AstraZeneca to Showcase Leadership in Treating Type 2 Diabetes and Cardiorenal Complications at ADA 2020

• Exploratory analysis from FARXIGA DAPA-HF Phase III trial will provide insights on the onset of type 2 diabetes in heart failure patients
• Sub-analyses from the DECLARE Phase III trial to highlight FARXIGA’s effect on fast renal decline

WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca will present new data from the landmark Phase III DAPA-HF and DECLARE-TIMI 58 trials at the upcoming 80^th American Diabetes Association (ADA) Virtual Scientific Sessions, June 12 – 16 2020. The data are among 23 accepted abstracts, including four oral presentations, covering trials that showcase the depth and breadth of potential cardio, renal and metabolic benefits for patients across AstraZeneca’s portfolio.

Highlights include:

• An oral presentation of data from the DAPA-HF trial showing the effect of FARXIGA® (dapagliflozin) on the incidence of new onset of type 2 diabetes (T2D) in patients with heart failure and reduced ejection fraction (HFrEF) (Abstract #271-OR)¹
• New sub analyses from the DECLARE-TIMI 58 trial, presented orally, providing insights on FARXIGA’s effect on fast kidney function decline in T2D patients with established or increased risk for cardiovascular disease (Abstract #303-OR)²
• An analysis of the DAPA-HF trial examining if background T2D therapy impacts the benefits of FARXIGA in heart failure (HF) (Abstract #1112-P)³
• A new analysis of the global observational DISCOVER real world evidence study, presented orally, reporting health-related quality of life factors in patients with T2D initiating a second-line glucose-lowering therapy (Abstract #40-OR)⁴
• An oral presentation of new Phase II data on investigational cotadutide, a dual receptor agonist with balanced GLP-1 and glucagon activity, showing positive effect on blood glucose levels and changes in liver fat and glycogen stores in patients with T2D (Abstract #354-OR)⁵
• BRILINTA® (ticagrelor) data on duration of T2D, baseline HbA1c levels as well as the impact of blood sugar-lowering background therapies on outcomes in T2D patients with coronary artery disease (THEMIS diabetes subgroup) (Abstract #403-P)⁶

Ruud Dobber, Executive Vice President, BioPharmaceuticals Business Unit, said: “An overwhelming majority of people with type 2 diabetes also have at least one other cardiovascular, renal or metabolic disease. The breadth and depth of data we are presenting at ADA 2020 demonstrates our commitment to developing treatment options for patients living with diabetes that go beyond glycemic control to also protect the heart, liver and kidneys.”

In addition to its robust clinical data, AstraZeneca will also present results from a global survey of more than 1,600 physicians in 18 countries examining primary care approaches and clinical inertia in the treatment of patients with T2D.

Key abstracts and other notable abstracts to be presented at ADA:

INDICATIONS AND LIMITATIONS OF USE for FARXIGA^® (dapagliflozin)

FARXIGA is indicated:

• as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
• to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple CV risk factors
• to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction

FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION for FARXIGA^® (dapagliflozin) 5 mg and 10 mg tablets

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) being treated for glycemic control without established CV disease or multiple CV risk factors
• Patients on dialysis

Warnings and Precautions

• Volume Depletion: FARXIGA can cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine. Acute kidney injury requiring hospitalization and dialysis has been reported in patients with type 2 diabetes receiving SGLT2 inhibitors, including FARXIGA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating FARXIGA in these patients, assess volume status and renal function. After initiating therapy, monitor for signs and symptoms of hypotension and renal function
• Ketoacidosis in Diabetes Mellitus has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. Some cases were fatal. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue FARXIGA, evaluate and treat promptly. Before initiating FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis
• Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the risk for urinary tract infections (UTIs) and serious UTIs have been reported with FARXIGA. Evaluate for signs and symptoms of UTIs and treat promptly
• Hypoglycemia: FARXIGA can increase the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with FARXIGA
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Rare but serious, life-threatening cases have been reported in patients with diabetes mellitus receiving SGLT2 inhibitors including FARXIGA. Cases have been reported in females and males. Serious outcomes have included hospitalization, surgeries, and death. Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue FARXIGA
• Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately

Adverse Reactions

In a pool of 12 placebo-controlled studies, the most common adverse reactions (≥5%) associated with FARXIGA 5 mg, 10 mg, and placebo respectively were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).

