Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
J Thromb Haemost. 2023 Jul;21(7):1692-1702. doi: 10.1016/j.jtha.2023.04.021. Epub 2023 Apr 26.
Oral anticoagulants are a mainstay for the prevention and treatment of arterial and venous thrombosis. Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists for many indications. Currently available DOACs include dabigatran, which inhibits thrombin, and apixaban, edoxaban, and rivaroxaban, which inhibit factor (F) Xa. A new class of DOACs is under development. These new DOACs, which include asundexian and milvexian, inhibit FXIa, which is positioned in the intrinsic pathway of coagulation. Anticoagulants that target FXIa have the potential to be safer than the current DOACs because there is emerging evidence that FXI is essential for thrombosis but mostly dispensable for hemostasis. In addition to the oral inhibitors of FXIa, parenteral inhibitors are also under development. These include fesomersen, an antisense oligonucleotide that reduces the hepatic synthesis of FXI; abelacimab, an antibody that binds to FXI and blocks its activation; and osocimab, an FXIa inhibitory antibody. Focusing on these new agents, this article describes the unmet needs in oral anticoagulation therapy, explains why FXI is a promising target for new oral anticoagulants, reviews phase 2 clinical data on new agents, describes ongoing phase 3 trials, and provides a perspective on the opportunities and challenges for FXI inhibitors.
口服抗凝剂是预防和治疗动脉和静脉血栓形成的主要药物。直接口服抗凝剂（DOAC）已经取代了维生素 K 拮抗剂用于许多适应症。目前可用的 DOAC 包括达比加群，其抑制凝血酶，以及阿哌沙班、依度沙班和利伐沙班，它们抑制因子（F）Xa。一类新的 DOAC 正在开发中。这些新的 DOAC 包括 asundexian 和 milvexian，抑制 FXIa，FXIa 位于凝血的内在途径中。靶向 FXIa 的抗凝剂可能比目前的 DOAC 更安全，因为有新的证据表明 FXI 对于血栓形成是必需的，但对于止血来说大多是可有可无的。除了口服 FXIa 抑制剂外，还在开发注射用抑制剂。这些包括 fesomersen，一种降低 FXI 肝合成的反义寡核苷酸；abelacimab，一种与 FXI 结合并阻断其激活的抗体；和 osocimab，一种 FXIa 抑制性抗体。本文重点介绍这些新的药物，描述口服抗凝治疗中的未满足需求，解释为什么 FXI 是新型口服抗凝剂的有前途的靶标，综述新型药物的 2 期临床数据，描述正在进行的 3 期试验，并对 FXI 抑制剂的机遇和挑战提供展望。
