AZN AstraZeneca PLC

Key data evaluating the efficacy and safety of dapagliflozin in combination with other type 2 diabetes therapies head-to-head vs. insulin or sulfonylurea

Latest data from the DEPICT clinical program evaluating dapagliflozin to address an unmet need for oral therapy in adult patients with type 1 diabetes

Debut of pre-clinical and clinical data for MEDI0382 in type 2 diabetes, a potential first-in-class oxyntomodulin-like peptide

AstraZeneca and its global biologics research and development arm, MedImmune, will present 45 abstracts including seven late-breaking data disclosures from the Company’s Cardiovascular (CV), Renal and Metabolism (CVRM) therapy area at the American Diabetes Association’s (ADA) 78th Scientific Sessions in Orlando, Florida, June 22-26, 2018.

This latest research will help to inform clinical practice with FARXIGA® (dapagliflozin) and BYDUREON® (exenatide extended-release) in type 2 diabetes (T2D), including data on their use alone and in combination with other diabetes therapies. Highlights also include data on the potential new use of dapagliflozin in type 1 diabetes (T1D) and the debut of pre-clinical and clinical data for MEDI0382, an oxyntomodulin-like peptide and potential new medicine. MEDI0382 has the potential to be a first- in- class therapy and is the latest candidate to advance in the Company’s CVRM pipeline.

Commenting on AstraZeneca’s scientific approach in CVRM, Ludovic Helfgott, Vice President, Cardiovascular, Renal and Metabolism, said: “At ADA this year, we are sharing data on novel approaches and potential new medicines as we continue to advance treatments for patients with diabetes. At AstraZeneca, we recognize the critical interconnectivity between cardiovascular, renal and metabolic diseases, and aim to deliver leading science that addresses patient needs across the global burden of these conditions.”

Clinical and real-world evidence data further evaluating dapagliflozin in T2D

Highlights include several abstracts evaluating the effects of dapagliflozin on glycemic control and additional endpoints, including blood pressure and body weight, alone and in combination with other diabetes treatments across a broad range of patients. Dapagliflozin is not indicated for weight loss or for the treatment of hypertension.

Presentations assessing the combination of dapagliflozin and saxagliptin, include 24-week results of dapagliflozin as add- on therapy to saxagliptin, in addition to metformin compared with insulin in patients with or without sulfonylurea therapy.

AstraZeneca will also present long-term data from the DURATION-8 trial over 104 weeks (Late-breaking Poster 104-LB), which evaluated the efficacy and safety of dapagliflozin once daily in combination with weekly exenatide extended-release vs. each treatment alone.

New analyses from the EXSCEL (Exenatide Study of Cardiovascular Event Lowering) CV outcomes trial will be presented in a late breaking poster which will evaluate the CV and renal effects in patients that received SGLT-2 inhibitor (SGLT-2i) in the placebo group, and a moderated poster will provide insights on the renal outcomes observed with exenatide extended-release. Exenatide extended-release and dapagliflozin are not indicated to reduce the risk of cardiovascular or renal outcomes.

A new analysis of the landmark CVD-REAL study presented as a late-breaking poster, comparing the risk of all-cause mortality, hospitalization for heart failure (hHF), myocardial infarction and stroke in patients with T2D starting treatment with dapagliflozin vs. any DPP-4 inhibitor, based on data from Canada, Israel, Japan and South Korea. CVD-REAL provides real-world evidence of dapagliflozin on these CV outcomes, while DECLARE (Dapagliflozin Effect on CardiovascuLAR Events) will evaluate the CV efficacy and safety of dapagliflozin in the largest SGLT-2i CV outcomes trial in a broad range of patients with T2D, including those with multiple CV risk factors or established CV disease. The trial is anticipated to read out in the second half of 2018. Dapagliflozin is not indicated to reduce the risk of death, hospitalization for heart failure, or CV outcomes.

