Investigational Compound Dapagliflozin with Metformin Extended-Release (XR) as Initial Combination Therapy Significantly Improved Blood Sugar Control in Previously-Untreated Adult Type 2 Diabetes Patients with High Blood Sugar Levels
SAN DIEGO--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN) today announced results from two 24-week Phase 3 clinical studies examining the investigational compound dapagliflozin at 5 mg or 10 mg (clinical trial dose) plus metformin extended-release (XR). In previously-untreated adults with type 2 diabetes who had high baseline blood sugar levels (glycosylated hemoglobin levels or HbA1c) of up to 12% (mean baseline of 9%), the studies showed that dapagliflozin plus metformin XR significantly reduced blood sugar levels compared to dapagliflozin or metformin XR alone plus placebo. There were no major hypoglycemia-related events in the studies. Minor hypoglycemia was observed more frequently in the combination arm than for either agent alone. The results of the two studies were presented at the 71st American Diabetes Association (ADA) Scientific Sessions in San Diego, CA.
The studies showed that dapagliflozin in combination with metformin XR improved morning blood sugar (fasting plasma glucose, or FPG), had a higher proportion of patients achieving a therapeutic glycemic response of HbA1c < 7% and improved weight reduction compared to dapagliflozin or metformin XR alone.
In addition, the clinical trial dose of dapagliflozin 10 mg was non-inferior compared to metformin XR in reducing blood sugar levels and was statistically superior to metformin XR in reducing morning blood sugar and weight.
Signs, symptoms and other reports suggestive of genital infections were more common in the dapagliflozin treatment groups in both studies, while signs, symptoms and other reports suggestive of urinary tract infections were more common in the dapagliflozin treatment groups in the 10 mg study. These events were proactively monitored, were generally mild to moderate in intensity and rarely led to study discontinuation, with most patients responding to standard treatment.
"These studies focused on type 2 diabetes patients with high baseline blood sugar levels who may benefit from a combination treatment as initial therapy to help improve blood sugar levels," said Alexander V. Murray, MD, Medical Director of Research, PharmQuest, a principal investigator of the study. "These studies showed that dapagliflozin as an initial combination therapy with metformin XR helped manage blood sugar levels and other measures of glycemic control in adults who previously had not been treated for type 2 diabetes."
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 Studies
Each study was a Phase 3 multicenter, randomized, double-blind, active-controlled, 24-week clinical trial designed to assess the safety and efficacy of dapagliflozin as an initial combination therapy with metformin XR compared to dapagliflozin plus placebo or metformin XR plus placebo in treatment-naïve patients with type 2 diabetes. One study examined dapagliflozin 5 mg, whereas the other study investigated the dapagliflozin 10 mg.
The studies included treatment-naïve patients with type 2 diabetes (ages 18-77) with inadequate glycemic control (HbA1c ≥ 7.5% and ≤ 12.0%). In the study examining dapagliflozin 5 mg, 598 patients were treated as follows: dapagliflozin 5 mg plus metformin XR (n=194), dapagliflozin 5 mg plus placebo (n=203) or metformin XR plus placebo (n=201). In the study examining dapagliflozin 10 mg, 638 patients were treated as follows: dapagliflozin 10 mg plus metformin XR (n=211), dapagliflozin 10 mg plus placebo (n=219) or metformin XR plus placebo (n=208). Metformin XR was titrated to a maximum of 2,000 mg daily (with a median dose of 2,000 mg).
The primary endpoint of both studies was mean change in HbA1c from baseline for dapagliflozin plus metformin XR, compared with dapagliflozin plus placebo or metformin XR plus placebo after 24 weeks. Secondary endpoints measured change from baseline in FPG, the proportion of patients achieving a therapeutic glycemic response of HbA1c < 7% and change from baseline in total body weight. The study examining dapagliflozin 10 mg had the additional secondary endpoints of measuring HbA1c, FPG and weight to determine non-inferiority of dapagliflozin plus placebo to metformin XR plus placebo (with superiority being tested if non-inferiority was confirmed).
