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New BMS/Astra Zeneca Diabetes Drug FDA Approved
  * FDA requires future study of Onglyza's heart effects
* Drug will compete with Merck's Januvia (Adds FDA comments, competing drug)
WASHINGTON, July 31 (Reuters) - AstraZeneca PLC (AZN.L) and Bristol-Myers Squibb Co (BMY.N) won U.S. approval on Friday to sell a new diabetes drug called Onglyza.
The Food and Drug Administration said it was requiring a post-approval study to evaluate the drug's cardiovascular safety in higher-risk patients. Onglyza was not linked to increased heart problems in low-risk diabetics, the FDA said.
The drug's most common side effects include upper respiratory tract and urinary tract infections and headaches, the FDA said. Allergic-like reactions such as rashes and hives also were reported.
The companies hope Onglyza will carve out substantial sales by competing against Merck & Co's (MRK.N) blockbuster drug, Januvia, which sold $1.4 billion worldwide in 2008.
Both Onglyza and Januvia enhance the body's ability to lower elevated blood sugar levels and are part of a class of drugs known as dipeptidyl peptidase-4 (DPP-4) inhibitors.
Saxagliptin - Treatment for Type 2 Diabetes
The product of a joint development programme between AstraZeneca and Bristol-Myers Squibb (BMS), saxagliptin is a member of a new class of oral antidiabetic agents known as dipeptidyl peptidase IV inhibitors (DPP-IV) inhibitors or "incretin enhancers".
Saxagliptin has now reached advanced-stage development for the treatment of type 2 diabetes with filing for regulatory approval in the US expected in 2008 and in Europe in 2009. If approved it will be marketed under the brand name Onglyzaa.
Incretins as a target for antidiabetic medications
In the search for new antidiabetic medications, the incretin system has emerged as an important target for new glucose-lowering drugs. Incretins, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitor peptide (GIP), are naturally occurring hormones that are released from cells in the gut in response to food. They bind to receptors on pancreatic beta cells stimulating the release of the hormone insulin, responsible for the regulation of blood sugar levels.
"DPP-IV inhibitors are one of several new classes of antidiabetic medications in development for type 2 diabetes."
GLP-1 also reduces the secretion of glugacon, a hormone produced by the pancreas that stimulates the liver to convert glycogen to glucose thus increasing blood sugar levels.
In type 2 diabetes incretin function is impaired and patients are unable to properly regulate their blood sugar levels. Saxagliptin inhibits DPP-IV, an enzyme responsible for the breakdown of GLP-1. By delaying GLP-1 degradation, saxagliptin extends the action of insulin while also suppressing the release of glucagon. This leads to a reduction in elevated blood glucose levels that characterises type 2 diabetes.
Saxagliptin effective for type 2 diabetes
The phase III trial programme for saxaglitpin includes studies in which it is being administered as monotherapy as well as in combination with other standard antidiabetic drugs such as metformin, sulphonylureas, and thiazolidinediones. In newly released data from a 24-week randomised, multicentre, double-blind, placebo-controlled study in treatment naive type 2 diabetic patients, treatment with saxagliptin produced significant reductions in levels of glycosylated haemoglobin (HbA1C), fasting plasma glucose and postprandial glucose.
At once-daily doses of 2.5, 5.0 and 10mg, the placebo-adjusted reductions in HbA1Cwere -0.6, -0.6 and -0.7% respectively (<0.0001). At the highest dose, over 40% of patients achieved an HbA1C of <7% compared with 24% of placebo recipients (p<0.05).
Treatment with saxagliptin appears well tolerated, with a side-effect profile similar to placebo. Encouragingly, there were no cases of confirmed hypoglycaemia in the placebo-controlled trial or any evidence of significant weight gain.
Partnership in diabetes research
Estimates from the WHO suggest that globally some 221 million people have diabetes, of whom over 18 million are in the US. Type 2 diabetes accounts for 90 -95% of all cases of diabetes. Worldwide the costs associated with treating diabetes and its complications are estimated to exceed $200bn a year. By 2030 the prevalence of diabetes is predicted to double, driven by adverse lifestyle changes that have seen an explosion in the incidence of obesity, a major risk factor for type 2 diabetes. Worldwide diabetes is a huge and growing problem, and for which new treatments are needed.
"Treatment with saxagliptin appears well tolerated, with a side-effect profile similar to placebo."
As part of their collaborative venture into the development of new antidiabetic medications that was formed in 2007, AstraZeneca and BMS are working on two investigational antidiabetic agents: saxagliptin and dapagliflozin. While saxagliptin targets the incretin system, dapagliflozin (BMS-512148) is designed to inhibit the sodium-glucose uptake transporter (SGLT) in the proximal renal tubule of the kidneys. It is the first in this new class of antidiabetic medications (called selective SGLT inhibitors) to enter clinical trials.
Marketing commentary
DPP-IV inhibitors are one of several new classes of antidiabetic medications in development for type 2 diabetes. Two, vildagliptin (Galvusa ) and sitagliptin (Januviaa ), are already approved and in clinical use.
The ability of these agents to achieve sustainable reductions in HbA1c, the primary measure of blood glucose control, with an orally administered, well tolerated agent is seen as a major advantage over many older oral antidiabetic drugs.
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