Data evaluating the potential of dapagliflozin to address an unmet need in patients with T1D

Currently, there are no oral treatment options approved for adult patients with T1D. The latest data from the DEPICT (Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes) clinical program will include results on the efficacy and safety of dapagliflozin as add on to insulin over 52 weeks (from DEPICT-1) and 24 weeks (from DEPICT-2), as well as a pooled analyses of continuous glucose monitoring (CGM) data from both trials. Dapagliflozin is not approved for T1D.

First pre-clinical and clinical data for MEDI0382 in T2D

From the Company’s promising CVRM pipeline, MedImmune will present primary results from its MEDI0382 Phase 2a trial. MEDI0382 is an oxyntomodulin-like peptide and potential new medicine designed to simultaneously activate the glucagon-like peptide 1 (GLP-1) and glucagon (GLU) receptors, with the goals of achieving glucose control, reduced body weight and increased energy expenditure in patients with T2D. Oxyntomodulin is a peptide hormone released from the gut that targets the GLP-1 and glucagon receptors, both of which are critical to controlling metabolic functions. In addition, two oral presentations will feature data on the effects of MEDI0382 on hepatic (liver) fat in patients with T2D, and its effects on pancreatic and incretin hormones, respectively.

Details of the key abstracts from AstraZeneca/MedImmune are as follows:

        Abstract title     Presentation details Short-term and long-term data for dapagliflozin in combination with other T2D therapies Effect of Dapagliflozin Plus Saxagliptin vs. Insulin Glargine on A1C in patients With Type-2 Diabetes Inadequately Controlled by Metformin with or without Sulfonylurea     Oral 260-OR, Monday, June 25, 09:30 - 09:45 EDT Dapagliflozin Plus Saxagliptin Add-On vs. Glimepiride Add-On to Metformin in Patients with Poorly Controlled Type-2 Diabetes     Oral 261-OR, Monday, June 25, 09:45 - 10:00 EDT Durability of Glycemic Control with Dapagliflozin vs Saxagliptin in Patients with Inadequately Controlled Type-2 Diabetes     Poster 1181-P, Sunday, June 24, 12:00 - 13:00 EDT Triple vs. Dual Therapy with Low-Dose Dapagliflozin Plus Saxagliptin vs. Each Monocomponent Added to Metformin in Uncontrolled Type-2 Diabetes     Poster 1149-P, Sunday, June 24, 12:00 - 13:00 EDT DURATION-8 Randomized Controlled Trial 104-Week Results: Once-Weekly Exenatide (ExQW) Plus Once-Daily Dapagliflozin (DAPA) Versus ExQW or DAPA Alone     Late-breaking Poster 104-LB, Monday, June 25, 12:00 - 13:00 EDT   Analyses of renal and SGLT-2i outcomes in the EXSCEL trial Impact of SGLT2 Inhibitors (SGLT2i) on Cardiovascular (CV) Risk and Estimated Glomerular Filtration Rate (eGFR) in the EXSCEL Placebo Group     Late-breaking Poster 130-LB, Monday, June 25, 12:00 - 13:00 EDT Renal Outcomes in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL)     Poster 522-P, General Session, Saturday, June 23, 11:30 - 12:30 EDT and Moderated Poster Session, Monday, June 25, 12:00 - 13:00 EDT   Real-world evidence evaluating CV outcomes with SGLT2i vs. DPP-4 Analysis of Risk of CV Events and Death Associated with Initiation of SGLT-2 vs. DPP-4 Inhibitors from the CVD-REAL 2 Study     Late-breaking Poster 124-LB, Monday, June 25, 12:00 - 13:00 EDT   Short-term and long-term data for dapagliflozin in T1D Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type-1 Diabetes: DEPICT-2 Study     Oral 213-OR, Sunday, June 24, 16:00 EDT Long-Term Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type-1 Diabetes: The DEPICT-1 Study     Late-breaking Poster 119-LB, Monday, June 25, 12:00 - 13:00 EDT Glucose Variables in T1D Studies with Dapagliflozin: Pooled Analysis of Continuous Glucose Monitoring Data from DEPICT-1 and 2     Late-breaking Poster 125-LB, Monday, June 25, 12:00 - 13:00 EDT   Clinical and pre-clinical data for MEDI0382, a novel oxyntomodulin-like (OXM) peptide Effect of MEDI0382 on Hepatic Fat Content in Subjects with Type-2 Diabetes Mellitus     Oral 78-OR, Saturday, June 23, 08:00 - 10:00 EDT Effects of MEDI0382 on Insulin, Glucagon and Incretin Hormone Profiles     Oral 79-OR, Saturday, June 23, 08:00 - 10:00 EDT Evaluation of Glucose Control and Weight Loss with MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, in a 6-week Phase 2A Study of T2DM Subjects     Poster 1067-P, Sunday, June 24, 12:00 PM - 13:00 EDT   Latest analyses of the leading global diabetes registries Vascular Events in Patients with Type-2 Diabetes in the Year Following Initiation of Second-line Therapy: the DISCOVER Study     Poster 1562-P, Sunday, June 24, 12:00-13:00 EDT Composite Cardiovascular Risk Factor Target Achievement and its Indicators in US Adults with Diabetes: The Diabetes Collaborative Registry     Poster 1487-P, Sunday, June 24, 12:00 - 13:00 EDT   CV outcomes and mortality in T2D with associated CV, renal and metabolic co-morbidities Cardiovascular Outcomes and Mortality in Type-2 Diabetes with Associated Cardio-Renal-Metabolic Co-Morbidities     Poster 1582-P, Sunday, June 24, 12:00 - 13:00 EDT    

