Schering-Plough’s Oral Thrombin Receptor Meets Primary Endpoint, Demonstrates No Increase In Bleeding

Schering-Plough Corporation (NYSE: SGP - News) announced today the results of a Phase II trial of its novel oral thrombin receptor antagonist (TRA) SCH 530348 in a late-breaking clinical trial session at the annual Scientific Sessions of the American College of Cardiology/i2 Summit in New Orleans. The trial 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).

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.

“These results are particularly noteworthy because the study demonstrated that this first-in-class TRA did not increase clinically significant bleeding in a group of at-risk patients. In addition, while further study is required, the 46 percent reduction in cardiovascular events represents an early signal of the activity for this novel antiplatelet compound. This is encouraging, particularly in light of the fact that this patient population requires advanced therapies and is difficult to treat,” said 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, who presented the results on behalf of the TRA-PCI Investigators.

“Atherothrombosis remains the leading cause of death worldwide and represents a significant unmet medical need for millions of patients globally at high risk for potentially fatal cardiovascular events. New treatments that can reduce this burden would provide a significant benefit for patients around the world,” added Robert Harrington, M.D., Director of the Duke Clinical Research Institute and lead investigator for the Phase II TRA-PCI Trial.

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 randomized to one of three oral loading doses of TRA (10mg, 20mg, 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 an independent 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) for those who had received a TRA loading dose, or randomized to 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 60 days post-treatment.

The primary endpoint was measured using the Thrombolysis in Myocardial Infarction (TIMI) bleeding scale. TIMI Major bleeding is defined as any intracranial (head) hemorrhage or overt sign of bleeding requiring intervention, associated with a decrease in hemoglobin concentration of greater than 5 g/dL. TIMI Minor bleeding is defined as an overt sign of bleeding requiring intervention that does not meet the requirements for TIMI Major bleed, associated with a decrease in hemoglobin concentration of 3 g/dL to less than or equal to 5 g/dL.

Study Results

In the primary cohort, i.e., patients treated with PCI, the incidence of TIMI Major and Minor bleeding in the collective TRA treatment arms was 2.8 percent compared to 3.3 percent in the standard care alone. Non-TIMI bleeding was also not significantly increased with TRA compared to standard care alone. Overall, TRA was well-tolerated, with discontinuations due to any adverse events of 6 percent compared to 5 percent with placebo.

Although not statistically significant, the incidence of death or major adverse cardiac event (MACE) was 8.6 percent in the placebo group compared to 5.9 percent across all TRA dosages (31 percent reduction). The reduction in MACE was predominantly due to a reduction in myocardial infarction (heart attack), 7.3 percent with placebo compared to 4.3 percent with TRA (41 percent reduction).

“We are encouraged that the Phase II trial of our thrombin receptor antagonist has met its primary endpoint,” said Rick Veltri, MD, Group Vice President, Global Clinical Development, Cardiovascular and Metabolic Diseases, Schering-Plough Research Institute. “We believe that our TRA has the potential to become a transformational antiplatelet medicine in the secondary prevention of cardiovascular morbidity and mortality.”

Status of Schering-Plough’s TRA Clinical Development

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 the FDA to expedite review of drugs and biologics for serious or life-threatening conditions which 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 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 SCH 530348.

Based on the results of the Phase II TRA-PCI Trial, large-scale Phase III trials are planned to begin in 2007, with specific details of trial design and timing to be announced.