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Investigational Compound Dapagliflozin Added to Metformin Sustained Reductions in Blood Sugar Levels in Adult Patients with Type 2 Diabetes in Two-Year Study

Update: Farxiga (dapagliflozin) Now FDA Approved - January 8, 2014

Episodes of low blood sugar were less frequent in patients treated with dapagliflozin added to metformin than in patients treated with glipizide added to metformin

SAN DIEGO--(BUSINESS WIRE)--Jun 26, 2011 - Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN) today announced results from a long-term (104 weeks) Phase 3 clinical study which showed that the investigational compound dapagliflozin added to metformin sustained reductions of blood sugar levels (glycosylated hemoglobin levels, or HbA1c) from 52-weeks to 104-weeks, in adults with type 2 diabetes when compared to glipizide (a common sulphonylurea treatment) added to metformin. The proportion of patients with adverse events was similar between the treatment groups. Within the new class of insulin-independent, investigational type 2 diabetes agents that inhibit sodium-glucose cotransporter-2 (SGLT2) in the kidney, 104-week results are the longest-term clinical data presented to date. These results announced today are from a 52-week extension period of an initial 52-week trial. The initial 52-week results were presented during the 46th European Association for the Study of Diabetes (EASD) Annual Meeting in 2010.

In addition to sustained reductions in blood sugar levels, the 104-week study, presented as a late breaking poster at the 71st American Diabetes Association (ADA) Scientific Sessions in San Diego, CA, reported that both the weight reduction achieved by patients taking dapagliflozin added to metformin and the weight gain experienced by patients taking glipizide added to metformin in the initial 52-week trial, were sustained at 104 weeks. Moreover, hypoglycemic (low blood sugar) episodes during the 104 weeks were reported approximately 10 times more frequently in patients treated with glipizide added to metformin (45.8%) than in patients treated with dapagliflozin added to metformin (4.2%).

Signs, symptoms and other reports suggestive of genital infections or urinary tract infections were more common in patients taking dapagliflozin added to metformin. These events were proactively monitored and were generally mild to moderate in intensity, with most patients responding to standard treatment. Events mostly occurred in the first year and rarely led to discontinuation.

“As we advance our knowledge of how SGLT2 inhibitors may work as a potential treatment for patients with type 2 diabetes, long-term data become critical to assess a compound's safety and its ability to sustain glycemic control,” said Michael A. Nauck, MD, Head of Diabetes Center, Bad Lauterberg (Germany), principal investigator of the study. “These two-year data demonstrated that patients taking dapagliflozin added to metformin sustained reductions in blood sugar levels over an extended period of time.”

A New Drug Application (NDA) for dapagliflozin was accepted for review by the U.S. Food and Drug Administration (FDA) in March 2011 with a Prescription Drug User Fee Act (PDUFA) date set for October 28, 2011. In addition, a Marketing Authorisation Application (MAA) was validated by the European Medicines Agency (EMA) in January 2011. If approved, dapagliflozin--an inhibitor of SGLT2, a target in the kidney -- would potentially be the first in a new class of insulin-independent, oral type 2 diabetes agents.

About the Study

This was a 52-week Phase 3, multicenter, randomized, parallel-group, double-blind, active-controlled study with a 52-week extension. The primary endpoint at 52 weeks was non-inferiority of dapagliflozin added to metformin compared to glipizide added to metformin for HbA1c mean change from baseline. The 52-week extension was designed to assess the maintenance of efficacy of dapagliflozin (up to 10 mg/day) added to metformin, as well as safety and tolerability, over 104 weeks of treatment compared to glipizide (up to 20 mg/day) added to metformin in patients with type 2 diabetes. The median dose of metformin was 2,000 mg/day.

The study included more than 800 adults with type 2 diabetes (aged ‰¥ 18) whose HbA1c was between 6.5% and 10% (mean baseline (%) ± (SD) 7.69 (0.86), 7.74 (0.89) for dapagliflozin added to metformin and glipizide added to metformin, respectively). Individuals were randomized to one of two treatment groups at the onset of the study: dapagliflozin added to metformin or glipizide added to metformin.

There were 624 patients when the 52-week extension began, and of these, 445 patients completed the extension.

Study Results

At the end of 104 weeks, change from baseline in HbA1c in patients taking dapagliflozin added to metformin compared to those taking glipizide added to metformin was -0.32% (95% CI -0.42, -0.21) vs. -0.14% (-0.25, -0.03). The weight reduction with dapagliflozin added to metformin at 52 weeks and the weight gain with glipizide added to metformin at 52 weeks were both sustained at 104 weeks: -3.70 kg (95% CI -4.16, -3.24) [3.70 kg = 8.14 lb] vs. +1.36 kg (0.88, 1.84) [1.36 kg = 2.99 lb], respectively. A low incidence of hypoglycemic episodes was reported throughout the trial in patients treated with dapagliflozin added to metformin (4.2%) compared to patients treated with glipizide added to metformin (45.8%). No major hypoglycemic episodes were reported with dapagliflozin treatment, whereas three were reported with glipizide treatment.

