Schering-Plough plans phase III trials for novel selective antiplatelet therapy

Schering-Plough Corporation has announced plans to initiate two global Phase III large-scale clinical outcomes trials for its novel selective oral antiplatelet therapy, the thrombin receptor antagonist (TRA) SCH 530348.

The investigational compound inhibits the most potent stimulus of platelet activation, thrombin, which is a driver of the clotting process. This compound is being evaluated to determine whether it has the potential to provide clinical benefit without the additional bleeding liabilities often found in current therapies. TRA is being developed by Schering-Plough for the treatment and prevention of cardiac events in patients with acute coronary syndrome and those with prior myocardial infarction (MI) or stroke, as well as in patients with existing peripheral arterial disease.

The Phase III clinical development program will include two large clinical trials to evaluate the risk reduction provided by TRA-SCH 530348 plus standard antiplatelet therapy (including aspirin and clopidogrel) compared to placebo plus standard antiplatelet therapy in two patient groups -- acute coronary syndrome (ACS) patients and in secondary prevention in patients who have had a prior MI (heart attack) or stroke, as well as patients with existing peripheral arterial disease. The trials will be conducted in approximately 30 countries at more than 800 sites for each trial.

"The advance of our novel selective antiplatelet TRA to Phase III represents a significant milestone for a compound discovered by scientists at Schering-Plough Research Institute that has the potential to treat a disease with a significant unmet medical need," said Thomas P. Koestler, Ph.D., Executive Vice President and President, Schering-Plough Research Institute.

The Phase II TRA-PCI Trial recently presented at the annual Scientific Sessions of the American College of Cardiology/i2 Summit in New Orleans met its primary endpoint of demonstrating no increase in major and minor bleeding, according to the TIMI bleeding scale, when this investigational antiplatelet compound was added to standard antiplatelet therapy (including aspirin and clopidogrel) among patients undergoing percutaneous coronary intervention (PCI). While not powered to establish efficacy, the study also reported a non-statistically significant 46 percent reduction in cardiovascular events at the highest TRA dose tested compared to standard antiplatelet therapy.

The Phase III Thrombin Receptor Antagonist in Acute Coronary Syndrome (TRA-ACS) trial will be a multinational, randomized, double-blind, placebo- controlled study in approximately 10,000 patients with non ST segment elevation acute coronary syndromes (unstable angina or non-ST elevation MI). Patients will be randomized to either placebo plus standard medical care (including aspirin and clopidogrel) or to TRA once daily plus standard medical care. The Phase III TRA-ACS 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 non-statistically significant, resulted in the greatest reduction in major adverse cardiac events (MACE).

The primary endpoint of the Phase III TRA-ACS 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.

"Nearly 1.5 million patients with ACS who are discharged annually from hospitals in the U.S., including both primary and secondary discharge diagnoses, are underserved by current treatments," said Robert A. Harrington, M.D., Director of the Duke Clinical Research Institute and lead investigator for the Phase III TRA-ACS Trial. "We are hopeful that encouraging results of the recently-presented Phase II TRA-PCI Trial will be borne out in the broader scale population of ACS patients."

The Phase III Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P-TIMI 50) trial will be 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 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.

"We have long known that patients who experience a heart attack or stroke are at high risk for another serious and potentially life-threatening cardiovascular event," commented Eugene Braunwald, MD, Distinguished Hersey Professor of Medicine, Harvard Medical School; Chairman, TIMI Study Group and Chair of the Phase III TRA 2P-TIMI 50 Trial. "One of our treatment goals is to identify a medication that can reduce that risk without the high incidence of bleeding that frequently accompanies currently available therapies."

The investigational antiplatelet TRA SCH 530348 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 that demonstrate the potential to address unmet medical needs. An important feature of Fast Track designation is that it emphasizes the critical nature of close, early communication between the FDA and the sponsor company to improve the efficiency of product development.

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, a tendency associated with drugs that block thromboxane or ADP pathways. Specifically, this compound is being investigated as a selective 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-SCH 530348.

In the Phase II TRA-PCI Trial, TRA was generally well-tolerated at each of the studied dosing regimens. The discontinuations due to any adverse events were 6 percent with TRA and 5 percent with placebo.

Adverse findings reported in preclinical animal toxicology studies have generally been at high doses and been species specific. Changes such as these are not uncommonly seen in animal toxicology studies at high doses. None of these findings is considered to predict human risk. These include reversible phospholipidosis, retinal vacuolation, hepatic thrombi, skeletal muscle degeneration and lymphoid necrosis in rats; urinary bladder, ureter, epididymidal and renal histopathology changes, sertoli cell vacuolation and phospholipidosis in mice; transient acute inflammatory changes, swollen lymph nodes, kupffer cell hyperplasia, tremors/convulsion and phospholipidosis in monkeys. These events occurred at multiples of >3 to >300 times the exposure at the human therapeutic dose.