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

开发首创的小分子临床前候选抗凝剂，靶向激活因子 XII，出血风险最小

• 批准号: 105439
• 金额: $ 400.39万
• 依托单位: LUNAC
• 依托单位国家: 英国
• 项目类别: Collaborative R&D
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=105439
• 关键词: Development; First; Class; Small; Molecule

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.

目前对有形成血栓风险的患者的治疗是有效的，但出血风险显著增加。口服抗凝剂包括维生素K依赖性拮抗剂（例如华法林）、直接凝血酶抑制剂和FXa抑制剂[非维生素K口服抗凝剂（NOAC）]。研究表明，与华法林相比，NOAC显著降低了卒中、脑出血和死亡，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，不可能完全阻止治疗中患者的血栓形成。因此，接受新的抗凝治疗（NOAC）的患者仍然具有血凝块（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）。该提议的目的是开发高度特异性的化合物，其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得到更安全的治疗，而无需监测，并使高风险患者能够安全剂量递增，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。Lunac Therapeutics有限公司的团队与英国的合同研究组织（分包商）合作，已经产生了一系列高质量的强效和高选择性的药物，这些药物可以阻断FXIIa的作用。当在我们的实验系统中进行测试时，与现有药物相比，这些药物产生高水平的抗凝血保护，而没有出血的风险，具有非常好的抗凝血作用。因此，这些化合物证实了阻断FXIIa的作用将在没有显著出血风险的情况下提供针对凝血的高保护的想法，这是抗凝治疗的“圣杯”。该项目将与利兹大学和Medicines Discovery Catapult合作，使用分包商生产可用于临床前测试的药物（临床前开发），以确保它是安全的人使用。该奖项的交付将是临床前候选人的选择（药物准备临床前开发）与精心设计的实验，以提高成功的机会，在下一阶段的临床前开发。