长期安全性也需要进一步验证。
一项针对lecanemab治疗AD患者的安全性和有效性的荟萃分析[17]中纳入了该药的Ⅱ/Ⅲ核心和开放标签试验，结果显示，lecanemab有利于稳定或改善CDR-SB评分，在早期AD患者的认知、功能和行为方面具有显著疗效。荟萃分析结果也显示lecanemab可显著增加淀粉样蛋白相关影像学异常（amyloid-related imaging abnormalities，ARIA）的发生风险。
经济学评价
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TAHAMI MONFARED等[18]基于lecanemabⅡ期临床试验数据等模拟了疾病改善和早期干预对疾病进展的影响。模型结果包括患者和护理人员质量调整生命年（QALYs）、总生命年和总护理成本，包括医疗资源使用的直接医疗和非医疗成本，以及终生护理的间接成本。研究结果显示，早期AD患者，与单独标准治疗相比，lecanemab联合标准治疗预计可增加0.61 QALYs，总非治疗费用减少8 707美元。lecanemab可能会改善长期健康结果，降低正式和非正式的护理成本，从而产生一系列潜在的临床、经济和社会价值。同时，TAHAMI MONFARED等[19]也模拟预测了lecanemab在早期AD患者中的长期健康结果。研究结果显示，lecanemab对早期AD具有潜在临床价值，可以减缓疾病的进展速度，增加轻度认知障碍和轻度AD的持续时间，缩短中度和重度AD持续时间。在lecanemab的Ⅲ期临床试验数据基础上，研究者用模型模拟评估了早期AD患者使用lecanemab加标准治疗与单独标准治疗相比的长期健康结果[20]。评估结果显示，lecanemab治疗可以减缓AD向中、重度进展；根据年龄、疾病严重程度和Tau病理学，尽早使用lecanemab治疗可以改善健康结果，QALYs预计可增加0.77~1.09年，而轻度AD亚组为0.4年。
安全性评价
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在Ⅱ期临床试验[9]中，609例AD患者应用了不同剂量梯度的lecanemab，在最高剂量10 mg·kg-1每2周1次给药时，lecanemab耐受性良好，ARIA水肿（ARIA-E）的发生率为9.9%，即出现大脑区域的暂时性肿胀，随着时间的推移会消退，通常表现为头痛、视觉障碍或者意识模糊，60%的患者发生在治疗的前3个月。ARIA-E与lecanemab血浆药物cmax相关，且载脂蛋白E4（ApoE4）纯合子携带者发病率较高[21]。最常见不良反应为输液相关反应，包括流感样症状、恶心、呕吐和血压变化，多数为轻至中度，大部分发生在第一次输液时，可以在后续给药前使用抗组胺药、非甾体抗炎药或皮质类固醇预防[11]。在Ⅲ期临床试验[14]中，lecanemab（10 mg·kg-1每2周1次）组与安慰剂组的整体不良反应发生率相似，但是严重不良反应发生率更高（lecanemab组为14%，安慰剂组为11.3%）。常见的严重不良反应有输液反应、ARIA-E、房颤、晕厥和心绞痛。lecanemab组26.4%的受试者发生了输注相关反应，12.6%的受试者出现了ARIA-E，安慰剂组发生率分别为7.4%和1.7%。相比于FDA批准的首款以Aβ为靶点的药物aducanumab注射剂，lecanemab不需要采用剂量滴定的给药方式，且常见不良反应无尿路感染或上呼吸道感染。
文献
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2024年第43卷第9期
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doi: 10.14109/j.cnki.xyylc.2024.09.04
  • 接收时间：2023-03-28
  • 首发时间：2026-03-18
  • 出版时间：2024-09-25
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  • 收稿日期：2023-03-28
  • 录用日期：2024-08-12
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    国家药品监督管理局执业药师资格认证中心，北京　100061
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
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