Inhibition Was Sustained and Dose-Dependent in Sub-Analysis of Phase II
TRA- PCI Trial
ORLANDO, Fla., Nov. 7 /PRNewswire-FirstCall/ -- SCH 530348 (TRA), the novel investigational antiplatelet agent in development by Schering-Plough Corporation (NYSE: SGP), was shown to be a potent inhibitor of platelet aggregation in a sub-analysis of the Thrombin Receptor Antagonist - Percutaneous Coronary Intervention (TRA-PCI) trial presented today at the American Heart Association Scientific Sessions.
The pharmacokinetic and pharmacodynamic analysis, conducted by the University of Tennessee Health Science Center, Memphis, showed that SCH 530348 (TRA), a potent thrombin receptor antagonist, demonstrated sustained, dose- dependent, specific agonist-induced inhibition of platelet aggregation in blood samples from patients undergoing non-urgent percutaneous coronary intervention (PCI).
"The inhibition of platelet aggregation plays a critical role in reducing the formation of deleterious blood clots in patients undergoing PCI," said Lisa K. Jennings, Ph.D., FAHA, Professor, Department of Medicine; Director, Vascular Biology Center of Excellence, University of Tennessee Health Science Center, Memphis, TN; and lead author. "TRA's potentially unique mechanism of action inhibits platelet aggregation through a different pathway from other antiplatelet agents currently available," added Jennings.
"Despite recent advances in cardiovascular care, current levels of morbidity and mortality make it clear that an unmet medical need exists for patients with acute coronary syndromes and those at risk of atherothrombosis. We believe these results add to the evidence indicating that TRA may be a promising therapeutic option for patients with unstable angina and non-ST elevation MI undergoing PCI ," said Rick Veltri, M.D., Group Vice President of Global Clinical Research, Cardiovascular and Metabolic Disease, Schering- Plough Research Institute. "With our global Phase III clinical development program underway, we are continuing to evaluate the potential for TRA as a novel agent in reducing the incidence of cardiovascular events with no incremental bleeding when added to standard of care in the treatment of patients with acute coronary syndromes or established vascular disease," added Veltri.
The results were presented today at the American Heart Association Scientific Sessions in Orlando, FL, in a session titled "Thrombin Receptor Antagonist Is a Selective, Potent Inhibitor of PAR-1 Activity With Predictable Pharmacokinetics."
The Phase II TRA-PCI Trial was a multinational, randomized, double-blind, placebo-controlled dose-ranging trial assessing oral loading doses and maintenance doses of TRA. The trial enrolled 1,030 patients randomized to one of three oral loading doses of TRA (10 mg, 20 mg, 40 mg) plus standard of care (clopidogrel + aspirin) or placebo plus standard of care in a 3:1 ratio of active drug to placebo. Patients who received a TRA-loading dose and subsequently underwent PCI (n=573) were randomized to one of three oral daily maintenance doses of TRA (0.5 mg, 1.0 mg, 2.5 mg). Patients who received placebo were randomized to receive standard of care alone. The total duration of treatment was 60 days. Patients were followed for an additional 60 days post-treatment.
A secondary endpoint in a sub-study within the primary evaluable patient cohort was inhibition of platelet aggregation (IPA) induced by appropriate agonists relative to baseline.
TRA-PCI results were first presented at a late-breaking clinical trial session at the March 2007 Scientific Sessions of the American College of Cardiology/i2 Summit in New Orleans.
IPA responses to the thrombin receptor agonist peptide (TRAP), adenosine diphosphate (ADP), collagen and arachidonic acid (AA) were measured using light transmission aggregometry at baseline and 30, 60, 90 and 120 minutes following a loading dose (10, 20 or 40 mg vs. placebo) and after a maintenance dose (0.5, 1.0 or 2.5 mg/day) at 30 and 60 days. PK was assessed at 30 and 60 minutes and 2 hours after loading dose administration.
TRA was active in inhibiting 15.M TRAP-induced platelet aggregation with onset of inhibition directly related to dose. The 40 mg loading dose resulted in 96.3 percent of patients achieving greater than 80 percent TRAP-induced platelet aggregation inhibition within two hours, compared with 52.9 percent of patients for the 20 mg loading dose and 42.9 percent of patients for the 10 mg loading dose.
The sub-study demonstrated that for the 1.0 mg and 2.5 mg maintenance dose groups, all patients exhibited greater than 80 percent IPA at both 30 and 60 days. Placebo-treated patients had, on average, less than or equal to 10 percent IPA to TRAP.
TRA had no significant effects on ADP, collagen or AA-induced platelet aggregation compared with placebo.
About the Phase III 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 will use 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 will use the oral 40 mg loading dose and the 2.5 mg maintenance dose. In the Phase II TRA-PCI trial, this dose was not statistically different from placebo in the combination of TIMI Major and Minor bleeding, and although not statistically significant, resulted in the greatest reduction in major adverse cardiac events, predominately periprocedural myocardial infarctions.
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.
These Phase III trials follow the results of two Japanese Phase II trials in ACS patients and in patients with previous ischemic events that further documented the lack of incremental bleeding with the use of TRA plus standard of care, and, for the first time, reported a statistically significant reduction in cardiovascular events, specifically periprocedural myocardial infarction (MI) in the ACS patients undergoing PCI.
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 on top of 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 the University of Tennessee Health Science Center
As the flagship statewide academic health system, the University of Tennessee Health Science Center is focused on a four-tier mission of education, research, clinical care and public service, all in support of a single goal: to improve the health of Tennesseans. Offering a broad range of postgraduate training opportunities, the main campus, which includes six colleges, is located in Memphis. UTHSC has additional College of Medicine and College of Pharmacy campuses in Knoxville and a College of Medicine campus in Chattanooga. For more information, visit http://www.utmem.edu.
Schering-Plough Corporation is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough's vision is to earn the trust of the physicians, patients and customers served by its more than 33,500 people around the world. The company's Web site is http://www.scheringplough.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 Part II, Item 1A, "Risk Factors" in Schering-Plough's third quarter 2007 10-Q.
|SOURCE Schering-Plough Corporation|
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