AstraZeneca Annual Report and Form 20-F Information 2008

Diabetes

The number of people affected by Type 2 diabetes continues to grow, driven by obesity in western markets. Type 2 diabetes is a chronic progressive disease and patients often require multiple medications to control their condition. There are a number of established oral generic and branded classes, such as sulfonylureas and thiazolidinediones (TZDs), however, newer classes, such as oral dipeptidyl peptidase-IV (DPP-IV) are entering the market successfully by offering effective blood sugar control and improved tolerability. Several new classes of drugs are in development in this area. The safety of anti-diabetic drugs continues to be an important focus of regulatory agencies and additional patient safety requirements for new medicines can be anticipated.

OUR FOCUS

In 2007, AstraZeneca and Bristol-Myers Squibb (BMS) announced the collaboration on a worldwide basis excluding Japan to develop and commercialise two compounds discovered by BMS (saxagliptin and dapagliflozin) being studied for the treatment of Type 2 diabetes. The development and commercial strategy for the two compounds is agreed jointly with BMS. In December 2008, AstraZeneca and BMS announced the extension of their collaboration to include dapagliflozin in Japan.

During 2008, AstraZeneca and BMS submitted a New Drug Application to the FDA and received the validation of a Marketing Authorisation Application to the European Medicines Agency for saxagliptin (Onglyza^™). Onglyza^™ was specifically designed to be a selective inhibitor with extended binding to the DPP-IV enzyme, with dual routes of clearance. Phase III data published during 2007 and 2008 showed improved glycaemic control when assessed as a monotherapy, as well as when assessed in combination with metformin, sulfonylureas and TZDs.

Dapagliflozin is a potential oral anti-diabetic belonging to the novel class of sodium-glucose cotransporter 2 (SGLT2) inhibitors. It is selective and designed to be used both as monotherapy and in combination with other therapies for Type 2 diabetes. Phase IIb data demonstrated that, when compared with a placebo, 12 weeks treatment with dapagliflozin improved blood glucose parameters, resulted in weight loss and was well tolerated in patients with Type 2 diabetes. An extensive Phase III programme is ongoing.

Our activities in the GKA (glucokinase activator) area continued during 2008, and clinical studies in Phase II are ongoing. The GKA mechanism of action induces insulin release from the pancreas and reduces glucose output from the liver, with marked blood glucose reducing effects in situations of hyperglycaemia.

We also progressed our AZD4017 (11-ßHDS inhibitor) project into early clinical testing which aims to increase insulin sensitivity and thereby induce better glycaemic control with potential beneficial effects also on body weight and blood lipids.

We have stopped work on cannabinoid receptor 1 inhibitors because the tolerability profile of these inhibitors was considered unacceptable.

In July 2008, AstraZeneca and Columbia University Medical Center announced a strategic research collaboration to develop novel therapeutics for Type 2 diabetes and obesity. The research will focus on discovering mechanisms and identifying new biological targets for successful and commercially viable treatments for these diseases.

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