Schering-Plough Reports Two Phase II Studies of Thrombin Receptor Antagonist (TRA) Build on Findings from Previous Phase II Study
No Increase in Bleeding Observed;Global Phase III Program Now Underway
KENILWORTH, N.J., Oct. 22 -- Schering-Plough Corporation today provided an update on the clinical development program for its novel oral thrombin receptor antagonist (TRA). Results from two randomized, double-blind, placebo-controlled Phase II studies in patients with vascular disease showed that TRA does not increase the rate of major or minor bleeding in patients with acute coronary syndrome or prior ischemic stroke when added to standard antiplatelet therapy. The trials were conducted in Japan as part of the global registration program for TRA.
"These findings confirm the results of the TRA-PCI Phase II trial, which were presented at the American College of Cardiology/i2 Summit earlier this year," said Rick Veltri, M.D., group vice president of global clinical research, cardiovascular and metabolic disease, Schering-Plough Research Institute. "We now have three Phase II trials involving a total of more than 1,200 patients with vascular disease which consistently demonstrate that TRA is well-tolerated and not associated with an increased rate of bleeding compared to patients who received standard of care therapy alone."
A secondary objective was to assess whether patients treated with TRA in addition to standard of care therapy had fewer major adverse cardiovascular events such as myocardial infarction (heart attack) compared to patients treated with the standard of care alone. While not powered to establish efficacy, in the acute coronary syndrome study patients undergoing percutaneous coronary intervention (PCI) treated with TRA had a statistically significant reduction in myocardial infarctions during the periprocedural period compared to standard of care alone.
"The significant reduction in periprocedural myocardial infarctions, which was not expected given the small size of the study, if confirmed in the larger Phase III studies could demonstrate the potential for TRA as a transformational drug in the treatment of patients with acute coronary syndrome," added Veltri.
Schering-Plough also announced that TRA has now begun dosing in patients in the global Phase III development program. The Phase III development program includes two randomized, double-blind, placebo-controlled trials enrolling nearly 30,000 patients with vascular disease. The first trial, in secondary prevention, involves approximately 19,500 patients with prior myocardial infarction or stroke, as well as patients with existing peripheral arterial disease. The second trial, in acute coronary syndrome, involves approximately 10,000 patients with non-ST segment elevation acute coronary syndrome.
About the Phase II trials
The Phase II Japanese trial in acute coronary syndrome involved 120 patients randomized 4 to 1 to TRA plus standard of care or standard of care alone, and treated for 60 days. Standard of care therapy in this study included aspirin, ticlodipine, and heparin.
The Phase II Japanese trial in patients with prior ischemic stroke involved 90 patients randomized 2 to 1 to TRA plus standard of care therapy or standard of care alone, and treated for 60 days. Standard of care therapy included aspirin and thienopyridine at the discretion of investigators.
Overall the incidence of adverse events in these trials was similar across treatment arms.
Full data from the trials will be presented at a future medical conference.
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.
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, 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 Schering-Plough Corporation
Schering-Plough 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 approximately 33,500 people 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 includes certain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the potential for TRA. 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, 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 the Company's 2007 second quarter 10-Q.