Exploration of efficacy and bleeding with combined phosphoinositide 3-kinase inhibition and aspirin in man

BackgroundBased on animal and human data, phosphoinositide 3-kinase (PI3K) is a promising antithrombotic target. However, the relation between efficacy and bleeding when combined with current antiplatelet therapies is unclear. ObjectiveTo strengthen the PI3K target validation using the short-acting inhibitor AZD6482 alone and in different combinations with P2Y(12) and cyclooxygenase (COX)-1 inhibition invitro (human platelets), invivo (dog), and in healthy subjects. Methods and ResultsEvaluation of complete target inhibition of PI3K (by AZD6482), P2Y(12) (by ticagrelor), and COX-1 (by aspirin) alone and in the different combinations vs. concentration responses for a panel of platelet agonists invitro (adenosine diphosphate, collagen, thrombin receptor activating peptide) indicates that the rank order of antiplatelet efficacy is P2Y(12)>PI3K>COX-1 as monotherapy and P2Y(12) plus PI3K >P2Y(12) plus COX-1>PI3K plus COX-1 as dual therapy, with little additional effect with triple therapy. Use of a conscious dog model to assess exvivo antiplatelet effect in parallel with bleeding time prolongation (standard incision in the ear) confirms the wide separation of efficacy vs. bleeding for PI3K inhibition and that this separation is reduced when combined with aspirin and more reduced when combined with clopidogrel. In healthy subjects, AZD6482, in combination with aspirin, shows a potential for greater antiplatelet potency but less bleeding potential compared with clopidogrel plus aspirin. ConclusionsPI3K inhibition, in comparison with P2Y(12) and COX-1, delivers medium antiplatelet effect but with minimal bleeding. PI3K inhibition, in combination with aspirin, in healthy subjects, provides a potential for greater overall antiplatelet effect compared with clopidogrel plus aspirin, but with significantly less bleeding potential.