用尼洛替尼治疗的路易体痴呆患者的安全性、认知及行为结局

Safety, Cognitive, and Behavioral Outcomes in Patients with Dementia with Lewy Bodies Treated with Nilotinib.

作者信息

Pagan Fernando, Torres-Yaghi Yasar, Hebron Michaeline, Wilmarth Barbara, Turner R Scott, Matar Sara, Liu Xiaoguang, Ferrante Dalila, Esposito Giuseppe, Ahn Jaeil, Moussa Charbel

机构信息

Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Lewy Body Dementia Association Research Center of Excellence, Georgetown University Medical Center, Building D, Room 265, 4000 Reservoir Rd NW, Washington, DC 20057, USA.

Department of Neurology, Movement Disorders Clinic, MedStar Georgetown University Hospital, PHC 7, 3300 Reservoir Rd NW, Washington, DC 20057, USA.

出版信息

J Clin Med. 2025 Jun 14;14(12):4245. doi: 10.3390/jcm14124245.

DOI:10.3390/jcm14124245

PMID:40565990

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12194573/

Abstract

We previously demonstrated that nilotinib can sufficiently enter the brain to pharmacologically inhibit discoidin domain receptors (DDR)-1 in patients with Parkinson's and Alzheimer's disease. We primarily hypothesized that nilotinib is safe, and may alter disease-related biomarkers to improve, motor, cognitive and/or behavioral features in dementia with Lewy bodies (DLB). : Forty-three participants were randomized 1:1 into nilotinib, 200 mg, or matching placebo in a single-center, phase 2, randomized, double-blind study. Study drug was taken orally once daily for 6 months followed by one-month wash-out. : Of 43 individuals enrolled, 14 were women (33%); age (mean ± SD) was 73 ± 8.5 years. Nilotinib was safe and well-tolerated, and more adverse events were noted in the placebo (74) vs. nilotinib (37) groups ( = 0.054). The number of falls were reduced in the nilotinib (six) compared to placebo (21) group ( = 0.006). Cerebrospinal fluid homovanillic acid, a biomarker of dopamine levels, was increased ( = 0.004), while the ratio of pTau181/Aβ42 was reduced ( = 0.034). The Alzheimer's Disease Assessment Scale-cognition 14 improved by 2.8 pts ( = 0.037), and no differences were observed in Movement Disorders Society-Unified Parkinson's Disease Rating Scale parts II and III. However, part I (cognition) improved ( = 0.044) in nilotinib compared to placebo. : Nilotinib demonstrates favorable safety, biomarkers, and efficacy outcomes in patients with DLB supporting further trials in DLB or advanced Parkinson's disease with dementia.

摘要

我们之前证明，在帕金森病和阿尔茨海默病患者中，尼罗替尼能够充分进入大脑，从药理学上抑制盘状结构域受体（DDR）-1。我们最初的假设是，尼罗替尼是安全的，并且可能改变与疾病相关的生物标志物，以改善路易体痴呆（DLB）患者的运动、认知和/或行为特征。在一项单中心、2期、随机、双盲研究中，43名参与者按1:1随机分为尼罗替尼200毫克组或匹配的安慰剂组。研究药物每日口服一次，持续6个月，随后为期1个月的洗脱期。在43名入组个体中，14名是女性（33%）；年龄（均值±标准差）为73±8.5岁。尼罗替尼安全且耐受性良好，安慰剂组（74例）比尼罗替尼组（37例）出现更多不良事件（P = 0.054）。与安慰剂组（21例）相比，尼罗替尼组（6例）的跌倒次数减少（P = 0.006）。脑脊液高香草酸（一种多巴胺水平的生物标志物）升高（P = 0.004），而pTau181/Aβ42比值降低（P = 0.034）。阿尔茨海默病评估量表-认知部分14改善了2.8分（P = 0.037），在运动障碍协会统一帕金森病评定量表第二和第三部分未观察到差异。然而，与安慰剂相比，尼罗替尼组的第一部分（认知）有所改善（P = 0.044）。尼罗替尼在DLB患者中显示出良好的安全性、生物标志物和疗效结果，支持在DLB或晚期帕金森病合并痴呆患者中进行进一步试验。