Meta-Analysis of Clinical Data on Cardiovascular Safety Presented for Investigational Compound Dapagliflozin in Adult Pati

PRINCETON, N.J. & WILMINGTON, Del.--(BUSINESS WIRE)-- Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN) today announced results from a pre-specified meta-analysis of cardiovascular (CV) safety data from 14 Phase 2b/3 trials in adult patients with type 2 diabetes, which showed that the investigational compound dapagliflozin was not associated with an unacceptable increase in CV risk relative to all comparators pooled in the clinical program. The meta-analysis, presented today at the American Heart Association (AHA) Scientific Sessions in Orlando, FL, was conducted in accordance with the U.S. Food and Drug Administration (FDA) guidelines for the assessment of CV safety in new anti-diabetic treatments.

The meta-analysis included 6,228 patients, with 4,287 patients in the dapagliflozin group and 1,941 patients in the control group. The primary endpoint was a composite endpoint of time to first event of CV death, myocardial infarction (MI), stroke or hospitalization for unstable angina. The relative risk between dapagliflozin and the control group, measured by hazard ratio, was 0.67 (98% CI: 0.38, 1.18).

“This comprehensive analysis provides valuable information that can be used to better understand the cardiovascular safety profile of dapagliflozin as a monotherapy or as an add-on therapy to common anti-diabetic treatments,” said Brian Daniels, M.D., senior vice president, Global Development and Medical Affairs, Bristol-Myers Squibb.

“We are pleased that the findings from this meta-analysis support the cardiovascular safety profile of dapagliflozin in adult patients with type 2 diabetes, and we look forward to conducting additional research to continue to expand our understanding of dapagliflozin,” said Howard Hutchinson, M.D., chief medical officer, AstraZeneca.

Dapagliflozin, an inhibitor of SGLT2, a target in the kidney, is under joint development by Bristol-Myers Squibb and AstraZeneca. Dapagliflozin, as an adjunct to diet and exercise, is being investigated to evaluate its safety and its efficacy on blood sugar levels (glycosylated hemoglobin levels, or HbA1c) in adults with type 2 diabetes, for use as a monotherapy and in combination with other anti-diabetic agents. A New Drug Application (NDA) for dapagliflozin was accepted for review by the FDA in March 2011. The FDA recently extended the Prescription Drug User Fee Act (PDUFA) date by three months, setting the new goal date at January 28, 2012.

If dapagliflozin is approved, Bristol-Myers Squibb and AstraZeneca plan to conduct a large, post-marketing, randomized, controlled clinical CV outcomes study of the drug in patients with type 2 diabetes which will provide data on the long-term safety profile of dapagliflozin and examine whether or not the drug may provide a cardio-protective effect.

About the Study

The pre-specified meta-analysis of 14 Phase 2b/3 studies was designed to assess the CV safety of dapagliflozin relative to all comparators pooled in the clinical program. The primary endpoint was a composite endpoint of time to first event of CV death, MI, stroke or hospitalization for unstable angina.

The meta-analysis included 6,228 patients with type 2 diabetes, including 4,287 patients treated with dapagliflozin (2.5 mg, 5 mg, 10 mg doses) with or without add-on/combination anti-diabetes medication and 1,941 patients in the control group, treated with a placebo or an active comparator, with or without add-on/combination anti-diabetes medication.

The proportion of patients with at least one CV risk factor in addition to type 2 diabetes was 88.0% in both groups. The proportion of patients with at least two CV risk factors in addition to type 2 diabetes was 64.1% in the dapagliflozin group and 65.2% in the control group.

Baseline characteristics of patients assessed in the meta-analysis were balanced between the dapagliflozin and control group as follows:

  • Mean age: 55.9 years (dapagliflozin group) vs. 56.5 years (control group)
  • Mean body mass index: 31.5 kg/m2 for both groups
  • Mean disease duration: 6.1 years vs. 5.9 years

Characteristics of the dapagliflozin group vs. the control group mirrored CV risk in the general type 2 diabetes population and included:

  • Hypertension: 61.5% (dapagliflozin group) vs. 64.3% (control group)
  • Hypercholesterolemia: 49.4% vs. 48.8%
  • Smoking history: 39.7% vs. 40.3%
  • Age ≥ 65 years: 20.5 % vs. 23.5%
  • Prior CV disease: 19.6% vs. 18.2%
  • Family history of premature CV disease: 15.0% vs. 15.1%
  • Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2: 11.3% vs. 10.9%
  • History of heart failure: 2.2% vs. 1.7%

CV events in the studies were systematically identified from investigator reports of adverse events and adjudicated by an independent committee.

Study Results

The primary endpoint was a composite endpoint of time to first event of CV death, MI, stroke or hospitalization for unstable angina. A total of 78 primary endpoint CV events were confirmed, with 48 in the dapagliflozin group (n = 4,287) and 30 in the control group (n = 1,941). The relative risk between dapagliflozin and the control group, measured by hazard ratio, was 0.67 (98% CI: 0.38, 1.18).

Primary endpoint analyses by dapagliflozin dose were comparable to the overall results, with the relative risk of dapagliflozin compared to the control group as follows:

  • Dapagliflozin 2.5 mg: 0.88 (98% CI: 0.37, 2.09)
  • Dapagliflozin 5 mg: 0.53 (98% CI: 0.22, 1.27)
  • Dapagliflozin 10 mg: 0.56 (98% CI: 0.26, 1.24)

About Type 2 Diabetes

The Centers for Disease Control and Prevention estimate that approximately one in every 11 adults in the United States has diagnosed diabetes. 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 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 nearly half of treated patients remain inadequately controlled on their current glucose-lowering regimen. Many patients with type 2 diabetes have additional comorbidities (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.

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:
Bristol-Myers Squibb
Phil McNamara, +1-609-240-3739
[email protected]
or
AstraZeneca
Rachelle Benson, +1-302-885-5853
[email protected]
or
AstraZeneca
Kirsten Evraire, +1-302-885-0435
[email protected]

Investors:
Bristol-Myers Squibb
John Elicker, +1-609-252-4611
[email protected]
or
AstraZeneca
Karl Hard, +44-20-7604-8123
[email protected]

KEYWORDS:   United States  North America  Delaware  Florida  New Jersey

INDUSTRY KEYWORDS:   Health  Biotechnology  Cardiology  Clinical Trials  Pharmaceutical  Communications  Public Relations/Investor Relations  Diabetes  General Health

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