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-突触核素病，是第二种最常见的 老年痴呆症。DLB与帕金森氏症在神经病理和临床上有显著的相似之处 疾病(PD)和阿尔茨海默病(AD)。尼洛替尼(Tasigna®，AMN107，瑞士诺华)获批 由FDA批准，每天口服600-800毫克的CML治疗耐受性良好。我们之前展示了 较低剂量的尼洛替尼会穿透大脑，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 阿尔法-突触核病和其他神经退行性疾病的模型。基于这些强大的临床前研究 尼洛替尼对神经退行性病变影响的证据：我们进行了一项开放标签试点临床试验 尼洛替尼在中晚期帕金森病伴痴呆(PDD)和DLB患者中的安全性研究 人口。受试者(N=12)被随机分为1：1至1次每日口服150 mg和300 mg尼洛替尼治疗 六个月。我们的数据表明，尼洛替尼可以穿透大脑并抑制脑脊液(CSF)的酪氨酸 蛋白激酶Abelson(Abl)活性与临床前数据一致。多项研究表明，脑脊液α- PD和DLB的突触核蛋白、Abeta42、总tau和p-tau181均发生改变。我们的数据显示脑脊液总量稳定 α-突触核蛋白，但低聚物：基线和6个月之间的总α-突触核蛋白比率下降 尼洛替尼150 mg~300 mg治疗。脑脊液高香草酸(HVA)是DA的最终副产物，... 脑脊液总tau和p-tau显著降低(N=5，P<0.05)。 尼洛替尼在基线治疗和6个月治疗之间。L-多巴替代疗法(包括单抗抑制剂) 在这项研究中，在2个月时减少，但统一帕金森病评定量表(UPDRS)I-IV 从基线到6个月分别改善150毫克(3.5分)和300毫克(11分)，恶化(13.7分 停药3个月后分别为150 mg和300 mg)和11.4分。认知能力也得到了改善 (3.5分)在基线和6个月之间使用简易精神状态检查(MMSE)。MMSE成绩 尼洛替尼停药3个月后恢复到基线水平。值得一提的是，获得 在这项I期开放标签研究中，每天口服150 mg尼洛替尼的患者均为DLB患者。我们进行了 进一步的第二阶段剂量寻找随机多剂量研究，包括安慰剂、100 mg、200 mg、300 mg和 非MOAB治疗的帕金森病患者腰椎穿刺术前1~4小时口服400 mg 在给药前至少服用6周的抑制剂。我们观察到口服200 mg尼洛替尼会导致 脑脊液中HVA和3.4-二羟基苯乙酸(DOPAC)显著增加，同时 脑脊液低聚α-突触核蛋白(中期分析NCT02954978)。总而言之，我们两项研究的数据 提示200 mg尼洛替尼可能是研究DLB患者的最佳剂量。我们的数据非常有说服力 随机、双盲、安慰剂对照II期临床试验评价200 mg尼洛替尼的疗效 DLB型患者。

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.