γ-分泌酶抑制剂阿伐加司他在轻度至中度阿尔茨海默病2期研究中的安全性和耐受性

Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

作者信息

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

机构信息

Neuroscience Global Clinical Research, Bristol-Myers Squibb, Wallingford, Connecticut 06492, USA.

出版信息

Arch Neurol. 2012 Nov;69(11):1430-40. doi: 10.1001/archneurol.2012.2194.

DOI:10.1001/archneurol.2012.2194

PMID:22892585

Abstract

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

摘要

目的

评估γ-分泌酶抑制剂阿伐加司他对轻至中度阿尔茨海默病（AD）患者的安全性、耐受性以及药代动力学和药效学作用。

设计

随机、双盲、安慰剂对照的24周2期研究。

地点

全球多中心试验。

患者

共有209例轻至中度AD门诊患者被随机分为双盲治疗阶段。患者的中位年龄为75岁，58.9%为APOE ε4携带者，各治疗组间疾病严重程度的基线测量值相似。

干预措施

阿伐加司他，每日25、50、100或125mg，或每日口服安慰剂。

主要观察指标

阿伐加司他的安全性和耐受性。

结果

25mg和50mg剂量的阿伐加司他停药率与安慰剂相当，但100mg和125mg剂量组的停药率更高。在100mg和125mg剂量组中，通过阿尔茨海默病评估量表认知子量表评分相对于基线的变化测量，观察到认知功能恶化的趋势。安慰剂组和治疗组中治疗引发的严重不良事件相似。停药的最常见原因是不良事件，主要为胃肠道和皮肤方面的不良事件。接受治疗的患者中更频繁出现的其他不良事件包括可逆性糖尿（无相关血清葡萄糖变化）、非黑色素瘤皮肤癌和无症状的磁共振成像结果。探索性脑脊液淀粉样蛋白亚型和tau生物标志物分析表明，在一小部分患者中，阿伐加司他有剂量依赖性但无统计学意义的降低。

结论

每日服用25mg和50mg剂量的阿伐加司他耐受性相对良好且停药率较低。100mg和125mg剂量组耐受性较差且有认知功能恶化的趋势。探索性脑脊液生物标志物子研究为γ-分泌酶靶点的作用提供了初步支持，但需要更多研究来更好地描述25mg和50mg剂量的药效学作用。本研究为未来阿伐加司他治疗AD的研究确定了可接受的安全性和耐受性剂量范围。