PHILADELPHIA--Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN) today announced results from a Phase 3 clinical study that showed the investigational compound dapagliflozin 10 mg demonstrated significant reductions in blood sugar levels (glycosylated hemoglobin levels, or HbA1c) compared with placebo at 24 weeks when either agent was added to existing sitagliptin therapy (with or without metformin) in adult patients with type 2 diabetes. The results were maintained over a 24-week extension and similar results were observed when the data were stratified by background therapy. The findings were presented today at the 72nd American Diabetes Association (ADA) Scientific Sessions in Philadelphia, PA.
The study also demonstrated significant reductions in total body weight and fasting plasma glucose (FPG) levels in patients taking dapagliflozin added to sitagliptin (with or without metformin), with results maintained throughout the duration of the study extension.
Patients were actively questioned at each study visit for signs, symptoms or events suggestive of genital infections and urinary tract infections. These events were more frequent with the dapagliflozin treatment group compared to the placebo treatment group, and were generally mild to moderate in intensity, with most patients responding to standard treatment.
"Type 2 diabetes is a complex disease that often requires patients to take multiple treatments to control their blood sugar levels, with DPP4 inhibitors being some of the most widely prescribed therapies," said Serge Jabbour, M.D., Division Director of Endocrinology, Thomas Jefferson University. "In this study, dapagliflozin, in addition to diet and exercise, resulted in reduced blood sugar levels when added to sitagliptin, a DPP4 inhibitor. These findings add to our understanding of the effect of dapagliflozin in combination with commonly prescribed type 2 diabetes treatments."
Dapagliflozin, an investigational oral compound, is a selective and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2), which works independently of insulin. Dapagliflozin is under joint development by Bristol-Myers Squibb and AstraZeneca, and is being investigated to evaluate its safety and efficacy in improving glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise, for once-daily use as a monotherapy and in combination with other glucose-lowering drugs. If approved, dapagliflozin would potentially be the first in the new SGLT2 inhibitor class for the treatment of type 2 diabetes, a disease where high unmet medical need exists. In a comprehensive clinical trial program of 19 studies, dapagliflozin has been studied together with diet and exercise as a monotherapy, and as an add-on therapy to commonly prescribed diabetes medications, including metformin, sulfonylurea (glimepiride), thiazolidinedione (pioglitazone), and insulin (with or without other diabetes therapies).
In January 2012, the U.S. Food and Drug Administration (FDA) issued a complete response letter regarding the New Drug Application (NDA) for dapagliflozin for the treatment of adults with type 2 diabetes, requesting additional clinical data to allow a better assessment of the benefit-risk profile for dapagliflozin. In April 2012, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending the approval of dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products including insulin, and as a monotherapy in metformin intolerant patients. The CHMP positive opinion for dapagliflozin will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union.
About the Study
This was a 24-week, Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with a 24-week blinded extension. The study compared the efficacy of dapagliflozin to placebo in patients with type 2 diabetes who are inadequately controlled on sitagliptin monotherapy or on sitagliptin plus metformin therapy. The primary efficacy endpoint at 24 weeks was mean change in HbA1c from baseline for dapagliflozin 10 mg compared to placebo, both added to sitagliptin (with or without metformin) in adults with type 2 diabetes who had inadequate glycemic control. The 24-week extension was designed to assess the maintenance of efficacy with the dapagliflozin treatment group, as well as safety and tolerability over 48 weeks.
The study included 447 adults with type 2 diabetes (aged ≥ 18 years) with inadequate glycemic control (HbA1c ≥ 7.0% and ≤ 10.0%) who were on a stable dose of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor (with or without metformin).
Patients were randomized equally to receive dapagliflozin or placebo added to sitagliptin alone (stratum 1) or added to sitagliptin plus metformin (stratum 2). Patients in stratum 1 received dapagliflozin 10 mg or placebo added to sitagliptin 100 mg/d. Patients in stratum 2 received dapagliflozin 10 mg or placebo added to sitagliptin 100 mg/d plus metformin ≥ 1500 mg/d.
Patients (n = 223) receiving dapagliflozin 10 mg added to sitagliptin with or without metformin demonstrated significantly greater improvements in glycemic control at the end of 24 weeks compared to patients (n = 224) taking placebo added to sitagliptin with or without metformin, with a change in baseline in HbA1c of -0.48% (p-value < 0.0001, Last Observation Carried Forward [LOCF]).
Additional results of the key primary and secondary endpoints included the following:
Dapagliflozin added to sitagliptin (stratum 1) resulted in a greater reduction in HbA1c compared to placebo added to sitagliptin, with a change in HbA1c of -0.56% (p-value < 0.0001, LOCF).
Dapagliflozin added to sitagliptin and metformin (stratum 2) resulted in a greater reduction in HbA1c compared to placebo added to sitagliptin plus metformin, with a change in HbA1c of -0.40% (p-value < 0.0001, LOCF).
Reductions in HbA1c were notable at four weeks (the first recorded time point) and maintained to 48 weeks.
Patients with a higher baseline HbA1c (≥ 8.0%) receiving treatment with dapagliflozin achieved greater reductions in HbA1c.
Significant reductions in body weight were observed with dapagliflozin compared to placebo in the entire treatment cohort (-1.89 kg, LOCF), stratum 1 (-1.85 kg, LOCF) and stratum 2 (-1.87 kg, LOCF), and were sustained out to 48 weeks.
Significant differences were also observed in adjusted mean FPG in patients who received dapagliflozin.
Patients in the dapagliflozin group did not show a statistically significant change from baseline in placebo subtracted seated systolic blood pressure (SBP, baseline ≥ 130 mm Hg) compared to placebo: -5.98 mm Hg (n = 101; dapagliflozin) vs. -5.12 mm Hg (n = 111; placebo) at week 24 (-0.86 [SE 1.47], p-value = 0.5583).
Over 24 weeks, 18.8% of patients receiving dapagliflozin discontinued for lack of efficacy or were rescued for meeting pre-specified rescue criteria vs. 41.5% receiving placebo.
Over the 48-week treatment period, the proportion of patients experiencing at least one adverse event was 66.2% in the dapagliflozin group compared to 61.1% in the placebo group. The most common adverse events occurring in ≥ 4.0% of the study population were as follows: nasopharyngitis, back pain, urinary tract infection, pharyngitis, arthralgia and headache.
The proportion of patients who experienced at least one serious adverse event was 6.7% in the dapagliflozin group compared to 8.0% in the placebo group. In either treatment group, 3.1% discontinued treatment due to an adverse event. Hypoglycemia was reported in 5.3% of the dapagliflozin group compared to 6.2% in the placebo group.
The proportion of patients with diagnoses of genital infections was 9.3% in the dapagliflozin group compared to 0.4% in the placebo group. The proportion of patients with diagnoses of urinary tract infections was 5.8% in the dapagliflozin group and 3.5% in the placebo group.
Adverse events suggestive of renal impairment or failure were observed in eight patients in the dapagliflozin group (3.6%) and four patients in the placebo group (1.8%). In four patients in the dapagliflozin group and in one patient in the placebo group, a decrease in renal creatinine clearance was reported.
About Type 2 Diabetes
In 2011, diabetes was estimated to affect more than 365 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 more than 550 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 disease characterized by insulin resistance and 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 still exist, as many patients remain inadequately controlled 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 a 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.
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 please visit: www.astrazeneca.com.
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 European Commission 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, 2011, 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 2011. Nothing contained herein should be construed as a profit forecast.