Donanemab in Early Alzheimer's Disease
Donanemab in Early Alzheimer's Disease
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DOI：
10.1056/nejmoa2100708
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发表时间：
2021-03-13
影响因子：
158.5
通讯作者：
Skovronsky, Daniel M.
中科院分区：
文献类型：
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作者：
Mintun, Mark A.;Lo, Albert C.;Skovronsky, Daniel M.
阿尔茨海默病的标志是淀粉样β（A β）肽的积累。Donanemab，一种抗体，目标是一个修改后的形式的沉积A β，正在研究用于治疗早期Alzheimer's disease. METHODS我们进行了2期试验donanemab的早期症状性阿尔茨海默氏病的患者有tau蛋白和淀粉样蛋白沉积的正电子发射断层扫描（PET）。患者以1：1的比例随机分配接受donanemab（前3次给药700 mg，之后1400 mg）或安慰剂静脉给药，每4周一次，持续72周。主要结局是76周时阿尔茨海默病综合评定量表（iADRS;范围：0 - 144，评分越低表明认知和功能障碍越大）评分较基线的变化。次要结局包括临床痴呆评定量表-方框总和（CDR-SB）评分的变化，CDR-SB是阿尔茨海默病评估量表的13项认知子量表（ADAS-Cog（13）），阿尔茨海默病合作研究-工具性日常生活活动量表（ADCS-iADL）和简易精神状态检查（MMSE），以及PET上淀粉样蛋白和tau蛋白负荷的变化。131例患者分配接受donanemab治疗，126例患者分配接受安慰剂治疗。两组的基线iADRS评分均为106。donanemab组第76周iADRS评分较基线的变化为-6.86，安慰剂组为-10.06（差异为3.20; 95%置信区间为0.12 - 6.27; P=0.04）。大多数次要结局的结果显示无实质性差异。在76周时，donanemab组的淀粉样蛋白斑块水平和总体tau负荷的降低分别比安慰剂组高85.06厘泊和0.01厘泊。Donanemab组发生淀粉样蛋白相关性脑水肿或脑积液（大部分无症状）。结论在早期阿尔茨海默病患者中，donanemab组在76周时的认知和日常生活活动能力的综合评分优于安慰剂组，尽管次要结局的结果好坏参半。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。
BACKGROUNDA hallmark of Alzheimer's disease is the accumulation of amyloid-beta (A beta) peptide. Donanemab, an antibody that targets a modified form of deposited A beta, is being investigated for the treatment of early Alzheimer's disease.METHODSWe 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-Cog(13)), 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.RESULTSA 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.CONCLUSIONSIn 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.