Hugo Geerts, Silke Bergeler, Mike Walker, Rachel H. Rose, Piet H. van der Graaf
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However, generating these answers using clinical trials or real-world evidence is not practical, nor feasible.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>This QSP platform could support clinical practice challenges to optimize real-world treatment paradigms for new and existing amyloid drugs.</p>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 2","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.12474","citationCount":"0","resultStr":"{\"title\":\"Quantitative systems pharmacology-based exploration of relevant anti-amyloid therapy challenges in clinical practice\",\"authors\":\"Hugo Geerts, Silke Bergeler, Mike Walker, Rachel H. 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However, generating these answers using clinical trials or real-world evidence is not practical, nor feasible.</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> RESULTS</h3>\\n \\n <p>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. 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Quantitative systems pharmacology-based exploration of relevant anti-amyloid therapy challenges in clinical practice
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.
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.
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