High-dose tirofiban as effective as abciximab in reducing ST-segment elevation in STEMI patients

March 30, 2008

PHILADELPHIA, PA, March 30, 2008 -- Data from a Phase III, open label, multi-national study of patients undergoing angioplasty for ST-elevation myocardial infarction (STEMI), showed that treatment with tirofiban (AGGRASTAT®) led to non-inferior ST-segment resolution compared to abciximab (ReoPro®). These findings were reported today at the 57th Annual Scientific Session of the American College of Cardiology and released online by the Journal of the American Medical Association (JAMA) to coincide with the conference. The study will be published in the April 16, 2008 issue of JAMA.

At least 50 percent recovery from ST-elevation occurred in 85.3 percent and 83.6 percent of patients in the tirofiban and abciximab groups, respectively (Relative Risk [RR]: 1.020; 97.5 percent confidence Interval [CI], 0.958 to 1.086; P <0.001 for non-inferiority). At 30 days, ischemic and hemorrhagic outcomes were similar in the tirofiban and abciximab groups, with the incidence of thrombocytopenia being significantly more common with abciximab compared to tirofiban (4.0 versus 0.8 percent, P=0.004). At 8 months, the incidence of major adverse cardiac events (MACE) was approximately 20 percent lower in patients treated with tirofiban compared to abciximab (9.8 percent versus 12.4 percent; P=0.30). The study also evaluated sirolimus-stent implantation versus uncoated stent implantation. While there was no interaction between tirofiban or abciximab and stent types (P=0.60), there was a significant reduction in incidence of MACE at 8months in patients treated with sirolimus-stent implantation versus uncoated stent implantation (7.8 percent versus 14.5 percent, P=0.0039), driven primarily by an increase in target vessel revascularization (3.2 percent versus 10.2 percent; P=0.0002).

"The results of MULTISTRATEGY demonstrate that in STEMI patients undergoing primary angioplasty, treatment with tirofiban results in similar clinical outcomes with improved safety, in terms of lower thrombocytopenia, relative to abxicimab," said Marco Valgimigli, MD, PhD, staff cardiologist at the University of Ferrara, Ferrara, Italy and lead study investigator.

AGGRASTAT is not currently approved for use in STEMI patients or as adjunctive therapy in patients undergoing percutaneous coronary intervention (PCI).

In January of 2008, Iroko acquired all non-US commercial rights to AGGRASTAT® (tirofiban HCl) from Merck & Co., Inc.

"These positive data add to the growing body of evidence illustrating AGGRASTAT's potential role in the management of high-risk patients," said John Vavricka, President and Chief Executive Officer of Iroko Pharmaceuticals. "We look forward to further data which will reinforce the utility of AGGRASTAT in this patient type."

Multicentre Evaluation of Single High-Dose Bolus Tirofiban versus Abciximab with Sirolimus Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study (MULTISTRATEGY)

The open-label trial of 745 patients presenting with STEMI or new left bundle-branch block was conducted in 16 referral centers in Italy, Spain and Argentina from October 2004 to April 2007. Patients were randomly assigned with the use of a 2-by-2 factorial design to one of four interventional strategies: abciximab with an uncoated-stent, abciximab with a sirolimus-eluting stent, tirofiban with an uncoated-stent, or tirofiban with a sirolimus-eluting stent.

The study's primary end points included evaluating tirofiban's noninferiority to abciximab for cumulative ST-segment resolution, expressed as the proportion of patients that achieve at least 50 percent recovery within 90 minutes after intervention, as well as whether the sirolimus-stent is superior to uncoated-stent in terms of the composite of death from any cause, reinfarction and clinically-driven target vessel revascularization within the first 8 months. Secondary endpoints included each component of the composite end point, stent thrombosis and bleedings according to the criteria of the Thrombolysis in Myocardial Infarction (TIMI) trials.

Either tirofiban or abciximab was administered at first medical contact, before arterial sheath insertion. Tirofiban was given as a bolus of 25 μg/kg, followed by an 18-24 hour infusion at 0.15 μg/kg/min. Abciximab was administered as a bolus of 0.25 mg/kg, followed by a 12-hour infusion at 0.125 μg/kg/min. Stenting, either sirolimus-eluting or any uncoated-stent, was the default strategy in patients with a reference vessel diameter 2.5 mm at visual estimation. Crossover from a sirolimus-eluting stent to other stent types was allowed only after failure of a sirolimus-stent implantation attempt, or when there were no available stent sizes that matched the coronary reference diameter.
AGGRASTAT is not currently approved for use in STEMI patients or as adjunctive therapy in patients undergoing percutaneous coronary intervention (PCI).

