Clinical efficacy of anti-amyloid antibodies in apolipoprotein E ε4 homozygotes: A Bayesian reanalysis of lecanemab and donanemab phase 3 results

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-04-09 DOI:10.1002/trc2.70083

Stefan Teipel, Yi Tang, Ara Khachaturian

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引用次数: 0

Abstract

INTRODUCTION

We aimed to determine the clinical efficacy of treating apolipoprotein E (ApoE) ε4 homozygotes with recently approved anti-amyloid antibodies.

METHODS

Data were derived from supplementary analyses in the regulatory studies Clarity (lecanemab) and TRAILBLAZER-ALZ2 (donanemab). We used Bayesian reanalysis with an independent t-statistic to determine evidence for or against an effect of antibody treatment on Clinical Dementia Rating scale Sum of Boxes (CDR-SB) in ApoE ε4 homozygotes, and a Bayesian random-effect meta-analysis to determine the effect size.

RESULTS

The Bayesian reanalysis showed moderate evidence of no effect for both antibodies. For donanemab and lecanemab, the odds of no difference in treatment effect were nearly three times greater than the odds of a difference. The meta-analysis revealed a small effect of −0.06 CDR-SB points in favor of treatment with a moderate heterogeneity estimate. The Bayes factor was 0.26, indicating that the absence of an effect was almost four times more likely than the presence of an effect.

DISCUSSION

The most likely explanation for our results is the lack of a treatment effect for lecanemab and donanemab in ApoE ε4 homozygotes. This could reflect inadequate exposure to the antibody due to more severe side effects, subsequent treatment interruptions, and lower dosing or a biologically driven lack of efficacy in a genetically determined disease. Our results support the view that excluding these cases from treatment is justifiable because of the higher risk of side effects and the lack of clinical efficacy.

Highlights

Lecanemab and donanemab were clinically ineffective in ApoE ε4 homozygotes.
ApoE ε4 homozygotes should not receive these treatments due to inefficacy.
Future trials should adopt Bayesian analysis strategies.
Bayesian analysis provides evidence for or against treatment effects.
Bayesian inference provides clinically interpretable results.

Abstract Image

查看原文本刊更多论文

载脂蛋白E ε4纯合子抗淀粉样蛋白抗体的临床疗效：lecanemab和donanemab 3期结果的贝叶斯再分析

我们的目的是确定最近批准的抗淀粉样蛋白抗体治疗载脂蛋白E (ApoE) ε4纯合子的临床疗效。方法数据来源于监管研究Clarity （lecanemab）和TRAILBLAZER-ALZ2 （donanemab）的补充分析。我们使用独立t统计量的贝叶斯再分析来确定抗体治疗对ApoE ε4纯合子临床痴呆评定量表（CDR-SB）影响的证据，并使用贝叶斯随机效应荟萃分析来确定效应大小。结果贝叶斯再分析显示两种抗体均无效果。对于donanemab和lecanemab，治疗效果无差异的几率几乎是差异几率的三倍。荟萃分析显示- 0.06 CDR-SB点对治疗的影响较小，异质性估计中等。贝叶斯因子为0.26，表明不存在影响的可能性几乎是存在影响的四倍。对我们的结果最可能的解释是lecanemab和donanemab在ApoE ε4纯合子中缺乏治疗效果。这可能反映了由于更严重的副作用、随后的治疗中断、低剂量或生物学驱动的对基因决定的疾病缺乏疗效而导致的抗体暴露不足。我们的结果支持这样的观点，即排除这些病例的治疗是合理的，因为副作用的风险较高，缺乏临床疗效。Lecanemab和donanemab对ApoE ε4纯合子临床无效。ApoE ε4纯合子不应接受这些治疗，因为无效。今后的试验应采用贝叶斯分析策略。贝叶斯分析提供了支持或反对治疗效果的证据。贝叶斯推理提供了临床可解释的结果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.