背景:已知遗传驱动的淀粉样蛋白途径失调和下游淀粉样蛋白β的过度产生会导致早发性阿尔茨海默病(EOAD)1。ALN-APP是一种研究性鞘内(IT)施用的RNAi治疗剂,旨在通过降低APPmRNA来降低上游细胞内和细胞外淀粉样前体蛋白(APP)水平。因此,我们假设ALN-APP可能会改变导致神经变性的级联事件,可能会放缓,停止,或逆转阿尔茨海默病的进展。
方法:ALN-APP-001(NCT05231785)A部分是一项正在进行的随机研究,双盲,安慰剂对照,EOAD患者的1期单次递增剂量研究。患者必须在年龄<65岁时发病,临床痴呆评分®全球评分为0.5或1.0,迷你精神状态检查评分>20。患者正在接受超过6个月的评估,根据需要进行长达6个月的进一步随访。主要终点是ALN-APP的安全性和耐受性。次要目标包括评价ALN-APP的药代动力学和药效学效应。
结果:12名患者被纳入并以2:1的比例随机分配,分别在25mg和75mg剂量组中接受ALN-APP或安慰剂。基线特征示于表1中。队列1(25mg)的研究平均(SD)持续时间为6.7(1.7)个月,队列2(75mg)为2.0(1.0)个月。单剂量ALN-APP后第15天,观察到脑脊液(CSF)中可溶性APPα和APPβ(sAPPα和sAPPβ)水平的剂量依赖性降低,平均从基线下降55%(sAPPα)和69%(sAPPβ),75mg队列(n=4)中最大减少71%(sAPPα)和83%(sAPPβ)(表2)。2023年1月17日数据截止日期的所有不良事件(AE)均为轻度或中度(表3),没有研究者认为与研究药物相关的AE。其他队列数据将在会议上介绍。
结论:CNS给药的RNAi治疗的第一个临床研究证明了APP的目标参与,随着CSFsAPPα和sAPPβ的减少。迄今为止,ALN-APP通常具有良好的耐受性,所有报告的AE均为轻度或中度。这些中期结果支持在EOAD患者中对ALN-APP的进一步评估。参考:1.HampelH等人。分子精神病学(2021)。26:5481-5503.
BACKGROUND: Genetic-driven deregulation of the amyloid pathway and overproduction of downstream amyloid-β are known to cause early-onset Alzheimer\'s disease (EOAD)1. ALN-APP is an investigational intrathecally (IT) administered RNAi therapeutic designed to reduce upstream intracellular and extracellular amyloid precursor protein (APP) levels by lowering APP mRNA. As a result, we hypothesize that ALN-APP may alter the cascade of events that result in neurodegeneration, potentially slowing, halting, or reversing Alzheimer\'s disease progression.
METHODS: ALN-APP-001 (NCT05231785) Part A is an ongoing randomized, double-blind, placebo-controlled, Phase 1 single-ascending dose study in patients with EOAD. Patients are required to have disease onset at age <65 years, Clinical Dementia Rating® global score of 0.5 or 1.0, and Mini Mental State Examination score >20. Patients are being evaluated over 6 months, with further follow-up of up to 6 months as needed. The primary endpoint is the safety and tolerability of ALN-APP. Secondary objectives include the evaluation of pharmacokinetics and pharmacodynamic effects of ALN-APP.
RESULTS: 12 patients were enrolled and randomized 2:1 to receive ALN-APP or placebo in 25mg and 75mg dose cohorts. Baseline characteristics are shown in Table 1. Mean (SD) duration on study was 6.7 (1.7) months for cohort 1 (25mg) and 2.0 (1.0) months for cohort 2 (75mg). Dose-dependent reductions of soluble APPα and APPβ (sAPPα and sAPPβ) levels in cerebrospinal fluid (CSF) at day 15 were observed following a single dose of ALN-APP, with mean reductions from baseline of 55% (sAPPα) and 69% (sAPPβ), and maximum reductions of 71% (sAPPα) and 83% (sAPPβ) in the 75mg cohort (n = 4) (Table 2). All adverse events (AEs) by data cut-off on 01/17/2023 were mild or moderate (Table 3), with no AEs deemed related to study drug by the investigators. Additional cohort data will be presented at the meeting.
CONCLUSIONS: This first clinical study of a CNS-administered RNAi therapeutic demonstrates target engagement of APP, with reductions in CSF sAPPα and sAPPβ. To date, ALN-APP remains generally well tolerated with all reported AEs mild or moderate. These interim results support further evaluation of ALN-APP in patients with EOAD. Reference: 1. Hampel H et al. Molecular Psychiatry (2021). 26:5481-5503.