γ-分泌酶抑制剂avagacestat在轻至中度阿尔茨海默病的2期研究中的安全性和耐受性

Vladimir Coric, Christopher H van Dyck, Stephen Salloway, Niels Andreasen, Mark Brody, Ralph W Richter, Hilkka Soininen, Stephen Thein, Thomas Shiovitz, Gary Pilcher, Susan Colby, Linda Rollin, Randy Dockens, Chahin Pachai, Erik Portelius, Ulf Andreasson, Kaj Blennow, Holly Soares, Charles Albright, Howard H Feldman, Robert M Berman
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引用次数: 312

摘要

目的:评价-分泌酶抑制剂阿瓦加司他在轻中度阿尔茨海默病(AD)患者中的安全性、耐受性、药代动力学和药效学作用。设计:随机、双盲、安慰剂对照、为期24周的2期研究。设置:全球,多中心试验。患者:209例轻中度AD门诊患者随机进入双盲治疗期。患者中位年龄为75岁,58.9%为APOE ε4携带者,各组间疾病严重程度基线指标相似。干预:Avagacestat, 25、50、100或125 mg /天,或安慰剂每日口服。主要观察指标:avagacestat的安全性和耐受性。结果:avagacestat 25mg和50mg剂量组的停药率与安慰剂相当,但100mg和125mg剂量组的停药率更高。通过基线阿尔茨海默病评估量表认知亚量表评分的变化来测量认知恶化的趋势,在100毫克和125毫克剂量组中观察到。治疗后出现的严重不良事件在安慰剂组和治疗组之间相似。停药最常见的原因是不良事件,主要是胃肠道和皮肤。在接受治疗的患者中更频繁发生的其他不良事件包括可逆性血糖(无相关血糖变化)、非黑色素瘤皮肤癌和无症状磁共振成像结果。探索性脑脊液淀粉样蛋白同型物和tau生物标志物分析显示,在一小部分患者中,淀粉样蛋白呈剂量依赖性减少,但在统计学上不显著。结论:阿瓦西他每日25和50 mg的耐受性相对较好,停药率较低。100毫克和125毫克剂量组耐受性差,有认知恶化的趋势。探索性脑脊液生物标志物亚研究为-分泌酶靶向作用提供了初步支持,但需要进一步的研究来更好地表征25和50毫克剂量的药效学效应。本研究建立了一个可接受的安全性和耐受性剂量范围,为未来阿瓦西司他在阿尔茨海默病中的研究。试验注册:clinicaltrials.gov标识符:NCT00810147
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

Objective: To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD).

Design: Randomized, double-blind, placebo-controlled,24-week phase 2 study.

Setting: Global, multicenter trial.

Patients: A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years,58.9% were APOE ε4 carriers, and baseline measures of disease severity were similar among groups.

Intervention: Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily.

Main outcome measures: Safety and tolerability of avagacestat.

Results: Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients.

Conclusions: Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for -secretase target engagement,but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses.This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD.

Trial registration: clinicaltrials.gov Identifier: NCT00810147

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Archives of neurology
Archives of neurology 医学-临床神经学
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