ADA: Exenatide Shows Positive Results in People With Type 2 Diabetes

Over 50% of Patients Reach Target A1C Levels, Despite Previous Failure With Oral Therapies.

Results from a Phase 3 open-label study of exenatide, a novel drug candidate for the treatment of type 2 diabetes, showed that more than half of the participants who completed 20 weeks of treatment achieved average glucose levels within the American Diabetes Association's (ADA) target range. The findings from the ongoing study were presented at the ADA's 63rd Scientific Sessions in New Orleans, Louisiana.

Exenatide was added to the treatment regimens of 155 patients who had failed to reach target glucose levels on metformin, sulfonylurea, or a combination of the two. Prior to adding exenatide, the average level of hemoglobin A1c (A1C), a measure that provides a three-month average of glucose levels, was 8.6 percent. In the 63 patients who completed 20 weeks of treatment, the average A1C dropped 1.4 points to 7.2 percent, very near the ADA recommended target. In addition, exenatide decreased both fasting and post-prandial glucose levels.

"The fact that exenatide enabled so many patients not only to reduce their A1C but to reach the recommended target range is very encouraging," said Ralph DeFronzo, MD, MS, Professor of Medicine and Chief, Diabetes Division, University of Texas Health Science Center at San Antonio. "Reaching that target range is crucial to managing the disease and potentially preventing its devastating and deadly complications."

Exenatide (synthetic exendin-4) is being studied for its potential to address important unmet medical needs of many people with type 2 diabetes. Clinical trials suggest that exenatide decreases blood glucose toward normal levels. This control of blood glucose is likely due to actions of exenatide that are similar to those of the naturally occurring incretin hormone GLP-1. These actions are stimulation of the body's ability to produce insulin in response to elevated levels of blood glucose, inhibition of the release of glucagon following meals, and slowing of gastric emptying. In animal studies GLP-1 administration resulted in preservation and formation of new beta cells, the insulin-producing cells in the pancreas that fail as type 2 diabetes develops(1,2,3,4).

"These open-label findings suggest exenatide could provide an important new treatment tool for physicians and patients struggling to reach target glucose levels but failing with current oral treatments," said Kenneth Polonsky, M.D., Adolphus Busch Professor and Chairman, Department of Medicine, Washington University in St. Louis. "If we continue to see these types of results in this and other studies, exenatide could offer new hope to millions of patients."
The findings from this open-label study are based on results from 63 patients who have been using exenatide for 20 weeks. These patients had been taking metformin, sulfonylureas or the combination of both metformin and sulfonylureas for at least three months prior to entering the study and had A1Cs between 7.5 and 12.0 percent. Researchers added twice-daily injections of exenatide to the patients' pre-study medication regimen, with an initial dose of 5 micrograms administered at breakfast and dinner, which was increased to 10 micrograms after four weeks. The most frequently reported adverse event was mild to moderate nausea, which decreased with continued treatment. Consistent with previous trials, mild to moderate hypoglycemia was observed in some patients taking sulfonylureas. Some emesis was also observed. Of the 77 subjects included in the 20-week analysis, the overall dropout rate was approximately 18 percent (n=14). The dropout rate due to nausea was less than 8 percent (n=6). Antibody formation was observed, however, the data indicate that there is no correlation between antibody formation and the effect on A1C. Additional data presented on these 63 subjects showed that the 1.4% reduction in A1C was sustained through 24 weeks of treatment with exenatide.
Additional Exenatide Research Results at ADA: Exenatide Long-Acting-Release (LAR)

Specific data from a poster presentation at the ADA's Scientific Sessions indicate that exenatide, when given in an extended-release formulation, continues to demonstrate a potent glucose-lowering effect as measured by A1C and fasting glucose levels in rats. An Investigational New Drug Application was submitted to the Food and Drug Administration (FDA) in March 2003 to support an independent program for exenatide LAR. The goal of the exenatide LAR program is to develop an extended-release, subcutaneous injection of exenatide, which could lead to weekly or monthly, rather than daily injections.

An animal study presented at the conference further examined the impact of exenatide on beta cell function and mass. These study results confirmed that exenatide preserves beta cell mass and stimulates beta cell neogenesis through a mechanism of action that is independent of the potential benefits gained from the compound's effect on weight loss and glucose control. SOURCE Amylin Pharmaceuticals, Inc. and Eli Lilly and Company

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