The full list of AstraZeneca/MedImmune scientific data can be accessed on the ADA website here. You can also follow us live during ADA 2018 on Twitter.

INDICATION AND LIMITATIONS OF USE FOR FARXIGA (dapagliflozin) tablets 5 mg and 10 mg

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

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

Please read US Full Prescribing Information and Medication Guide for FARXIGA.

IMPORTANT SAFETY INFORMATION FOR FARXIGA

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Severe renal impairment (eGFR <30 mL/min/1.73 m2), end-stage renal disease, or patients on dialysis

Warnings and Precautions

• Hypotension: FARXIGA causes intravascular volume contraction, and symptomatic hypotension can occur. Assess and correct volume status before initiating FARXIGA in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for hypotension
• Ketoacidosis 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
• Acute Kidney Injury and Impairment in Renal Function: FARXIGA causes intravascular volume contraction and renal impairment, with reports of acute kidney injury requiring hospitalization and dialysis. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat.FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating FARXIGA, evaluate renal function and monitor periodically. FARXIGA is not recommended in patients with an eGFR persistently between 30 and <60 mL/min/1.73 m2

• 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
• Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur with FARXIGA. Monitor LDL-C and treat per standard of care
• Bladder cancer: An imbalance in bladder cancers was observed in clinical trials. There were too few cases to determine whether the emergence of these events is related to FARXIGA, and insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. FARXIGA should not be used in patients with active bladder cancer. Use with caution in patients with a history of bladder cancer
• Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA

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

INDICATION AND LIMITATIONS OF USE FOR BYDUREON® (exenatide extended-release) for injectable suspension 2mg

BYDUREON and BYDUREON BCise are both 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
• Not recommended for use with insulin
• 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 ABOUT BYDUREON AND BYDUREON BCISE, INCLUDING BOXED WARNING

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 or BYDUREON BCise cause 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 and BYDUREON BCise are 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 or 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 or BYDUREON BCise

CONTRAINDICATIONS

• Personal or family history of MTC, patients with MEN 2
• Prior serious hypersensitivity reactions to exenatide or product components

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 or BYDUREON BCise
• Acute Kidney Injury and Impairment of Renal Function Altered renal function, including 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 severe renal impairment or end-stage renal disease. Use caution in patients with renal transplantation or moderate renal impairment
• 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- or 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 or BYDUREON BCise and promptly seek medical advice
• Injection-Site Reactions Serious reactions (eg, abscess, cellulitis, and necrosis), with or without subcutaneous nodules, have been reported
• Macrovascular Outcomes No clinical studies establishing conclusive evidence of macrovascular risk reduction with exenatide

