Development of First-In Class Small Molecule Preclinical Candidate Anticoagulant Targeting Activated Factor XII with Minimal Risk of Bleeding

对于有血栓形成风险的患者，目前的治疗方法是有效的，但会显著增加出血的风险。口服抗凝剂包括维生素K依赖性拮抗剂（如华法林）、直接凝血酶抑制剂和FXa抑制剂[非维生素K口服抗凝剂（NOACs）]。研究表明，与华法林相比，NOACs在卒中、脑出血和死亡方面显著降低，但肠道出血增加，发生大出血事件的患者数量与华法林相似（其中1 / 8导致死亡）[Lancet.2014:15;383(9921):955-62]。此外，由于出血的风险，在接受治疗的患者中不可能完全阻止血栓的形成。因此，接受新型抗凝血治疗（NOACs）的患者仍发生血栓（2.2-3.8%）和出血（3.6-20.7%）事件，其中一些导致死亡（Nat Rev Cardiol.2014,11(12):693-703）。该提案的目的是开发高度特异性的化合物，阻断活化的凝血酶，因子XII (FXIIa)，并且有强有力的证据表明抑制不会增加出血的风险。这一令人兴奋的发展将使患者在不需要监测的情况下得到更安全的治疗，并使高风险患者能够安全地增加剂量，而不像目前的药物在有益效果和不良出血事件之间有一个很小的窗口期。其目的是每天口服一次或两次治疗。Lunac Therapeutics有限公司的团队与英国一家合同研究组织（分包商）合作，已经开发出一系列高质量的有效和高选择性的药物，可以阻断FXIIa的作用。在我们的实验系统中进行测试时，与目前的药物相比，这些药物可以产生高水平的抗凝血保护，而不会有出血的风险，具有非常好的抗凝血效果。因此，这些化合物验证了阻断FXIIa的作用将在没有显著出血风险的情况下提供高凝血保护的想法，这是抗凝治疗的“圣杯”。该项目将与利兹大学和药物发现弹射器合作，通过分包商生产一种药物，该药物将准备好进行临床前测试（临床前开发），以确保它可以安全地用于人体。该奖项的交付成果将是选择临床前候选药物（准备进行临床前开发的药物），通过精心设计的实验来提高下一阶段临床前开发的成功机会。

Current treatments for patients who have a risk of forming blood clots are effective but carry a significant increase in the risk of bleeding. Anticoagulants taken by mouth include vitamin-K dependent antagonists (e.g. warfarin), direct thrombin inhibitors and FXa inhibitors [Non-vitamin K Oral Anticoagulants (NOACs)]. Studies have shown that NOACs significant reductions in stroke, bleeding in the brain, and death than warfarin but there is increased bleeding in the gut with a similar numbers of patients having major bleeding events (of which 1 in 8 result in death) compared with warfarin[Lancet.2014:15;383(9921):955-62]. Furthermore, because of the risk of bleeding, it is not possible to completely stop clots from forming in patients on treatment. As a result, patients on the new anticlotting treatment (NOACs) are still having blood clots (2.2-3.8%) and bleeding (3.6-20.7%) events with some resulting in death(Nat Rev Cardiol.2014,11(12):693-703).The objective of this proposal is to develop highly specific compounds which block an activated clotting enzyme, Factor XII (FXIIa) and for which there is strong evidence that inhibition will not increase the risk of bleeding. This exciting development will allow patients to be treated more safely, without the need for monitoring and enable safe dose escalation in high risk patients, unlike current medicines that have a small window between beneficial effects and undesirable bleeding events. The aim is to produce an orally administered once or twice daily treatment.The team at Lunac Therapeutics Limited, working with a UK based contract research organisation (sub-contractor), have generated a quality lead series of potent and highly selective agents which block the effects of FXIIa. These agents produce a high level of protection against clotting without the risk of bleeding in comparison with current medicines when tested in our experimental systems with very good anti-clotting effects. Thus, these compounds validate the idea that blocking the effects of FXIIa will deliver high protection against clotting in the absence of a significant bleeding risk, "the holy grail" of anticoagulant treatment. This project will work in collaboration with the University of Leeds and the Medicines Discovery Catapult using sub-contractors to generate a drug that will be ready for preclinical testing (Preclinical Development) to ensure it is safe to use in man. The deliverable of the award will be selection of a preclinical candidate (drug ready for preclinical development) with carefully designed experiments to improve the chances of success in the next stage of Preclinical Development.