First Phase II Short-term Study on Dapagliflozin Shows Results on Safety, Tolerability and Glycemic Markers in Subjects with Type 2 Diabetes

The data were from a double-blind, placebo-controlled, randomized, parallel-group study of 47 subjects with an established diagnosis of Type 2 diabetes (ages 18-77) who were either drug-naïve or on a stable dose of metformin for at least 4 weeks prior to randomization with hemoglobin A1C levels between 6 and 10 percent with a FSG of less than or equal to 240 mg/dL. Subjects were randomized to receive either placebo (n=8) or dapagliflozin 5 mg (n=11), 25 mg (n=12), or 100 mg (n=16) once daily for 14 days in addition to their stable metformin dose and/or diet alone in an in-patient clinical research unit. The primary endpoint of the study was to assess both the safety and tolerability profiles of multiple doses of dapagliflozin in subjects with Type 2 diabetes. The secondary endpoints of the study included assessing the fasting serum glucose and post challenge glucose excursion. The presentation, “Dapagliflozin, a Selective Inhibitor of the Sodium-Glucose Uptake Transporter 2 (SGLT2), Reduces Fasting Serum Glucose and Glucose Excursion in Type 2 Diabetes Mellitus Patients Over 14 Days”, was presented by Bernard Komoroski, PharmD, Ph.D., Senior Research Investigator, Bristol-Myers Squibb.

On Day 13, the FSG was significantly reduced in participants receiving dapagliflozin with or without metformin as compared to their FSG levels two days prior to first dose: -14.5 percent (p-value less than 0.05), -17.3 percent (p-value less than 0.05), -21.9 percent (p-value less than 0.001) for dapagliflozin at 5 mg, 25 mg and 100 mg, respectively. FSG was reduced by -6.3 percent in participants receiving placebo with or without metformin.

There were no discontinuations due to adverse events and no serious adverse events were reported. Adverse events included two events of hypoglycemia in subjects receiving dapagliflozin co-administered with metformin. There were two events of vulvovaginal infection in the study (one subject receiving dapagliflozin alone and one subject receiving dapagliflozin+metformin). Adverse events occurred with similar frequency in subjects receiving dapagliflozin or placebo. The most frequently reported adverse events were: constipation (n=7; 1/19 on dapagliflozin+metformin, 3/20 on dapagliflozin alone, 2/6 on placebo+metformin, 1/2 on placebo alone), nausea (n=5; 4/19 on dapagliflozin+metformin, 1/6 on placebo+metformin), and diarrhea (n=4; 3/19 on dapagliflozin+metformin, 1/6 on placebo+metformin).

Preclinical Data Also Presented at 2007 American Diabetes Association Annual Meeting

In a second presentation this week – “Dapagliflozin, A Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats” by Jean Whaley, Sc.D., Director, Diabetes Drug Discovery, Bristol-Myers Squibb, the effect of dapagliflozin on glucose homeostasis in normal and diabetic rats was reported. In diabetic rats, dapagliflozin acutely induced renal glucose excretion at doses ranging from 0.01-1.0 mg/kg of body weight without inducing hypoglycemia. Additionally, as early as two hours after a single oral dose, there was a statistically significant reduction in plasma glucose levels in diabetic rats treated with dapagliflozin compared to untreated diabetic rats at doses of 0.1 mg/kg and 1.0 mg/kg (-101 mg/dL and -128 mg/dL), respectively (p-value less than 0.0001 at both doses).

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