A randomized, double blind, placebo-controlled study to evaluate the impact of Nilotinib treatment on safety, tolerability, pharmacokinetics and biomarkers in Dementia with Lewy Bodies (DLB)

一项随机、双盲、安慰剂对照研究，旨在评估尼罗替尼治疗对路易体痴呆 (DLB) 的安全性、耐受性、药代动力学和生物标志物的影响

• 批准号: 10412927
• 负责人: Charbel Moussa
• 金额: $ 141.73万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412927
• 关键词: 3,4-Dihydroxyphenylacetic Acid; Acids; Activities of Daily Living; Adverse event; Agreement; Alzheimer' s Disease; Amyloid beta-42; Animal Model; Antineoplastic Agents; Behavior; Behavioral; Behavioral Symptoms; Biological Markers; Brain; Cerebrospinal Fluid; Chemicals; Clinical; Clinical Data; Clinical Trials; Clinical assessments; Cognition; Cognitive; Data; Dementia; Dementia with Lewy Bodies; Dopamine; Dose; Double-Blind Method; Drug Kinetics; Elderly; Equipment and supply inventories; FDA approved; Homovanillic Acid; Hour; Individual; Levodopa; Liver diseases; Motor; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Myelosuppression; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Oral; Outcome; Pamphlets; Pancreatic Diseases; Parkinson Disease; Parkinson' s Dementia; Participant; Pathology; Patients; Phase; Placebos; Plasma; Population; Protein Tyrosine Kinase; Proteins; Randomized; Replacement Therapy; Research Personnel; Safety; Spinal Puncture; Switzerland; Trail Making Test; Withdrawal; alpha synuclein; base; cognitive testing; cooperative study; double-blind placebo controlled trial; drug repurposing; improved; inhibitor; interest; mental state; motor symptom; neuropsychiatry; neurotoxic; open label; placebo controlled study; pre-clinical; primary outcome; safety study; secondary outcome; synucleinopathy; tau Proteins; tau-1

Abstract Dementia with Lewy Bodies (DLB) is an alpha-synucleinopathy and the second most common form of dementia in the elderly. DLB shares striking neuropathological and clinical similarities with both Parkinson's disease (PD) and Alzheimer's disease (AD). Nilotinib (Tasigna®, AMN107, Novartis, Switzerland) is approved by the FDA and is well tolerated for CML treatment at oral doses of 600-800mg daily. We previously showed that lower doses of Nilotinib penetrates the brain and facilitates autophagic degradation of neurotoxic proteins, promotes survival of dopamine (DA) and other neurons and improve motor and cognitive behavior in animal models of alpha-synucleinopathy and other neurodegenerative diseases. Based on these strong pre-clinical evidence of the effects of Nilotinib on neurodegenerative pathologies, we conducted an open label pilot clinical trial in individuals with mid-advanced PD with dementia (PDD) and DLB to study the safety of Nilotinib in this population. Participants (N=12) were randomized 1:1 to once daily oral dose of 150mg and 300mg Nilotinib for 6 months. Our data suggest that Nilotinib penetrates the brain and inhibits cerebrospinal fluid (CSF) tyrosine kinase Abelson (Abl) activity in agreement with pre-clinical data. Several studies show that CSF alpha- synuclein, Abeta42, total tau and p-tau181 are altered in PD and DLB. Our data show stabilization of total CSF alpha-synuclein but a reduction in oligomeric:total alpha-synuclein ratio between baseline and 6-months treatment with 150mg-300mg Nilotinib. CSF homovanillic acid (HVA), which is an end by-product of DA, was also significantly increased; and CSF total tau and p-tau were significantly reduced (N=5, P<0.05) with 300mg Nilotinib between baseline and 6-month treatment. L-Dopa replacement therapies (including MOAB inhibitors) were reduced at 2 months in this study, but the Unified Parkinson’s Disease Rating Scale (UPDRS) I-IV improved with 150mg (3.5 points) and 300mg (11 points) from baseline to 6 months and worsened (13.7 points and 11.4 points) after 3-month withdrawal of 150mg and 300mg, respectively. Cognition was also improved (3.5 points) using both the Mini-Mental Status Exam (MMSE) between baseline and 6 months. MMSE scores returned to baseline after 3 months of Nilotinib withdrawal. It is important to note that participants who received oral daily dose of 150mg Nilotinib in this phase I open label study were all individuals with DLB. We conducted further phase II dose-finding random multiple dose studies that included placebo, 100mg, 200mg, 300mg and 400mg administered orally once 1-4 hours prior to lumbar puncture (LP) in PD patients who were not on MOAB inhibitors for at least 6 weeks prior to dosing. We observed that 200mg oral dose of Nilotinib results in a significant increase in CSF HVA and 3.4-didydroxyphenylacetic acid (DOPAC) concurrent with a decrease in CSF oligomeric alpha-synuclein (Interim analysis NCT02954978). Taken together, data from our two studies indicate that 200mg Nilotinib may be an optimal dose to study in DLB patients. Our data are very compelling to evaluate the effects of 200mg Nilotinib in a phase II, randomized, double-blinded, placebo-controlled trial in patients with DLB.

