背景:Niemann-Pick病C1型(NPC1)是一种细胞内胆固醇和脂质运输障碍,导致胆固醇和脂质在晚期内体/溶酶体区室中积累,导致全身表现(包括肝脾肿大和肺浸润)和神经变性。临床前研究表明,全身给药的2-羟丙基-β-环糊精(HPβCD;Trappsol®Cyclo™)可恢复外周器官和组织以及中枢神经系统(CNS)中的胆固醇代谢和稳态。这里,我们评估了安全性,药代动力学,在患有NPC1的成年受试者中,外周组织和CNS中HPβCD的药效学。
方法:第一阶段,随机,双盲,平行组研究纳入了13名NPC1患者,他们每2周静脉内接受1,500mg/kg或2,500mg/kgHPβCD,共7剂(14周).受试者18岁或以上,与NPC1的确诊和全身参与临床评估的证据。在第一次和第七次输注时进行血浆和脑脊液(CSF)中的药代动力学评估。药效学评估包括全身性胆固醇合成(血清甾醇)和降解(血清4β-羟基胆固醇)的生物标志物,继发性鞘磷脂储存(血浆溶鞘磷脂-509,现在更准确地称为N-棕榈酰-O-磷酸胆碱[PPCS]),神经变性(CSF总Tau)和胆固醇代谢(血清24(S)-羟基胆固醇[24(S)-HC])的CNS特异性生物标志物。安全性监测包括评估肝肾功能,输液相关不良事件,和听力评估。
结果:10名受试者完成了研究,其中6在1500mg/kg剂量和4在2500mg/kg剂量。一名受试者在经历过敏性肺炎后首次输注后退出,2名受试者在满足与听力损失相关的停止规则后退出。总的来说,HPβCD具有可接受的安全性。第一次和第七次输注后观察到的HPβCD的药代动力学特征相似,血浆半衰期为2小时,在6至8小时时达到最大浓度,也没有积累的证据.胆固醇代谢的血清生物标志物显示合成减少和降解增加。与基线相比,在第14周时,肝组织的filipin染色显示在两种剂量水平下捕获的未酯化胆固醇的显著减少。血浆PPCS水平也降低。在CSF中检测到低浓度的HPβCD(最大值,33μM)在两种剂量水平下,并且在CSF中的持续时间比在血浆中更长。大多数受试者的CSF中的总Tau水平降低。血清24(S)-HC,一种来自中枢神经系统的胆固醇代谢物,通过血脑屏障进入血液循环,在第一和第七剂量后都有所下降。因此,外周组织和CNS相关组织的药效学评估均显示目标参与.虽然不是研究的目的,受试者报告对他们的生活质量有有利的影响。
结论:以两种静脉内剂量水平给予NPC1受试者的HPβCD的血浆药代动力学和药效学与在临床前模型中观察到的那些相当。HPβCD清除了肝脏中的胆固醇,并改善了胆固醇稳态的外周生物标志物。在低CSF浓度下,基于24(S)-HC的外排增加和CSF总Tau的减少,HPβCD在CNS中似乎具有药理活性。中枢神经系统神经变性的生物标志物。这些数据支持启动长期临床试验,以评估静脉内HPβCD在NPC1受试者中的安全性和有效性。(ClinicalTrials.gov编号:本试验,NCT02939547;本试验的开放标签扩展,NCT03893071;全球关键试验,NCT04860960)。
BACKGROUND: Niemann-Pick Disease Type C1 (NPC1) is a disorder of intracellular cholesterol and lipid trafficking that leads to the accumulation of cholesterol and lipids in the late endosomal/lysosomal compartment, resulting in systemic manifestations (including hepatosplenomegaly and lung infiltration) and neurodegeneration. Preclinical studies have demonstrated that systemically administered 2-hydroxypropyl-β-cyclodextrin (HPβCD; Trappsol® Cyclo™) restores cholesterol metabolism and homeostasis in peripheral organs and tissues and in the central nervous system (CNS). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of HPβCD in peripheral tissues and the CNS in adult subjects with NPC1.
METHODS: A Phase 1, randomized, double-blind, parallel group
study enrolled 13 subjects with NPC1 who received either 1500 mg/kg or 2500 mg/kg HPβCD intravenously every 2 weeks for a total of 7 doses (14 weeks). Subjects were 18 years or older, with a confirmed diagnosis of NPC1 and evidence of systemic involvement on clinical assessment. Pharmacokinetic evaluations in plasma and cerebrospinal fluid (CSF) were performed at the first and seventh infusions. Pharmacodynamic assessments included biomarkers of systemic cholesterol synthesis (serum lathosterol) and degradation (serum 4β-hydroxycholesterol), secondary sphingomyelin storage (plasma lysosphingomyelin-509, now more accurately referred to as N-palmitoyl-O-phosphocholineserine [PPCS]), and CNS-specific biomarkers of neurodegeneration (CSF total Tau) and cholesterol metabolism (serum 24(S)-hydroxycholesterol [24(S)-HC]). Safety monitoring included assessments of liver and kidney function, infusion related adverse events, and hearing evaluations.
RESULTS: Ten subjects completed the
study, with 6 at the 1500 mg/kg dose and 4 at the 2500 mg/kg dose. One subject withdrew following the first infusion after experiencing hypersensitivity pneumonitis, and 2 subjects withdrew after meeting a stopping rule related to hearing loss. Overall, HPβCD had an acceptable safety profile. The observed pharmacokinetic profile of HPβCD was similar following the first and seventh infusions, with a plasma half-life of 2 h, a maximum concentration reached at 6 to 8 h, and no evidence of accumulation. Serum biomarkers of cholesterol metabolism showed reduced synthesis and increased degradation. Compared to Baseline, filipin staining of liver tissue showed significant reductions of trapped unesterified cholesterol at both dose levels at Week 14. Plasma PPCS levels were also reduced. HPβCD was detected at low concentrations in the CSF (maximum, 33 μM) at both dose levels and persisted longer in CSF than in plasma. Total Tau levels in CSF decreased in most subjects. Serum levels of 24(S)-HC, a cholesterol metabolite from the CNS that is exported across the blood-brain barrier and into the circulation, decreased after both the first and seventh doses. Hence, pharmacodynamic assessments in both peripheral and CNS-related tissue show target engagement. While not the aim of the
study, subjects reported favorable impacts on their quality of life.
CONCLUSIONS: The plasma pharmacokinetics and pharmacodynamics of HPβCD administered at two intravenous dose levels to subjects with NPC1 were comparable to those observed in preclinical models. HPβCD cleared cholesterol from the liver and improved peripheral biomarkers of cholesterol homeostasis. At low CSF concentrations, HPβCD appeared to be pharmacologically active in the CNS based on the increased efflux of 24(S)-HC and reduction in CSF total Tau, a biomarker of CNS neurodegeneration. These data support the initiation of longer-term clinical trials to evaluate the safety and efficacy of intravenous HPβCD in subjects with NPC1. (ClinicalTrials.gov numbers: present
trial, NCT02939547; open-label extension of the present
trial, NCT03893071; global pivotal
trial, NCT04860960).