背景:淀粉样β蛋白(Aβ)是阿尔茨海默病(AD)的治疗靶标。降低其母体蛋白质的产量,APP,在临床前模型中有好处。Posiphen,口服小分子,与APPmRNA中的铁响应性元素结合,并减少APP和Aβ的翻译。为了增加Posiphen的人类数据,我们评估了安全性,使用稳定同位素标记动力学(SILK)分析,耐受性和药代动力学和药效学(PD)对Aβ代谢的影响。
方法:双盲1b期随机递增剂量临床试验,在五个地点,根据IRB批准的方案。通过低CSFAβ42/40证实的轻度认知障碍或轻度AD(早期AD)的参与者被随机分配(在每个剂量组内)到Posiphen或安慰剂。治疗前评估包括腰椎穿刺脑脊液。参与者服用Posiphen或安慰剂21-23天,然后接受了脑脊液导管放置,静脉输注13C6-亮氨酸,和CSF采样36小时。通过参与者报告评估安全性和耐受性,心电图和实验室测试。CSFSILK分析用免疫沉淀-质谱法测量Aβ40、38和42。基线和第21天CSFAPP,用免疫测定法测量Aβ和其他生物标志物。在基线和第21天进行迷你精神状态检查和ADAS-cog12。
结果:从2017年6月到2021年12月,19名参与者被注册,在60mg/天和60mg/天2次的剂量队列(5名活性剂:3名安慰剂)内随机分组;1名参与者入组并完成60mg/天3次.10名活性药物和5名安慰剂参与者完成了所有研究程序。泊尼芬是安全且耐受性良好的。8名参与者有与CSF导管插入相关的头痛;5名需要血贴。对CSFAβ40的分数合成率(FSR)的预先确定的SILK分析显示,Posiphen与Posiphen没有明显的总体或剂量依赖性影响。安慰剂。APP动力学的综合多参数模型支持Posiphen剂量依赖性降低APP产量。Posiphen的认知测量和CSF生物标志物从基线到21天没有显着变化与安慰剂组。
结论:Posiphen在早期AD中安全且耐受性良好。多中心SILK研究是可行的。研究结果受样本量小的限制,但提供了额外的支持性安全性和PK数据。使用SILK数据对生物标志物动力学进行综合建模可以揭示微妙的药物效应。
背景:关于clinicaltrials.gov(2016年10月24日注册)的NCT02925650。
BACKGROUND: Amyloid beta protein (Aβ) is a treatment target in Alzheimer\'s Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.
METHODS: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21.
RESULTS: From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups.
CONCLUSIONS: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.
BACKGROUND: NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).