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 (Cmax [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.

中文翻译：

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重组人 ADAMTS-13：评估 cTTP 患者药代动力学、安全性和耐受性的首次人体研究

在 15 名诊断为严重先天性 ADAMTS-13 缺乏症（血浆 ADAMTS-13 活性）的患者中研究了重组 ADAMTS-13（一种具有 1 型血小板反应蛋白基序的解聚素和金属蛋白酶，成员 13；BAX 930；SHP655）的安全性、耐受性和药代动力学<6%) 在一项前瞻性 1 期、首次人体、多中心剂量递增研究中。BAX 930 耐受性良好，没有发生严重的不良事件，也没有观察到抗 ADAMTS-13 抗体。对青少年和成人以 5、20 或 40 U/kg 体重单剂量给药 BAX 930 后，与最大血浆浓度 (Cmax [U/mL]) 和浓度下面积近似呈剂量比例-时间曲线（AUC [h∙U/mL]）。观察到个体 ADAMTS-13:Ag 和活性的剂量相关增加，并在 1 小时内达到最大值。随着 BAX 930 剂量的增加，观察到 ADAMTS-13 介导的血管性血友病因子 (VWF) 裂解产物的剂量依赖性持久性和 VWF 多聚体大小的减小。该研究表明，BAX 930 的药代动力学参数与之前血浆输注研究中估计的参数相当，并提供了药效学活性的证据。该研究在 www.clinicaltrials.gov 上注册为#NCT02216084。