Von Willebrand Factor (VWF) and Factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary haemostasis 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, randomised, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favourable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: Single ascending dose of BT200 (0.18-48mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterised, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin induced aggregation, platelet function under high shear rates, and thrombin generation. Mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dosedependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagenadenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (p.

中文翻译：

---

von Willebrand 因子 A-1 结构域结合适体 BT200 提高 VWF 和因子 VIII 的血浆水平：首次人体试验。

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循环，分别促进原发性止血和凝血。一种新的 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较长的半衰期。这项首次人体、随机、安慰剂对照、双盲试验在 112 名志愿者中测试了 BT200 耐受性良好且具有良好药代动力学和药效学作用的假设。参与者接受以下其中一项：皮下单次递增剂量的 BT200（0.18-48mg）、静脉内剂量、BT200 联合去氨加压素或多剂量。对药代动力学进行了表征，通过 VWF 水平、FVIII 凝血活性、瑞斯托菌素诱导的聚集、血小板在高剪切率下的功能和凝血酶的产生。平均半衰期为 7-12 天，6-48 mg 剂量的皮下生物利用度剂量依赖性增加超过 55%。通过阻断游离 A1 结构域，BT200 剂量依赖性地降低瑞斯托菌素诱导的聚集，并延长胶原腺苷二磷酸和剪切诱导的血小板栓形成时间。然而，BT200 也将 VWF 抗原和 FVIII 水平提高了 4 倍（p.