PRINCETON, N.J. & WILMINGTON, Del.--(BUSINESS WIRE)--Results from an interim analysis of a long-term Phase 3 study at 102 weeks with ONGLYZA^™ (saxagliptin), an investigational, selective, reversible inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme under joint development by Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN), when added to metformin in people with inadequately controlled type 2 diabetes, demonstrated an overall profile of adverse events consistent with that seen at 24 weeks, and produced long-term glycemic improvement [as measured by glycosylated hemoglobin level (A1C)]. Results were presented at the 69^th American Diabetes Association Annual Scientific Sessions.

“Type 2 diabetes is a progressive and chronic disease, with patients struggling every day to control their blood glucose levels,” said Roland Chen, MD, group director, Cardiovascular/ Metabolics, Bristol-Myers Squibb.

“It is, therefore, important for us to understand how investigational diabetes medicines work over an extended period of time,” said Peter Ohman, medical science director, Cardiovascular/Gastrointestinal Therapy Area, AstraZeneca.

About the Study: Saxagliptin Added To Metformin Over 102 Weeks

The study is an interim analysis of a 42-month long-term extension study designed to assess the safety, tolerability and efficacy of saxagliptin when added to metformin in people with inadequately controlled type 2 diabetes, compared to metformin plus placebo. The current data represent interim findings after 102 weeks for this randomized, double blind, placebo controlled, multi-center international study of 743 individuals with type 2 diabetes (ages 18 - 77) whose A1C level was greater than or equal to 7 percent and less than or equal to 10 percent on a stable metformin dose alone (1500 to 2500 mg/day). Individuals were randomized to one of four separate treatment arms: saxagliptin 2.5 mg + metformin 1500 to 2500 mg/day (n=192), saxagliptin 5 mg + metformin 1500 to 2500 mg/day (n=191), saxagliptin 10 mg + metformin 1500 to 2500 mg/day (n=181), or placebo + metformin 1500 to 2500 mg/day (n=179), given once daily.

All individuals who completed the 24-week short-term study were eligible to enroll in the long-term extension study, including individuals who met prespecified glycemic rescue criteria during the short-term study period and received open-label pioglitazone 15 to 45 mg + blinded study medication. Pioglitazone rescue therapy was also available during the long-term extension study based on a prespecified glycemic criteria.

The primary endpoint of the study was the long-term safety and tolerability of saxagliptin when added to metformin. The efficacy endpoints of the study included changes from baseline in A1C, fasting plasma glucose (FPG), and post-prandial glucose (PPG), measured during an oral glucose tolerance test [OGTT], and the proportion of individuals achieving the American Diabetes Association recommended A1C target of less than 7 percent. Study results were based on the Last Observation Carried Forward (LOCF) method.

Study Results

Safety and Tolerability

After 102 weeks, results from the interim analysis demonstrated that the incidence of adverse events was similar for saxagliptin 5 mg + metformin compared to placebo + metformin; the rates of adverse events were slightly greater for saxagliptin 2.5 mg + metformin and saxagliptin 10 mg + metformin versus placebo + metformin.

Adverse event rates were as follows: 89.6 percent for saxagliptin 2.5 mg + metformin, 78 percent for saxagliptin 5 mg + metformin, and 86.7 percent for saxagliptin 10 mg + metformin; the incidence of adverse events was 78.8 percent for placebo + metformin. The percentages of the most commonly reported adverse events for the saxagliptin 2.5 mg + metformin, saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin and placebo + metformin treatment arms, were: nasopharyngitis [13.0, 11.0, 13.8, 10.6], influenza [10.4, 11.5, 12.7, 12.8], upper respiratory tract infection [12.0, 8.9, 10.5, 7.8], urinary tract infection [9.9, 7.9, 9.4, 6.7], bronchitis [6.3, 9.4, 5.0, 6.1], diarrhea [14.1, 7.3, 9.4, 12.8] back pain [7.8, 7.9, 5.0, 8.9] and headache [13.5, 8.9, 12.2, 11.2].

The rate of reported hypoglycemic events was similar among all treatment arms: 10.4 percent for saxagliptin 2.5 + metformin, 8.9 percent for saxagliptin 5 mg + metformin, and 11 percent for saxagliptin 10 mg + metformin; the incidence of reported hypoglycemic events was 10.1 percent for placebo + metformin. The occurrence of confirmed hypoglycemia (symptoms of hypoglycemia with a fingerstick glucose less than or equal to 50 mg/dL) was less than or equal to 1.1 percent for all treatment arms.

The proportion of individuals who discontinued the long-term study for lack of glycemic control or were rescued for meeting prespecified glycemic criteria was lower in the saxagliptin treatment arms compared to the placebo arm: 58.3 percent for saxagliptin 2.5 mg + metformin, 51.8 percent for saxagliptin 5 mg + metformin, 56.9 percent for saxagliptin 10 mg + metformin, and 71.5 percent for placebo + metformin.

