Safety, tolerability, and pharmacokinetics of recombinant ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; BAX 930; SHP655) were investigated in 15 patients diagnosed with severe congenital ADAMTS-13 deficiency (plasma ADAMTS-13 activity <6%) in a prospective phase 1, first-in-human, multicenter dose escalation study. BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed. After single-dose administration of BAX 930 at 5, 20, or 40 U/kg body weight to adolescents and adults, there was approximate dose proportionality with respect to maximum plasma concentration (C_max [U/mL]) and area under the concentration–time curve (AUC [h∙U/mL]). Dose-related increases of individual ADAMTS-13:Ag and activity were observed and reached a maximum within 1 hour. With escalating BAX 930 doses administered, a dose-dependent persistence of ADAMTS-13-mediated von Willebrand factor (VWF) cleavage products and reduced VWF multimeric size were observed. This study demonstrated that pharmacokinetic parameters of BAX 930 were comparable to those estimated in previous plasma infusion studies and provided evidence of pharmacodynamic activity. This study was registered at www.clinicaltrials.gov as #NCT02216084.

在15名被诊断患有严重先天性ADAMTS-13缺乏症（血浆ADAMTS-13活性）的患者中研究了重组ADAMTS-13（具有血小板反应蛋白1型基序的整合素和金属蛋白酶，成员13； BAX 930； SHP655）的安全性，耐受性和药代动力学。 （<6％）在前瞻性阶段1，首次在人体中进行的多中心剂量递增研究。BAX 930具有良好的耐受性，没有发生严重的不良事件，也未观察到抗ADAMTS-13抗体。在以5、20或40 U / kg体重向青少年和成人单剂量给予BAX 930之后，就最大血浆浓度而言，剂量呈近似比例关系（C _max[U / mL]）和浓度-时间曲线下的面积（AUC [h∙U / mL]）。观察到个体ADAMTS-13：Ag和活性的剂量相关增加，并且在1小时内达到最大值。随着BAX 930剂量的增加，观察到ADAMTS-13介导的von Willebrand因子（VWF）裂解产物的剂量依赖性持续存在和VWF多聚体大小减小。这项研究表明，BAX 930的药代动力学参数与以前的血浆输注研究中估计的参数相当，并提供了药代动力学活性的证据。该研究已在www.clinicaltrials.gov上注册为＃NCT02216084。