Quantitative systems pharmacology-based exploration of relevant anti-amyloid therapy challenges in clinical practice

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2024-05-21 DOI:10.1002/trc2.12474

Hugo Geerts, Silke Bergeler, Mike Walker, Rachel H. Rose, Piet H. van der Graaf

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引用次数: 0

Abstract

INTRODUCTION

Addressing practical challenges in clinical practice after the recent approvals of amyloid antibodies in Alzheimer's disease (AD) will benefit more patients. However, generating these answers using clinical trials or real-world evidence is not practical, nor feasible.

METHODS

Here we use a Quantitative Systems Pharmacology (QSP) computational model of amyloid aggregation dynamics, well validated with clinical data on biomarkers and amyloid-related imaging abnormality–edema (ARIA-E) liability of six amyloid antibodies in clinical trials to explore various clinical practice challenges.

RESULTS

Treatment duration to reach amyloid negativity ranges from 12 to 44, 16 to 40, and 6 to 20 months for lecanemab, aducanumab, and donanemab, respectively, for baseline central amyloid values between 50 and 200 Centiloids (CL). Changes in plasma cerebrospinal fluid Aβ42 and the plasma Aβ42/ Aβ40 ratio—fluid biomarkers to detect central amyloid negativity—is greater for lecanemab than for aducanumab and donanemab, indicating that these fluid amyloid biomarkers are only suitable for lecanemab. After reaching amyloid negativity an optimal maintenance schedule consists of a 24-month, 48-month and 64-month interval for 10 mg/kg (mpk) lecanemab, 10 mpk aducanumab, and 20 mpk donanemab, respectively, to keep central amyloid negative for 10 years. Cumulative ARIA-E liability could be reduced to almost half by introducing a drug holiday in the first months. For patients experiencing ARIA-E, restarting treatment with a conservative titration strategy resulted in an additional delay ranging between 3 and 4 months (donanemab), 5 months (lecanemab), and up to 7 months (aducanumab) for reaching amyloid negativity, depending upon the timing of the incident. Clinical trial designs for Down syndrome patients suggested the same rank order for central amyloid reduction, but higher ARIA-E liability especially for donanemab, which can be significantly mitigated by adopting a longer titration period.

DISCUSSION

This QSP platform could support clinical practice challenges to optimize real-world treatment paradigms for new and existing amyloid drugs.

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基于定量系统药理学探索临床实践中相关的抗淀粉样蛋白治疗难题

引言在最近批准使用淀粉样蛋白抗体治疗阿尔茨海默病（AD）之后，解决临床实践中的实际难题将使更多患者受益。然而，利用临床试验或真实世界的证据来得出这些答案既不实际，也不可行。方法在这里，我们使用淀粉样蛋白聚集动力学定量系统药理学（QSP）计算模型，并结合临床试验中六种淀粉样蛋白抗体的生物标志物和淀粉样蛋白相关成像异常水肿（ARIA-E）责任的临床数据进行了充分验证，以探讨各种临床实践挑战。结果对于基线中心淀粉样蛋白值在 50 到 200 厘泊（CL）之间的患者，莱卡单抗、阿杜单抗和多那单抗达到淀粉样蛋白阴性的治疗时间分别为 12 到 44 个月、16 到 40 个月和 6 到 20 个月。血浆脑脊液Aβ42和血浆Aβ42/ Aβ40比值--检测中心淀粉样蛋白阴性的体液生物标志物--的变化对利卡尼单抗来说大于阿杜单抗和多那尼单抗，这表明这些体液淀粉样蛋白生物标志物只适用于利卡尼单抗。在达到淀粉样蛋白阴性后，最佳的维持计划包括 10 mg/kg (mpk) lecanemab、10 mpk aducanumab 和 20 mpk donanemab 分别间隔 24 个月、48 个月和 64 个月，以保持中心淀粉样蛋白阴性 10 年。通过在最初几个月实行药物休药期，可将累积的 ARIA-E 负荷降至近一半。对于出现 ARIA-E 的患者，采用保守滴定策略重新开始治疗会导致达到淀粉样蛋白阴性的时间延迟 3 到 4 个月（多那尼单抗）、5 个月（莱卡内单抗）和长达 7 个月（阿杜卡单抗）不等，这取决于事件发生的时间。针对唐氏综合征患者的临床试验设计表明，中心淀粉样蛋白减少率的排名顺序相同，但 ARIA-E 负荷较高，尤其是多那单抗，而采用较长的滴注期可以显著减轻这种负荷。讨论该 QSP 平台可支持临床实践挑战，优化新药和现有淀粉样蛋白药物的实际治疗范例。

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.