New Drugs, Devices Mount Assault On Diabetes

Scientists are racing to find the grail of diabetes research, a therapy that will eliminate the need for insulin injection. New products, innovative clinical trials, and a boost in federal funding all are contributing to a multifaceted effort to control one of America's most complex and dangerous ailments. With research getting promising results in several different fields, skilled people are in demand. TRANSPLANT SUCCESS: Transplantation of the whole pancreas should be performed more often, surgeon David Sutherland suggests. "The main areas where R&D appears to be having practical ramifications are in developing different medications and delivery systems," says Frank Vinicor, director of the division of diabetes at the Centers for Disease Control and Prevention in Atlanta. "Transplantation is another area." R&D ADVANCES: New medications, delivery systems, and transplantation are all making progress in combating diabetes, says CDC's Frank Vinicor. Such R&D efforts are warranted: Diabetes is America's fourth leading cause of death by disease, costing an estimated $138 billion in direct health care and indirect productivity losses annually, according to the American Diabetes Association (ADA). Among an estimated 16 million diabetics in the United States, half are undiagnosed. At the ADA's 57th annual scientific sessions in Boston last June, an international committee of doctors and scientists recommended lowering the test value number of glucose levels for diagnosing diabetes. This measure, combined with wide-scale adult screening for early detection, could result in diagnosis of another 2 million diabetics. The committee also recommended that two misleading terms used to classify diabetes mellitus, the most commonly occurring among a group of diabetes diseases, be abandoned. The terms describe the two main types of diabetes mellitus, "insulin-dependent" for type 1 and "insulin-independent" for type 2. The committee noted that either type may require insulin therapy, and the terms don't indicate the underlying problems. In diabetes mellitus, the body is unable to metabolize glucose, which is the major form of carbohydrates assimilated by animals. All the body's cells need glucose, but its entry from the bloodstream into the cells requires the binding of insulin to receptors. Glucose normally spurs this process by stimulating the secretion of insulin from the pancreas. Beta cells in the pancreas fail to produce insulin in type 1 diabetes, which affects about 700,000 Americans. Type 1 occurs in two forms. The first is a chronic, autoimmune disease that usually afflicts children or young adults. In this form of the disease, the immune system mistakenly identifies the beta cells as foreign bodies, attacking and destroying them. The second form of type 1 is idiopathic and rare. Type 2 diabetes may involve problems with both insulin secretion and insulin resistance. In the latter case, the cells' insulin receptors malfunction, preventing glucose from entering the cells. The resultant hyperglycemia or glucose toxicity further impairs insulin secretion. About 15.3 million Americans are thought to have this type of diabetes, which typically plagues people over age 45 who are overweight and sedentary and have a family history of the disease. Both types of diabetes prevent glucose from entering the cells, resulting in high blood-sugar levels and lack of cell nourishment. Debilitating complications can follow, including nerve degeneration, chronic pain, arteriosclerosis, loss of limbs due to peripheral vascular disease, blindness, and kidney failure. Aside from proper diet and exercise, which are essential to treatment of both diabetes types, the main therapy for type 1 currently is insulin injection, while a number of oral medications are available for type 2. Diabetes research got a boost in August when the president signed the Balanced Budget Act, which set aside $300 million for diabetes research over the next five years. Much of these funds will likely be allocated to the National Institutes of Health, which already has an annual diabetes budget of $300 million. Half of the new money is earmarked for R&D on type 1 diabetes. "I think there's a lot of improvement in therapy right now for type 2, but for type 1, we're not quite there yet," says Judith Fradkin, acting chief of the diabetes programs branch in NIH's National Institute of Diabetes and Digestive and Kidney Diseases. "Different preparations of insulin are being developed, such as micropens [extremely small needles] and inhalers, but they don't get to what you really want, which is some sort of regulated insulin secretion in response to the body's glucose levels." Four classes of pills now on the market give doctors an array of options in helping a patient's body to utilize insulin for type 2 treatment. These drugs, however, do not deliver new insulin and therefore are not useful for type 1 sufferers. Each class has a specific action: It stimulates insulin production, decreases the amount of sugar secreted by the liver, interferes with the digestive process to slow down sugar absorption into the bloodstream, or reduces insulin resistance. The last of these effects is produced by the newest drug, Rezulin (troglitazone), from Morris Plains, N.J.