A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody

作者：Chad J. Swanson, Yong Zhang, Shobha Dhadda, Jinping Wang, June M. Kaplow, Robert Y. K. Lai, Lars Lannfelt, Heather M. Bradley, Martin P. Rabe, Akihiko Koyama, Larisa Reyderman, Donald A. Berry, Scott Berry, Robert J. Gordon, Lynn Darden Kramer, Jeffrey L. Cummings · 发表于：Alzheimer s Research & Therapy · 年份：2021 · DOI：10.1186/s13195-021-00813-8 · 被引用次数：844 · 研究领域：Alzheimer's disease research and treatments、Dementia and Cognitive Impairment Research、Neuroinflammation and Neurodegeneration Mechanisms

BACKGROUND: 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. METHODS: 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. RESULTS: 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...