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New Data Suggests Results of PLATO Genetic Sub-Study Outcomes for BRILINTA® (Ticagrelor) Not Driven by Poor Metabolizers of Clopidogrel

Sunday, March 25, 2012

New Data Suggests Results of PLATO Genetic Sub-Study Outcomes for BRILINTA® (Ticagrelor) Not Driven by Poor Metabolizers of Clopidogrel11:00 EDT Sunday, March 25, 2012 CHICAGO (Business Wire) -- AstraZeneca (NYSE: AZN) today announced results from a sub-analysis of the PLATO genetic sub-study that evaluated the impact of poor metabolizers of clopidogrel. Data suggests results were consistent with the overall outcome of the PLATO study, with BRILINTA (ticagrelor) compared to clopidogrel, even after poor clopidogrel metabolizers were excluded. Results of this sub-analysis were presented today at the American College of Cardiology Scientific Sessions (ACC), in Chicago, Ill. “These data suggest the robust results in PLATO were not driven by the poor metabolizers of clopidogrel,” said Alex Gold, MD, Executive Director of Clinical Development, BRILINTA, AstraZeneca. “In the analysis, after excluding poor metabolizers, the remaining majority of patients showed a result consistent with the overall outcome of the PLATO study.” A poor metabolizer to clopidogrel is defined as a patient with two loss-of-function (LOF) CYP2C19 alleles, one of the main genetic factors affecting the conversion of clopidogrel to its active form. In this sub-analysis, 10,285 DNA samples from patients in the PLATO trial, (which randomized 18,624 ACS patients to ticagrelor or clopidogrel for 6 – 12 months), underwent CYP2C19 genotyping for wildtype (*1); LOF alleles *2, *3, *4, *5, *6, *7, & *8; and gain of function allele *17. Patients with any combination of two LOF alleles were denoted as a poor metabolizer. Analysis of PLATO primary efficacy and safety outcomes were conducted after excluding poor metabolizers from both treatment groups. Below are the results from the sub-analysis: After removal of poor metabolizers (121 of 5,137 ticagrelor patients; 125 of 5,148 clopidogrel patients), the remaining non-poor metabolizers cohort (n=10,039) showed a reduction in the primary endpoint consistent with overall results of the PLATO study with ticagrelor compared to clopidogrel at 12 months (8.8% vs 10.4 %; hazard ratio [HR] 0.85, 95% confidence interval 0.74-0.96, P=0.01) Rates of total major bleeding at 12 months did not differ between treatment groups, 10.7%; non-CABG major bleeding trended higher with ticagrelor (4.0%) than with clopidogrel (3.3%) Ticagrelor similarly reduced the primary endpoint in the poor metabolizers group at 12 months (8.8% vs 9.7%, HR=0.87), although there were only 22 events in this very small subgroup of patients These data suggest that the effects of BRILINTA compared to clopidogrel on thrombotic events and bleeding were not affected by CYP2C19 genotype, and data suggests results were consistent with the overall outcomes of the PLATO study, regardless of the 2C19 clopidogrel genetic metabolizer status in patients with ACS. BRILINTA is indicated to reduce the rate of thrombotic cardiovascular 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, 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 an artery-opening procedure known as percutaneous coronary intervention (PCI), BRILINTA reduces the rate of stent thrombosis. BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily. IMPORTANT SAFETY INFORMATION ABOUT BRILINTAWARNING: BLEEDING RISKBRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleedingDo not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhageDo 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 surgerySuspect 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 BRILINTAIf possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular eventsWARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESSMaintenance 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 dayCONTRAINDICATIONS BRILINTA is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is also 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 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. This information can be found at www.brilintatouchpoints.com. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. ABOUT PLATO The PLATO trial was a large (18,624 patients in 43 countries) head-to-head outcomes study of ticagrelor versus clopidogrel, both given in combination with aspirin and other standard therapy, designed to establish whether ticagrelor could achieve a clinically meaningful reduction in cardiovascular end points in ACS patients, above and beyond those afforded by clopidogrel. The PLATO study demonstrated that treatment with BRILINTA led to a greater reduction in the primary end point – a composite of CV death, MI, or stroke – compared to patients who received clopidogrel (9.8% vs 11.7% at 12 months; 1.9% absolute risk reduction [ARR]; 16% relative risk reduction [RRR]; 95% CI, 0.77 to 0.92; P<0.001). The difference in treatments was driven by CV death and MI with no difference in stroke. In PLATO, the absolute difference in treatment benefit versus clopidogrel was seen at 30 days and the Kaplan-Meier survival curves continue to diverge throughout the 12-month treatment period. It's important to know that BRILINTA does have a Boxed Warning for bleeding risks. BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding. In addition, BRILINTA has a Boxed Warning concerning 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. The PLATO study also demonstrated that treatment with BRILINTA for 12 months was associated with a 21 percent RRR in CV death (4% vs 5.1%; 1.1% ARR; P=0.001) and a 16 percent RRR in MI compared to clopidogrel at 12 months (5.8% vs 6.9%; 1.1% ARR; P<0.005). The primary safety end point in the PLATO study was Total Major Bleeding (11.6% for BRILINTA and 11.2% for clopidogrel). In PLATO, non-CABG (coronary artery bypass graft) major + minor bleeding events (8.7% vs. 7%) were more common with BRILINTA versus clopidogrel. The rate of non–CABG-related major bleeding was higher for BRILINTA (4.5%) vs clopidogrel (3.8%). In a post hoc analysis of PLATO, it was determined that more than 80 percent of patients worldwide, with approximately 40 percent of patients in the US, received low maintenance doses of aspirin (100 mg or less). Results for US and non-US patients taking BRILINTA with these low maintenance doses of aspirin were similar. As with any unplanned subset analysis, the post hoc analysis should be treated with caution. Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. The PI states that maintenance doses of aspirin above 100mg reduce the effectiveness of BRILINTA, and should be avoided. After any initial dose, BRILINTA should be used with maintenance aspirin doses of 75 mg - 100 mg per day. About BRILINTA (ticagrelor) tablets BRILINTA is an oral antiplatelet treatment for acute coronary syndrome (ACS) in a new chemical class called cyclopentyltriazolopyrimidines (CPTPs). BRILINTA works by inhibiting platelet activation and has been shown to reduce the rate of thrombotic cardiovascular events, such as a heart attack or cardiovascular death, in patients with ACS. BRILINTA is a reversibly binding oral platelet P2Y12 adenosine diphosphate (ADP) receptor antagonist. BRILINTA is available in 90-mg tablets to be administered with a single 180-mg oral loading dose (two 90-mg tablets) followed by a twice daily, 90-mg maintenance dose. Following an initial loading dose of aspirin, BRILINTA should be used with a maintenance dose of 75 mg - 100 mg aspirin once daily, 81-mg aspirin dose in the US. BRILINTA is a 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 range from unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI), or ST-elevation myocardial infarction (STEMI). NOTES TO EDITORSAbout AstraZeneca AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information about AstraZeneca in the US or our AZ&Me™ Prescription Savings programs, please visit: www.astrazeneca-us.com or call 1-800-AZandMe (292-6363). 1687000 3/12 AstraZenecaMedia Inquiries USStephanie Jacobson, +1 302-885-5924mob. +1 302-379-0443orJulia Walker, +1 302-885-5172mob. +1 610-350-8240orInvestor EnquiriesEd Seage, +1 302-886-4065mob: +1 302-373-1361orJorgen Winroth, +1 212-579-0506mob: +1 917-612-4043