Results of a Schering-Plough Corporation Phase II trial of SCH 530348, a novel oral thrombin receptor antagonist (TRA), were published today 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, MD, 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, M.D., 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 percent 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, M.D., 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 Phase II TRA-PCI trial was a multinational, randomized, double-blind, placebo-controlled dose-ranging trial assessing both oral loading doses as well as maintenance doses of Schering-Plough's TRA. The trial enrolled 1,030 patients 45 years or older, with coronary artery disease for whom PCI was planned, and randomized to one of three oral loading doses of TRA (10mg, 20mg or 40mg) or placebo in a 3:1 ratio of active drug to placebo. The loading doses were increased in a sequential fashion based on a blinded review by a Safety Review Committee. Those patients who subsequently underwent PCI (n=573) were randomized to one of three oral daily maintenance doses of TRA (0.5mg, 1.0mg, 2.5mg) plus standard of care (aspirin and clopidogrel) for those who had received a TRA loading dose, or randomized to placebo plus standard of care for those who had received a placebo loading dose. The total duration of treatment was 60 days, and patients were followed for an additional 120 days post-enrollment.
The primary endpoint was measured using the TIMI bleeding scale. TIMI major bleeding is defined as any intracranial (head) hemorrhage or overt sign of bleeding associated with a decrease in hemoglobin concentration of greater than 50 g/L (or hematocrit greater than 15 percent). TIMI minor bleeding is defined as an overt sign of bleeding that does not meet the requirements for TIMI major bleed, associated with a decrease in hemoglobin concentration of 30g/L to less than or equal to 50 g/L (or hematocrit 9-15 percent).
In the primary cohort, i.e., patients treated with PCI, the incidence of TIMI major and minor bleeding was 3 percent in both the collective TRA treatment arms and the current standard care alone arm (p=0.7713). Non-TIMI bleeding was also not significantly increased with TRA compared to current standard care alone (p=0.0650). Overall, TRA was well tolerated, with discontinuations due to any adverse events (mostly non-TIMI bleeding and non-specific gastrointestinal symptoms, e.g., nausea) of 6 percent compared to 4 percent with placebo. Although not statistically significant, the incidence of death or major adverse cardiac event (MACE) at 60 days was 9 percent in the placebo group compared to 6 percent across all TRA dosages (33 percent reduction). The reduction in MACE was predominantly due to a reduction in myocardial infarction (heart attack), 7 percent with placebo compared to 4 percent with TRA (43 percent reduction).
TRAP-induced platelet aggregation inhibition was also measured. In those receiving the three oral loadings doses, platelet inhibition of greater than or equal to 80 percent was seen in 42.9 percent, 52.9 percent and 96.3 percent of study patients at each respective dose 120 minutes post-TRA administration. In maintenance doses, inhibition greater than or equal to 80 percent was seen in 90.9 percent, 100 percent and 100 percent of patients at each respective dose at 30 and 60 days compared to 9.1 and 11.1 percent at 30 and 60 days for patients receiving standard of care.
TRA is currently being evaluated in two large-scale multinational, randomized, double-blind, placebo-controlled Phase III clinical trials.