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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）

Donanemab in Early Alzheimer's Disease. ​

文献信息 ​

DOI10.1056/NEJMoa2100708
PMID33720637
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2021
被引次数717
关键词多纳单抗, 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 II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码1691-1704
期号384(18)
作者Mark A Mintun, Albert C Lo, Cynthia Duggan Evans, Alette M Wessels, Paul A Ardayfio, Scott W Andersen, Sergey Shcherbinin, JonDavid Sparks, John R Sims, Miroslaw Brys, Liana G Apostolova, Stephen P Salloway, Daniel M Skovronsky

一句话小结 ​

本研究探讨了donanemab在早期阿尔茨海默病患者中的疗效，发现与安慰剂相比，donanemab在76周时显著改善了患者的认知能力和日常生活能力，尽管次要结果未显示一致性差异。这一发现为针对淀粉样β肽的治疗提供了新的可能性，提示需要进一步的大规模临床试验以验证其长期效果和安全性。

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多纳单抗 · 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
阿尔茨海默病的一个标志性特征是淀粉样β（Aβ）肽的积累。Donanemab是一种针对沉积的Aβ改性形式的抗体，目前正在研究用于早期阿尔茨海默病的治疗。

方法
我们对早期症状性阿尔茨海默病患者进行了donanemab的第二阶段临床试验，这些患者在正电子发射断层扫描（PET）中显示有tau和淀粉样沉积。患者以1:1的比例随机分配，接受donanemab（前三剂为700毫克，随后为1400毫克）或安慰剂，每4周静脉注射一次，持续时间最长为72周。主要结果是在76周时，基线时综合阿尔茨海默病评定量表（iADRS；范围0到144，分数越低表示认知和功能障碍越严重）的变化。次要结果包括临床痴呆评定量表-盒子总和（CDR-SB）、阿尔茨海默病评估量表的13项认知子量表（ADAS-Cog13）、阿尔茨海默病合作研究-日常生活工具清单（ADCS-iADL）和简易精神状态检查（MMSE）分数的变化，以及PET上淀粉样和tau负担的变化。

结果
共招募257名患者，其中131名接受donanemab，126名接受安慰剂。两组的基线iADRS分数均为106。在76周时，donanemab组的iADRS分数变化为-6.86，而安慰剂组为-10.06（差异为3.20；95%置信区间为0.12至6.27；P = 0.04）。大多数次要结果显示没有显著差异。在76周时，donanemab组的淀粉样斑块水平和全球tau负担的减少分别为85.06 centiloids和0.01，均高于安慰剂组。使用donanemab时出现了与淀粉样相关的脑水肿或积液（大多数为无症状）。

结论
在早期阿尔茨海默病患者中，donanemab在76周时的认知能力和日常生活活动能力的综合评分优于安慰剂，尽管次要结果的表现不一。需要更长时间和更大规模的试验来研究donanemab在阿尔茨海默病中的疗效和安全性。（由礼来公司资助；TRAILBLAZER-ALZ临床试验登记号，NCT03367403。）

英文摘要 ​

BACKGROUND A hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for the treatment of early Alzheimer's disease.

METHODS We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog13), the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET.

RESULTS A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab.

CONCLUSIONS In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.).

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主要研究问题 ​

  1. donanemab在早期阿尔茨海默病患者中的作用机制是什么？
  2. 在临床试验中，donanemab的副作用与其他阿尔茨海默病治疗药物相比如何？
  3. 除了认知评分，donanemab对患者日常生活能力的影响如何评估？
  4. donanemab在不同阶段的阿尔茨海默病患者中的疗效是否存在差异？
  5. 未来的研究方向中，donanemab是否会考虑联合其他疗法以增强疗效？

核心洞察 ​

1. 研究背景和目的 ​

阿尔茨海默病（AD）的一个显著特征是淀粉样β（Aβ）肽的积累。Donanemab是一种针对沉积的Aβ改性形式的抗体，正在研究其在早期阿尔茨海默病治疗中的有效性。本研究旨在评估donanemab对早期有症状的阿尔茨海默病患者的治疗效果，特别是其对认知和日常生活能力的影响。

2. 主要方法和发现 ​

本研究为一项第二阶段临床试验，共招募257名患者，随机分为donanemab组和安慰剂组，各131人和126人。患者接受donanemab（初始剂量700 mg，随后每四周1400 mg）或安慰剂，持续72周。主要结果为76周时综合阿尔茨海默病评分量表（iADRS）的变化。研究发现，donanemab组的iADRS评分变化为-6.86，而安慰剂组为-10.06，两者之间的差异为3.20（P=0.04），表明donanemab在认知和日常生活能力上优于安慰剂。此外，donanemab组在阿淀粉样斑块和全局tau负担方面的减少值也优于安慰剂组。然而，大部分次要结果未显示显著差异，并且观察到donanemab使用者出现阿淀粉样相关的脑水肿或渗出（大多数为无症状）。

3. 核心结论 ​

在早期阿尔茨海默病患者中，donanemab在76周时表现出比安慰剂更好的认知和日常生活能力的综合评分，但次要结果的表现较为混杂。尽管donanemab能有效减少阿淀粉样斑块和tau负担，但长时间和大规模的临床试验仍然是必要的，以进一步评估其在阿尔茨海默病治疗中的有效性和安全性。

4. 研究意义和影响 ​

本研究为早期阿尔茨海默病的治疗提供了新的视角，显示了donanemab在改善认知功能和日常生活能力方面的潜力，可能为患者带来新的治疗选择。尽管结果显示出一定的疗效，但由于次要结果的不一致性和潜在的安全性问题，后续更大规模的研究将是关键。这项研究能够推动对阿尔茨海默病治疗的深入探索，并可能影响未来治疗策略的制定。

引用本文的文献 ​

  1. Strategies to reduce sample sizes in Alzheimer's disease primary and secondary prevention trials using longitudinal amyloid PET imaging. - Isadora Lopes Alves;Fiona Heeman;Lyduine E Collij;Gemma Salvadó;Nelleke Tolboom;Natàlia Vilor-Tejedor;Pawel Markiewicz;Maqsood Yaqub;David Cash;Elizabeth C Mormino;Philip S Insel;Ronald Boellaard;Bart N M van Berckel;Adriaan A Lammertsma;Frederik Barkhof;Juan Domingo Gispert - Alzheimer's research & therapy (2021)
  2. Alzheimer's Disease-Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran. - Klaus Grossmann - International journal of molecular sciences (2021)
  3. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. - Jeffrey Cummings;Paul Aisen;Cynthia Lemere;Alireza Atri;Marwan Sabbagh;Stephen Salloway - Alzheimer's research & therapy (2021)
  4. Alzheimer disease. - David S Knopman;Helene Amieva;Ronald C Petersen;Gäel Chételat;David M Holtzman;Bradley T Hyman;Ralph A Nixon;David T Jones - Nature reviews. Disease primers (2021)
  5. Neuroprotective Natural Products for Alzheimer's Disease. - Xin Chen;Joshua Drew;Wren Berney;Wei Lei - Cells (2021)
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  7. New Hope for Alzheimer's Disease. - B Vellas;P Aisen - The journal of prevention of Alzheimer's disease (2021)
  8. Critical Appraisal of Amyloid Lowering Agents in AD. - Boris Decourt;Fadel Boumelhem;Evans D Pope;Jiong Shi;Zoltan Mari;Marwan Noel Sabbagh - Current neurology and neuroscience reports (2021)
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