用于轻中度阿尔茨海默病的 solanezumab 的 3 期临床试验。

Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease.

机构信息

From the Alzheimer's Disease and Memory Disorders Center, Department of Neurology, Baylor College of Medicine, Houston (R.S.D.); Alzheimer's Disease Cooperative Study, Department of Family and Preventive Medicine (R.G.T., R.R., X.S.), and the Department of Neurosciences (R.G.T., R.R., P.S.A., R.M.), University of California at San Diego, San Diego; Indiana Alzheimer Disease Center, Indiana University (M.F.), and Eli Lilly (E.S., H.L.-S., R.M.) - both in Indianapolis; the Department of Neuropathology, School of Medicine, and the Department of Neuropathology and Neuroscience, School of Pharmacological Science, University of Tokyo, Tokyo (T.I.); Gerontopole, Unité Mixte de Recherche 1027, Centre Hospitalier Universitaire Toulouse, Toulouse, France (B.V.); the Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia (S.J.); and the Center for Human Experimental Therapeutics, University of Rochester Medical Center, Rochester, NY (K.K.).

出版信息

N Engl J Med. 2014 Jan 23;370(4):311-21. doi: 10.1056/NEJMoa1312889.

DOI:10.1056/NEJMoa1312889

PMID:24450890

Abstract

BACKGROUND

Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain.

METHODS

In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease.

RESULTS

Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P=0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P=0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P=0.06) and 1.6 points (95% CI, -0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P=0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49).

CONCLUSIONS

Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.).

摘要

背景

阿尔茨海默病的特征是淀粉样β斑块、神经原纤维缠结、神经胶质增生和神经元丧失。Solanezumab 是一种人源化单克隆抗体，优先结合可溶性形式的淀粉样蛋白，并在临床前研究中促进其从大脑中清除。

方法

在两项 3 期、双盲试验（EXPEDITION 1 和 EXPEDITION 2）中，我们分别随机分配 1012 名和 1040 名轻度至中度阿尔茨海默病患者接受安慰剂或 solanezumab（静脉注射剂量为 400mg），每 4 周一次，持续 18 个月。主要结局是从基线到第 80 周时，阿尔茨海默病评估量表的 11 项认知子量表（ADAS-cog11；范围 0 到 70，得分越高表示认知障碍越严重）和阿尔茨海默病合作研究日常生活活动量表（ADCS-ADL；范围 0 到 78，得分越低表示功能越差）的变化。在分析了 EXPEDITION 1 的数据后，EXPEDITION 2 的主要结果改为轻度阿尔茨海默病患者 ADAS-cog14 认知子量表的评分变化（范围 0 到 90，得分越高表示损害越严重）。

结果

两项研究均未显示主要结局有显著改善。组间（solanezumab 组减去安慰剂组）从基线的变化的模型差异为 ADAS-cog11 评分（95%置信区间[CI]，-2.1 至 0.5；P=0.24）为-0.8 分，ADCS-ADL 评分（95%CI，-2.3 至 1.4；P=0.64）为-0.4 分，在 EXPEDITION 1 中，分别为 -1.3 分（95%CI，-2.5 至 0.3；P=0.06）和 1.6 分（95%CI，-0.2 至 3.3；P=0.08），在 EXPEDITION 2 中。轻度阿尔茨海默病患者 ADAS-cog14 评分变化的组间差异为-1.7 分（95%CI，-3.5 至 0.1；P=0.06），中度阿尔茨海默病患者为-1.5 分（95%CI，-4.1 至 1.1；P=0.26）。在联合安全性数据集中，淀粉样相关成像异常伴水肿或出血的发生率为 solanezumab 组为 0.9%，安慰剂组为 0.4%（水肿，P=0.27）；出血分别为 4.9%和 5.6%（P=0.49）。