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)

摘要 路易体痴呆（DLB）是一种α-突触核蛋白病，是路易体痴呆的第二种最常见形式。 老年痴呆症DLB与帕金森氏症和帕金森氏症在神经病理学和临床上有着惊人的相似性。 疾病（PD）和阿尔茨海默病（AD）。尼洛替尼（Tasigna®，AMN 107，Novartis，Switzerland）已获批 并且对于每日600- 800 mg的口服剂量的CML治疗耐受良好。We previously showed 较低剂量的尼洛替尼穿透大脑并促进神经毒性蛋白的自噬降解， 促进多巴胺（DA）和其他神经元的存活，并改善动物的运动和认知行为 α-突触核蛋白病和其他神经退行性疾病的模型。基于这些强大的临床前 为了证实尼洛替尼对神经退行性病变的作用，我们进行了一项开放标签的初步临床试验， 在中晚期PD伴痴呆（PDD）和DLB患者中开展的一项试验，旨在研究尼洛替尼在 人口参与者（N=12）以1：1的比例随机分配至每日一次口服剂量150 mg和300 mg尼洛替尼， 6个月我们的数据表明，尼洛替尼渗透大脑，抑制脑脊液（CSF）酪氨酸 激酶Abelson（Abl）活性与临床前数据一致。一些研究表明，CSF α- 突触核蛋白、A β 42、总tau和p-tau 181在PD和DLB中改变。我们的数据显示总CSF稳定 α-突触核蛋白，但基线和6个月之间寡聚体：总α-突触核蛋白比值降低 150 mg-300 mg尼洛替尼治疗。CSF高香草酸（HVA）是DA的最终副产物， 300 mg组与对照组相比，CSF总tau蛋白和p-tau蛋白水平显著降低（N=5，P<0.05 基线和6个月治疗之间的尼洛替尼。左旋多巴替代疗法（包括MOAB抑制剂） 在这项研究中，在2个月时降低，但统一帕金森病评定量表（UMRS）I-IV 从基线至6个月，150 mg（3.5分）和300 mg（11分）组改善，恶化（13.7分 停药3个月后分别为150 mg和300 mg，平均得分分别为11.4分。认知能力也得到了提高 (3.5在基线和6个月之间使用简易精神状态检查（MMSE）。MMSE评分 尼洛替尼停药3个月后恢复至基线水平。值得注意的是， 在这项I期开放标签研究中，口服每日剂量为150 mg尼洛替尼的患者均为DLB患者。我们进行 进一步的II期剂量探索随机多次给药研究，包括安慰剂、100 mg、200 mg、300 mg和 未接受MOAB的PD患者在腰穿（LP）前1-4小时口服400 mg一次 在给药前至少6周给予抑制剂。我们观察到，200 mg口服尼洛替尼导致 CSF HVA和3.4-二羟基苯乙酸（DOPAC）显著增加，同时 CSF寡聚体α-突触核蛋白（中期分析NCT 02954978）。综合来看，我们两项研究的数据 表明200 mg尼洛替尼可能是DLB患者研究的最佳剂量。我们的数据非常有说服力， 在一项II期、随机化、双盲、安慰剂对照试验中评价200 mg尼洛替尼对 DLB患者

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.