Results of a Schering-Plough Corporation phase-II trial of SCH 530348, a novel oral thrombin receptor antagonist (TRA), were published in The Lancet and demonstrated that the investigational antiplatelet compound met its primary endpoints of safety and tolerability. TRA showed no increase in major and minor Thrombolysis in Myocardial Infarction (TIMI)-scale bleeding when given with current standard antiplatelet therapy (aspirin and clopidogrel) for patients undergoing percutaneous coronary intervention (PCI), commonly known as balloon angioplasty with stenting.
"The results of this study are encouraging as they support the viability of TRA as a potential new antiplatelet therapy option," said Richard Becker, director of the Duke Cardiovascular Thrombosis Center and lead author of the study. "TRA appears to work in a novel way that is complementary to current antiplatelet therapies," he further commented.
Another important result from the Thrombin Receptor Antagonist Percutaneous Coronary Intervention (TRA-PCI) trial was the rate of thrombin-receptor agonist peptide (TRAP)-induced platelet aggregation inhibition, a secondary endpoint. Thrombin is the most potent platelet activator, which leads to platelet aggregation and the development of blood clots. In the study, TRA showed a much higher TRAP-induced platelet aggregation inhibition compared to standard of care alone in both loading and maintenance doses.
"In this study, TRA, when given with aspirin and clopidogrel, was able to inhibit the aggregation of platelets even when exposed to a very potent stimulant (TRAP-thrombin receptor agonist peptide)," said Enrico Veltri, group vice president of global clinical research, cardiovascular and metabolic disease, Schering-Plough Research Institute. "These data, along with subsequent data from phase-II acute coronary syndromes (ACS) and stroke studies conducted in Japan, suggest that TRA is a novel medication that targets a pathway to platelet aggregation not addressed by existing medications."
The 1,030-patient TRA-PCI trial was designed to evaluate the safety and tolerability of TRA in patients undergoing PCI. A secondary objective was to assess whether patients treated with the compound in addition to standard-of-care therapies had fewer cardiovascular events such as heart attack, need for urgent coronary revascularization, or death at 60 days compared to patients treated with the standard of care alone. While not powered to establish efficacy, the study did report a non-statistically significant 46 per cent reduction in cardiovascular events at the highest TRA dose tested compared to standard of care alone. Preliminary results were presented in March 2007 at the American College of Cardiology/i2 Summit in New Orleans by David J Moliterno, chief of Cardiovascular Medicine, University of Kentucky College of Medicine, and Medical Director of the Linda and Jack Gill Heart Institute, on behalf of the TRA-PCI investigators.
The investigational antiplatelet TRA is being developed by Schering-Plough for the prevention and treatment of atherothrombotic events in patients with acute coronary syndrome and in those with prior myocardial infarction or stroke, as well as in patients with existing peripheral arterial disease.