Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A
Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A
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DOI：
10.1056/nejmoa1511769
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发表时间：
2016-05-26
影响因子：
158.5
通讯作者：
Nogami, Keiji
中科院分区：
文献类型：
--
作者：
Shima, Midori;Hanabusa, Hideji;Nogami, Keiji
背景对于重度血友病A患者，标准治疗是定期预防性和间歇性静脉输注凝血因子VIII。然而，这些治疗是繁重的，特别是对儿童，并可能导致形成抗因子VIII同种抗体（因子VIII抑制剂）。Emicizumab（ACE 910），一个人源化的双特异性抗体模仿因子VIII的辅因子功能，开发来减轻这些problems.METHODSWe招募了18名日本严重血友病A患者（有或无因子VIII抑制剂）在一个开放标签，非随机，个体间剂量递增研究emicizumab。患者接受皮下注射emicizumab，每周一次，持续12周，剂量为0.3、1.0或3.0 mg/kg体重（分别为队列1、2和3）。终点为安全性、药代动力学和药效学特征。另一个探索性终点是年出血率，计算为出血事件次数的365.25倍，除以治疗期间与入组前6个月相比的天数。emicizumab的血浆浓度以剂量依赖性方式增加。在整个研究期间，活化部分凝血活酶时间保持较短。队列1、2和3的中位年出血率分别从32.5降至4.4、18.3降至0.0和15.2降至0.0。11例使用因子VIII抑制剂的患者中有8例（73%）和7例未使用因子VIII抑制剂的患者中有5例（71%）未发生出血。减少了使用凝血因子控制出血的情况。抗体emicizumab没有development. CONCLUSIONSONS每周一次皮下注射emicizumab显着降低出血率血友病A与或不凝血因子VIII抑制剂的患者。（中外制药出资，日本CTI编号121934）
BACKGROUNDIn patients with severe hemophilia A, standard treatment is regular prophylactic and episodic intravenous infusions of factor VIII. However, these treatments are burdensome, especially for children, and may lead to the formation of anti-factor VIII alloantibodies (factor VIII inhibitors). Emicizumab (ACE910), a humanized bispecific antibody mimicking the cofactor function of factor VIII, was developed to abate these problems.METHODSWe enrolled 18 Japanese patients with severe hemophilia A (with or without factor VIII inhibitors) in an open-label, nonrandomized, interindividual dose-escalation study of emicizumab. The patients received subcutaneous emicizumab weekly for 12 weeks at a dose of 0.3, 1.0, or 3.0 mg per kilogram of body weight (cohorts 1, 2, and 3, respectively). The end points were safety and pharmacokinetic and pharmacodynamic profiles. An additional, exploratory end point was the annualized bleeding rate, calculated as 365.25 times the number of bleeding episodes, divided by the number of days in the treatment period as compared with the 6 months before enrollment.RESULTSEmicizumab was associated with neither serious adverse events nor clinically relevant coagulation abnormalities. Plasma concentrations of emicizumab increased in a dose-dependent manner. Activated partial-thromboplastin times remained short throughout the study. The median annualized bleeding rates in cohorts 1, 2, and 3 decreased from 32.5 to 4.4, 18.3 to 0.0, and 15.2 to 0.0, respectively. There was no bleeding in 8 of 11 patients with factor VIII inhibitors (73%) and in 5 of 7 patients without factor VIII inhibitors (71%). Episodic use of clotting factors to control bleeding was reduced. Antibodies to emicizumab did not develop.CONCLUSIONSOnce-weekly subcutaneous administration of emicizumab markedly decreased the bleeding rate in patients who had hemophilia A with or without factor VIII inhibitors. (Funded by Chugai Pharmaceutical; JapicCTI number, 121934.)