About GP IIb/IIIa Antagonists

Platelets are blood cells that provide an early defense from the potential complications of vascular injury. When a blood vessel is damaged, platelets adhere to the site and promote blood clot formation. Clot formation prevents bleeding and recruits other cells to help heal the damage. While usually a beneficial process, these effects can be harmful when a clot forms on a ruptured lipid plaque within the coronary vasculature.

GP IIb/IIIa antagonists block the ability of platelets to aggregate, inhibiting clot formation and reducing the potential for cardiac ischemia. Over the last 8-10 years, several large-scale, placebo-controlled clinical trials have established the efficacy of intravenous GP IIb/IIIa inhibitors for patients with acute coronary syndrome who are medically managed or go to the cath lab.


Important Information about AGGRASTAT® Injection.

AGGRASTAT® is indicated for the prevention of early myocardial infarction in patients presenting with unstable angina or non-Q-wave myocardial infarction with the last episode of chest pain occurring within 12 hours and with ECG changes and/or elevated cardiac enzymes. Patients most likely to benefit from AGGRASTAT® treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA.

In most patients, AGGRASTAT® should be administered intravenously, at an initial rate of 0.4 mcg/kg/min for 30 minutes and then continued at 0.1 mcg/kg/min. For complete information, please refer to the product's prescribing information. AGGRASTAT® is intended for use with acetylsalicylic acid and unfractionated heparin.

AGGRASTAT® (tirofiban hydrochloride) is contraindicated in patients with known hypersensitivity to any component of the product; active internal bleeding or a history of bleeding diathesis within the previous 30 days; or a history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm. Other contraindications to AGGRASTAT® include: a history of thrombocytopenia following prior exposure to AGGRASTAT®; history of stroke within 30 days or any history of hemorrhagic stroke; major surgical procedure or severe physical trauma within the previous month; or history, symptoms, or findings suggestive of aortic dissection. AGGRASTAT® is also contraindicated in patients with: severe hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >110 mmHg); concomitant use of another parenteral GP IIb/IIIa inhibitor; or acute pericarditis.

Bleeding is the most common complication encountered during therapy with AGGRASTAT®. Administration of AGGRASTAT® is associated with an increase in bleeding events classified as both major and minor bleeding events, by criteria developed by the Thrombolysis in Myocardial Infarction Study group (TIMI). Most major bleeding associated with AGGRASTAT® occurs at the arterial access site for cardiac catheterization. Fatal bleedings have been reported. AGGRASTAT® should be used with caution in patients with platelet count <150,000/mm3, in patients with hemorrhagic retinopathy, and in chronic hemodialysis patients. Because AGGRASTAT® inhibits platelet aggregation; caution should be employed when it is used with other drugs that affect hemostasis. The safety of AGGRASTAT® when used in combination with thrombolytic agents has not been established. During therapy with AGGRASTAT®, patients should be monitored for potential bleeding. When bleeding cannot be controlled with pressure, infusion of AGGRASTAT® and heparin should be discontinued.

The following additional adverse reactions have been reported in post- marketing experience: bleeding, intracranial bleeding, retroperitoneal bleeding, hemopericardium, and pulmonary (alveolar) hemorrhage. Fatal bleedings have been reported; body as a whole: acute and/or severe decreases in platelet counts which may be associated with chills, low grade fever, or bleeding complications; hypersensitivity; rash and/or hives.

Please refer to the specific Prescribing Information for your country for complete warnings and precautions.

About Iroko

Iroko is a pharmaceutical company focused on acquiring, developing, and maximizing the potential of currently marketed pharmaceutical products on a worldwide basis. Iroko applies concentrated selling and marketing efforts and product life cycle management strategies focused on developing new and relevant formulations and indications that benefit patient health. For more information, visit www.iroko.com.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service.

For more information about AGGRASTAT®, visit www.iroko.com.

Dorland Global Public Relations

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