AstraZeneca Announces Initiation of Development Program for BRILINTA (ticagrelor) Reversal Agent

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca (NYSE: AZN) today announced that it has begun a pre-clinical development program to evaluate the ability of investigational antibody, MEDI2452, to rapidly and specifically reverse the antiplatelet effects of ticagrelor in rare emergency situations such as urgent surgery, or in the event of major bleeding. MEDI2452 is being developed by MedImmune, AstraZeneca's biologics research and development arm.

"In certain emergencies, doctors need to have the option to swiftly reverse the effects of oral antiplatelet agents, in order to enable emergency surgery or a quick response to a major bleeding event without having to wait for the effects of the medicine to wear off. Currently there are no FDA approved medications to counteract the antiplatelet effect in these situations," said Marc Ditmarsch, Global Development Lead for BRILINTA. "If the circumstances demand it, we believe MEDI2452 has the potential to help address this need for patients treated with BRILINTA."

The development of MEDI2452 sits alongside the wider PARTHENON clinical program for ticagrelor, which includes five registration studies involving around 80,000 patients across the broad spectrum of atherothrombotic disease. The PEGASUS-TIMI 54 study, involving more than 21,000 patients, will be the next study within the program to complete, with top line results expected in the first quarter of 2015. PEGASUS-TIMI 54 aims to assess the efficacy and safety of ticagrelor on a background of low-dose aspirin, for the long-term prevention of atherothrombotic events in patients, aged 50 and older, who suffered a heart attack one to three years prior to study enrollment, and who have one additional cardiovascular risk factor.

"Current guidelines generally recommend 12 months of dual antiplatelet therapy following an acute coronary syndrome event, however atherothrombotic disease is a chronic, progressive and in some cases fatal condition," Marc Ditmarsch continued. "The PEGASUS trial will help us evaluate the potential long-term benefit of therapy with ticagrelor for the chronic condition. This will be important information for patients with a history of myocardial infarction and their physicians, to determine the management of their condition following a heart attack beyond 12 months."

The initiation of the development program for MEDI2452 comes ahead of the AHA Scientific Sessions taking place in Chicago from November 15-19, 2014. Nine abstracts will be presented across the AstraZeneca pipeline and marketed products at the meeting. AstraZeneca will also showcase its strength in cardiovascular and metabolic diseases as a core therapy area.

Data to be presented includes:

• Pharmacodynamic Profiles of Ticagrelor in Patients With ST-Elevation Myocardial Infarction: A Prospective Randomized Comparison of Escalating Loading Dose Regimens
  Board #6002, 9:00 a.m. – 5:00 p.m. CT, Sunday, November 16, 2014.

• The Effect of Omega-3 Fatty Acids on Apolipoprotein CIII Containing Lipoproteins in Moderate to Severe Hypertriglyceridemia
  Board #2254, 9:00 a.m. – 5:00 p.m. CT, Sunday, November 16, 2014.

• Lipoprotein Subclasses, Size, and Statin-Associated Incident Diabetes: An Analysis From the JUPITER Trial
  Board #2026, 9:00 a.m. – 5:00 p.m. CT, Monday, November 17, 2014.

The AHA Scientific Sessions come at a significant time for BRILINTA with the recent update to the AHA and American College of Cardiology guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), which will also be discussed at the meeting. The guidelines support differentiation among currently available P2Y12 inhibitors. In a Class IIa (LOE:B) recommendation, BRILINTA is now preferred over clopidogrel for the management of NSTE-ACS patients who undergo an early invasive. (angiography with intent for percutaneous coronary intervention, if appropriate), ischemia-guided (i.e., medically managed) strategy, or those who receive a coronary stent. The guidelines also include BRILINTA as a Class I (LOE:B) as a treatment option in the management of NSTE-ACS patients.

BRILINTA is indicated to reduce the rate of thrombotic cardiovascular (CV) events in patients with ACS (unstable angina [UA], non–ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). BRILINTA has been shown to reduce the rate of a combined end point of CV death, myocardial infarction (MI), or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with percutaneous coronary intervention (PCI), it also reduces the rate of stent thrombosis.

BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin > 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin > 100 mg daily.

