Geerts Hugo, Bergeler Silke, Walker Mike, Rose Rachel H, van der Graaf Piet H
Certara Predictive Technologies Berwyn Pennsylvania USA.
BMS Lawrenceville New Jersey USA.
Alzheimers Dement (N Y). 2024 May 21;10(2):e12474. doi: 10.1002/trc2.12474. eCollection 2024 Apr-Jun.
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.
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.
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.
This QSP platform could support clinical practice challenges to optimize real-world treatment paradigms for new and existing amyloid drugs.
在近期阿尔茨海默病（AD）淀粉样蛋白抗体获批后，应对临床实践中的实际挑战将使更多患者受益。然而，利用临床试验或真实世界证据来得出这些答案既不实际，也不可行。
在此，我们使用淀粉样蛋白聚集动力学的定量系统药理学（QSP）计算模型，该模型已通过生物标志物的临床数据以及六种淀粉样蛋白抗体在临床试验中的淀粉样蛋白相关成像异常-水肿（ARIA-E）风险进行了充分验证，以探索各种临床实践挑战。
对于基线中枢淀粉样蛋白值在50至200 Centiloids（CL）之间的情况，lecanemab、aducanumab和donanemab达到淀粉样蛋白阴性的治疗持续时间分别为12至44个月、16至40个月和6至20个月。lecanemab导致的血浆脑脊液Aβ42以及血浆Aβ42/Aβ40比值（用于检测中枢淀粉样蛋白阴性的液体生物标志物）的变化比aducanumab和donanemab更大，这表明这些液体淀粉样蛋白生物标志物仅适用于lecanemab。达到淀粉样蛋白阴性后，最佳维持方案分别为：10mg/kg（mpk）的lecanemab间隔24个月、10mpk的aducanumab间隔48个月、20mpk的donanemab间隔64个月，以使中枢淀粉样蛋白在10年内保持阴性。通过在最初几个月引入药物假期，累积ARIA-E风险可降低至近一半。对于发生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额外延迟，延迟时间在3至4个月（donanemab）、5个月（lecanemab）和长达7个月（aducanumab）之间，具体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，中枢淀粉样蛋白减少的排名顺序相同，但ARIA-E风险更高，尤其是donanemab，通过采用更长的滴定期可显著降低该风险。
这个QSP平台可以支持临床实践挑战，以优化新的和现有的淀粉样蛋白药物的真实世界治疗模式。
