Abstract：
BACKGROUND: Emicizumab promotes effective haemostasis in people with haemophilia A (PwHA). It is indicated for routine prophylaxis of bleeding episodes in PwHA with or without factor (F)VIII inhibitors.
OBJECTIVE: To investigate the effect of emicizumab dose up-titration in PwHA with suboptimal bleeding control.
METHODS: Data from seven completed or ongoing phase III studies were pooled. Pharmacokinetics, pharmacodynamics and bleeding events were evaluated before and after dose up-titration. Adverse events (AEs) were compared between PwHA with and without dose up-titration.
RESULTS: Of 675 PwHA evaluable for the analysis, 24 (3.6%) had their maintenance dose up-titrated to 3 mg/kg once weekly (QW). Two participants had neutralising antibodies (nAbs) associated with decreased emicizumab exposure, and dose increase did not compensate for the effect of nAbs. In the other 22 participants, mean emicizumab steady-state trough concentrations increased from 44.0 to 86.2 μg/mL after up-titration. The median (interquartile range [IQR]) efficacy period prior to up-titration was 24.6 (24.0-32.0) weeks. The model-based annualised bleed rate for \'treated bleeds\' and \'all bleeds\' decreased by 70.2% and 72.9%, respectively, after a median (IQR) follow-up of 97.1 (48.4-123.3) weeks in the up-titration period. Incidences of injection-site reactions and serious AEs were higher in PwHA with up-titration; however, this was already observed in these participants before the dose up-titration. Overall, the safety profile appeared similar between PwHA with and without up-titration.
CONCLUSIONS: The dose up-titration to 3 mg/kg QW was well tolerated. Bleed control improved in most participants whose bleeding tendency was inadequately controlled during clinical trials.
OBJECTIVE: To investigate the effect of emicizumab dose up-titration in PwHA with suboptimal bleeding control.
METHODS: Data from seven completed or ongoing phase III studies were pooled. Pharmacokinetics, pharmacodynamics and bleeding events were evaluated before and after dose up-titration. Adverse events (AEs) were compared between PwHA with and without dose up-titration.
RESULTS: Of 675 PwHA evaluable for the analysis, 24 (3.6%) had their maintenance dose up-titrated to 3 mg/kg once weekly (QW). Two participants had neutralising antibodies (nAbs) associated with decreased emicizumab exposure, and dose increase did not compensate for the effect of nAbs. In the other 22 participants, mean emicizumab steady-state trough concentrations increased from 44.0 to 86.2 μg/mL after up-titration. The median (interquartile range [IQR]) efficacy period prior to up-titration was 24.6 (24.0-32.0) weeks. The model-based annualised bleed rate for \'treated bleeds\' and \'all bleeds\' decreased by 70.2% and 72.9%, respectively, after a median (IQR) follow-up of 97.1 (48.4-123.3) weeks in the up-titration period. Incidences of injection-site reactions and serious AEs were higher in PwHA with up-titration; however, this was already observed in these participants before the dose up-titration. Overall, the safety profile appeared similar between PwHA with and without up-titration.
CONCLUSIONS: The dose up-titration to 3 mg/kg QW was well tolerated. Bleed control improved in most participants whose bleeding tendency was inadequately controlled during clinical trials.
摘要：
背景：Emicizumab促进A型血友病（PwHA）患者的有效止血。适用于有或没有因子（F）VIII抑制剂的PwHA出血发作的常规预防。
目的：研究emicizumab剂量上调对出血控制欠佳的PwHA的影响。
方法：收集7项已完成或正在进行的III期研究的数据。药代动力学，在剂量上调前后评估药效学和出血事件.比较有和没有剂量上调的PwHA之间的不良事件（AE）。
结果：分析可评估的675个PwHA，24（3.6％）的维持剂量每周一次（QW）增加至3mg/kg。两名参与者的中和抗体（nAbs）与emicizumab暴露减少相关，和剂量增加并不能弥补nAbs的影响。在其他22名参与者中，向上滴定后,平均埃米珠单抗稳态谷浓度从44.0μg/mL增加至86.2μg/mL.在向上滴定之前的中值(四分位距[IQR])效力期为24.6(24.0-32.0)周。“治疗出血”和“所有出血”的基于模型的年化出血率分别下降了70.2%和72.9%，分别,在向上滴定期间的中位数（IQR）随访97.1（48.4-123.3）周之后。在向上滴定的情况下，PwHA的注射部位反应和严重不良事件发生率较高；然而，在剂量上调前,这些参与者已经观察到了这一点.总的来说,使用和不使用向上滴定的PwHA的安全性特征相似.
结论：剂量向上滴定至3mg/kgQW具有良好的耐受性。在临床试验中，出血倾向未得到充分控制的大多数参与者的出血控制得到改善。
目的：研究emicizumab剂量上调对出血控制欠佳的PwHA的影响。
方法：收集7项已完成或正在进行的III期研究的数据。药代动力学，在剂量上调前后评估药效学和出血事件.比较有和没有剂量上调的PwHA之间的不良事件（AE）。
结果：分析可评估的675个PwHA，24（3.6％）的维持剂量每周一次（QW）增加至3mg/kg。两名参与者的中和抗体（nAbs）与emicizumab暴露减少相关，和剂量增加并不能弥补nAbs的影响。在其他22名参与者中，向上滴定后,平均埃米珠单抗稳态谷浓度从44.0μg/mL增加至86.2μg/mL.在向上滴定之前的中值(四分位距[IQR])效力期为24.6(24.0-32.0)周。“治疗出血”和“所有出血”的基于模型的年化出血率分别下降了70.2%和72.9%，分别,在向上滴定期间的中位数（IQR）随访97.1（48.4-123.3）周之后。在向上滴定的情况下，PwHA的注射部位反应和严重不良事件发生率较高；然而，在剂量上调前,这些参与者已经观察到了这一点.总的来说,使用和不使用向上滴定的PwHA的安全性特征相似.
结论：剂量向上滴定至3mg/kgQW具有良好的耐受性。在临床试验中，出血倾向未得到充分控制的大多数参与者的出血控制得到改善。
