两项评估 bapineuzumab 治疗轻度至中度阿尔茨海默病的 3 期临床试验。
Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.
机构信息
From Butler Hospital, Providence, RI (S.S.); Brigham and Women's Hospital, Boston (R.S.); University College London, Institute of Neurology, London (N.C.F.); University of Göteborg, Sahlgrenska University Hospital, Mölndal, Sweden (K.B.); University of Pittsburgh, Pittsburgh (W.K.); Veterans Affairs Medical Center, Seattle (M.R.); Cleo Roberts Center for Clinical Research/Sun Health Research Institute, Sun City, AZ (M.S.); Columbia University (L.S.H.) and New York University Langone Medical Center (S.F.), New York; University of Rochester School of Medicine and Dentistry, Rochester, NY (A.P.P.); Janssen Alzheimer Immunotherapy Research and Development, South San Francisco, CA (M.R., N.K., B.N., V.G., M.M., D.W., Y.L., I.C.T., E.L., E.Y., H.R.B.); Janssen Research and Development, Titusville, NJ (J.L.); Global R&D Partners and the University of California, San Diego - both in San Diego (M.G.); and Pfizer, Collegeville, PA (R.B.).
出版信息
N Engl J Med. 2014 Jan 23;370(4):322-33. doi: 10.1056/NEJMoa1304839.
BACKGROUND
Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease.
METHODS
We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations.
RESULTS
There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers.
CONCLUSIONS
Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).
背景
Bapineuzumab 是一种人源化抗淀粉样β单克隆抗体，目前正在进行临床试验，用于治疗阿尔茨海默病。
方法
我们进行了两项双盲、随机、安慰剂对照、3 期临床试验，涉及轻度至中度阿尔茨海默病患者——一项涉及 1121 名载脂蛋白 E（APOE）ε4 等位基因携带者，另一项涉及 1331 名非携带者。Bapineuzumab 或安慰剂，剂量根据研究而变化，每 13 周静脉输注一次，共 78 周。主要结局指标是阿尔茨海默病评估量表的 11 项认知子量表（ADAS-cog11，得分 0-70，得分越高表示损伤越严重）和失智症残疾评估（DAD，得分 0-100，得分越高表示损伤越轻）的评分。共有 1090 名携带者和 1114 名非携带者纳入疗效分析。次要结局指标包括使用匹兹堡化合物 B（PIB-PET）进行正电子发射断层扫描淀粉样蛋白成像和脑脊液磷酸化 tau（磷酸化 tau）浓度的结果。
结果
主要结局无组间差异。在第 78 周，ADAS-cog11 和 DAD 评分从基线变化的组间差异（bapineuzumab 组减去安慰剂组）在携带者研究中分别为 -0.2（P=0.80）和 -1.2（P=0.34）；在非携带者研究中，分别为 -0.3（P=0.64）和 2.8（P=0.07），bapineuzumab 剂量为 0.5mg/kg；0.4（P=0.62）和 0.9（P=0.55），bapineuzumab 剂量为 1.0mg/kg。主要的安全性发现是接受 bapineuzumab 治疗的患者出现与淀粉样蛋白相关的影像学异常伴水肿，其随 bapineuzumab 剂量和 APOE ε4 等位基因数量增加而增加，并导致 2.0mg/kg 剂量的停药。在 APOE ε4 等位基因携带者中观察到 PIB-PET 和脑脊液磷酸化 tau 浓度的组间差异，但在非携带者中未观察到。
结论
尽管在 APOE ε4 携带者中观察到生物标志物治疗差异，但 bapineuzumab 并未改善阿尔茨海默病患者的临床结局。（由 Janssen Alzheimer Immunotherapy 和 Pfizer 资助；Bapineuzumab 301 和 302 临床试验编号，NCT00575055 和 NCT00574132，以及 EudraCT 编号，2009-012748-17。）
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