At 102 weeks, there was a numerically higher incidence of skin-related adverse events in the saxagliptin + metformin treatment arms compared to the placebo + metformin treatment arm: 15.6 percent for saxagliptin 2.5 mg + metformin, 13.6 percent for saxagliptin 5 mg + metformin, 22.7 percent for saxagliptin 10 mg plus metformin, and 11.2 percent for placebo plus metformin.

Small decreases in mean body weight at week 102 (before rescue, last observation carried forward) versus baseline were observed in all treatment arms: -1.0 kg, -0.4 kg and -0.5 kg for saxagliptin 2.5 + metformin, saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin, respectively, compared to -0.8 kg for placebo + metformin.

Glycemic Efficacy

After 102 weeks, individuals in the saxagliptin + metformin treatment arms demonstrated a placebo-adjusted mean change in A1C from baseline of -0.62 percent for saxagliptin 2.5 mg + metformin, -0.72 percent for saxagliptin 5 mg + metformin, and -0.52 percent for saxagliptin 10 mg + metformin. Changes in other measures of glycemic control were consistent with the observed changes in A1C.

About ONGLYZA

ONGLYZA, the trade name for saxagliptin, is an investigational DPP-4 inhibitor, under joint development by Bristol-Myers Squibb and AstraZeneca for the treatment of type 2 diabetes. Saxagliptin is being studied in clinical trials as a once-daily therapy to determine its efficacy and safety. Saxagliptin was specifically designed to be a selective inhibitor with extended binding to the DPP-4 enzyme, with dual routes of clearance.

Saxagliptin Phase 3 data have previously been presented as a monotherapy, as well as in combination with metformin, sulfonylureas and thiazolidinediones, commonly prescribed oral anti-diabetic medications. The overall clinical development program included over 5,000 individuals – more than 4,000 of whom were given saxagliptin.

The companies submitted a New Drug Application to the U.S. Food & Drug Administration (FDA) on June 30, 2008, which has been officially filed by the FDA, and a Marketing Authorization Application to the European Medicines Agency (EMEA) on July 1, 2008, which has been accepted for review by the Agency.

About DPP-4 Inhibitors

DPP-4 inhibitors are a class of compounds that are believed to work by affecting the action of natural hormones in the body called incretins. Incretins decrease elevated blood sugar levels (glucose) by increasing the body’s utilization of sugar, mainly through increasing insulin production in the pancreas, and by reducing the liver’s production of glucose.

About Type 2 Diabetes

Diabetes (diabetes mellitus) is a chronic disease in which the body does not produce or properly use insulin. Insulin is a hormone that is needed to convert sugar, starches (carbohydrates) and other nutrients into energy needed for daily life. The cause of diabetes continues to be investigated, and both genetic and environmental factors such as obesity and lack of exercise appear to play a role. Diabetes is associated with long-term complications that affect almost every part of the body. The disease may lead to blindness, heart and blood vessel disease, stroke, kidney failure, amputations, and nerve damage.

There are two primary underlying causes associated with type 2 diabetes: the body does not produce enough insulin (insulin deficiency), or the cells ignore the insulin (insulin resistance). Symptoms of type 2 diabetes develop gradually, and their onset is not as sudden as in type 1 diabetes. Symptoms may include fatigue, frequent urination, increased thirst and hunger, weight loss, blurred vision, and slow healing of wounds or sores. Some people, however, have no symptoms.

Type 2 diabetes is most often associated with older age, obesity, family history of diabetes, previous history of gestational diabetes, physical inactivity and certain ethnicities. People with type 2 diabetes often are characterized with: insulin resistance, abdominal obesity, a sedentary lifestyle, having low HDL-C (“good”) cholesterol levels, and high triglyceride levels and hypertension.

Type 2 diabetes accounts for approximately 90 to 95 percent of all diabetes. This equates to roughly 221 million people with type 2 diabetes globally, and 21.2 million people in the U.S. alone.

The American Diabetes Association recommends a hemoglobin A1C measurement of less than 7 percent for most people with type 2 diabetes. Hemoglobin A1C is a measurement of a person’s average blood glucose level over a two-to-three month period and is considered an important marker of long-term glucose control. Other important markers for type 2 diabetes include fasting plasma glucose, a measure of a person’s blood glucose after at least eight hours of fasting and post-prandial glucose, a measure of a person’s blood glucose after a meal.

Bristol-Myers Squibb and AstraZeneca Collaboration

Bristol-Myers Squibb and AstraZeneca entered into collaboration in January 2007 to enable the companies to research, develop and commercialize two investigational drugs for type 2 diabetes – ONGLYZA and dapagliflozin. 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 extend and enhance human life. For more information visit http://www.bms.com.

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of US $31.6 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. For more information about AstraZeneca, please visit: http://www.astrazeneca.com/.

ONGLYZA^™ is a trademark of the Bristol-Myers Squibb Company.