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文献精选 > 近年高分"阿尔茨海默病"研究（IF≥30，近5年）

Lecanemab in Early Alzheimer's Disease. ​

文献信息 ​

DOI10.1056/NEJMoa2212948
PMID36449413
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2023
被引次数2132
关键词利卡那单抗, 早期阿尔茨海默病, 淀粉样蛋白, 认知功能, 临床试验
文献类型Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码9-21
期号388(1)
作者Christopher H van Dyck, Chad J Swanson, Paul Aisen, Randall J Bateman, Christopher Chen, Michelle Gee, Michio Kanekiyo, David Li, Larisa Reyderman, Sharon Cohen, Lutz Froelich, Sadao Katayama, Marwan Sabbagh, Bruno Vellas, David Watson, Shobha Dhadda, Michael Irizarry, Lynn D Kramer, Takeshi Iwatsubo

一句话小结 ​

本研究评估了单克隆抗体lecanemab在早期阿尔茨海默病患者中的疗效，结果显示其能显著降低淀粉样标志物，并在认知和功能测评中优于安慰剂，但伴随一定的不良反应。这一发现为阿尔茨海默病的治疗提供了新的潜在选择，需进一步研究其长期效果和安全性。

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利卡那单抗 · 早期阿尔茨海默病 · 淀粉样蛋白 · 认知功能 · 临床试验

摘要 ​

背景
可溶性和不溶性聚集的淀粉样β（Aβ）的积累可能会引发或增强阿尔茨海默病的病理过程。Lecanemab是一种人源化IgG1单克隆抗体，具有高度亲和力，可以结合可溶性Aβ原纤维，目前正在对早期阿尔茨海默病患者进行测试。

方法
我们开展了一项为期18个月的多中心、双盲、第三阶段临床试验，参与者为50至90岁之间、具有早期阿尔茨海默病（轻度认知障碍或轻度阿尔茨海默病痴呆）并在正电子发射断层扫描（PET）或脑脊液检测中显示有淀粉样物质的患者。参与者按照1:1的比例随机分配接受静脉注射lecanemab（每两周10毫克每公斤体重）或安慰剂。主要终点是18个月时临床痴呆评分-总分（CDR-SB；范围0至18，分数越高表示功能损害越严重）与基线的变化。关键次要终点包括PET上淀粉样负担的变化、阿尔茨海默病评估量表的14项认知子量表（ADAS-cog14；范围0至90；分数越高表示功能损害越严重）的变化、阿尔茨海默病综合评分（ADCOMS；范围0至1.97；分数越高表示功能损害越严重）的变化，以及阿尔茨海默病合作研究-轻度认知障碍日常生活活动量表（ADCS-MCI-ADL；范围0至53；分数越低表示功能损害越严重）的变化。

结果
共招募了1795名参与者，其中898人接受了lecanemab，897人接受了安慰剂。基线时两组的平均CDR-SB评分约为3.2。18个月时，调整后的最小二乘均值变化为lecanemab组1.21，安慰剂组1.66（差异，-0.45；95%可信区间[CI]，-0.67至-0.23；P<0.001）。在一项涉及698名参与者的子研究中，使用lecanemab组的脑淀粉样负担减少显著高于安慰剂组（差异，-59.1 centiloids；95% CI，-62.6至-55.6）。两个组在基线变化上的其他均值差异，均偏向于lecanemab，具体如下：ADAS-cog14评分为-1.44（95% CI，-2.27至-0.61；P<0.001）；ADCOMS为-0.050（95% CI，-0.074至-0.027；P<0.001）；ADCS-MCI-ADL评分为2.0（95% CI，1.2至2.8；P<0.001）。在26.4%的参与者中，lecanemab引发了输注相关反应，12.6%的参与者出现了与淀粉样相关的影像学异常伴水肿或渗出。

结论
Lecanemab降低了早期阿尔茨海默病患者的淀粉样标志物，并在认知和功能测评中显示出比安慰剂更少的中度下降，但伴随有不良事件。需要更长时间的试验以确定lecanemab在早期阿尔茨海默病中的疗效和安全性。（本研究由Eisai和Biogen资助；Clarity AD临床试验注册号，NCT03887455。）

英文摘要 ​

BACKGROUND The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer's disease.

METHODS We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).

RESULTS A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.

CONCLUSIONS Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

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主要研究问题 ​

  1. Lecanemab的作用机制是什么，它是如何影响阿尔茨海默病的病理过程的？
  2. 在临床试验中，Lecanemab与其他抗阿尔茨海默药物相比效果如何？
  3. Lecanemab在不同年龄段的早期阿尔茨海默病患者中的效果是否存在差异？
  4. Lecanemab的副作用在长期使用中会如何变化，是否会对患者的生活质量产生影响？
  5. 未来的研究方向是什么，是否有可能结合Lecanemab与其他治疗方法来增强疗效？

核心洞察 ​

研究背景和目的 ​

阿尔茨海默病（AD）中可溶性和不可溶性聚集的淀粉样β（Aβ）可能引发或加剧病理过程。Lecanemab是一种人源化IgG1单克隆抗体，能够高亲和力结合Aβ可溶性原纤维，正在对早期阿尔茨海默病患者进行测试。

