AstraZeneca PLC Release: Phase III Combination Trial Of BYDUREON And FARXIGA Shows Significant Blood Sugar Reduction In Patients With Type 2 Diabetes

DURATION-8 trial met primary and secondary endpoints, significantly reducing blood sugar (HbA1c), weight and systolic blood pressure versus either medicine alone

The first Phase III trial to assess GLP-1RA/SGLT-2i combination therapy

WILMINGTON, Del.--(BUSINESS WIRE)--Positive results from the Phase III DURATION-8 trial demonstrated that BYDUREON (exenatide extended-release) for injectable suspension 2 mg once-weekly in combination with FARXIGA (dapagliflozin) 10 mg once-daily significantly reduced blood sugar as measured by HbA1c, versus the individual medicines alone in patients with type 2 diabetes inadequately controlled on metformin.¹

“Because of the progressive nature of type 2 diabetes, patients often require multiple anti-diabetic medicines to achieve and maintain glycemic control. The results of DURATION-8 show that combining medicines that work in different ways can significantly reduce HbA1c, as well as weight and systolic blood pressure.”

This was the first clinical trial to combine these two different anti-diabetes medicines, a GLP-1 receptor agonist and an SGLT-2 inhibitor, as an addition to standard-of-care therapy to evaluate potential benefits for patients with type 2 diabetes with inadequate glycemic control. The results were presented today at the 52nd Annual Meeting of the European Association for the Study of Diabetes (EASD) in Munich, Germany, and simultaneously published in The Lancet Diabetes & Endocrinology.¹

The trial achieved its primary endpoint with the combination of exenatide once-weekly and dapagliflozin significantly reducing HbA1c from baseline compared with exenatide once-weekly or dapagliflozin alone (-2.0% versus -1.6% and -1.4% respectively, both P<0.01), at 28 weeks.¹

Serge A. Jabbour, MD, FACP, FACE, Professor of Medicine, Director of the Division of Endocrinology and Director of the Diabetes Center at the Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, said: “Because of the progressive nature of type 2 diabetes, patients often require multiple anti-diabetic medicines to achieve and maintain glycemic control. The results of DURATION-8 show that combining medicines that work in different ways can significantly reduce HbA1c, as well as weight and systolic blood pressure.”

Elisabeth Björk, Vice President, Head of Cardiovascular and Metabolic Diseases, Global Medicines Development at AstraZeneca, said: “With DURATION-8, AstraZeneca is the first company to highlight the results of combining a GLP-1 receptor agonist and SGLT-2 inhibitor as a potential treatment alternative to existing non-insulin therapies for patients with severe, uncontrolled type 2 diabetes. Further, it reinforces our commitment to pushing the boundaries of science in the treatment of a disease that affects an estimated 415 million adults worldwide.”²

Secondary endpoints for the trial included changes in body weight and systolic blood pressure. Patients receiving the combination of exenatide once-weekly and dapagliflozin versus either exenatide once-weekly or dapagliflozin alone experienced:

• Significantly greater body weight reduction (–3.4 kg versus –1.5 kg and –2.2 kg, respectively; both P<0.01)
• Significantly greater systolic blood pressure reduction (–4.2 mmHg vs –1.3 mmHg and –1.8 mmHg respectively; both P<0.05)¹

This combination of products is not FDA approved, and neither product is approved for weight loss or the treatment of hypertension.

The combination of exenatide once-weekly and dapagliflozin exhibited similar rates of adverse events and serious adverse events to the individual medicine treatment groups. The most common adverse events (=5% of patients in any group) were diarrhea, injection-site nodule, nausea and urinary tract infection.¹

Indication and Important Limitations of Use for BYDUREON^® (exenatide extended-release) for injectable suspension

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

• BYDUREON is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans. Prescribe only to patients for whom potential benefits are considered to outweigh potential risk.
• Not a substitute for insulin, should not be used in patients with type 1 diabetes or diabetic ketoacidosis, and cannot be recommended for use with insulin.
• BYDUREON and BYETTA^® (exenatide) injection both contain the same active ingredient, exenatide, and should not be used together.
• Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, based on postmarketing data. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using BYDUREON; consider other antidiabetic therapies for these patients.
• BYDUREON is not indicated for weight loss.
• BYDUREON is not indicated for the treatment of hypertension.

