Population Modeling of Factor IX Activity Following Administration of Fidanacogene Elaparvovec Gene Therapy in Participants with Hemophilia B.

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Clinical Pharmacokinetics Pub Date : 2025-10-01 Epub Date: 2025-08-01 DOI:10.1007/s40262-025-01535-y

Jessica Wojciechowski, Puneet Gaitonde, Jim H Hughes, Patanjali Ravva

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引用次数: 0

Abstract

Background and objective: Fidanacogene elaparvovec (BEQVEZ™), an adeno-associated virus-based gene therapy approved for the treatment of hemophilia B, enables endogenous production of factor IX (FIX), preventing bleeding and reducing the need for FIX replacement. Nonlinear mixed-effects models are routinely used for population pharmacokinetic analyses of FIX replacement therapies but have not previously been applied to FIX activity observations from gene therapy trials. A nonlinear mixed-effects modeling approach was used to characterize FIX activity following fidanacogene elaparvovec and/or FIX replacement, identify covariates affecting FIX activity, and estimate the longer-term durability of FIX activity after a single dose of fidanacogene elaparvovec.

Methods: Population modeling using NONMEM^® was performed with FIX activity data pooled from 11 clinical trials in participants with hemophilia B (three fidanacogene elaparvovec studies [n = 63]; eight nonacog alfa studies [n = 274]). FIX activity was assessed by one-stage clotting assays.

Results: FIX activity was described by a compartmental model for gene and protein expression and a three-compartment model for FIX disposition. Covariates included age and body weight on gene-therapy-related parameters. Following fidanacogene elaparvovec administration, model-predicted FIX activity reached a median (90% prediction interval) peak of 13.5 (3.12-41.3) IU/dL and remained within 50% of the peak for a median of 8.67 (0.411-15.0) years. At 15 years post-infusion, median predicted FIX activity was 4.11 (1.15-17.6) IU/dL.

Conclusions: Model-based estimates showed that a single dose of fidanacogene elaparvovec elicited long-lasting elevations in FIX activity, suggesting most individuals would not require prophylactic FIX replacement for at least 15 years post-infusion.

Clinicaltrials:

Gov identifier: NCT00364182, NCT01335061, NCT00037557, NCT00093171, NCT00093210, NCT03861273, NCT03307980, NCT02484092.

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B型血友病患者接受非达那科基因治疗后因子IX活性的群体模型。

背景和目的：Fidanacogene elaparvovec （BEQVEZ™）是一种基于腺相关病毒的基因疗法，被批准用于治疗B型血友病，能够内源性产生IX因子（FIX），预防出血并减少FIX替代的需要。非线性混合效应模型通常用于FIX替代疗法的群体药代动力学分析，但以前尚未应用于基因治疗试验中的FIX活性观察。采用非线性混合效应建模方法来表征fidanacogene elaparvovec和/或FIX替代后的FIX活性，确定影响FIX活性的协变量，并估计单剂量fidanacogene elaparvovec后FIX活性的长期持久性。方法：使用NONMEM®进行群体建模，并收集来自11项血友病B患者临床试验的FIX活性数据(3项fidanacogene elaparvovec研究[n = 63]；8项非acog α研究[n = 274])。通过一期凝血试验评估FIX活性。结果：FIX活性通过基因和蛋白表达的室室模型和FIX处置的三室模型来描述。协变量包括年龄和体重对基因治疗相关参数的影响。在给药后，模型预测的FIX活性达到13.5 (3.12-41.3)IU/dL的中位（90%预测区间）峰值，并在8.67（0.411-15.0）年的中位时间内保持在峰值的50%以内。在输注后15年，FIX的中位预测活性为4.11 (1.15-17.6)IU/dL。结论：基于模型的估计显示，单剂量的elaparvovec引起FIX活性的长期升高，这表明大多数个体在输注后至少15年内不需要预防性的FIX替代。临床试验：政府识别码：NCT00364182， NCT01335061, NCT00037557, NCT00093171, NCT00093210, NCT03861273, NCT03307980, NCT02484092。

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来源期刊

Clinical Pharmacokinetics 医学-药学

CiteScore

8.80

自引率

4.40%

发文量

审稿时长

6-12 weeks

期刊介绍： Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.