A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody.
A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody.
复制标题
一项随机、双盲、2b期概念验证临床试验，用于早期阿尔茨海默病的抗Aβ原纤维抗体lecanemab。
DOI：
10.1186/s13195-021-00813-8
复制
发表时间：
2021-04-17
期刊：
影响因子：
--
通讯作者：
Cummings JL
中科院分区：
文献类型：
--
作者：
Swanson CJ;Zhang Y;Dhadda S;Wang J;Kaplow J;Lai RYK;Lannfelt L;Bradley H;Rabe M;Koyama A;Reyderman L;Berry DA;Berry S;Gordon R;Kramer LD;Cummings JL
Lecanemab（BAN 2401）是一种IgG 1单克隆抗体，优先靶向可溶性聚集淀粉样蛋白β（Aβ），对寡聚体、原纤维和不溶性原纤维具有活性。BAN 2401-G 000 -201是一项随机化双盲临床试验，采用反应适应性随机化的贝叶斯设计，在早期阿尔茨海默病、阿尔茨海默病（AD）所致轻度认知功能障碍和轻度AD痴呆患者中评估了2种方案的3种剂量的lecanemab与安慰剂。BAN 2401-G 000 -201旨在确定90%有效剂量（ED 90），定义为达到≥90%最大治疗效果的最简单剂量。主要终点是对ED 90剂量的阿尔茨海默病综合评分（ADCOMS）的12个月临床变化进行贝叶斯分析，其要求与安慰剂相比，下降的临床降低≥25%的概率为80%。关键次要终点包括使用正电子发射断层扫描进行的脑淀粉样蛋白减少的18个月贝叶斯和频率论分析; ADCOMS、临床痴呆评分总和（CDR-SB）和阿尔茨海默病评估量表-认知子量表（ADAS-Cog 14）的临床下降; CSF核心生物标志物的变化;以及使用体积磁共振成像进行的总海马体积（HV）。共854例随机化受试者接受治疗（lecanemab，609例;安慰剂，245例）。在12个月时，10 mg/kg每两周一次的ED 90剂量显示出64%的概率在ADCOMS方面优于安慰剂25%，这错过了主要结局的80%阈值。在18个月时，根据贝叶斯和频率论分析，10 mg/kg lecanemab每两周一次降低脑淀粉样蛋白（−0.306 SUVr单位），同时显示药物-安慰剂差异，ADCOMS组为27%和30%，ADAS-Cog 14组为56%和47%，CDR-SB组为33%和26%。CSF生物标志物支持治疗效果。Lecanemab耐受性良好，10 mg/kg每两周一次剂量下淀粉样蛋白相关成像异常-水肿/渗出的发生率为9.9%。BAN 2401-G 000 -201不符合12个月主要终点。然而，预先规定的18个月贝叶斯和频率论分析表明，脑淀粉样蛋白减少伴随着几个临床和生物标志物终点的临床下降的一致减少。早期阿尔茨海默病的3期研究（Clarity AD）正在进行中。Clinical Trials.govNCT01767311.在线版本包含补充材料，可通过10.1186/s13195-021-00813-8获得。
Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia. BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer’s disease is underway. Clinical Trials.govNCT01767311. The online version contains supplementary material available at 10.1186/s13195-021-00813-8.
登录
查看更多内容
DOI：
10.1186/s13195-017-0318-y
发表时间：
2017-12-08
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Ostrowitzki S;Lasser RA;Dorflinger E;Scheltens P;Barkhof F;Nikolcheva T;Ashford E;Retout S;Hofmann C;Delmar P;Klein G;Andjelkovic M;Dubois B;Boada M;Blennow K;Santarelli L;Fontoura P;SCarlet RoAD Investigators
通讯作者：
SCarlet RoAD Investigators
影响因子：
3.7
作者：
Sehlin D;Englund H;Simu B;Karlsson M;Ingelsson M;Nikolajeff F;Lannfelt L;Pettersson FE
通讯作者：
Pettersson FE
影响因子：
5.3
作者：
Knobloch, Marlen;Farinelli, Melissa;Mansuy, Isabelle M.
通讯作者：
Mansuy, Isabelle M.
影响因子：
25
作者：
Nilsberth, C;Westlind-Danielsson, A;Lannfelt, L
通讯作者：
Lannfelt, L
影响因子：
14.5
作者：
Sur, Cyrille;Kost, James;Egan, Michael F.
通讯作者：
Egan, Michael F.