A group of 743 subjects (ages 18-77) with Type 2 diabetes whose hemoglobin A1C level was within the range of greater than or equal to 7 percent or less than or equal to 10 percent and on a stable metformin dose alone (1500 to 2550 mg/day) were randomized 1:1:1:1 to add-on saxagliptin 2.5 mg, 5 mg, 10 mg, or placebo once daily. The primary endpoint of the study was the change from baseline in hemoglobin A1C levels. After 24 weeks, the subjects receiving saxagliptin+metformin demonstrated statistically significant decreases in hemoglobin A1C levels compared to placebo+metformin: -0.73 percent, -0.83 percent, and -0.72 percent at the 2.5 mg, 5 mg and 10 mg doses, respectively (p-value at all dosage levels less than 0.0001 vs. placebo+metformin).

Saxagliptin+metformin also statistically significantly reduced fasting plasma glucose (secondary endpoint) as compared to placebo+metformin: -16 mg/dL, -23 mg/dL, and -22 mg/dL for saxagliptin 2.5 mg, 5 mg and 10 mg, respectively (p-value at all dosage levels less than 0.0001 vs.

placebo+metformin). The percentage of subjects with hemoglobin A1C less than 7 percent at Week 24 (secondary endpoint) was 17 percent for placebo+metformin and 37 percent, 44 percent and 44 percent for the 2.5 mg, 5 mg and 10 mg doses of saxagliptin respectively (p-value at all dosage levels less than 0.0001 vs. placebo+metformin).

In this study, the number of subjects with investigator-reported hypoglycemia, with or without confirmation, were: 9 on placebo+metformin, and 15, 10 and 7, for 2.5 mg, 5 mg, and 10 mg on saxagliptin+metformin, respectively. There was one subject with confirmed hypoglycemia in each of the four arms (as measured by blood glucose less than or equal to 50 mg/dL with symptoms). The most common adverse events seen in more than 5 percent of subjects randomized to either placebo+metformin or saxagliptin+metformin (all doses combined) were: nasopharyngitis 7.8% vs. 8.7 %, headache 7.3% vs. 8.0%, diarrhea 11.2% vs. 7.1%, upper respiratory infection 5.0% vs. 6.6%, influenza 7.3% vs. 6.0%, and urinary tract infection 4.5% vs. 5.1%.

Phase I Studies Also Presented at 2007 American Diabetes Association Annual Meeting
In the presentation "Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Once-Daily Oral Doses of Saxagliptin for 2 Weeks in Type 2 diabetic and Healthy Subjects" by David Boulton, Ph.D., Principal Scientist, Bristol-Myers Squibb, results from two Phase I studies were reported. Study 1 was conducted in subjects with Type 2 diabetes; Study 2 was conducted in healthy subjects. Both studies were placebo-controlled, randomized, double-blind, sequential, multiple ascending dose studies. The primary objective of these two studies was to assess the safety and tolerability profiles of multiple daily oral doses of saxagliptin in subjects with Type 2 diabetes and in healthy subjects.

Study 1 consisted of 40 subjects (ages 18-70) who had been diagnosed with Type 2 diabetes for less than 10 years, had hemoglobin A1C in the range of 6.5 to 9.5 percent, and fasting plasma glucose in the range 125-250 mg/dL. Participants were randomized to receive 2.5, 5, 15, 30, or 50 mg of saxagliptin or matched placebo once-daily for 14 days (3 saxagliptin, 1 placebo ratio, n=8 subjects/dose panel).

Study 2 consisted of 50 healthy subjects (ages 18-45) who were randomized to receive 40, 100, 150, 200, 300 or 400 mg saxagliptin or matching placebo once daily for 14 days. Within each panel, 6 subjects received 100, 150, 200, 300 or 400 mg saxagliptin, 2 subjects received 40 mg saxagliptin and 2 subjects received matching placebo.

In both studies, there were no deaths or serious adverse events. Additionally, no adverse events of hypoglycemia were reported by investigators. In Study 2, one participant experienced an adverse event (mild rash), which resulted in discontinuation from the study while taking 200 mg of saxagliptin once daily.