Samantha Budd Haeberlein, Biogen, Cambridge, Massachusetts, 617-679-3159,
J Prev Alzheimers Dis. 2022;9(2):197-210. doi: 10.14283/jpad.2022.30.
Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta.
We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease.
EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease.
These studies involved 348 sites in 20 countries.
Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study.
Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks.
The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints.
EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema.
Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer's disease was observed in both trials.
阿尔茨海默病是一种进行性、不可逆转和致命的疾病，其发病机制被认为与淀粉样β的积累有关。Aducanumab 是一种针对淀粉样β聚集的可溶性和不溶性形式的人源单克隆抗体。
评估 aducanumab 在早期阿尔茨海默病中的疗效和安全性。
EMERGE 和 ENGAGE 是两项随机、双盲、安慰剂对照、全球性的 3 期 aducanumab 临床试验，纳入了早期阿尔茨海默病患者。
这些研究涉及 20 个国家的 348 个地点。
包括 1638 名（EMERGE）和 1647 名（ENGAGE）患者（年龄 50-85 岁，确认有淀粉样蛋白病理学），符合因阿尔茨海默病导致的轻度认知障碍或轻度阿尔茨海默病痴呆的临床标准，其中 1812 名（55.2%）完成了研究。
参与者随机分配 1:1:1 接受 aducanumab 低剂量（目标剂量 3 或 6mg/kg）、高剂量（目标剂量 10mg/kg）或安慰剂，通过静脉输注，每 4 周一次，共 76 周。
主要终点是从基线到第 78 周的临床痴呆评定量表总和评分（CDR-SB）的变化，这是一个综合评分，评估功能和认知。其他测量包括安全性评估；评估认知、功能和行为的次要和三级临床结局；以及生物标志物终点。
根据前约 50%入组患者数据的无效性分析，EMERGE 和 ENGAGE 提前终止；随后的疗效分析包括更大数据集的数据，这些数据是在无效性声明后收集的，并遵循了预设的统计分析。EMERGE 达到了主要终点（高剂量 aducanumab 与安慰剂相比差异为-0.39[95%CI，-0.69 至-0.09；P=0.012；22%减少]），但 ENGAGE 未达到（差异为 0.03[95%CI，-0.26 至 0.33；P=0.833；2%增加]）。生物标志物亚研究的结果证实了目标结合和剂量依赖性降低阿尔茨海默病病理生理学标志物。最常见的不良事件是淀粉样相关影像异常-水肿。
EMERGE 的数据显示，所有四个主要和次要临床终点均有统计学意义的变化。ENGAGE 未达到其主要或次要终点。在两项试验中均观察到阿尔茨海默病病理生理学标志物的剂量和时间依赖性减少。
