β淀粉样蛋白免疫疗法（AN1792）在一项中断试验中对阿尔茨海默病患者的临床疗效。

Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial.

作者信息

Gilman S, Koller M, Black R S, Jenkins L, Griffith S G, Fox N C, Eisner L, Kirby L, Rovira M Boada, Forette F, Orgogozo J-M

机构信息

Department of Neurology, University of Michigan, 300 N. Ingalls 3D15, Ann Arbor, MI 48109-0489, USA.

出版信息

Neurology. 2005 May 10;64(9):1553-62. doi: 10.1212/01.WNL.0000159740.16984.3C.

DOI:10.1212/01.WNL.0000159740.16984.3C

PMID:15883316

Abstract

BACKGROUND

AN1792 (beta-amyloid [Abeta]1-42) immunization reduces Abeta plaque burden and preserves cognitive function in APP transgenic mice. The authors report the results of a phase IIa immunotherapy trial of AN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted because of meningoencephalitis in 6% of immunized patients.

METHODS

This randomized, multicenter, placebo-controlled, double-blind trial of IM AN1792 225 microg plus the adjuvant QS-21 50 microg (300 patients) and saline (72 patients) included patients aged 50 to 85 years with probable AD, Mini-Mental State Examination (MMSE) 15 to 26. Injections were planned for months 0, 1, 3, 6, 9, and 12. Safety and tolerability were evaluated, and pilot efficacy (AD Assessment Scale-Cognitive Subscale [ADAS-Cog], MRI, neuropsychological test battery [NTB], CSF tau, and Abeta42) was assessed in anti-AN1792 antibody responder patients (immunoglobulin G titer > or = 1:2,200).

RESULTS

Following reports of meningoencephalitis (overall 18/300 [6%]), immunization was stopped after one (2 patients), two (274 patients), or three (24 patients) injections. Of the 300 AN1792(QS-21)-treated patients, 59 (19.7%) developed the predetermined antibody response. Double-blind assessments were maintained for 12 months. No significant differences were found between antibody responder and placebo groups for ADAS-Cog, Disability Assessment for Dementia, Clinical Dementia Rating, MMSE, or Clinical Global Impression of Change, but analyses of the z-score composite across the NTB revealed differences favoring antibody responders (0.03 +/- 0.37 vs -0.20 +/- 0.45; p = 0.020). In the small subset of subjects who had CSF examinations, CSF tau was decreased in antibody responders (n = 11) vs placebo subjects (n = 10; p < 0.001).

CONCLUSION

Although interrupted, this trial provides an indication that Abeta immunotherapy may be useful in Alzheimer disease.

摘要

背景

AN1792（β-淀粉样蛋白[Abeta]1-42）免疫疗法可减轻APP转基因小鼠的Abeta斑块负担并维持其认知功能。作者报告了一项针对轻度至中度阿尔茨海默病（AD）患者的AN1792（QS-21）IIa期免疫治疗试验结果，该试验因6%的免疫患者发生脑膜脑炎而中断。

方法

这项随机、多中心、安慰剂对照、双盲试验，对300例患者注射IM AN1792 225微克加佐剂QS-21 50微克，72例患者注射生理盐水，纳入年龄在50至85岁、可能患有AD、简易精神状态检查表（MMSE）评分为15至26分的患者。计划在第0、1、3、6、9和12个月进行注射。评估安全性和耐受性，并在抗AN1792抗体反应者（免疫球蛋白G滴度≥1:2200）中评估初步疗效（AD评估量表-认知子量表[ADAS-Cog]、MRI、神经心理测试组套[NTB]、脑脊液tau蛋白和Abeta42）。

结果

在报告脑膜脑炎（共18/300例[6%]）后，分别在注射1次（2例患者）、2次（274例患者）或3次（24例患者）后停止免疫治疗。在300例接受AN1792（QS-21）治疗的患者中，59例（19.7%）出现了预定的抗体反应。双盲评估维持了12个月。在ADAS-Cog、痴呆症残疾评估、临床痴呆评定量表、MMSE或临床总体印象变化方面，抗体反应者组与安慰剂组之间未发现显著差异，但对NTB的z评分综合分析显示，抗体反应者组有优势（0.03±0.37对-0.20±0.45；p=0.020）。在进行脑脊液检查的小部分受试者中，抗体反应者（n=11）的脑脊液tau蛋白水平较安慰剂受试者（n=10）降低（p<0.001）。