抽象的 Lewy Bodies（DLB）的痴呆症是一种α-核酸，是第二常见的形式 最古老的痴呆症。 DLB与帕金森氏症具有惊人的神经病理学和临床相似之处 疾病（PD）和阿尔茨海默氏病（AD）。 Nilotinib（Tasigna®，AMN107，瑞士诺华）被批准 通过FDA，以每天600-800mg的口服剂量为CML治疗，可容忍CML治疗。我们以前显示了 较低剂量的尼洛替尼可以穿透大脑，并促进神经毒性蛋白的自噬降解 促进多巴胺（DA）和其他神经元的生存，并改善动物的运动和认知行为 α-核疾病和其他神经退行性疾病的模型。基于这些强大的临床前 尼洛替尼对神经退行性病理的影响的证据，我们进行了开放式标签临床临床 在患有痴呆症（PDD）和DLB的中级PD的个体中，在此研究Nilotinib的安全性 人口。参与者（n = 12）随机分别为1：1，每天口服150mg和300mg尼罗替尼 6个月。我们的数据表明，尼洛替尼穿透大脑并抑制脑脊液（CSF）酪氨酸 激酶阿伯森（ABL）活性与临床前数据一致。几项研究表明，CSFα- 突触核蛋白，Abeta42，Total Tau和P-Tau181在PD和DLB中发生了变化。我们的数据显示总CSF的稳定 α-核蛋白，但低聚的降低：基线和6个月之间的总α-突触核蛋白比率 用150mg-300mg尼罗替尼进行治疗。 DA的最终副产品的CSF同源酸（HVA）为 也显着增加；和CSF总tau和p-tau显着降低（n = 5，p <0.05），300mg 基线和6个月治疗之间的尼洛替尼。 L-DOPA替代疗法（包括MoAb抑制剂） 在这项研究中2个月后减少了，但是统一的帕金森氏病评级量表（UPDRS）I-IV 从基线到6个月的150毫克（3.5点）和300mg（11分）改善，并恶化（13.7分） 和11.4分）分别撤离150mg和300mg后。认知也得到了改善 （3.5分）使用基线至6个月之间的小型门票状态考试（MMSE）。 MMSE分数 尼洛替尼撤离3个月后，返回基线。重要的是要注意，收到的参与者 在这一阶段I开放标签研究中，口服每日剂量为150mg尼洛替尼，均为DLB的个体。我们进行了 进一步的II期剂量调查随机多种剂量研究，包括安慰剂，100mg，200mg，300mg和 不在MOAB上的PD患者中，在腰椎穿刺（LP）前1-4小时口服的400mg服用。 给药前至少6周抑制剂。我们观察到200mg口服尼洛替尼导致A CSF HVA和3.4-二氧苯基乙酸（DOPAC）的显着增加，同时减少 CSF低聚α-核蛋白（临时分析NCT02954978）。总之，我们的两项研究的数据 表明200mg尼洛替尼可能是DLB患者研究的最佳剂量。我们的数据非常引人注目 在II期，随机，双盲，安慰剂对照试验中评估200mg Nilotinib的影响 DLB患者。