ADVERSE REACTIONS

• Most common (≥5%) and occurring more frequently than comparator in BYDUREON clinical trials: nausea (16.9%), diarrhea (12.7%), headache (8.0%), vomiting (6.8%), constipation (5.9%), injection-site pruritus (5.9%), injection-site nodule (5.3%), dyspepsia (5.1%)
• Most common (≥5%) in BYDUREON BCise clinical trials: injection-site nodule (10.5%), nausea (8.2%)

DRUG INTERACTIONS

• Oral Medications BYDUREON and BYDUREON BCise slow 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 or BYDUREON BCise

PREGNANCY

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

Please click here for Prescribing Information and Medication Guide for BYDUREON BCise.

Please click here for Prescribing Information and Medication Guide for BYDUREON.

INDICATIONS AND LIMITATIONS OF USE FOR ONGLYZA® (saxagliptin) tablets 5mg

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

ONGLYZA is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Important Safety Information for ONGLYZA

Contraindications

Prior serious hypersensitivity reaction to ONGLYZA

Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA, and in the SAVOR cardiovascular outcomes trial. Observe for pancreatitis. If pancreatitis is suspected, discontinue ONGLYZA.

Heart Failure: In the SAVOR cardiovascular outcomes trial, more patients treated with ONGLYZA were hospitalized for heart failure compared to placebo. Patients with a prior history of heart failure or renal impairment had a higher risk for hospitalization for heart failure. Consider the risks and benefits of ONGLYZA in patients who have known risk factors for heart failure. Monitor for signs and symptoms. If heart failure develops, consider discontinuation of ONGLYZA.

Hypoglycemia: When ONGLYZA was used in combination with a sulfonylurea or with insulin, the incidence of confirmed hypoglycemia was increased over that of placebo. Consider lowering the dose of these agents when coadministered with ONGLYZA.

Hypersensitivity Reactions: Serious reactions have been reported in patients treated with ONGLYZA, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with ONGLYZA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA. Use caution in patients with a history of angioedema to another DPP-4 inhibitor.

Severe and Disabling Arthralgia has been reported in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider discontinuing drug if appropriate.

Bullous Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If suspected, discontinue ONGLYZA.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA.

Most Common Adverse Reactions

Most common adverse reactions reported in ≥5% of patients treated with ONGLYZA and more commonly than in patients treated with placebo were upper respiratory tract infection (7.7%, 7.6%), urinary tract infection (6.8%, 6.1%), and headache (6.5%, 5.9%).

Peripheral edema was reported more commonly in patients treated with the combination of ONGLYZA 5 mg and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD (8.1% vs 4.3%, respectively).

Drug Interactions

Strong CYP3A4/5 inhibitors (eg, ketoconazole): Coadministration with ONGLYZA significantly increases saxagliptin concentrations. Recommend limiting ONGLYZA dosage to 2.5 mg once daily.

Use in Specific Populations

In patients with moderate or severe renal impairment, or end-stage renal disease (eGFR <45 mL/min/1.73 m2), recommended dosage is 2.5 mg once daily regardless of meals. ONGLYZA should be administered following hemodialysis. Assess renal function before starting ONGLYZA and periodically thereafter.

Please see US Full Prescribing Information and Medication Guide for ONGLYZA.

NOTES TO EDITORS

About AstraZeneca in Cardiovascular, Renal & Metabolism (CVMD)

Cardiovascular, renal and metabolic diseases together form one of AstraZeneca’s main therapy areas and platforms for future growth. By following the science to understand more clearly the underlying links between the heart, kidney 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 even regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and cardiovascular health for millions of patients worldwide.

About MedImmune

MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of small molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across Oncology, Respiratory, Cardiovascular, Renal and Metabolic Diseases, and Infection and Vaccines. The MedImmune headquarters is located in Gaithersburg, Md., one of AstraZeneca’s three global R&D centers, with additional sites in Cambridge, UK and South San Francisco, CA. For more information, please visit www.medimmune.com.

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. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit http://www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

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For AstraZeneca:Michele Meixell, 302-885-2677orAbby Bozarth, 302-885-2677