主要方法/材料/实验设计 ​

本研究为一项为期18个月的多中心、双盲、三期临床试验，参与者为50至90岁早期阿尔茨海默病患者（轻度认知障碍或轻度痴呆），并通过正电子发射断层扫描（PET）或脑脊液检测证实存在淀粉样物质。参与者按1:1的比例随机分配接受静脉注射lecanemab（每公斤体重10毫克，每两周一次）或安慰剂。

主要终点为18个月后临床痴呆评定量表-总分变化（CDR-SB，范围0至18，分数越高表示损害越大）。关键次要终点包括：

  • PET上淀粉样负荷的变化
  • 阿尔茨海默病评估量表14项认知子量表（ADAS-cog14，范围0至90，分数越高表示损害越大）
  • 阿尔茨海默病综合评分（ADCOMS，范围0至1.97，分数越高表示损害越大）
  • 阿尔茨海默病合作研究-日常生活活动量表（ADCS-MCI-ADL，范围0至53，分数越低表示损害越大）
Mermaid diagram

关键结果和发现 ​

在1795名参与者中，898人接受lecanemab，897人接受安慰剂。两组基线CDR-SB评分均约为3.2。18个月后，lecanemab组的调整后均值变化为1.21，而安慰剂组为1.66（差异为-0.45；95%置信区间[CI]，-0.67至-0.23；P<0.001）。在698名参与者的亚组研究中，lecanemab组的脑淀粉样负荷减少显著高于安慰剂组（差异为-59.1 centiloids；95% CI，-62.6至-55.6）。其他结果显示：

  • ADAS-cog14评分变化：lecanemab组为-1.44（95% CI，-2.27至-0.61；P<0.001）
  • ADCOMS评分变化：lecanemab组为-0.050（95% CI，-0.074至-0.027；P<0.001）
  • ADCS-MCI-ADL评分变化：lecanemab组为2.0（95% CI，1.2至2.8；P<0.001）

lecanemab还导致26.4%的参与者出现输注相关反应，以及12.6%出现与淀粉样相关的影像学异常（包括水肿或积液）。

主要结论/意义/创新性 ​

Lecanemab在早期阿尔茨海默病中减少了淀粉样标志物，并在认知和功能评估中表现出较安慰剂更少的下降，尽管伴随有不良事件。这项研究的结果为早期阿尔茨海默病的治疗提供了新的治疗选择，并表明淀粉样β的清除可能对疾病进展有积极影响。

研究局限性和未来方向 ​

本研究的局限性包括研究时间较短，需进一步的长期试验以验证lecanemab在早期阿尔茨海默病中的疗效和安全性。未来研究应考虑不同人群的反应及长期使用的安全性评估。

引用本文的文献 ​

  1. The science events to watch for in 2023. - Miryam Naddaf - Nature (2023)
  2. TREM2 dependent and independent functions of microglia in Alzheimer's disease. - Jinchao Hou;Yun Chen;Gary Grajales-Reyes;Marco Colonna - Molecular neurodegeneration (2022)
  3. Aβ42 oligomer-specific antibody ALZ-201 reduces the neurotoxicity of Alzheimer's disease brain extracts. - Anders Sandberg;Ernesto Berenjeno-Correa;Rosa Crespo Rodriguez;Michael Axenhus;Sophia Schedin Weiss;Kevin Batenburg;Jeroen J M Hoozemans;Lars O Tjernberg;Wiep Scheper - Alzheimer's research & therapy (2022)
  4. Multiple Cerebral Hemorrhages in a Patient Receiving Lecanemab and Treated with t-PA for Stroke. - Nicholas J Reish;Pouya Jamshidi;Brian Stamm;Margaret E Flanagan;Elizabeth Sugg;Mengxuan Tang;Kelly L Donohue;Matthew McCord;Chase Krumpelman;Marek-Marsel Mesulam;Rudolph Castellani;Sherry H-Y Chou - The New England journal of medicine (2023)
  5. Moving the Needle on Alzheimer's Disease with an Anti-Oligomer Antibody. - Sam Gandy;Michelle E Ehrlich - The New England journal of medicine (2023)
  6. Lecanemab trial in AD brings hope but requires greater clarity. - Madhav Thambisetty;Robert Howard - Nature reviews. Neurology (2023)
  7. FDA approves Alzheimer's drug lecanemab amid safety concerns. - Sara Reardon - Nature (2023)
  8. Application of 89Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody. - N Stergiou;T E Wuensche;M Schreurs;I Mes;M Verlaan;E J M Kooijman;A D Windhorst;L Helboe;S Vergo;S Christensen;A A Asuni;A Jensen;G A M S Van Dongen;B Bang-Andersen;D J Vugts;W Beaino - European journal of nuclear medicine and molecular imaging (2023)
  9. Editorial: Accelerating Innovations for Enhanced Brain Health. Can Artificial Intelligence Advance New Pathways for Drug Discovery for Alzheimer's and other Neurodegenerative Disorders? - A S Khachaturian;A Dengel;V Dočkal;P Hroboň;M Tolar - The journal of prevention of Alzheimer's disease (2023)
  10. Initial non-amnestic symptoms relate to faster rate of functional and cognitive decline compared to amnestic symptoms in neuropathologically confirmed dementias. - Jagan A Pillai;James Bena;Emily F Maly;James B Leverenz - Alzheimer's & dementia : the journal of the Alzheimer's Association (2023)

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