Amylin Pharmaceuticals, Eli Lilly and Alkermes announced on 26 March, 2009 that a meta-analysis of primary cardiovascular events across controlled clinical studies of three months or greater, from the exenatide (Byetta) injection database, showed no increased risk of cardiovascular events associated with exenatide use.
This analysis was done in a manner consistent with FDA’s updated guidance for evaluating cardiovascular risk in type 2 diabetes agents.
Results of this analysis indicate that the relative risk of cardiovascular events in exenatide-treated patients, compared to controls, was .70 with a 95% confidence interval of .38-1.31. In this analysis, cardiovascular events included cardiovascular mortality, myocardial infarction, stroke, hospitalisation for acute coronary syndrome and revascularisation procedures. This finding suggests there is no increased risk of exenatide on cardiovascular outcomes and will be used to support the cardiovascular safety of exenatide once weekly, a phase III investigational formulation of exenatide.
To determine if there are favorable cardiovascular effects of exenatide treatment, Lilly and Amylin intend to initiate a large cardiovascular outcomes trial with a superiority design that will evaluate the effects of exenatide once weekly on major cardiovascular events, compared to standard of care with traditional antidiabetes medications. The global study will be sponsored by Amylin and Lilly, and active discussions are ongoing to have the study led by two academic research centres, The Diabetes Trial Unit at the Oxford Centre for Diabetes (Oxford, UK) and Duke Clinical Research Institute at Duke University (Durham, USA). The steering committee for this study is chaired by Professor Rury Holman, Diabetes Trial Unit, Oxford University, and Dr Robert M Califf, Duke University.
“There is a major unmet need for proven therapies that can help reduce the excess cardiovascular morbidity and mortality associated with type 2 diabetes,” said Holman. “This trial is designed to determine the extent to which exenatide may reduce cardiovascular risk, in addition to lowering glucose.”
The analyses to demonstrate comparability necessary for the regulatory submission of exenatide once weekly have been successfully completed and will be part of the new drug application submitted to FDA by the end of the second quarter 2009. These analyses include data from the ongoing extension of the DURATION-1 study, and will be used to support comparability between intermediate-scale clinical trial material made in Alkermes’ manufacturing facility and commercial-scale drug product made at Amylin’s manufacturing facility.
The companies have initiated DURATION-5, a new phase IIIb study in which patients with type 2 diabetes will use exenatide once weekly commercial-scale drug product in its final commercial configuration. This randomised, 26-week, open-label study in approximately 240 patients has broad utility and is designed to show superiority of exenatide once weekly compared to Byetta, support regulatory submissions outside the United States and provide additional controlled clinical data on the commercially manufactured product.
Byetta is the first and only FDA-approved incretin mimetic for the treatment of type 2 diabetes. Bytta exhibits many of the same effects as the human incretin hormone glucagon like peptide-1 (GLP-1). GLP-1 improves blood sugar after food intake through multiple effects that work in concert on the stomach, liver, pancreas and brain. Byetta is approved by the FDA for use by people with type 2 diabetes who are unsuccessful at controlling their blood sugar levels. Byetta is an add-on therapy for people currently using metformin, a sulfonylurea, or a thiazolidinedione. It provides sustained A1C control and low incidence of hypoglycemia when used with metformin or a thiazolidinedione, with potential weight loss.