The percentage of patients with signs, symptoms and other reports suggestive of genital infections was higher for dapagliflozin added to metformin compared to glipizide added to metformin, was as follows:

 

  • Signs, symptoms and other reports suggestive of genital infections were 14.8% (8.0% in men, 23.3% in women) with dapagliflozin added to metformin compared to 2.9% (0.4% in men, 5.9% in women) with glipizide added to metformin during the 104 weeks.
    • Of the patients who experienced an event suggestive of a genital infection (60 in the dapagliflozin and 12 in the glipizide group), the majority had only one infection (60.0% in the dapagliflozin group and 83.3% in the glipizide group).

The percentage of patients with signs, symptoms and other reports suggestive of urinary tract infections was higher for dapagliflozin added to metformin compared to glipizide added to metformin, was as follows:

 

  • Signs, symptoms and other reports suggestive of urinary tract infections were 13.5% with dapagliflozin added to metformin vs. 9.1% with glipizide added to metformin.
    • Of the patients who experienced an event suggestive of a urinary tract infection (53 in the dapagliflozin and 37 in the glipizide group), the majority had only one infection (71.7% in the dapagliflozin group and 73.0% in the glipizide group).

The majority of events occurred in the first year, were mild to moderate in intensity and responded to standard treatment. Three cases of genital infections in the first year led to discontinuation in the dapagliflozin treatment group. One case of urinary tract infection in the dapagliflozin group and one case in the glipizide group led to discontinuation, respectively, in the first year. No discontinuations due to genital infections or urinary tract infections occurred in the second year.

No kidney infections were reported in the dapagliflozin group, whereas in the glipizide group, two patients reported pyelonephritis and one patient reported pyelonephritis followed by pyelocystitis. There was no clinically relevant change in renal function during the 104 weeks.

Update on Malignancies in the Overall Dapagliflozin Safety Profile

In the overall dapagliflozin clinical program, there was no overall imbalance in malignant tumors. However, there were imbalances in two tumor types in the dapagliflozin clinical trial program. Nine bladder cancers have been observed in 5,478 patients on dapagliflozin and one bladder cancer has been observed in 3,156 patients in control groups. Six of these 10 subjects had hematuria (blood in the urine) at baseline and five were diagnosed within a year after study start. Nine breast cancers have been observed in 2,223 women on dapagliflozin and one has been observed in 1,053 women in control groups. All were diagnosed within a year after study start.

In preclinical studies, dapagliflozin was not shown to be genotoxic or carcinogenic and the investigational agent has no known off-target pharmacology. SGLT2 is not expressed in the breast or in the bladder.

These clinical and preclinical data have been shared with FDA and other health authorities and will be reviewed fully at the scheduled Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) on July 19, 2011.

About Type 2 Diabetes

In 2010, diabetes was estimated to affect nearly 300 million people aged 20-79 worldwide. Because of the aging population and the growing trend of obesity, the prevalence of diabetes is projected to reach nearly 440 million by 2030. Type 2 diabetes accounts for approximately 90 to 95% of all cases of diagnosed diabetes in adults. Type 2 diabetes is a chronic, progressive disease characterized by insulin resistance and/or dysfunction of beta cells in the pancreas, which decreases insulin sensitivity and secretion, leading to elevated glucose levels. Over time, this sustained hyperglycemia contributes to worsening insulin resistance and further beta cell dysfunction. To date, treatments for type 2 diabetes have focused primarily on insulin-dependent mechanisms. An approach that acts independently of insulin could provide an additional option for adults with type 2 diabetes.

Significant unmet needs exist as nearly half of treated patients remain uncontrolled on their current glucose-lowering regimen. Many patients with type 2 diabetes have additional co-morbidities (such as obesity) which may complicate glycemic control.

About SGLT2 Inhibition

The kidney plays an important role in glucose balance, normally filtering ~180g of glucose each day, with virtually all glucose being reabsorbed back into circulation. SGLT2 is the major sodium-glucose cotransporter in the kidney and is an insulin-independent pathway for the reabsorption of glucose back into the blood.

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 www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information about AstraZeneca in the U.S. or our AZ&Me™ Prescription Savings programs, please visit: www.astrazeneca-us.com or call 1-800-AZandMe (292-6363).

Bristol-Myers Squibb Forward-Looking Statement

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, 2010, 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.

AstraZeneca Forward-Looking Statement

The statements contained herein include forward-looking statements. Although we believe our expectations are based on reasonable assumptions, any forward-looking statements, by their very nature, involve risks and uncertainties and may be influenced by factors that could cause actual outcomes and results to be materially different from those predicted. The forward-looking statements reflect knowledge and information available at the date of the preparation of this press release and the Company undertakes no obligation to update these forward-looking statements. Important factors that could cause actual results to differ materially from those contained in forward-looking statements, certain of which are beyond our control, include, among other things, those risk factors identified in the Company's Annual Report and Form 20-F Information 2010. Nothing contained herein should be construed as a profit forecast.

 

Contact: Media:
Phil McNamara, Bristol-Myers Squibb, +1 609-240-3739, phil.mcnamara@bms.com
Corey Windett, AstraZeneca, +1 302-885-0034, corey.windett@astrazeneca.com
Kirsten Evraire, AstraZeneca, +1 302-885-0435, kirsten.evraire@astrazeneca.com
or
Investors:
John Elicker, Bristol-Myers Squibb, +1 609-252-4611, john.elicker@bms.com
Karl Hard, AstraZeneca, +44 20 7604 8123, karl.j.hard@astrazeneca.com

 

 

Posted: June 2011

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