Use in Specific Populations

• Pregnancy: Advise females of potential risk to a fetus especially during the second and third trimesters
• Lactation: FARXIGA is not recommended when breastfeeding

DOSING

• To improve glycemic control in patients with T2D, the recommended starting dose of FARXIGA is 5 mg orally once daily, taken in the morning. In patients tolerating FARXIGA 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily
• To reduce the risk of hospitalization for heart failure in patients with T2D and established CV disease or multiple CV risk factors, the recommended dose of FARXIGA is 10 mg orally once daily
• To reduce the risk of CV death and hospitalization for heart failure in patients with HFrEF, the recommended dose of FARXIGA is 10 mg orally once daily

Please see accompanying US Full Prescribing Information and Medication Guide for FARXIGA.

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.

INDICATION AND LIMITATIONS OF USE

BYDUREON BCise is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

• Not recommended as first-line therapy for patients inadequately controlled on diet and exercise
• Not a substitute for insulin. Should not be used to treat type 1 diabetes or diabetic ketoacidosis
• Use with prandial insulin has not been studied
• Do not coadminister with other exenatide-containing products
• Not studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF THYROID C-CELL TUMORS

• Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared to controls. It is unknown whether BYDUREON BCise causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC) in humans, as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors has not been determined
• BYDUREON BCise is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with the use of BYDUREON BCise and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for detection of MTC in patients treated with BYDUREON BCise

CONTRAINDICATIONS

• Personal or family history of MTC, patients with MEN 2
• Prior serious hypersensitivity reactions to exenatide or product components
• History of drug-induced, immune-mediated thrombocytopenia from exenatide products

WARNINGS AND PRECAUTIONS

• Acute Pancreatitis including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been reported. After initiation, observe patients carefully for symptoms of pancreatitis. If suspected, discontinue promptly and do not restart if confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis
• Hypoglycemia Risk of hypoglycemia is increased when exenatide is coadministered with insulin or insulin secretagogues. Consider lowering the dose of these agents when coadministered with BYDUREON BCise
• Acute Kidney Injury May induce nausea and vomiting with transient hypovolemia and may worsen renal function. Increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis and kidney transplantation have been reported. Not recommended in patients with eGFR <45 mL/min/1.73 m²
• Gastrointestinal Disease Because exenatide is commonly associated with gastrointestinal adverse reactions, not recommended in patients with severe gastrointestinal disease (eg, gastroparesis)
• Immunogenicity Patients may develop antibodies to exenatide. Patients with higher titer antibodies may have an attenuated HbA1c response. In clinical trials, attenuated glycemic response was associated with BYDUREON BCise-treated patients. If worsening of or failure to achieve adequate glycemic control occurs, consider alternative antidiabetic therapy
• Hypersensitivity Reports of serious hypersensitivity reactions (eg, anaphylaxis and angioedema). If this occurs, patients should discontinue BYDUREON BCise and promptly seek medical advice
• Drug-induced, immune-mediated thrombocytopenia and associated bleeding has been reported with exenatide. Serious bleeding, which may be fatal, has been reported. Discontinue promptly if suspected and avoid re-exposure to exenatide

• Injection-Site Reactions Serious reactions (eg, abscess, cellulitis, and necrosis), with or without subcutaneous nodules, have been reported
• Acute Gallbladder Disease has been reported in GLP-1 receptor agonist trials, including exenatide. If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated

ADVERSE REACTIONS

Most common (≥5%) in clinical trials: injection-site nodule (10.5%), nausea (8.2%).

DRUG INTERACTIONS

• Oral Medications BYDUREON BCise slows gastric emptying and may reduce the rate of absorption of orally administered drugs
• Warfarin Increased international normalized ratio (INR) sometimes associated with bleeding has been reported with concomitant use of exenatide with warfarin. Monitor INR frequently until stable upon initiation of BYDUREON BCise

PREGNANCY

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Please see full Prescribing Information, including Boxed WARNINGS, for BYDUREON, and BYDUREON BCise.

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.

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