Study Results
In both studies, a statistically significant reduction in HbA1c from baseline, the primary study endpoint, was seen in individuals treated with dapagliflozin plus metformin XR compared to dapagliflozin plus placebo or metformin XR plus placebo, respectively (p-value < 0.0001 for all treatment groups):
Dapagliflozin 5 mg: -2.05% (dapagliflozin plus metformin XR) vs. -1.19% (dapagliflozin plus placebo) or -1.35% (metformin XR plus placebo)
Dapagliflozin 10 mg: -1.98% (dapagliflozin plus metformin XR) vs. -1.45% (dapagliflozin plus placebo) or -1.44% (metformin XR plus placebo)
Both studies also showed the following differences in secondary endpoints comparing dapagliflozin plus metformin XR to either treatment alone:
Statistically significant reduction of mean change of FPG with dapagliflozin plus metformin XR compared to dapagliflozin plus placebo or metformin XR plus placebo, respectively (p-value < 0.0001 for all treatment groups)
Dapagliflozin 5 mg: -61.0 mg/dL (dapagliflozin plus metformin XR) vs. -42.0 mg/dL (dapagliflozin plus placebo) or -33.6 mg/dL (metformin XR plus placebo)
Dapagliflozin 10 mg: -60.4 mg/dL (dapagliflozin plus metformin XR) vs. -46.4 mg/dL (dapagliflozin plus placebo) or -34.8 mg/dL (metformin XR plus placebo)
A statistically higher proportion of individuals treated with dapagliflozin plus metformin XR achieved a therapeutic glycemic response of HbA1c < 7% compared to dapagliflozin plus placebo or metformin XR plus placebo, respectively:
Dapagliflozin 5 mg: 52% (dapagliflozin plus metformin XR) vs. 23% (dapagliflozin plus placebo) [p-value <0.0001] or 35% (metformin XR plus placebo) [p-value ≤ 0.0003]
Dapagliflozin 10 mg: 47% (dapagliflozin plus metformin XR) vs. 32% (dapagliflozin plus placebo) [p-value = 0.0012] or 35% (metformin XR plus placebo) [p-value ≤ 0.02]
A progressive mean change in total body weight over 24 weeks was observed in all treatment groups, with numerically greater weight reduction in the dapagliflozin plus metformin XR group and dapagliflozin plus placebo groups compared to the metformin XR group, respectively:
Dapagliflozin 5 mg: -2.66 kg (-5.85 lb; dapagliflozin plus metformin XR) and -2.61 kg (-5.74 lb; dapagliflozin plus placebo) [p-value = 0.8769] vs. -1.29 kg (-2.84 lb; metformin XR plus placebo) [p-value < 0.0001]
Dapagliflozin 10 mg: -3.33 kg (-7.33 lb; dapagliflozin plus metformin XR) and -2.73 kg (-6.00 lb; dapagliflozin plus placebo) [p-value < 0.0001] vs. -1.36 kg (-2.99 lb; metformin XR plus placebo) [p-value < 0.0001]
The study investigating dapagliflozin 10 mg also demonstrated non-inferiority of dapagliflozin 10 mg plus placebo compared to metformin XR plus placebo in reducing HbA1c (-0.01%, 95% CI -0.22 to 0.20 for HbA1c) and superiority in reducing FPG (difference in adjusted mean was -11.6 mg/dL, 95% CI -18.6 to -4.6) [p-value = 0.0012] and weight at 24 weeks (difference in adjusted mean was -1.37 kg (3.01 lb; 95% CI -2.03 to -0.71) [p-value < 0.002.]
The most common adverse events for dapagliflozin 5 mg and 10 mg were as follows: diarrhea 3.9% and 2.7%, respectively, and nausea 2.0% and 3.7%, respectively.
The most common adverse events for the combination of dapagliflozin 5 mg and metformin and dapagliflozin 10 mg and metformin were as follows: diarrhea 7.7% and 7.1%, respectively and 5.7 % and 4.7%, respectively.
The most common adverse events for metformin alone were diarrhea (7.0% in the 5mg study and 9.6% in the 10mg study) and nausea (2.4% in the 5mg study and 4.0% in the 10mg study).
Overall discontinuations due to adverse events seen in individuals treated with dapagliflozin plus metformin XR compared with dapagliflozin plus placebo or metformin XR plus placebo were:
Dapagliflozin 5 mg: 1.0% (dapagliflozin plus metformin XR) vs. 2.5% (dapagliflozin plus placebo) or 3.0% (metformin XR plus placebo)
Dapagliflozin 10 mg:1.9% (dapagliflozin plus metformin XR) vs. 4.1% (dapagliflozin plus placebo) or 3.8% (metformin XR plus placebo)
Signs, symptoms, and other reports suggestive of genital infection were reported for 31 and 51 individuals in the dapagliflozin 5 mg and 10 mg studies, respectively. The proportion of individuals with signs, symptoms and other reports suggestive of genital infection was higher in the dapagliflozin plus metformin XR and dapagliflozin plus placebo groups compared with the metformin XR plus placebo groups, respectively:
Dapagliflozin 5 mg: 6.7% (dapagliflozin plus metformin XR) and 6.9% (dapagliflozin plus placebo) vs. 2.0% (metformin XR plus placebo)
Dapagliflozin 10 mg: 8.5% (dapagliflozin plus metformin XR) and 12.8% (dapagliflozin plus placebo) vs. 2.4% (metformin XR plus placebo)
Signs, symptoms, and other reports suggestive of urinary tract infection were reported for 46 and 49 individuals in the dapagliflozin 5 mg and 10 mg studies, respectively. The proportion of individuals with signs, symptoms and other reports suggestive of urinary tract infection was as follows for dapagliflozin plus metformin XR compared to dapagliflozin plus placebo or metformin XR plus placebo groups, respectively:
Dapagliflozin 5 mg: 7.7% (dapagliflozin plus metformin XR) vs. 7.9% (dapagliflozin plus placebo) or 7.5% (metformin XR plus placebo)
Dapagliflozin 10 mg: 7.6% (dapagliflozin plus metformin XR) vs. 11.0% (dapagliflozin plus placebo) or 4.3% (metformin XR plus placebo)
There were no major events of hypoglycemia. Minor hypoglycemia was observed more frequently in the combination arms than for either agent alone, with events as follows:
Dapagliflozin 5 mg: 2.6% (dapagliflozin plus metformin XR) vs. 0% (dapagliflozin plus placebo) or 0% (metformin XR plus placebo)
Dapagliflozin 10 mg: 3.3% (dapagliflozin plus metformin XR) vs. 0.9% (dapagliflozin plus placebo) or 2.9% (metformin XR plus placebo)
Major hypoglycemia is defined in the study as symptomatic episodes requiring external (3rd party) assistance due to severe impairment in consciousness or behavior with a capillary or plasma glucose value < 54 mg/dL, whereas minor hypoglycemia is defined as a symptomatic episode with capillary or plasma glucose measurement below 63 mg/dL regardless of need for external assistance or an asymptomatic capillary or plasma glucose measurement below 63 mg/dL, that does not qualify as a major episode.
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&MeTM Prescription Savings programs, please visit: www.astrazeneca-us.com or call 1-800-AZandMe (292-6363).