Abstract：
BACKGROUND: Valoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8-1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8-1 enrolment since emicizumab was an investigational therapy at the time of trial initiation.
OBJECTIVE: Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec.
METHODS: To estimate bleeding risk at weekly intervals following valoctocogene roxaparvovec infusion, a published emicizumab pharmacokinetic model was used to simulate emicizumab concentrations and merged with FVIII activity time-course data for participants in GENEr8-1. The analysis investigated three approved emicizumab dosing regimens for two transition scenarios that varied whether the last dose of emicizumab was administered on the same day or 4 weeks after valoctocogene roxaparvovec infusion.
RESULTS: Simulations demonstrated administering the last emicizumab dose the day of valoctocogene roxaparvovec infusion and 4 weeks after offered similar levels of haemostatic control, and bleeding risk was similar for all emicizumab dosing regimens. An algorithm was developed to provide guidance for discontinuation of emicizumab. Theoretical cases based on GENEr8-1 participants are presented to illustrate how decisions may vary among individuals.
CONCLUSIONS: Pharmacokinetic simulations demonstrated no clinically meaningful difference in bleeding risk caused by decaying emicizumab levels and rising gene therapy-derived endogenous FVIII for all examined emicizumab doses and dosing regimens. Therefore, multiple approaches can safely transition individuals from emicizumab prophylaxis to valoctocogene roxaparvovec.
OBJECTIVE: Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec.
METHODS: To estimate bleeding risk at weekly intervals following valoctocogene roxaparvovec infusion, a published emicizumab pharmacokinetic model was used to simulate emicizumab concentrations and merged with FVIII activity time-course data for participants in GENEr8-1. The analysis investigated three approved emicizumab dosing regimens for two transition scenarios that varied whether the last dose of emicizumab was administered on the same day or 4 weeks after valoctocogene roxaparvovec infusion.
RESULTS: Simulations demonstrated administering the last emicizumab dose the day of valoctocogene roxaparvovec infusion and 4 weeks after offered similar levels of haemostatic control, and bleeding risk was similar for all emicizumab dosing regimens. An algorithm was developed to provide guidance for discontinuation of emicizumab. Theoretical cases based on GENEr8-1 participants are presented to illustrate how decisions may vary among individuals.
CONCLUSIONS: Pharmacokinetic simulations demonstrated no clinically meaningful difference in bleeding risk caused by decaying emicizumab levels and rising gene therapy-derived endogenous FVIII for all examined emicizumab doses and dosing regimens. Therefore, multiple approaches can safely transition individuals from emicizumab prophylaxis to valoctocogene roxaparvovec.
摘要：
背景：Valoctocogeneroxaparvovec，在3期GENEr8-1试验中评估的基因治疗，支持内源性因子VIII（FVIII）的产生，以防止严重血友病患者的出血。一种模拟活化FVIII功能的抗体，被排除在GENEr8-1入组外,因为在试验开始时,emicizumab是一种研究性治疗.
目的：利用药代动力学模拟为维持止血控制的最佳实践提供指导，同时从emicizumab预防过渡到valoccogeneroxaparvovervec。
方法：为了在输注roxaparvovecValoccogene后每周一次评估出血风险，已发表的emicizumab药代动力学模型用于模拟emicizumab浓度,并与GENEr8-1参与者的FVIII活性时程数据合并.该分析调查了三种批准的emicizumab给药方案，用于两种过渡方案，这些方案是在Valoccogeneroxapavovec输注后的同一天还是4周给予最后剂量的emicizumab。
结果：模拟表明，在输注roxaparvovecValoccogene当天和提供相似水平的止血控制后4周，施用最后一次剂量的emicizumab。所有emicizumab给药方案的出血风险相似.开发了一种算法来为停药emicizumab提供指导。提出了基于GENEr8-1参与者的理论案例，以说明个人之间的决策如何变化。
结论：药代动力学模拟表明，对于所有已检查的emicizumab剂量和给药方案，由衰败的emicizumab水平和升高的基因治疗衍生的内源性FVIII引起的出血风险没有临床意义的差异。因此,多种方法可以安全地将个体从emicizumab预防转换为valoctocogeneroxaparvovec.
目的：利用药代动力学模拟为维持止血控制的最佳实践提供指导，同时从emicizumab预防过渡到valoccogeneroxaparvovervec。
方法：为了在输注roxaparvovecValoccogene后每周一次评估出血风险，已发表的emicizumab药代动力学模型用于模拟emicizumab浓度,并与GENEr8-1参与者的FVIII活性时程数据合并.该分析调查了三种批准的emicizumab给药方案，用于两种过渡方案，这些方案是在Valoccogeneroxapavovec输注后的同一天还是4周给予最后剂量的emicizumab。
结果：模拟表明，在输注roxaparvovecValoccogene当天和提供相似水平的止血控制后4周，施用最后一次剂量的emicizumab。所有emicizumab给药方案的出血风险相似.开发了一种算法来为停药emicizumab提供指导。提出了基于GENEr8-1参与者的理论案例，以说明个人之间的决策如何变化。
结论：药代动力学模拟表明，对于所有已检查的emicizumab剂量和给药方案，由衰败的emicizumab水平和升高的基因治疗衍生的内源性FVIII引起的出血风险没有临床意义的差异。因此,多种方法可以安全地将个体从emicizumab预防转换为valoctocogeneroxaparvovec.
