Department of Neurosciences, UC San Diego, 9444 Medical Center Drive, Suite 1-100, La Jolla, San Diego, CA, 9209, USA.
Indiana University, Indianapolis, IN, USA.
Alzheimers Res Ther. 2024 Jul 5;16(1):151. doi: 10.1186/s13195-024-01490-z.
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.
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 C-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.
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.
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.
NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).
淀粉样β蛋白（Aβ）是阿尔茨海默病（AD）的治疗靶点。降低其母体蛋白 APP 的产生在临床前模型中具有益处。Posiphen 是一种口服小分子药物，与 APP mRNA 中的铁反应元件结合，降低 APP 和 Aβ 的翻译。为了增加 Posiphen 的人体数据，我们使用稳定同位素标记动力学（SILK）分析评估了其安全性、耐受性以及对 Aβ 代谢的药代动力学和药效学（PD）影响。
在一个经过 IRB 批准的方案下，在五个地点进行了双盲 1b 期随机递增剂量临床试验。轻度认知障碍或轻度 AD（早期 AD）患者通过低 CSF Aβ42/40 确认，然后按剂量组（每个剂量组内）随机分配 Posiphen 或安慰剂。预处理评估包括腰椎穿刺获取 CSF。参与者服用 Posiphen 或安慰剂 21-23 天，然后进行 CSF 导管放置、静脉输注 C-亮氨酸和 36 小时 CSF 采样。通过参与者报告、心电图和实验室测试评估安全性和耐受性。CSF SILK 分析使用免疫沉淀-质谱法测量 Aβ40、38 和 42。使用免疫测定法在基线和第 21 天测量 CSF APP、Aβ 和其他生物标志物。在基线和第 21 天进行 Mini-Mental State Exam 和 ADAS-cog12 测试。
从 2017 年 6 月至 2021 年 12 月，共招募了 19 名参与者，按 60mg 每日一次和 60mg 每日两次（每组 6 名活性药物和 5 名安慰剂）以及 60mg 每日三次（1 名参与者）进行分组随机。10 名活性药物和 5 名安慰剂参与者完成了所有研究程序。Posiphen 安全且耐受性良好。8 名参与者与 CSF 导管插入相关的头痛；5 名需要血补丁。对 CSF Aβ40 的分数合成率（FSR）进行了预设的 SILK 分析，结果显示 Posiphen 与安慰剂相比，没有显示出总体或剂量依赖性的影响。对 APP 动力学的综合多参数建模支持 Posiphen 降低 APP 产生的剂量依赖性。与安慰剂组相比，认知测量和 CSF 生物标志物在 Posiphen 组从基线到第 21 天没有显著变化。
Posiphen 在早期 AD 中安全且耐受性良好。多中心 SILK 研究是可行的。研究结果受到样本量小的限制，但提供了额外的支持安全性和 PK 数据。使用 SILK 数据对生物标志物动态进行综合建模可能会揭示药物的细微作用。
NCT02925650 于 clinicaltrials.gov 注册（于 2016 年 10 月 24 日注册）。