BRILINTA is not approved for secondary prevention in patients with a history of previous MI.

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA (ticagrelor) tablets

WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

A. BLEEDING RISK

• BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding
• Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage
• Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery
• Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA
• If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

• Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg - 100 mg per day

CONTRAINDICATIONS

• BRILINTA is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins. BRILINTA is also contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product

WARNINGS AND PRECAUTIONS

• Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor
• Premature discontinuation increases the risk of MI, stent thrombosis, and death
• Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea resulting from BRILINTA is self-limiting. Rule out other causes
• BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers. Avoid simvastatin and lovastatin doses >40 mg
• Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy

ADVERSE REACTIONS

• The most commonly observed adverse reactions associated with the use of BRILINTA vs clopidogrel were Total Major Bleeding (11.6% vs 11.2%) and dyspnea (14% vs 8%)
• In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment

Please read full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1-800-FDA-1088.

Patients can find out more information about BRILINTA at www.BRILINTAtouchpoints.com or by calling 1-888-412-7454.

AstraZeneca offers the AZ&MeTM Prescription Savings Program. To determine eligibility, patients can visit www.AZandMe.com or call 1-800-AZandMe (292-6363).

NOTES TO EDITORS

About MEDI2452

MEDI2452 is a neutralising antibody that binds to ticagrelor and AR-C124910XX, the ticagrelor active metabolite, and is being investigated as an agent to reverse the antiplatelet effects of ticagrelor.

About BRILINTA® (ticagrelor) tablets

BRILINTA is an oral antiplatelet treatment for acute coronary syndrome (ACS). BRILINTA is a direct-acting P2Y12 receptor antagonist in a chemical class called cyclopentyltriazolopyrimidines (CPTPs), providing doctors with a different treatment option to the thienopyridine class of oral antiplatelets. BRILINTA works by inhibiting platelet activation and has been shown to reduce the rate of thrombotic CV events, such as a heart attack or CV death, in patients with ACS. The difference between treatments was driven by CV death and MI with no difference in stroke.

BRILINTA is a registered trademark of the AstraZeneca group of companies.

About Acute Coronary Syndrome (ACS)

ACS is an umbrella term for conditions that result from insufficient blood supply to the heart muscle. These conditions include unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). The conditions are defined by ECG changes and heart muscle enzyme leakage. Non–ST-elevation acute coronary syndrome (NSTE-ACS) includes unstable angina (UA) and non–ST-elevation myocardial infarction (NSTEMI); the term is usually used before heart muscle enzymes have been analyzed. The goal of treating ACS is to restore, improve, and/or stabilize blood flow to the heart muscle and to reduce the risk of recurrent cardiovascular (CV) events. Depending on the severity of the condition and the resources available, the patient will either be managed with medicines or undergo more invasive procedures. These procedures may include using catheters, balloons, and/or stents that treat the narrowed arteries of the heart called percutaneous coronary intervention (PCI) and/or a type of surgery that improves blood flow to the heart called coronary artery bypass grafting (CABG).

About the PARTHENON Program

AstraZeneca is currently collaborating with over 4,000 clinical investigators in more than 30 countries as part of the PARTHENON program, and has established partnerships with a number of pre-eminent research institutions. In addition to PEGASUS; EUCLID, SOCRATES and THEMIS, are other ongoing studies for the treatment of patients with peripheral arterial disease (PAD), ischemic stroke and transient ischemic attack (TIA) and for the prevention of CV events in patients with diabetes and coronary atherosclerosis.

BRILINTA is currently not approved for the treatment of patients with ischemic stroke, TIA, PAD, for the prevention of CV events in patients with diabetes and coronary atherosclerosis, or for secondary prevention in patients with a history of previous MI.

About MedImmune

MedImmune is the global biologics research and development arm of AstraZeneca. MedImmune is pioneering innovative research and exploring novel pathways across key therapeutic areas, including respiratory, inflammation and autoimmunity; cardiovascular and metabolic disease; oncology; neuroscience; and infection and vaccines. The MedImmune headquarters is located in Gaithersburg, Md., one of AstraZeneca's three global R&D centers. For more information, please visit www.medimmune.com.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com

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