Background: Nilotinib, a tyrosine kinase Abelson inhibitor, exhibits neuroprotective effects in preclinical Parkinson disease (PD) models. Methods: This Phase 2A double-blind placebo-controlled study in moderate/advanced PD randomized participants 1:1:1 to placebo:150:300 mg nilotinib once daily for 6 months. The primary outcomes were safety and tolerability, the latter defined as ability to complete the study on assigned dose. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS), Part 3 OFF/ON). Exploratory outcomes included serum and cerebrospinal fluid (CSF) pharmacokinetic (PK) profile, and CSF dopamine metabolites. Findings: The study screened 125 and enrolled 76 participants (39% screen failure) between November 2017 and December 2018 at 25 US sites. At baseline, mean (standard deviation) age was 64.6 years (7.5), disease duration 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score 66.4(19.3) and ON score 48.4(16.2), Montreal Cognitive Assessment (MoCA) score 27.1(2.2). Tolerability was 21(84%):19 (76%):20 (77%) in placebo:150:300 mg arm, respectively. Both active doses were safe. The most common reasons for drug suspension were dose dependent elevations of amylase and/or lipase. There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between the groups (p=0.17). CSF/serum PK ratio was 0.2-0.3%. There was no evidence of treatment-related elevation of dopamine metabolites. Interpretation: Both doses of nilotinib were safe and tolerable. There was no evidence of any symptomatic benefit of nilotinib. The drug had low CSF exposure and failed to change dopamine metabolites. These findings do not warrant further testing of nilotinib in PD. Funding: The study was funded by Funded by Michael J Fox Foundation for Parkinsons Research / The Cure Parkinson Trust / Van Andel Institute. Clinicaltrials.gov NCT03205488

中文翻译：

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帕金森病晚期患者的尼罗替尼：一项随机化的2A期研究（NILO-PD）

背景：酪氨酸激酶Abelson抑制剂Nilotinib在临床前帕金森病（PD）模型中表现出神经保护作用。方法：该2A期双盲安慰剂对照研究在中度/高级PD随机参与者中以每天1：1：1的比例服用安慰剂：150：300 mg尼洛替尼，持续6个月。主要结果是安全性和耐受性，后者是指完成指定剂量研究的能力。次要结果包括PD残疾的变化（运动障碍学会统一帕金森病疾病评分量表（MDS-UPDRS），第3部分“ OFF / ON”）。探索性结果包括血清和脑脊液（CSF）药代动力学（PK）谱以及CSF多巴胺代谢产物。调查结果：该研究筛选了2017年11月至2018年12月期间在美国25个站点的125位参与者，并招募了76位参与者（39％的屏幕故障）。在基线时 平均（标准差）年龄为64.6岁（7.5），疾病持续时间9.9年（4.7），MDS-UPDRS第1-3部分的OFF评分为66.4（19.3）和ON评分为48.4（16.2），蒙特利尔认知评估（MoCA）评分为27.1 （2.2）。安慰剂：150：300 mg组的耐受性分别为21（84％）：19（76％）：20（77％）。两种有效剂量都是安全的。药物悬浮的最常见原因是淀粉酶和/或脂肪酶的剂量依赖性升高。两组之间从基线到6个月的MDS-UPDRS-3 OFF变化无差异（p = 0.17）。脑脊液/血清PK比为0.2-0.3％。没有证据表明与治疗相关的多巴胺代谢产物升高。解释：两种剂量的尼洛替尼都是安全且可耐受的。没有证据表明尼洛替尼有任何症状上的益处。该药物的脑脊液暴露量低，并且未能改变多巴胺代谢产物。这些发现不能保证尼罗替尼在PD中的进一步检测。资金：这项研究由迈克尔·J·福克斯（Michael J Fox）帕金森研究基金会（The Park of Parkinsons Research）/治愈帕金森信托基金（Cure Parkinson Trust）/范安德尔学院（Van Andel Institute）资助。Clinicaltrials.gov NCT03205488