Department of Clinical Pharmacology.
Clinical Institute of Laboratory Medicine, Medical University of Vienna.
Haematologica. 2022 Sep 1;107(9):2121-2132. doi: 10.3324/haematol.2021.279948.
Von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomized, placebo-controlled, doubleblind trial tested the hypothesis that BT200 is well tolerated and has favorable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: a single ascending dose of BT200 (0.18-48 mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterized, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin-induced aggregation, platelet function under high shear rates, and thrombin generation. The mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dose-dependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagen-adenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (P<0.001), without increasing VWF propeptide levels, indicating decreased VWF/FVIII clearance. This, in turn, increased thrombin generation and accelerated clotting. Desmopressin-induced VWF/FVIII release had additive effects on a background of BT200. Tolerability and safety were generally good, but exaggerated pharmacology was seen at saturating doses. This trial identified a novel mechanism of action for BT200: BT200 dose-dependently increases VWF/FVIII by prolonging half-life at doses well below those which inhibit VWF-mediated platelet function. This novel property can be exploited therapeutically to enhance hemostasis in congenital bleeding disorders.
血管性血友病因子 (VWF) 和因子 VIII (FVIII) 在血液中以非共价复合物形式循环，分别促进初级止血和凝血。一种新型 VWF A1 结构域结合适体 BT200，在非人类灵长类动物中表现出良好的皮下生物利用度和长半衰期。这是一项首次在人体中进行的、随机、安慰剂对照、双盲试验，旨在检验 BT200 在 112 名志愿者中是否具有良好的耐受性，并具有良好的药代动力学和药效学效应的假设。参与者接受以下治疗之一：BT200 皮下单次递增剂量（0.18-48mg）、静脉剂量、BT200 联合去氨加压素或多次剂量。对药代动力学进行了特征描述，并通过 VWF 水平、FVIII 凝血活性、瑞斯托霉素诱导的聚集、高剪切率下血小板功能和凝血酶生成来测量药效学效应。平均半衰期范围为 7-12 天，皮下生物利用度呈剂量依赖性增加，6-48mg 剂量超过 55%。通过阻断游离 A1 结构域，BT200 剂量依赖性地降低瑞斯托霉素诱导的聚集，并延长胶原-腺苷二磷酸和剪切诱导的血小板栓子形成时间。然而，BT200 还使 VWF 抗原和 FVIII 水平增加了 4 倍（P<0.001），而没有增加 VWF 前肽水平，表明 VWF/FVIII 清除减少。这反过来又增加了凝血酶的生成并加速了凝血。去氨加压素诱导的 VWF/FVIII 释放在 BT200 的背景下具有附加作用。耐受性和安全性通常良好，但在饱和剂量下观察到药效学夸大。该试验确定了 BT200 的一种新作用机制：BT200 通过在低于抑制 VWF 介导的血小板功能的剂量下延长半衰期，剂量依赖性地增加 VWF/FVIII。这种新特性可以在治疗中得到利用，以增强先天性出血性疾病的止血作用。
