By Nancy Volkers

Special To BioWorld Financial Watch

More than 16 million Americans have diabetes; about a third of them don't know they have it. Most people with diabetes have Type 2, or non-insulin-dependent diabetes, which usually starts in adulthood. Type 1, insulin-dependent diabetes, is an autoimmune disease diagnosed in childhood and requiring lifelong treatment.

The prevalence of diabetes has increased six-fold in the past 30 years. According to the Pharmaceutical Research and Manufacturers of America, diabetes costs the U.S. nearly $100 billion each year, more than twice as much as stroke ($43.3 billion) and nearly as much as cancer ($107 billion).

Diabetes can result in complications including kidney failure, limb amputation, blindness, and neurological and cardiovascular conditions. A study published in an April issue of the Journal of the American Medical Association reported that coronary artery disease remains a major killer of diabetics, compared with non-diabetics.

The FDA's approval in 1982 of Humulin (recombinant human insulin) was a watershed in diabetes treatment, not to mention a major advance for biotech. Humulin, manufactured and marketed by Eli Lilly and Co. under a license from Genentech Inc., was the first genetically engineered drug to hit the market.

Alternative insulin delivery became the next obstacle Type 1 diabetics must self-inject insulin up to four times a day. (Some Type 2 diabetics also take insulin, and/or hypoglycemic drugs, and are prescribed diet and exercise programs.) Though oral insulin once was portrayed as the next major advancement in diabetes treatment, several biotechnology firms are researching other methods of insulin administration. One, inhalable insulin, is showing promise in clinical trials.

"Clearly, there is growing interest in the concept of inhaled insulin," said Peter Ginsberg, senior research analyst at US Bancorp Piper Jaffray in Minneapolis. "We believe the market for inhaled insulin is well over $1 billion dollars. There are more than 4 million diabetics who could benefit."

Last month, Inhale Therapeutics Inc. announced it had begun dosing patients in a Phase III trial of inhalable insulin. Inhale, based in San Carlos, Calif., is collaborating with Pfizer Inc. and Aventis on the product. The Phase III program involves protocols for both types of diabetes, and is expected to involve more than 117 sites nationwide.

The pulmonary delivery system administers fine aerosol powders of insulin to the lung. The insulin is transported through lung tissue to the bloodstream. Inhale has tested six drugs in human clinical trials using its delivery system.

According to Robert Chess, chairman and co-CEO of Inhale, Aventis has begun construction of a large facility in Frankfurt, Germany, for manufacturing inhalable insulin. "It's one of the largest of its kind in the world," Chess said. "There's a lot of support for the product."

Aradigm Corp., of Hayward, Calif., announced results of a Phase II study of the company's AERx Diabetes Management System, also an inhalable product. When used immediately before a meal, the AERx system achieved glucose control comparable to that obtained when regular insulin is injected 30 minutes before a meal. The study included 20 insulin-dependent adults with Type 1 diabetes. Aradigm is collaborating with Novo Nordisk A/S on the work.

"It's a really important opportunity," said Mark Olbert, Aradigm's vice president of finance and administration and chief financial officer. Olbert said the company expects the product to penetrate first with newly diagnosed Type 2 diabetics.

"Newly diagnosed Type 2 [diabetics] will do almost anything to avoid injecting themselves," Olbert said. "It's painful, it carries a social stigma, and people associate injections with being really sick. They're used to taking pills, but not to injections."

Because the amount of insulin a diabetic needs varies from dose to dose, accurate dosing is important. Inhale uses a powdered insulin formulation; Aradigm uses a liquid formulation. Olbert said Aradigm's system allows patients to adjust the dose each time. In addition, he said, "the device has a monitor that monitors the way you breathe. It gives you feedback using red and green lights. Until you are breathing properly, the device will not deliver the drug. None of the competing systems has that."

Besides alternative methods of insulin delivery, other products are in the works for diabetes. At the end of June, Amylin Pharmaceuticals Inc. began a Phase II, multiple-dose clinical study of AC2993 (exendin-4) in Type 2 diabetics. The study will include people who use diet and exercise to manage their diabetes, those who take oral hypoglycemic agents, and those who use insulin. Results are expected in the fourth quarter of this year.

Exendin-4 is the synthetic form of a molecule isolated from the salivary glands of the Gila monster. Amylin licensed the rights to the protein from a researcher at the Bronx VA Hospital.

The protein "appears to lower plasma glucose," said Orville Kolterman, Amylin's senior vice president of clinical affairs. "It's injectable, but this peptide is so potent that it should be amenable to routes of alternative administration. At present, we think this would be almost exclusively a Type 2 product."

Last month, Amylin also presented results of a trial of Symlin (pramlintide), a synthetic analogue of the hormone amylin. The compound was given as an adjunct to insulin therapy to 499 people with Type 2 diabetes. The 26-week, double-blind, placebo-controlled study, conducted in Europe and Canada, showed that the addition of pramlintide led to significant improvements in glucose control and weight control.

Hemoglobin a1c, a measure of fasting plasma glucose, decreased significantly more in pramlintide-treated patients than in those who took placebo. Patients taking pramlintide also experienced weight loss during the study, while subjects receiving placebo gained weight.

"Amylin appears to complement the actions of insulin," Kolterman said. "This is targeted at patients who have severe impairments of beta cell function (Type 1 diabetics), as well as late-stage Type 2 patients. We think that adding this peptide to insulin treatment will compensate for some of the problems associated with insulin therapy, such as wide swings in blood sugar. We can improve glucose control without increasing severe hypoglycemic episodes."

Amylin currently is in two large pivotal trials, Kolterman said, and data are anticipated in the fall. "If those data are positive, we would be in a position to file [with the FDA]," he said

The recent approval of Avandia (rosiglitazone maleate) for Type 2 diabetes brings SmithKline Beecham plc's drug to market. Avandia was approved by the FDA as monotherapy or in combination with metformin in patients with Type 2 diabetes. The drug is a thiazolidinedione, a class of novel, oral antidiabetic agents that directly target insulin resistance.

SmithKline presented data in June showing that Avandia also improves blood sugar levels when used in combination with sulfonylureas or insulin. Sulfonylureas stimulate the pancreas to produce more insulin.

Also last month, Celtrix Pharmaceuticals Inc. presented final Phase IIa data on SomatoKine in patients with Type I diabetes. According to the company, SomatoKine decreased average daily insulin requirements by 49 percent and reduced average daily blood glucose by 23 percent from the levels attained by conventional insulin therapy.

Celtrix initiated the trial last year. SomatoKine is the company's novel IGF-BP3 complex; in addition to the inability to produce sufficient insulin, patients with Type 1 diabetes typically have low levels of IGF-1 (insulin-like growth factor-1). Studies have shown that treatment with IGF-1 increases insulin sensitivity, which reduces the requirement for exogenous insulin. BP3 is the regulatory binding protein of IGF-1.