Avandia

NEW YORK -- New treatments for people with diabetes are headed for pharmacy shelves now as the Food and Drug Administration recently approved one first-in-class pharmaceutical with blockbuster potential to help treat the disease for type 2 diabetics and currently is considering a second first-in-class diabetes drug.

The FDA in April approved Eli Lilly's Byetta (exenatide), a one-of-a-kind pharmaceutical that belongs to a class known as incretin mimetic agents, which mimic the hormone produced in the intestines that helps stimulate insulin production without risking the hypoglycemia associated with insulin injections.

Byetta is a synthetic version of exendin-4, a hormone in the saliva of the Gila monster, a lizard native to several southwestern U.S. states. The Gila monster only eats four times per year, and during the time it is not eating, its insulin-producing pancreas is not active. When the lizard eats, the exendin-4 found in its saliva makes the pancreas active again.

By mimicking the mechanisms of a naturally occurring human hormone that's similar to exendin-4, Byetta stays in the blood system, working actively only when blood sugar levels are too high.

Like insulin, however, Byetta is an injectable that will be administered by a pen-delivery system.

Analysts predict sales of Byetta could reach in excess of $800 million by 2009. However, Eli Lilly is expected to seek approval for a long-acting release formulation by 2007, and analysts speculate that a Byetta LAR could top $1.5 billion in sales.

Meanwhile, Bristol-Myers Squibb and Merck's joint application of Pargluva (muraglitazar), a first-in-class pharmaceutical that is expected to help control both blood glucose and lipid levels, gained approval from an FDA advisory panel last month, despite concerns over increased risk of cardiovascular events.

The panel did recommend that the drug not be prescribed with sulfonylurea drugs, a common class of diabetes medicines, because it may increase risk of heart problems. Analysts have predicted that Pargluva could reach blockbuster status by 2009, but that enthusiasm may be tempered somewhat based on the panel's recommendations. However, establishing a clear link between the diabetes treatment and an increased risk of heart disease may be more difficult to determine than it was for the cox-2 inhibitor. Patients with diabetes are already predisposed to increased heart disease risk, for instance.

According to Phase II trial results, Pargluva may help maintain glucose control over time by sensitizing cells to insulin and by reducing triglycerides.

"[Pargluva] provided effective and durable blood glucose lowering," stated David Kendall, chief of clinical services and medical director of the International Diabetes Center. In addition, Pargluva was found to lower triglycerides while raising HDL levels, which may reduce the risk of cardiovascular disease in people with type 2 diabetes.

"[In addition,] the patients on [Pargluva] went from poor control--an average A1C of 8 percent--to an excellent level of control--an average of 6.5 percent by the 20th week--and then maintained that level of control over two years," Kendall said.

The American Diabetes Association's recommended A1C target in type 2 diabetes is 7 percent or less.

Pargluva will face entrenched competition from GlaxoSmithKline's Avandia and Takeda Pharmaceutical's Actos, two blockbuster drugs that help sensitize cells to insulin, but that also tend to cause weight gain.

Actos one day may gain a new indication, judging from the results of a study presented at the American Diabetes Association annual meeting in June. According to the research, Actos helped reduce C-reactive protein, a marker of inflammation and a risk factor for cardiovascular disease.

"This study contributes to increasing data suggesting that Actos may have benefits beyond blood glucose control and an improvement in insulin resistance, although further studies are required, stated Robert Spanheimer, medical director for diabetes and metabolism at Takeda Pharmaceuticals North America.

Looking down the diabetes drug development road, Merck recently announced a research and development collaboration with Metabasis Therapeutics to find medicines for type 2 diabetics, among other disease states. The companies will be researching and developing AMP-activated protein kinase pharmaceuticals. AMPK is a component of a protein that acts as an intracellular energy sensor maintaining the energy balance within the cell. This pivotal role of AMPK places it in an ideal position for regulating whole-body energy metabolism, and AMPK might play a part in protecting the body from metabolic diseases, such as type 2 diabetes and obesity.

And another new drug currently under FDA review, Sanofi-Aventis' Acomplia, has demonstrated that it can help multiple problems associated with type 2 diabetes by lowering blood glucose and reducing weight and waist circumference, as well as modifying the disordered lipids associated with diabetic dyslipidemia, according to a report presented at the American Diabetes Association's annual meeting.

With a new drug application filed in June, the drug currently is being considered for weight loss and smoking cessation.

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