Development of a Novel Oral Anticoagulant with Minimal Bleeding Risk

The generation of a blood clot in a vein or artery is a very serious condition, ultimately causing 225,000 deaths per year in the UK alone. Anticoagulants are prescribed to prevent or treat blood clots. Patients that have an abnormal heart rhythm [atrial fibrillation (AF)] are 5 times more likely to have a blood clot in the brain (stroke). Warfarin, an anticoagulant drug, can reduce this high risk of stroke by 64%. However, warfarin is a difficult drug to administer as it needs to be monitored with a blood sample every month to ensure the correct level of drug is in the body. Furthermore, warfarin carries a risk of causing major bleeding for up to 3 in 100 patients taking the drug of which 1 in 8 will die. Recently a new drug, dabigatran has been approved for long term use to treat patients with AF. The benefit of this new drug is that patients no longer need to be monitored with a blood sample. However, one problem that all existing anticoagulant drugs and the new ones that are being developed have is that they still carry a very high risk of bleeding. In this proposal, we are developing for the first time a new anticoagulant drug that will not need monitoring and is not likely to result in bleeding when used. If we are successful, this has the potential to transform anticoagulation treatment, improve patient quality of life and make large savings to the cost of patient healthcare through not having to treat bleeding complications.

Thrombosis is a very serious condition and, annually in the UK, results in 25,000 and 200,000 fatalities from venous and arterial thrombosis, respectively. Current treatments of thrombosis target either platelet aggregation or coagulation (anticoagulants). At present, anticoagulants are used to prevent stroke in patients with atrial fibrillation, and to prevent deep venous thrombosis and pulmonary embolism in medical or surgical patients. However current anticoagulant treatments, including those in development, are associated with a significant risk of bleeding. As many as 1-3% of patients experience major bleeding, of which 13% is life-threatening. The proposal describes our approach to discover a new class of orally administered therapeutic agents acting via a clinically novel mechanism that will deliver effective anticoagulation with minimal bleeding risk. The preclinical data we have generated to date supports this mechanistic approach and will address this major unmet clinical need. The proposed programme aims to identify quality small molecule leads in preparation for a lead optimisation programme which will require additional funding beyond the scope of this application. If successful, this approach will transform the treatment of thrombosis with safer clinical outcomes for patients and reduced healthcare costs arising from reduced bleeding complications and the concomitant requirement for monitoring.