van Dyck Christopher H, Nygaard Haakon B, Chen Kewei, Donohue Michael C, Raman Rema, Rissman Robert A, Brewer James B, Koeppe Robert A, Chow Tiffany W, Rafii Michael S, Gessert Devon, Choi Jiyoon, Turner R Scott, Kaye Jeffrey A, Gale Seth A, Reiman Eric M, Aisen Paul S, Strittmatter Stephen M
Alzheimer's Disease Research Unit, Yale School of Medicine, New Haven, Connecticut.
Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
JAMA Neurol. 2019 Oct 1;76(10):1219-1229. doi: 10.1001/jamaneurol.2019.2050.
Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease.
To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018.
AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks.
Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers.
Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness.
Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures.
ClinicalTrials.gov identifier: NCT02167256.
寡聚淀粉样β肽与神经元细胞表面的细胞朊蛋白结合，激活细胞内的fyn激酶，介导突触毒性和tau蛋白病变。AZD0530是一种针对Src家族（包括fyn）的研究性激酶抑制剂，已被重新用于治疗阿尔茨海默病。
确定AZD0530治疗是否能减缓葡萄糖脑代谢率（CMRgl）的下降，以及是否安全且耐受性良好。
设计、地点和参与者：这项多中心2a期随机临床试验于2014年12月23日至2016年11月30日招募参与者。参与者（n = 159）患有轻度阿尔茨海默病痴呆症，且有正电子发射断层扫描（PET）证据表明淀粉样β肽水平升高。所有主要和次要结局的疗效分析均在改良意向性治疗人群中进行。最终分析于2018年2月9日至2018年7月25日进行。
AZD0530（每日100 mg或125 mg）与安慰剂治疗52周。
主要结局是在52周时，通过18F-氟脱氧葡萄糖（18F-FDG）PET在阿尔茨海默病相关的预先指定的统计感兴趣区域测量的相对CMRgl降低情况。次要终点包括认知、功能和其他生物标志物的变化。
159名参与者中，79名被随机分配接受AZD0530，80名接受安慰剂。159名参与者中，87名（54.7%）为男性，平均（标准差）年龄为71.0（7.7）岁。根据第2周的血浆药物水平（目标值 = 180 ng/mL；游离30nM），15名参与者（19.2%）将其AZD0530剂量从100 mg增加至125 mg。第13周至52周的平均血浆水平为220 ng/mL和游离36nM。与安慰剂相比，更多接受AZD0530治疗的参与者停止治疗（21例对11例），最常见的原因是不良事件。最常见的不良事件是胃肠道疾病（主要是腹泻），在接受AZD0530治疗的38名参与者（48.1%）和接受安慰剂治疗的23名参与者（28.8%）中发生。在主要结局方面，治疗组在52周时相对CMRgl的下降无差异（平均差异：-0.006单位/年；95%置信区间，-0.017至0.006；P = 0.34）。治疗组在阿尔茨海默病评估量表-认知子量表、阿尔茨海默病协作研究-日常生活活动、临床痴呆评定量表、神经精神科问卷或简易精神状态检查评分的变化率方面也无差异。次要容积磁共振成像分析显示，对全脑或脑室容积无治疗效果，但确实显示出减缓海马体容积和内嗅皮层厚度减少的趋势。
未发现AZD0530治疗在阿尔茨海默病相关感兴趣区域的相对CMRgl降低或次要临床或生物标志物测量方面有统计学显著效果。
ClinicalTrials.gov标识符：NCT02167256。
