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New Drug Application Submitted for Ximelagatran

WILMINGTON, Del., December 23, 2003 /PRNewswire-FirstCall/ -- AstraZeneca announced today that it has submitted a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) seeking marketing clearance for its investigational oral direct thrombin inhibitor EXANTA (ximelagatran) for the prevention of venous thromboembolism (VTE) in patients undergoing knee- replacement surgery; for the prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF); and for the long-term secondary prevention of VTE after standard treatment for an episode of acute VTE.

AstraZeneca also announced that regulatory submissions for EXANTA have been made in Europe to the Reference Member State, France, as part of the Mutual Recognition Procedure for use of EXANTA in prevention of stroke and other thromboembolic complications associated with AF and the treatment of VTE.

The US submission is based on data from more than 30,000 patients enrolled in all clinical studies, including the landmark SPORTIF program, involving 7,329 patients in total, examining the use of EXANTA as an alternative to warfarin for the prevention of stroke in patients with nonvalvular atrial fibrillation. In the clinical trial program for EXANTA, more than 17,000 patients received EXANTA.

EXANTA is the first oral anticoagulant to reach late-stage clinical trials since the development of warfarin more than 50 years ago. The intended mechanism of action of EXANTA is to inhibit the activity of an enzyme called thrombin, which is critical to the final step in the formation of blood clots. Clinical studies with EXANTA utilize a fixed dose without coagulation monitoring.

About Stroke and AF
According to the American Heart Association, AF is found in about two million Americans and is a major risk factor for stroke. AF increases the risk of stroke five fold, accounting for about 15 percent of all strokes nationally.

The stroke rate among patients with AF averages about five percent per year, rising to almost 25 percent for those over the age of 80. Older patients with risk factors such as hypertension or diabetes are at increased risk. Patients with AF tend to have more serious first strokes compared to those without AF. The number of patients with AF is likely to increase by 2.5 times during the next 50 years, reflecting the growing elderly population.

In AF, the two small upper chambers of the heart, called the atria, quiver instead of beating effectively. Blood in these quivering chambers can pool and clot. If a section of the blood clot in the left atrium breaks off, travels to an artery in the brain and becomes lodged, a stroke may result.

The results of several prospective randomized stroke prevention trials show that the relative risk of stroke in AF patients can be reduced by 62 percent using oral anticoagulant therapy. Treatment guidelines of the American College of Chest Physicians and the combined guidelines of the American College of Cardiology, American Heart Association and the European Society of Cardiology recommend the use of warfarin for most AF patients. However, many eligible patients are not receiving oral anticoagulant therapy.

VTE, which includes deep-vein thrombosis and pulmonary embolism, is a term used to describe the formation of a clot in a vein. Each year in the United States, approximately two million people experience deep vein thrombosis (DVT), a condition where a clot forms in the deep veins, usually in the leg, impeding blood flow. Many conditions predispose patients to DVT and, according to the American Academy of Orthopaedic Surgeons, patients undergoing the more than 300,000 knee replacement surgeries in the United States each year are a group at high risk of developing DVT.

If a section of a clot in a patient with DVT breaks off, it may travel through the blood stream to the lungs and lodge in a pulmonary artery. This is known as pulmonary embolism (PE), a serious condition that can cause death. Approximately 600,000 PEs occur each year in the United States, and more than 10 percent of patients who develop a PE die from it.

The incidence of recurrent DVT or PE in patients treated with an anticoagulant for three months has been shown to range from 17.5 percent after two years to 25 percent after five years. These rates challenge the widely accepted use of short-course anticoagulation therapy in patients with symptomatic DVT.

Source: AstraZeneca

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