Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid
Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid
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DOI：
10.1002/ana.25513
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发表时间：
2019-08-01
影响因子：
11.2
通讯作者：
Selkoe, Dennis J.
中科院分区：
文献类型：
--
作者：
Yang, Ting;Dang, Yifan;Selkoe, Dennis J.
目的β-淀粉样蛋白（oA β）寡聚体被认为是阿尔茨海默病（AD）神经毒性的主要原因，但抗β-淀粉样蛋白抗体是否能降低oA β水平尚不清楚。方法我们开发了一种超灵敏的免疫测定法，并使用它来测量来自104名AD受试者的脑脊液（CSF）中的oA β，这些受试者参加了抗A β抗体crenezumab的ABBY和BLAZE 2期试验。患者每2周接受皮下（SC）crenezumab（300 mg）或安慰剂，或每4周接受静脉内（IV）crenezumab（15 mg/kg）或安慰剂，持续68周。104例患者中有98例具有可测量的基线oA β水平，并将其与安慰剂（n = 28）、SC（n = 35）和IV（n = 35）治疗患者第69周的水平进行比较。结果在接受crenezumab的患者中，89%的SC和86%的IV患者在第69周时的oA β水平低于基线水平。两个治疗组中水平降低的患者比例差异显著：SC组p = 0.0035，IV克瑞珠单抗组p = 0.01。SC组和IV组的中位百分比变化分别为-48%和-43%。安慰剂组未观察到系统性变化，中位变化为-13%，相当部分为阴性和阳性变化。解释Crenezumab降低了大多数接受治疗的患者的CSF oA β水平。这些结果支持AD中主要病理生物学靶点的参与，并将CSF oA β确定为用于抗A β药物试验的新型药效学生物标志物。神经网络2019;86：215-224
Objective Oligomeric forms of amyloid beta protein (oA beta) are believed to be principally responsible for neurotoxicity in Alzheimer disease (AD), but it is not known whether anti-A beta antibodies are capable of lowering oA beta levels in humans. Methods We developed an ultrasensitive immunoassay and used it to measure oA beta in cerebrospinal fluid (CSF) from 104 AD subjects participating in the ABBY and BLAZE phase 2 trials of the anti-A beta antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every 2 weeks, or intravenous (IV) crenezumab (15mg/kg) or placebo every 4 weeks for 68 weeks. Ninety-eight of the 104 patients had measurable baseline oA beta levels, and these were compared to levels at week 69 in placebo (n = 28), SC (n = 35), and IV (n = 35) treated patients. Results Among those receiving crenezumab, 89% of SC and 86% of IV patients had lower levels of oA beta at week 69 versus baseline. The difference in the proportion of patients with decreasing levels was significant for both treatment arms: p = 0.0035 for SC and p = 0.01 for IV crenezumab versus placebo. The median percentage change was -48% in the SC arm and -43% in the IV arm. No systematic change was observed in the placebo group, with a median change of -13% and equivalent portions with negative and positive change. Interpretation Crenezumab lowered CSF oA beta levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oA beta as a novel pharmacodynamic biomarker for use in trials of anti-A beta agents. ANN NEUROL 2019;86:215-224