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

Summary Background Based on animal and human data, phosphoinositide 3-kinase (PI3K)[beta] is a promising antithrombotic target. However, the relation between efficacy and bleeding when combined with current antiplatelet therapies is unclear. Objective To strengthen the PI3K[beta] target validation using the short-acting inhibitor AZD6482 alone and in different combinations with P2Y12 and cyclooxygenase (COX)-1 inhibition in vitro (human platelets), in vivo (dog), and in healthy subjects. Methods and Results Evaluation of complete target inhibition of PI3K[beta] (by AZD6482), P2Y12 (by ticagrelor), and COX-1 (by aspirin) alone and in the different combinations vs. concentration responses for a panel of platelet agonists in vitro (adenosine diphosphate, collagen, thrombin receptor activating peptide) indicates that the rank order of antiplatelet efficacy is P2Y12 > PI3K[beta] > COX-1 as monotherapy and P2Y12 plus PI3K[beta] > P2Y12 plus COX-1 > PI3K[beta] plus COX-1 as dual therapy, with little additional effect with triple therapy. Use of a conscious dog model to assess ex vivo antiplatelet effect in parallel with bleeding time prolongation (standard incision in the ear) confirms the wide separation of efficacy vs. bleeding for PI3K[beta] 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. Conclusions PI3K[beta] inhibition, in comparison with P2Y12 and COX-1, delivers medium antiplatelet effect but with minimal bleeding. PI3K[beta] 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.