Blood:2期临床试验:Concizumab可有效预防各型血友病患者出血

2019-08-28 MedSci MedSci原创

先天性血友病患者因VIII因子(A型)或IX(B型)因子缺陷导致出血倾向增加。用患者缺乏的凝血因子进行预防治疗是目前推荐的预防致命性出血及出血相关并发症的标准疗法。但目前的治疗需通过静脉点滴,操作不便,而且预后也不尽如人意。此外,抗外源性FVIII或FIX抗体(抑制剂)的出现使得血友病患者的治疗难上加难。Concizumab是一种高亲和力的人源化抗组织因子通路抑制剂(TFPI)的单克隆抗体,可阻断

先天性血友病患者因VIII因子(A型)或IX(B型)因子缺陷导致出血倾向增加。用患者缺乏的凝血因子进行预防治疗是目前推荐的预防致命性出血及出血相关并发症的标准疗法。但目前的治疗需通过静脉点滴,操作不便,而且预后也不尽如人意。此外,抗外源性FVIII或FIX抗体(抑制剂)的出现使得血友病患者的治疗难上加难。

Concizumab是一种高亲和力的人源化抗组织因子通路抑制剂(TFPI)的单克隆抗体,可阻断TFPI对FXa和FVIIa/TF的抑制,以产生充足的FXa,恢复血友病患者的止血潜能。

Shapiro等人开展相应临床试验,评估每日皮下注射concizumab预防的效果及安全性和免疫原性。共招募了36位抑制剂(抗外源性FVIII或FIX抗体)阴性的A型患者(HA)、9位抑制剂阳性的HA患者(HAwI)和8位抑制剂阳性的B型血友病患者(HBwI)。予以0.15 mg/kg concizumab,如果concizumab治疗12周内有3次及以上自发出血事件,可递增至0.2 和0.25 mg/kg。

大部分抑制剂阳性的患者(15/17,88.2%)未增加剂量,所有患者都选择继续参加扩展试验。explorer4 试验和explorer5 试验均证明concizumab可预防血友病患者的出血事件。

HAwI和HBwI患者的预计年出血率(ABRs)低于HA患者的:3.0 (95% CI 1.7-5.3)和5.9(4.2-8.5)vs 7.0(4.6-10.7)。concizumab在各亚组患者中的药物代谢动力学和药效动力学参数无明显差异,不受TFPI、血栓的产生、凝血酶原 F1+2和D-二聚体的影响。

Concizumab安全且耐受性良好。每项试验各有三位患者的抗药物抗体(ADA)试验阳性(轻至中度),但未观察到临床效应。本研究结果支持concizumab用作所有血友病患者日常预防出血的治疗措施。

原始出处:

Amy D. Shapiro, et al.Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: Phase 2 trial results.Blood 2019 :blood.2019001542; doi: https://doi.org/10.1182/blood.2019001542

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