24-Week Phase 3 Study Found Investigational Drug Dapagliflozin Improved Glycosylated Hemoglobin (HbA1c) When Added to Glimepiride in Adults With Type 2 Diabetes Mellitus

STOCKHOLM, September 20, 2010 /PRNewswire-FirstCall/ -- Bristol-Myers Squibb Company (NYSE: BMY)(http://www.bms.com) and AstraZeneca (NYSE: AZN)(http://www.astrazeneca-us.com) today announced results from a randomized, double blind Phase 3 clinical study, which demonstrated that the addition of the investigational drug dapagliflozin to existing glimepiride (sulphonylurea) therapy produced significant reductions in glycosylated hemoglobin levels (HbA1c) in adult patients with type 2 diabetes compared to glimepiride alone. The study also demonstrated that dapagliflozin plus glimepiride achieved reductions in the secondary efficacy endpoints of change in total body weight, oral glucose tolerance test (OGTT) and fasting plasma glucose (FPG) levels from baseline at week 24 compared to placebo plus glimepiride. More people taking dapagliflozin and glimepiride were able to achieve a target HbA1c of less than 7% compared to patients taking glimepiride alone. Results from the study were presented at the 46th European Association for the Study of Diabetes (EASD) Annual Meeting.

Overall, the frequency of drug-related adverse events was reported at a similar rate between treatment groups, although signs, symptoms and other reports suggestive of genital tract infections, but not urinary tract infections, were more frequently reported in dapagliflozin treated subjects.

Dapagliflozin, an investigational compound, is a first-in-class sodium-glucose cotransporter-2 (SGLT2) inhibitor and is currently in Phase 3 trials under joint development by Bristol-Myers Squibb and AstraZeneca as a once-daily oral therapy for the treatment of adult patients with type 2 diabetes. SGLT2 inhibitors, which act independently of insulin mechanisms, facilitate the excretion of glucose and associated calories in the urine, thereby lowering blood glucose levels.

"With type 2 diabetes, we often see a progressive deterioration of glycemic control in patients, which may require treatment intensification with additional drug therapy," said Krzysztof Strojek, Professor, Department of Internal Diseases Diabetology & Nephrology Silesian Medical University, Zabrze (Poland), principal investigator of the study. "This study, which adds to the Phase 3 data available for this investigational compound, demonstrated that dapagliflozin improved glycemic control, as measured by HbA1c, FPG and PPG, in adult patients with type 2 diabetes when added to the commonly used oral diabetic agent - glimepiride."

About The Study

The study was a 24-week, multicenter, international, randomized, parallel-group, double-blind, placebo-controlled Phase 3 study, which was designed to assess the efficacy of dapagliflozin (2.5 mg, 5 mg or 10 mg per day) compared to placebo as add-on therapy to glimepiride (4 mg/day) in improving glycemic control in adult patients with type 2 diabetes, as determined by the change in HbA1c levels from baseline at week 24, and includes a 24-week double-blind extension. The study included 597 type 2 diabetes patients (aged greater than or equal to 18 years) with inadequate glycemic control (HbA1c greater or equal to 7.0% and less than or equal to 10% at baseline) on at least half maximal recommended dose of glimepiride alone. Individuals were equally randomized to one of four treatment groups: dapagliflozin 2.5 mg plus glimepiride, dapagliflozin 5 mg plus glimepiride, dapagliflozin 10 mg plus glimepiride or placebo plus glimepiride.

The primary endpoint of the study was to assess the change from baseline in HbA1c at 24 weeks. Key secondary endpoints included the change from baseline in body weight, change in oral glucose tolerance test (OGTT), proportion of patients achieving an HbA1c of less than 7% and reduction in fasting plasma glucose (FPG) levels at week 24.

Study Results

Individuals taking dapagliflozin plus glimepiride achieved significant dose-dependent reductions from baseline in HbA1c of -0.58%, -0.63% and -0.82% for dapagliflozin 2.5 mg, 5 mg and 10 mg, respectively compared to -0.13% for placebo plus glimepiride (p-value of less than 0.0001 for all three treatment arms).

Patients treated with dapagliflozin plus glimepiride achieved greater weight loss compared to those treated with placebo plus glimepiride: -1.18 kg, -1.56 kg, -2.26 kg for dapagliflozin 2.5 mg, 5 mg and 10 mg, respectively compared to -0.72 kg for glimepiride plus placebo at week 24 (p-value less than 0.01 and less than 0.0001 for dapagliflozin 5 mg and 10 mg, respectively; p-value of dapagliflozin 2.5 mg was not statistically significant).

Individuals treated with dapagliflozin plus glimepiride achieved significant reductions from baseline in the OGTT of -32.0 mg/dL and -34.9 mg/dL for dapagliflozin 5 mg and 10 mg, respectively compared to -6.0 mg/dL for placebo plus glimepiride (p-value less than 0.01 and less than 0.0001 for dapagliflozin 5 mg and 10 mg, respectively). Dapagliflozin 2.5 mg reduced OGTT by 37.5 mg/dL.

