BRILINTA Significantly Reduced the Rate of the Composite of Stroke and Death in Patients Who Had an Acute Ischemic Stroke or Transient Ischemic Attack in the Phase III THALES Trial

WILMINGTON, Del.--(BUSINESS WIRE)--Detailed results from the positive Phase III THALES trial showed AstraZeneca’s BRILINTA^® (ticagrelor) 90mg used twice daily and taken with daily aspirin for 30 days, reduced the rate of the primary composite endpoint of stroke and death by 17% (HR 0.83 [95% CI 0.71, 0.96], p=0.02), compared to aspirin alone in patients who had an acute ischemic stroke or transient ischemic attack (TIA).

This was a statistically significant and clinically meaningful reduction. Furthermore, aspirin plus BRILINTA significantly reduced the rate of the first secondary endpoint of ischemic stroke by 21%, compared to aspirin alone up to day 30. The risk for severe bleeding events was 0.5% in the aspirin plus BRILINTA group and 0.1% in the aspirin group. The results were in line with the known safety profile of BRILINTA.

Dr. Clay Johnston, lead investigator for the THALES trial and Dean of the Dell Medical School at The University of Texas in Austin, US, said: “About one in four stroke survivors go on to experience a second stroke, and the risk is particularly high within the first month after the initial event. Early treatment is important to prevent a subsequent stroke that may be disabling or fatal. It is also expected to improve long-term outcomes.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “Patients who had an acute ischemic stroke or transient ischemic attack may experience a subsequent, potentially avoidable stroke. Results from the Phase III THALES trial confirm that aspirin plus BRILINTA has the potential to be a new effective treatment option for these high-risk patients and we look forward to continuing discussions with regulatory authorities.”

Key efficacy and safety data from the THALES trial

	Ticagrelor 90 mg BID (N=5523)		Placebo (N=5493)
Variable	Patients with events (%)	KM%	Patients with events (%)	KM%	Hazard ratio (95% CI) p-value
Composite of stroke/death:	303 (5.5)	5.4	362 (6.6)	6.5	0.83 (0.71, 0.96) p= 0.02
- Stroke	284 (5.1)	5.1	347 (6.3)	6.3	0.81 (0.69, 0.95)
- Death	36 (0.7)	0.6	27 (0.5)	0.5	1.33 (0.81, 2.19)
Ischemic Stroke (Secondary Endpoint)	276 (5.0)	5.0	345 (6.3)	6.2	0.79 (0.68, 0.93) p=0.004
Severe bleeding*	28 (0.5)	0.5	7 (0.1)	0.1	3.99 (1.74, 9.14)
Intracranial hemorrhage or fatal bleeding	22 (0.4)	0.4	6 (0.1)	0.1	3.66 (1.48, 9.02)
Fatal bleeding	11 (0.2)		2 (<0.1)

Results from the THALES trial were published in The New England Journal of Medicine.

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

This month, AstraZeneca announced that the Food and Drug Administration (FDA) accepted a supplemental New Drug Application (sNDA) and granted Priority Review for BRILINTA for the reduction of subsequent stroke in patients who experienced an acute ischemic stroke or transient ischemic attack (TIA) based on the phase III THALES trial. The Prescription Drug User Fee Act date, the FDA action date for this supplemental application, is scheduled for the fourth quarter of 2020.

BRILINTA is approved in more than 110 countries for the prevention of atherothrombotic events in adult patients with acute coronary syndrome (ACS) and in more than 70 countries for the secondary prevention of cardiovascular events among high-risk patients who have experienced a heart attack. In May 2020, the Food and Drug Administration (FDA) approved a label update for BRILINTA in the US to include the reduction of the risk of a first heart attack or stroke in high-risk patients with coronary artery disease

INDICATIONS

BRILINTA is indicated to reduce the risk of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction. For at least the first 12 months following ACS, it is superior to clopidogrel. BRILINTA also reduces the risk of stent thrombosis in patients who have been stented for treatment of ACS.

BRILINTA is indicated to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events. While use is not limited to this setting, the efficacy of ticagrelor was established in a population with type 2 diabetes.

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.

In patients with CAD but no prior stroke or MI, 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

WARNINGS:

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 more frequently with BRILINTA than in patients treated with control agents. Dyspnea 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. Clinical trials excluded patients at increased risk of bradyarrhythmias not protected by a pacemaker, and they may be at increased risk of developing bradyarrhythmias
• 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 (>5%) associated with the use of BRILINTA included bleeding and dyspnea

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.

Stroke

Stroke is the second leading cause of death worldwide, with 6.2 million stroke-related deaths in 2017, from which 2.7 million were due to ischemic stroke. Patients who experience an acute ischemic stroke or TIA are at high risk of developing subsequent ischemic events, with particularly high risk within 30 days after the initial event and the highest risk period being the first 24 hours after the initial event.

THALES

THALES is an AstraZeneca-sponsored, randomized, placebo-controlled, double-blinded, international, multicenter, event-driven trial involving more than 11,000 patients from 28 countries. It tested the hypothesis whether aspirin plus BRILINTA is superior to aspirin alone in preventing the composite of stroke and death in patients with non-cardioembolic 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, which includes fatal bleedings, intracranial hemorrhage; and bleeding causing hemodynamic compromise requiring intervention. Patients were followed for an additional 30 days on standard of care.

AstraZeneca in CV, Renal & Metabolism (CVMD)

CV, renal and 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 co-morbidities. 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.