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BIVV001融合蛋白作为血友病A的因子Ⅷ替代疗法
BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A


Barbara A. Konkle ... 其他 • 2020.09.10
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• AAV5-凝血因子Ⅷ转基因治疗重度血友病A

摘要


背景

因子Ⅷ替代制品改进了血友病A患者的治疗,但这些制品较短的半衰期影响了患者的生活质量。由于冯·维勒布兰德因子的伴侣蛋白效应,重组因子Ⅷ的半衰期范围为15~19小时。BIVV001(rFⅧFc-VWF-XTEN)是一种新型融合蛋白,旨在打破这一半衰期上限,同时维持高且持续的因子Ⅷ活性水平。目前缺乏单剂BIVV001的安全性和药代动力学数据。

 

方法

在这项1~2a期开放标签试验中,我们将16例接受过治疗的重度血友病A(因子Ⅷ活性<1%)男性患者(18~65岁)序贯分组,分别以剂量25 IU/kg体重(小剂量组)或65 IU/kg体重(大剂量组)接受重组因子Ⅷ单剂静脉注射。注射后间隔至少3日的洗脱期,然后以相同对应剂量25 IU/kg或65 IU/kg接受BIVV001单剂静脉注射。本研究评估了不良事件和药代动力学测定值。

 

结果

截至单剂BIVV001注射后28日,本研究未检测到因子Ⅷ抑制物,也未报告超敏反应或过敏反应事件。BIVV001半衰期的几何平均值是重组因子Ⅷ的3~4倍(小剂量组37.6小时vs. 9.1小时,大剂量组42.5小时vs. 13.2小时);在两个剂量组中,BIVV001制品暴露水平的曲线下面积(AUC)是重组因子Ⅷ的6~7倍(小剂量组4,470小时vs. 638小时×IU/dL,大剂量组12,800小时vs. 1,960小时×IU/dL)。大剂量组BIVV001注射后,因子Ⅷ平均水平处于正常范围内(≥51%)的时间达到4日,第7日时为17%,因此提示有可能实施每周一次给药。

 

结论

在这项对重度血友病A男性患者进行的小规模早期研究中,BIVV001单剂静脉注射使患者达到了高且持续的因子Ⅷ活性水平,半衰期长达重组因子Ⅷ半衰期的4倍,这一较长的半衰期预示着有可能实施每周一次给药的新一类因子Ⅷ替代疗法。本研究在给药后28日期间未报告安全性问题(由赛诺菲和Sobi资助,在ClinicalTrials.gov注册号为NCT03205163)。





作者信息

Barbara A. Konkle, M.D., Amy D. Shapiro, M.D., Doris V. Quon, M.D., Ph.D., Janice M. Staber, M.D., Roshni Kulkarni, M.D., Margaret V. Ragni, M.D., M.P.H., Ekta S. Chhabra, Ph.D., Stacey Poloskey, M.D., Kara Rice, M.S., Suresh Katragadda, Ph.D., Joachim Fruebis, Ph.D., and Craig C. Benson, M.D.
From Bloodworks Northwest and the University of Washington, Seattle (B.A.K.); Indiana Hemophilia and Thrombosis Center, Indianapolis (A.D.S.); the Orthopaedic Hemophilia Treatment Center, Los Angeles (D.V.Q.); the University of Iowa, Iowa City (J.M.S.); Michigan State University, East Lansing (R.K.); the Department of Medicine, University of Pittsburgh, and the Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.); and Sanofi (E.S.C., S.P., S.K., C.C.B.) and Bioverativ (K.R., J.F.) — both in Waltham, MA. Address reprint requests to Dr. Konkle at Bloodworks Northwest, 921 Terry Ave., Seattle, WA 98104, or at barbarak@bloodworksnw.org.

 

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