A Phase II Study Published in The Lancet of Fast-Tracked Antiplatelet Agent Showed No Increase in TIMI Major and Minor Bleeding and was Well Tolerated When Given With Standard Platelet Therapy
KENILWORTH, N.J., March 12 /PRNewswire-FirstCall/ -- 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.
Study Design
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).
Study Results
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.
About the Phase III Trials
TRA is currently being evaluated in two large-scale multinational, randomized, double-blind, placebo-controlled Phase III clinical trials.
The Phase III Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P-TIMI 50) trial is a multinational, randomized, double-blind, placebo-controlled study in approximately 19,500 patients with prior MI or stroke, as well as patients with existing peripheral arterial disease. Patients will be randomized to either placebo plus standard medical care (including aspirin and clopidogrel) or to TRA once daily plus standard medical care. This Phase III trial uses the 2.5 mg maintenance dose. The primary endpoint of the trial is the composite of cardiovascular death, MI, urgent coronary revascularization or stroke. The key secondary endpoint is the composite of cardiovascular death, MI or stroke. Patients will be followed for a minimum of one year. This Phase III trial is being conducted by the Thrombolysis in Myocardial Infarction (TIMI) Study Group.
The Phase III Thrombin Receptor Antagonist Clinical Event Reduction in acute coronary syndrome (TRA-CER) trial is a multinational, randomized, double-blind, placebo-controlled study in approximately 10,000 patients with non-ST-segment elevation acute coronary syndrome. Patients will be randomized to either placebo plus standard medical care (including aspirin or clopidogrel) or to TRA plus standard medical care. The Phase III TRA-CER trial uses the oral 40 mg loading dose and the 2.5 mg maintenance dose. The primary endpoint of the Phase III TRA-CER trial is the composite of cardiovascular death, MI, rehospitalization for ACS, urgent coronary revascularization or stroke. The key secondary endpoint is the composite of cardiovascular death, MI or stroke. Patients will be followed for a minimum of one year. This Phase III trial is being conducted by the Duke Clinical Research Institute, Durham, NC.
About the Thrombin Receptor Antagonist
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.
The U.S. Food and Drug Administration (FDA) had previously granted Fast Track designation to the compound. Fast Track designation allows FDA to expedite review of drugs and biologics for serious or life-threatening conditions which demonstrate the potential to address unmet medical needs.
Thrombosis may result in partial or complete blockage of arteries in the heart, brain or periphery. This process is the underlying mechanism of most acute vascular events, including acute coronary syndromes (ACS), such as myocardial infarction (MI), and ischemic stroke, which are the leading causes of death. Platelets are activated at the site of atherosclerotic plaque rupture in arteries and release substances that initiate aggregation and clot formation, and thrombin is the most potent activator of platelets. Drugs that block platelet activation by other mechanisms, such as the thromboxane- or ADP-mediated pathways, have shown reduction in such clinical events, but events continue to occur despite these therapies. There is, thus, a need for novel agents that specifically modify the actions of thrombin, the most potent activator of platelets.
TRA binds selectively to the thrombin receptor on platelets (PAR-1), and is therefore a member of a potentially new class of drugs called thrombin receptor antagonists.
Importantly, Schering-Plough’s TRA is being investigated to determine whether it has the potential to provide clinical benefit through inhibition of this thrombin-mediated platelet activation without the liability of increased bleeding (when added to standard of care), a tendency associated with drugs that block thromboxane or ADP pathways. Specifically, this compound is being investigated as an oral antiplatelet agent for patients with established vascular disease, with the intent to demonstrate incremental benefit when given with current standard antiplatelet (including aspirin and clopidogrel) and other antithrombotic therapies, with no significant increase in bleeding. Clinical studies have shown no increase in bleeding time or prolongation in coagulation times (aPTT or PT) with TRA.
About Schering-Plough
Schering-Plough is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription, animal health and consumer health care products. Schering-Plough’s vision is to “Earn Trust, Every Day” with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., and its Web site is www.schering-plough.com.
SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release contains certain “forward-looking” statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements related to potential of SCH 530348 (TRA) and further actions under the clinical trials. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough’s forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough’s Securities and Exchange Commission filings, including Item 1A. “Risk Factors” in the 2008 10-K, filed February 27, 2009.
CONTACT: Lee A. Davies, +1-908-298-7127; or Investors: Janet Barth or
Joseph Romanelli, +1-908-298-7436, all of Schering-Plough
Web site: http://www.schering-plough.com/
