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

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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.