Long-Term Neuropsychological Outcomes from an Open-Label Phase I/IIa Trial of 2-Hydroxypropyl-β-Cyclodextrins (VTS-270) in Niemann-Pick Disease, Type C1
Long-Term Neuropsychological Outcomes from an Open-Label Phase I/IIa Trial of 2-Hydroxypropyl-β-Cyclodextrins (VTS-270) in Niemann-Pick Disease, Type C1
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DOI：
10.1007/s40263-019-00642-2
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发表时间：
2019-07-01
期刊：
影响因子：
6
通讯作者：
Porter, Forbes D.
中科院分区：
文献类型：
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作者：
Farmer, Cristan A.;Thurm, Audrey;Porter, Forbes D.
研究背景C1型尼曼-匹克病（NPC 1）是一种由NPC 1基因突变引起的神经退行性疾病，常发生于儿童。最近，一些药物试验已经实施，以尽量减少神经变性，包括2-羟丙基-β-环糊精（VTS-270）的试验。ObjectiveThe当前的研究通过描述基线后36个月的神经心理学结果，扩展了先前18个月疾病严重程度数据报告的结果。在4- 23岁的NPC 1参与者中进行VTS-270的剂量递增I/IIa期研究。方法14名参与者被顺序分配每月接受初始鞘内VTS-270，剂量为50，200，300，或每月400毫克。初始给药后，受试者在耐受范围内剂量递增（至600或1200 mg）。参与者每隔6个月使用标准化神经心理电池进行评估，包括认知和适应行为测试。一个随机效应模型与限制的最大似然估计构建每个结果，和斜率是参数的interests.ResultsFindings的基础上智商分数和标准分数和年龄相当于适应功能表明，在研究期间，在这些领域没有意义的下降。全量表IQ的平均年变化为负值：B=-1.28，SE =0.70，t（34.2）=-1.83，p=0.076。Vineland-II适应行为综合标准评分每年下降1.76分[SE=0.67，t（59.1）=-2.62，p=0.011]，但每个领域年龄当量的年化斜率为正值：通信[B=0.71，SE=3.12，t（60.7）=0.23，p=0.82]，社会化[B=2.99，SE=2.92，t（60.4）=1.03，p=0.30]，日常生活技能[B=2.76，SE=2.76，t（60.3）=1.18，p=0.24]和运动技能[B=1.42，SE=0.94，t（50.5）=1.51，p=0.14]，表明没有恶化，但低于平均水平的技能获得。这些结果支持了在开始鞘内注射VTS-270.RegistrationClinicalTrials.gov标识符NCT 01747135：用于尼曼-匹克C1型疾病的羟丙基β-环糊精后长达36个月的疾病进展减缓。
BackgroundNiemann-Pick disease, type C1 (NPC1) is a neurodegenerative condition that arises from mutations of NPC1 and is often diagnosed in children. Recently, several drug trials have been implemented to minimize neurodegeneration, including a trial of 2-hydroxypropyl-beta-cyclodextrins (VTS-270).ObjectivesThe current study extends findings from a previous report of 18months of disease severity data by describing neuropsychological outcomes over the course of 36months post-baseline.DesignAn open-label, dose-escalation phase I/IIa study of VTS-270 was performed in participants with NPC1 aged 4-23years.MethodsFourteen participants were sequentially assigned to receive monthly initial intrathecal VTS-270 at doses of 50, 200, 300, or 400mg per month. After initial dosing, participants were dose-escalated (to 600 or 1200mg) as tolerated. Participants were evaluated at 6-month intervals using a standardized neuropsychological battery, including tests of cognition and adaptive behavior. A random effects model with restricted maximum likelihood estimation was constructed for each outcome, and the slope was the parameter of interest.ResultsFindings based on IQ scores and both standard scores and age equivalents of adaptive functioning indicate that there were not meaningful declines in these areas during the study period. The average annualized change in Full Scale IQ was negative: B=-1.28, standard error (SE)=0.70, t(34.2)=-1.83, p=0.076. The Vineland-II Adaptive Behavior Composite standard score decreased by 1.76 points per year [SE=0.67, t(59.1)=-2.62, p=0.011], but annualized slopes for each of the domain age equivalents were positive: Communication [B=0.71, SE=3.12, t(60.7)=0.23, p=0.82], Socialization [B=2.99, SE=2.92, t(60.4)=1.03, p=0.30], Daily Living Skills [B=2.76, SE=2.76, t(60.3)=1.18, p=0.24], and Motor Skills [B=1.42, SE=0.94, t(50.5)=1.51, p=0.14], indicating not worsening but slower-than-average acquisition of skills.ConclusionIn conjunction with previous findings, these results provide support for the slowing of disease progress up to 36months post-initiation of intrathecal VTS-270.RegistrationClinicalTrials.gov identifier NCT01747135: Hydroxypropyl Beta Cyclodextrin for Niemann-Pick type C1 Disease.