The study demonstrated that more patients taking dapagliflozin plus glimepiride achieved an HbA1c level of less than 7% compared to placebo plus glimepiride at week 24: 30.3% and 31.7% for dapagliflozin 5 mg and 10 mg, respectively compared to 13.0% for glimepiride plus placebo (p-value less than 0.01 and less than 0.0001 for dapagliflozin 5 mg and 10 mg, respectively). For patients treated with dapagliflozin 2.5 mg, 26.8% achieved HbA1c <7%.

Individuals treated with dapagliflozin 5 mg and 10 mg plus glimepiride demonstrated significant improvements in FPG from baseline at week 24: -21.2 mg/dL for dapagliflozin 5 mg and -28.5 mg/dL for dapagliflozin 10 mg, compared to -2.0 mg/dL for placebo plus glimepiride (p-value less than 0.0001 for both treatment arms). Dapagliflozin 2.5 mg reduced FPG by -16.8 mg/dL.

The number of individuals experiencing adverse events after 24 weeks was 51.9%, 48.3% and 50.3% for dapagliflozin 2.5 mg, 5 mg, and 10 mg plus glimepiride, respectively compared to 47.3% for glimepiride plus placebo. The percentage of patients experiencing the most common adverse events for dapagliflozin 2.5 mg, 5 mg, 10 mg and placebo when added to glimepiride, respectively was as follows: back pain (1.9%, 2.1%, 4.6% vs. 2.7%), upper respiratory tract infection (3.2%, 4.1%, 4.6% vs. 2.7%) and bronchitis (1.3%, 2.1%, 3.3% vs. 0.7%). Most cases of adverse events were mild to moderate. Discontinuations due to adverse events were 3.2%, 3.4%, 2.6% for dapagliflozin 2.5 mg, 5 mg, and 10 mg plus glimepiride vs. 2.1% for glimepiride plus placebo.

Adverse events suggestive of urinary tract infection and genital infection were analyzed based on predefined groupings of preferred terms for each of these two categories. The percentage of patients with signs, symptoms and other reports suggestive of urinary tract infection was similar across treatment groups: 3.9%, 6.9% and 5.3% for dapagliflozin 2.5 mg, 5 mg, and 10 mg, respectively compared to 6.2% for glimepiride plus placebo. One patient discontinued due to a urinary tract infection. Signs, symptoms and other reports suggestive of genital infection were higher for the dapagliflozin 2.5 mg, 5 mg, and 10 mg plus glimepiride treatment groups compared to the glimepiride plus placebo group: 3.9%, 6.2% and 6.6% vs. 0.7%, respectively.

Serious adverse events were 7.1%, 6.9% and 6.0% for dapagliflozin 2.5 mg, 5 mg, and 10 mg plus glimepiride, respectively compared to 4.8% for glimepiride plus placebo.

The percentage of individuals with any hypoglycemic event at week 24 for patients treated with dapagliflozin 2.5 mg, 5 mg, and 10 mg plus glimepiride was 7.1%, 6.9% and 7.9%, respectively compared to 4.8% for those treated with placebo plus glimepiride.

Effects upon blood pressure were examined as exploratory endpoints. Changes in seated systolic blood pressure were -4.7 mmHg, -4.0 mmHg and -5.0 mmHg and in seated diastolic blood pressure were -1.1 mmHg, -1.7 mmHg and -2.8 mmHg in the dapagliflozin 2.5, 5 and 10 mg treatment groups respectively compared to changes in seated systolic blood pressure of -1.2 mmHg and seated diastolic blood pressure -1.4 mmHg for those treated with placebo plus glimepiride.

About Type 2 Diabetes

Type 2 diabetes (diabetes mellitus) is a chronic, progressive disease that is characterized by dysfunction of beta cells in the pancreas, which decreases insulin secretion and leads to elevated glucose levels. Over time, this sustained hyperglycemia contributes to worsening insulin resistance and further beta cell dysfunction.

Many patients with type 2 diabetes have co-morbidities such as obesity and hypertension. Significant unmet needs exist as nearly half of treated patients remain uncontrolled on their current glucose-lowering regimen and even fewer are controlled across multiple parameters. In the past, treatments for type 2 diabetes have focused primarily on insulin-dependent mechanisms. An approach that acts independently of insulin may provide an option for adults with type 2 diabetes in helping manage their glucose levels.

About SGLT2 Inhibition

The renal SGLT system plays a major role in overall glucose balance in the body. Normally, the kidney filters ~180g of glucose each day, and virtually all is reabsorbed back into circulation. Glucose reabsorbtion occurs in the proximal tubule of the kidney via the SGLT system. Selective inhibition of SGLT2 by an insulin independent mechanism of action facilitates the excretion of glucose and associated calories in the urine, thereby lowering blood glucose levels.

Bristol-Myers Squibb and AstraZeneca Collaboration

Bristol-Myers Squibb and AstraZeneca entered into a collaboration in January 2007 to enable the companies to research, develop and commercialize select investigational drugs for type 2 diabetes. The Bristol-Myers Squibb/AstraZeneca Diabetes collaboration is dedicated to global patient care, improving patient outcomes and creating a new vision for the treatment of type 2 diabetes.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding product development. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that dapagliflozin will receive regulatory approval or, if approved, that it will become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2009, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialisation of prescription medicines. As a leader in gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease medicines, AstraZeneca generated global revenues of US $32.8 billion in 2009. For more information please visit: http://www.astrazeneca.com

SOURCE AstraZeneca & Bristol-Myers Squibb