Eli Lilly and Company, Indianapolis, Indiana.
Boston Center for Memory and Boston University Alzheimer's Disease Center, Boston, Massachusetts.
JAMA. 2023 Aug 8;330(6):512-527. doi: 10.1001/jama.2023.13239.
There are limited efficacious treatments for Alzheimer disease.
To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.
DESIGN, SETTING, AND PARTICIPANTS: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).
Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.
The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.
Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.
Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.
ClinicalTrials.gov Identifier: NCT04437511.
重要性：目前针对阿尔茨海默病的有效治疗方法有限。
目的：评估靶向清除脑淀粉样斑块的抗体药物 donanemab 的疗效和不良事件。
设计、地点和参与者：这是一项多中心（277 个医疗研究中心/医院，分布在 8 个国家）、随机、双盲、安慰剂对照的 18 个月 3 期临床试验，共纳入 1736 名早期有症状的阿尔茨海默病（轻度认知障碍/轻度痴呆）患者，这些患者基于正电子发射断层扫描（PET）成像有淀粉样蛋白和低/中或高 tau 病理，试验于 2020 年 6 月至 2021 年 11 月期间入组（主要结局的最后一次患者访视为 2023 年 4 月）。
干预措施：参与者以 1:1 的比例随机接受 donanemab（n=860）或安慰剂（n=876）静脉输注，每 4 周 1 次，共 72 周。如果符合剂量完成标准，donanemab 组的参与者将以盲法方式转为接受安慰剂。
主要结局和测量指标：主要结局为从基线到 76 周时的综合阿尔茨海默病评定量表（iADRS）评分变化（范围，0-144；评分越低表示损伤越严重）。共有 24 个门控结局（主要、次要和探索性结局），包括次要结局为临床痴呆评定量表（CDR-SB）评分总和的变化（范围，0-18；评分越高表示损伤越严重）。统计检验将 α 值分配给低/中 tau 人群结局的.04，其余的.01 用于联合人群结局。
结果：在 1736 名随机参与者中（平均年龄 73.0 岁；996[57.4%]名女性；1182[68.1%]名有低/中 tau 病理，552[31.8%]名有高 tau 病理），1320 名（76%）完成了试验。在 24 个门控结局中，有 23 个具有统计学意义。在低/中 tau 人群中，donanemab 组的 iADRS 评分在 76 周时的最小二乘均数（LSM）变化为-6.02（95%CI，-7.01 至-5.03），安慰剂组为-9.27（95%CI，-10.23 至-8.31）（差异，3.25[95%CI，1.88-4.62]；P<0.001）；在联合人群中，donanemab 组的 LSM 变化为-10.2（95%CI，-11.22 至-9.16），安慰剂组为-13.1（95%CI，-14.10 至-12.13）（差异，2.92[95%CI，1.51-4.33]；P<0.001）。在低/中 tau 人群中，76 周时 CDR-SB 评分的 LSM 变化为 donanemab 组 1.20（95%CI，1.00-1.41），安慰剂组 1.88（95%CI，1.68-2.08）（差异，-0.67[95%CI，-0.95 至-0.40]；P<0.001），在联合人群中，donanemab 组为 1.72（95%CI，1.53-1.91），安慰剂组为 2.42（95%CI，2.24-2.60）（差异，-0.7[95%CI，-0.95 至-0.45]；P<0.001）。在 donanemab 组中，有 205 名（24.0%；52 名有症状）参与者发生与淀粉样蛋白相关的影像学异常，包括水肿或渗出，安慰剂组有 18 名（2.1%；0 名有症状）；在 donanemab 组中，有 74 名（8.7%）参与者发生输注相关反应，安慰剂组有 4 名（0.5%）。donanemab 组有 3 例死亡，安慰剂组有 1 例死亡，被认为与治疗有关。
结论和相关性：在有早期有症状的阿尔茨海默病和淀粉样蛋白和 tau 病理的患者中，donanemab 在 76 周时显著减缓了低/中 tau 患者以及低/中 tau 和高 tau 病理联合人群的临床进展。
试验注册：ClinicalTrials.gov 标识符：NCT04437511。
