在临床前阿尔茨海默病中进行的 Solanezumab 试验。
Trial of Solanezumab in Preclinical Alzheimer's Disease.
机构信息
From the Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School (R.A.S., G.A.M.), and the Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School (K.J.) - both in Boston; Alzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego (M.C.D., R.R., M.S.R., P.S.A.); the Florey Institute, University of Melbourne, Melbourne, VIC, Australia (C.L.M.); the Departments of Psychiatry, Neurology, and Neuroscience, Yale School of Medicine, New Haven, CT (C.H.D.); the Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo (T.I.); and Eli Lilly, Indianapolis (R.Y., M.M., K.C.H., M.C., J.R.S.).
出版信息
N Engl J Med. 2023 Sep 21;389(12):1096-1107. doi: 10.1056/NEJMoa2305032. Epub 2023 Jul 17.
BACKGROUND
Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer's disease have had mixed results.
METHODS
We tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer's disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini-Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks.
RESULTS
A total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was -1.43 in the solanezumab group and -1.13 in the placebo group (difference, -0.30; 95% confidence interval, -0.82 to 0.22; P = 0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group.
CONCLUSIONS
Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.).
背景
针对不同阶段阿尔茨海默病中各种形式淀粉样蛋白的单克隆抗体试验结果喜忧参半。
方法
我们在一项涉及有临床前阿尔茨海默病的患者的 3 期试验中测试了靶向单体淀粉样蛋白的 solanezumab。年龄在 65 岁至 85 岁之间、总体临床痴呆评定量表评分为 0 分（范围为 0 至 3 分，0 分表示无认知障碍，3 分表示严重痴呆）、简易精神状态检查量表评分为 25 分或以上（范围为 0 至 30 分，分数越低表示认知越差）且氟 18 氟脱氧葡萄糖正电子发射断层扫描（PET）显示脑内淀粉样蛋白水平升高的患者被纳入研究。参与者以 1:1 的比例随机分配接受高达 1600 mg 静脉注射每 4 周一次的 solanezumab 或安慰剂治疗。主要终点是在 240 周期间，使用 Preclinical Alzheimer Cognitive Composite（PACC）评分（计算为四个 z 分数的总和，分数越高表示认知表现越好）的变化。
结果
共有 1169 名患者接受了随机分组：578 名患者被分入 solanezumab 组，591 名患者被分入安慰剂组。参与者的平均年龄为 72 岁，约 60%为女性，75%有痴呆家族史。240 周时，solanezumab 组的 PACC 评分平均变化为-1.43，安慰剂组为-1.13（差值，-0.30；95%置信区间，-0.82 至 0.22；P=0.26）。脑 PET 上的淀粉样蛋白水平在 solanezumab 组中平均增加了 11.6 个 centiloids，在安慰剂组中增加了 19.3 个 centiloids。每个组中不到 1%的患者出现与淀粉样蛋白相关的影像学异常（ARIA）伴水肿。在 solanezumab 组中，29.2%的患者出现 ARIA 伴微出血或含铁血黄素沉着，安慰剂组中为 32.8%。
结论
与安慰剂相比，在有临床前阿尔茨海默病的患者中，靶向脑内淀粉样蛋白水平升高的单体淀粉样蛋白的 solanezumab 并不能在 240 周内减缓认知能力下降。（由美国国立卫生研究院和其他机构资助；A4 临床试验.gov 编号，NCT02008357。）
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