BRILINTA Met Primary Endpoint in the Phase III THALES Trial in Stroke

High-level results from the Phase III THALES trial showed AstraZeneca's BRILINTA (ticagrelor) 90 mg used twice daily and taken with aspirin for 30 days, reached a statistically significant and clinically meaningful reduction in the risk of the primary composite endpoint of stroke and death, compared to aspirin alone.

THALES was conducted in over 11,000 patients who had a minor acute ischemic stroke or high-risk transient ischemic attack (TIA) in the 24 hours prior to treatment initiation. The preliminary safety findings in the THALES trial were consistent with the known profile of BRILINTA, with an increased bleeding rate in the treatment arm.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: "Results of the Phase III THALES trial showed BRILINTA, in combination with aspirin, improved outcomes in patients who had experienced a minor acute ischemic stroke or high-risk transient ischemic attack. We look forward to sharing the detailed results with health authorities."

Dr. Clay Johnston, lead investigator for the THALES trial and Dean of the Dell Medical School at The University of Texas at Austin, said: "The risk of having a subsequent stroke is highest in the first few days and weeks after a minor acute ischemic stroke or high-risk transient ischemic attack. While an expected increase in bleeding was observed, the findings from THALES showed that BRILINTA, in combination with aspirin, reduced the risk of potentially devastating events in this crucial time."

The full THALES trial results will be presented at a forthcoming medical meeting.

BRILINTA is not indicated in patients with minor acute ischemic stroke or high-risk transient ischemic attack.

BRILINTA is indicated to reduce the rate of CV death, myocardial infarction (MI), and stroke in patients with ACS or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel.

BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

Dosing: In the management of ACS, initiate BRILINTA treatment with a 180-mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily. Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg.

IMPORTANT SAFETY INFORMATION FOR BRILINTA® (ticagrelor) 60-MG AND 90-MG 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 undergoing urgent coronary artery bypass graft surgery
• 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

CONTRAINDICATIONS

• BRILINTA is contraindicated in patients with a history of intracranial hemorrhage or active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is also contraindicated in patients with hypersensitivity (eg, angioedema) to ticagrelor or any component of the product

WARNINGS AND PRECAUTIONS

• Dyspnea was reported in about 14% of patients treated with BRILINTA, more frequently than in patients treated with control agents. Dyspnea resulting from BRILINTA is often self-limiting
• Discontinuation of BRILINTA will increase the risk of MI, stroke, and death. When possible, interrupt therapy with BRILINTA for 5 days prior to surgery that has a major risk of bleeding. If BRILINTA must be temporarily discontinued, restart as soon as possible
• Ticagrelor can cause ventricular pauses. Bradyarrhythmias including AV block have been reported in the post-marketing setting. PLATO and PEGASUS excluded patients at increased risk of bradyarrhythmias not protected by a pacemaker, and they may be at increased risk of developing bradyarrhythmias with ticagrelor
• Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor and there are no studies of BRILINTA in these patients
• In patients with Heparin Induced Thrombocytopenia (HIT): False negative results for HIT-related platelet functional tests, including the heparin-induced platelet aggregation (HIPA) assay, have been reported with BRILINTA. BRILINTA is not expected to impact PF4 antibody testing for HIT

ADVERSE REACTIONS

• The most common adverse reactions associated with the use of BRILINTA included bleeding and dyspnea: In PLATO, for BRILINTA vs clopidogrel, non-CABG PLATO-defined major bleeding (3.9% vs 3.3%) and dyspnea (14% vs 8%); in PEGASUS, BRILINTA vs aspirin alone, TIMI Total Major bleeding (1.7% vs 0.8%) and dyspnea (14% vs 6%)

DRUG INTERACTIONS

• Avoid use with strong CYP3A inhibitors and strong CYP3A inducers. BRILINTA is metabolized by CYP3A4/5. Strong inhibitors substantially increase ticagrelor exposure and so increase the risk of adverse events. Strong inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor
• As with other oral P2Y₁₂ inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor. Consider use of a parenteral anti-platelet in ACS patients requiring co-administration
• Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse events
• Monitor digoxin levels with initiation of, or change in, BRILINTA therapy

SPECIAL POPULATIONS

• Lactation: Breastfeeding not recommended

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

NOTES TO EDITORS

About THALES

THALES is an AstraZeneca-sponsored, randomized, placebo-controlled, double-blinded, international, multicenter, event-driven trial involving more than 11,000 patients to test the hypothesis whether BRILINTA and aspirin is superior to aspirin alone in preventing the composite of stroke and death in patients with minor acute ischemic stroke or high-risk TIA. Patients were randomized within 24 hours of onset of acute ischemic stroke or high-risk TIA symptoms and followed-up for 30 days of treatment. Trial treatments were BRILINTA 180mg loading dose on day 1 as soon as possible after randomization, followed by 90mg twice daily on days 2?30, or matching placebo. All patients received open-label aspirin 300?325mg on day 1, followed by 75?100mg once daily on days 2?30. The primary efficacy outcome was the time to the composite endpoint of stroke and death at 30 days. The primary safety outcome is time to first severe bleeding event according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) definition. Patients were followed for an additional 30 days on standard of care.

About BRILINTA

BRILINTA (ticagrelor) is an oral, reversible, direct-acting P2Y₁₂ receptor antagonist that works by inhibiting platelet activation. BRILINTA, together with aspirin, has been shown to significantly reduce the risk of major adverse cardiovascular events (myocardial infarction [MI], stroke or CV death) in patients with acute coronary syndrome (ACS) or a history of MI.

About AstraZeneca in CVMD

CV, renal & metabolism together form one of AstraZeneca's main therapy areas and a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling comorbidities. Our ambition is to modify or halt the natural course of CVMD diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

US-35105 Last updated 1/20