Abstract：
BACKGROUND: Befovacimab (formerly BAY 1093884) is a fully human monoclonal antibody able to bind to tissue factor pathway inhibitor (TFPI) and developed as a non-replacement therapy for individuals with haemophilia A/B, with or without inhibitors.
OBJECTIVE: To assess the safety of multiple escalating doses of befovacimab in individuals with severe haemophilia A/B with or without inhibitors.
METHODS: In this non-randomised, open-label Phase 2 study (NCT03597022), adult males with <1% factor VIII or <2% factor IX and ≥4 bleeds in the previous six months were enrolled in three dose cohorts (100/225/400 mg). Participants received befovacimab subcutaneously once weekly. The primary endpoint was safety; secondary endpoints included annualised bleeding rate (ABR) and pharmacokinetics/pharmacodynamics (PK/PD) of befovacimab.
RESULTS: A total of 24 participants (n = 8 in each dose cohort) were treated for 2-47 weeks. Patients treated with 100 mg and 225 mg doses of befovacimab demonstrated improved bleeding control compared with pre-study bleeding rates, with a dose-dependent effect. Dosing was suspended and the study prematurely terminated following three drug-related thrombotic serious adverse events (SAEs): two at the 225 mg dose and one at the 400 mg dose. These occurred in the absence of bleeding episodes or concomitant use of replacement/bypass therapies. No laboratory abnormalities were observed, and PK/PD data did not show correlation between SAE occurrence and levels of circulating befovacimab or free TFPI.
CONCLUSIONS: Despite favourable initial results from preclinical and clinical studies, a positive safety profile of befovacimab was not confirmed. The lack of SAE-related laboratory abnormalities or differentiating PK/PD characteristics in participants experiencing SAEs raises concerns about the predictability of thrombosis following befovacimab treatment and emphasises the need for further investigation into the therapeutic window of anti-TFPI treatment.
OBJECTIVE: To assess the safety of multiple escalating doses of befovacimab in individuals with severe haemophilia A/B with or without inhibitors.
METHODS: In this non-randomised, open-label Phase 2 study (NCT03597022), adult males with <1% factor VIII or <2% factor IX and ≥4 bleeds in the previous six months were enrolled in three dose cohorts (100/225/400 mg). Participants received befovacimab subcutaneously once weekly. The primary endpoint was safety; secondary endpoints included annualised bleeding rate (ABR) and pharmacokinetics/pharmacodynamics (PK/PD) of befovacimab.
RESULTS: A total of 24 participants (n = 8 in each dose cohort) were treated for 2-47 weeks. Patients treated with 100 mg and 225 mg doses of befovacimab demonstrated improved bleeding control compared with pre-study bleeding rates, with a dose-dependent effect. Dosing was suspended and the study prematurely terminated following three drug-related thrombotic serious adverse events (SAEs): two at the 225 mg dose and one at the 400 mg dose. These occurred in the absence of bleeding episodes or concomitant use of replacement/bypass therapies. No laboratory abnormalities were observed, and PK/PD data did not show correlation between SAE occurrence and levels of circulating befovacimab or free TFPI.
CONCLUSIONS: Despite favourable initial results from preclinical and clinical studies, a positive safety profile of befovacimab was not confirmed. The lack of SAE-related laboratory abnormalities or differentiating PK/PD characteristics in participants experiencing SAEs raises concerns about the predictability of thrombosis following befovacimab treatment and emphasises the need for further investigation into the therapeutic window of anti-TFPI treatment.
摘要：
背景：Begovacimab（以前称为BAY1093884）是一种能够与组织因子途径抑制剂（TFPI）结合的完全人单克隆抗体，被开发为A/B血友病患者的非替代疗法，有或没有抑制剂。
目的：评估多次递增剂量的贝福伐单抗在有或没有抑制剂的重度A/B血友病患者中的安全性。
方法：在这个非随机的，开放标签第二阶段研究（NCT03597022），在前6个月有<1%因子VIII或<2%因子IX和≥4次出血的成年男性纳入3个剂量组(100/225/400mg).参与者每周一次皮下接受bevacimab。主要终点是安全性；次要终点包括bevacimab的年度出血率（ABR）和药代动力学/药效学（PK/PD）。
结果：总共24名参与者（每个剂量队列中n=8）接受了2-47周的治疗。与研究前的出血率相比，用100mg和225mg剂量的贝福伐单抗治疗的患者显示出改善的出血控制。具有剂量依赖性效应。在三个药物相关的血栓性严重不良事件(SAE)后,暂停给药并提前终止研究:两个在225mg剂量,一个在400mg剂量。这些发生在没有出血事件或伴随使用置换/旁路疗法的情况下。未观察到实验室异常，和PK/PD数据未显示SAE发生与循环贝福伐单抗或游离TFPI水平之间的相关性。
结论：尽管临床前和临床研究的初步结果良好，贝福伐单抗的阳性安全性未得到证实.在经历SAE的参与者中缺乏SAE相关的实验室异常或区分PK/PD特征，这引起了人们对贝福伐单抗治疗后血栓形成的可预测性的担忧，并强调需要进一步研究抗TFPI治疗的治疗窗口。
目的：评估多次递增剂量的贝福伐单抗在有或没有抑制剂的重度A/B血友病患者中的安全性。
方法：在这个非随机的，开放标签第二阶段研究（NCT03597022），在前6个月有<1%因子VIII或<2%因子IX和≥4次出血的成年男性纳入3个剂量组(100/225/400mg).参与者每周一次皮下接受bevacimab。主要终点是安全性；次要终点包括bevacimab的年度出血率（ABR）和药代动力学/药效学（PK/PD）。
结果：总共24名参与者（每个剂量队列中n=8）接受了2-47周的治疗。与研究前的出血率相比，用100mg和225mg剂量的贝福伐单抗治疗的患者显示出改善的出血控制。具有剂量依赖性效应。在三个药物相关的血栓性严重不良事件(SAE)后,暂停给药并提前终止研究:两个在225mg剂量,一个在400mg剂量。这些发生在没有出血事件或伴随使用置换/旁路疗法的情况下。未观察到实验室异常，和PK/PD数据未显示SAE发生与循环贝福伐单抗或游离TFPI水平之间的相关性。
结论：尽管临床前和临床研究的初步结果良好，贝福伐单抗的阳性安全性未得到证实.在经历SAE的参与者中缺乏SAE相关的实验室异常或区分PK/PD特征，这引起了人们对贝福伐单抗治疗后血栓形成的可预测性的担忧，并强调需要进一步研究抗TFPI治疗的治疗窗口。