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 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 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 and inform them of symptoms of thyroid tumors (e.g., 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

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

• Pancreatitis Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. 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 BYDUREON increased the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with BYDUREON
• Renal Impairment Altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis and kidney transplantation has 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 failure
• Severe 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. In 5 registration trials, attenuated glycemic response was associated in 6% of BYDUREON-treated patients with antibody formation. 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 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 BYDUREON or any other antidiabetic drug

ADVERSE REACTIONS

Most common (=5%) and occurring more frequently than comparator in 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%), and dyspepsia (5.1%)

DRUG INTERACTIONS

• Oral Medications BYDUREON 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

PREGNANT AND NURSING WOMEN

• Pregnant Women Based on animal data, may cause fetal harm. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Report drug exposure during pregnancy at 1- 800-633-9081
• Nursing Women Discontinue BYDUREON or discontinue nursing

Please click here for Full Prescribing Information and click here for Medication Guide for BYDUREON 2 mg, including Boxed WARNING regarding risk of thyroid C-cell tumors.

Indication 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.

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

FARXIGA is not indicated for weight loss or the treatment of hypertension.

10 mg is not the recommended starting dose for FARXIGA.

Important Safety Information for FARXIGA^® (dapagliflozin)

Contraindications

• History of a 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 or any other antidiabetic drug

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

• Pregnant Women: There are no adequate and well-controlled studies of FARXIGA in pregnant women. Consider appropriate alternative therapies, especially during the second and third trimesters. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus
• Nursing Mothers: Discontinue FARXIGA or discontinue nursing

Please click here for US Full Prescribing Information and Medication Guide for FARXIGA.

NOTES TO EDITORS

About DURATION-8

DURATION-8 was a Phase III, randomized, multi-center, double-blind, active-controlled trial which evaluated the safety and efficacy of simultaneous administration of exenatide once-weekly and dapagliflozin once-daily compared to treatment with the individual medicines in adult patients with type 2 diabetes who were inadequately controlled on metformin.¹

The trial was conducted over a 28-week treatment period, with an extension to two years, and enrolled approximately 700 patients in six countries. Eligible participants included adult patients with type 2 diabetes who had uncontrolled HbA1c (a protein within red blood cells that when bound with glucose is measurable to determine average blood sugar levels during a specific period) levels at baseline ranging from 8.0% to 12.0%. The primary endpoint was change in HbA1c from baseline to week 28. Secondary endpoints included changes in body weight, systolic blood pressure, fasting plasma glucose, two hour postprandial glucose and the proportion of patients achieving HbA1c <7.0% over the 28-week treatment period.¹

About AstraZeneca in Diabetes

AstraZeneca is pushing the boundaries of science with the goal of developing life-changing medicines that aim to reduce the global burden and complications of diabetes. As a core therapy area for the company, we are focusing our research and development efforts on diverse populations and patients with significant co-morbidities, such as cardiovascular disease, obesity, non-alcoholic steatohepatitis (NASH), and chronic kidney disease.

Our commitment to diabetes is exemplified by the depth and breadth of our global clinical research program. This commitment is advancing understanding of the treatment effects of our diabetes medicines in broad patient populations, as well as exploring combination product approaches to help more patients achieve treatment success earlier in their disease progression. Our ambition is to reduce the long-term impact of diabetes.

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 – Respiratory and Autoimmunity, Cardiovascular and Metabolic Diseases, and Oncology. The company is also active in inflammation, infection and neuroscience through numerous collaborations. 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

References

1. Frias JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicenter, double-blind, phase 3, randomized controlled trial [published online ahead of print September 16, 2016]. Lancet Diabetes Endocrinol. 2016. http://dx.doi.org/10.1016/S2213-8587(16)30267-4. Accessed September 16, 2016.
2. International Diabetes Federation. IDF Diabetes Atlas, 7th ed. Brussels, Belgium: International Diabetes Federation, 2015. http://www.idf.org/about-diabetes/facts-figures. Accessed September 15, 2015.