AstraZeneca presents new positive phase III data on triple therapy approach with dapagliflozin, saxagliptin and metformin for type 2 diabetes

Data in oral presentation demonstrate that the investigational combination of dapagliflozin, saxagliptin and metformin resulted in statistically significant reductions in HbA1c in patients uncontrolled on saxagliptin and metformin

AstraZeneca today announced positive results from a Phase III study comparing the efficacy and safety of dapagliflozin versus placebo as an add-on to saxagliptin and metformin immediate release (IR) in adults with type 2 diabetes who had inadequate glycaemic control (baseline HbA1c 7% - 10.5%).¹ The study met its primary endpoint, with patients receiving the investigational triple combination of dapagliflozin 10 mg, saxagliptin 5 mg and metformin achieving significantly greater mean reductions in HbA1c compared to those treated with placebo, saxagliptin 5 mg and metformin at 24 weeks (–0.82% vs. -0.10%, respectively; p-value<0.0001).¹ The results were presented today as an oral presentation (#105-OR) at the 75^th Scientific Sessions of the American Diabetes Association (ADA) in Boston.

“In this study, when dapagliflozin was added to saxagliptin and metformin, patients demonstrated greater HbA1C reductions than those in the placebo and metformin group,” said lead investigator Chantal Mathieu, MD, PhD, Chair of Endocrinology at the University Hospital Gasthuisberg Leuven, Belgium. “With nearly 50% of type 2 diabetes patients estimated to be uncontrolled on metformin, new treatment approaches are needed, and these data add to the growing body of knowledge for combination therapies.”

Among secondary endpoints, the dapagliflozin combination group achieved a significantly greater adjusted mean reduction from baseline in two-hour postprandial glucose (-74 mg/dL vs -38 mg/dL, respectively; p-value<0.0001)¹ and fasting plasma glucose versus the placebo group (-33 mg/dL vs -5 mg/dL, respectively; p-value<0.0001).¹ More patients in the dapagliflozin combination group also achieved a HbA1c level of less than 7% compared to patients in the placebo group at week 24 (38% vs 12%, respectively, p-value<0.0001).¹ In addition, patients in the dapagliflozin combination group had a greater reduction in weight (mean -1.9 kg vs -0.4 kg, respectively; p-value<0.0001)¹ than those in the placebo group. Adverse events were similar across treatment groups. The most common adverse events (≥ 5%) were headache, urinary tract infection, influenza and genital infections. The rate of hypoglycaemia was 1.3% in the dapagliflozin combination group and 0.0% in the placebo group.¹

Elisabeth Björk, Vice President, Head of Cardiovascular and Metabolic Diseases, Global Medicines Development, AstraZeneca, said: “We are focused on investigating combination therapies with complementary mechanisms of action and our broad diabetes portfolio positions us well in this area.These positive results reinforce our belief that combination therapies have the potential to be used as early add-on therapy to help patients with type 2 diabetes achieve their treatment goals.”

The study included an open-label lead-in period in which patients on metformin (baseline HbA1c 8.0%–11.5%) received open-label saxagliptin 5 mg and metformin for 16 weeks, while patients on metformin and any DPP-4 inhibitor (baseline HbA1c 7.5%–10.5%) received open-label saxagliptin 5 mg and metformin for 8 weeks. Following the end of the open-label period, patients with inadequate glycaemic control (HbA1c 7%–10.5%) were randomised to receive either placebo or dapagliflozin 10 mg in addition to open-label saxagliptin and metformin.

Data further detailing this lead-in period was accepted as a late-breaker poster (#133-LB) on display in Poster Hall B on Sunday, June 7 from noon to 2 p.m. EST.²

AstraZeneca has filed a New Drug Application (NDA) with the US Food and Drug Administration (FDA) for the approval of an investigational fixed-dose combination of saxagliptin and dapagliflozin for the treatment of type 2 diabetes and the Prescription Drug User Fee Act (PDUFA) goal date will be in the fourth quarter of 2015.

NOTES TO EDITORS

About the Study

This 24-week, Phase III, randomised, double-blind study of 320 adult patients (aged ≥ 18 years) with type 2 diabetes was designed to compare the efficacy and safety of dapagliflozin versus placebo as an add-on to dual treatment of saxagliptin and metformin in adult patients with type 2 diabetes who were uncontrolled on saxagliptin and metformin. The primary endpoint was change in HbA1c from baseline at week 24. Secondary endpoints included fasting plasma glucose, two-hour postprandial glucose, body weight and the proportion of patients achieving A1c<7%.¹

About DPP-4 inhibitors and SGLT2 inhibitors

Saxagliptin (marketed as Onglyza^®) belongs to the class of medicines called DPP-4 inhibitors, which work by increasing the activity of the incretin hormones, increasing the release of insulin when glucose levels are elevated and reducing the levels of sugar produced by the liver (glucagon). Dapagliflozin (marketed as Farxiga^® in the US and Forxiga^® outside the US) is part of a newer class of medicines called sodium-glucose cotransporter 2 (SGLT2) inhibitors, which remove glucose via the kidneys.

About Type 2 Diabetes

Diabetes is estimated to affect 29.1 million people in the US and more than 387 million people worldwide. The prevalence of diabetes is projected to reach more than 592 million people worldwide by 2035. Type 2 diabetes accounts for approximately 90-95 percent of all cases of diagnosed diabetes in the US. Type 2 diabetes is a chronic diseasecharacterised by pathophysiologic defects leading to elevated glucose levels. Significant unmet needs still exist, as many patients remain inadequately controlled on their current glucose-lowering regimen. It is estimated that more than half of people living with type 2 diabetes are not achieving recommended HbA1c goals based on guidelines established by professional societies and advocacy organisations for diabetes management.

About AstraZeneca in Diabetes

AstraZeneca is pushing the boundaries of science to create life-changing medicines that aim to reduce the global burden and complications of diabetes. Driven to redefine outcomes for diabetes patients, our current portfolio consists of the three newest classes of non-insulin, anti-diabetic treatments that support individualised treatment approaches: SGLT-2 inhibitors, GLP-1 receptor agonists and DPP-4 inhibitors. Our commitment to diabetes is exemplified by the depth and breadth of our global clinical research programme. This commitment is advancing understanding of the treatment effects of our diabetes medicines in broad patient populations, as well as exploring combination treatment approaches resulting in more patients achieving treatment success earlier in their disease progression. Our ambition is to reduce the long-term impact of diabetes. As a core strategic area for the company, we are focusing our research and development efforts indiverse populations and patients with significant co-morbidities, such as cardiovascular disease, heart failure, obesity, non-alcoholic steatohepatitis (NASH), and chronic kidney disease.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.

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¹Mathieu, C., et al. “A Randomized Double-Blind Phase 3 Trial of Dapagliflozin Add-On to Saxagliptin + Metformin in Type 2 Diabetes.” American Diabetes Association Scientific Sessions 2015. Abstract #105-OR.

²Mathieu, C., et al. “Triple Therapy with Dapagliflozin Add-on to Saxagliptin Plus Metformin: Characterization of the Open-Label Saxagliptin + Metformin Lead-in Period of a Phase 3 Trial.” American Diabetes Association Scientific Sessions 2015. Abstract #133-LB.