-based Warner-Lambert Co.'s Parke-Davis division. Rezulin was approved by the Food and Drug Administration (FDA) in January. IMMUNE RESPONSE: Oral tolerance therapy is all about an immogenic response rather than a metabolic effect, says AutoImmune's Robert Bishop. There also is a new pill being developed to help type 1 sufferers. AutoImmune Inc., a Lexington, Mass., biopharmaceutical firm, is applying its "oral tolerance therapy" technology to diabetes. AutoImmune has developed a formulation of recombinant human insulin called AI-401, which is designed to stop progression of type 1 diabetes. "We are giving the drug in dosages so small that it's incapable of causing changes in the blood glucose level," notes Robert Bishop, AutoImmune president and chief executive officer. "What we're after is not a metabolic effect, but an immunogenic response." That response is achieved by stimulating the natural mucosal immune mechanisms of the small intestine. A precisely calculated dose of insulin is broken down to fragments during digestion, and the resultant peptides activate regulatory T cells in the immune system. They then release immunoregulatory substances called cytokines to suppress "autoreactive" T cells that have been attacking the pancreas. AI-401 is now in clinical trials in the U.S., France, and Italy, all of which are being supported by Indianapolis-based Eli Lilly and Co. in a $40 million partnership. Clinical trials of other methods to induce tolerance are under way in Canada, Australia, and Europe (A. Skolnick, JAMA-Journal of the American Medical Association, 277:1101-2,1997). These trials were inspired, in part, by a recent discovery that the thymus gland in the chest produces beta cells. The thymus trains the immune system to tolerate its own tissues, so administering insulin to the thymus via the nose or mouth has the potential to curb the disease. Among the most promising new therapies is powdered insulin inhalation, from Inhale Therapeutic Systems of Palo Alto, Calif. Phase IIb clinical trials of the pulmonary system are being completed by New York-based Pfizer Inc. If further trials and FDA approval occur, it could reach the market by 2000 or 2001. The 6-inch-tall device forces compressed air into a chamber at sonic velocity, breaking the fine, dry powder into respirable particles that form a "standing cloud." With one slow, deep breath, the patient takes in medicine followed by air that pushes the drug down into the deep lung, where it is quickly absorbed into the bloodstream. "There's been tremendous interest lately in the pulmonary route," says John Patton, Inhale's vice president of research. "Our system is a fabulous way to get proprietary extension," he adds. "It's like a rebirth of an old compound. You know, the adage in drug delivery is, you don't need new drugs, you only need new ways to deliver them." Inhale has 10 projects sponsored by a handful of partners and made its initial public offering in 1994. Patton won't say how much the diabetes pulmonary system is costing Inhale and Pfizer to develop, but he notes that an industry rule of thumb is $200 million to $300 million for a new drug and $10 million to $40 million for a delivery system. Patton is impressed by the entry onto the market last year of Humalog (lispro) insulin, from Eli Lilly. According to Lilly, this is the first new insulin developed in 14 years. It is approximately as fast-acting as Inhale's aerosol insulin and can be taken 15 minutes before a meal rather than the usual 30 minutes to 60 minutes before eating. However, Humalog is injected, whereas Inhale's product would be noninvasive. American Diabetes Association www.diabetes.org/ Autoimmune Inc. www.autoimmuneinc.com Eli Lilly and Co. www.lilly.com/diabetes Pfizer Inc. www.pfizer.com Warner-Lambert Co. www.warner-lambert.com Conventional insulin therapy requires one or two injections daily, but a more effective way to slow the complications of diabetes is "tight control," which requires vigilant glucose monitoring and multiple injections. The therapy has met with resistance from both patients and doctors, leading to a new emphasis by researchers on "closed loop" systems, in which the glucose level is monitored and the hormone delivered in response to metabolic demand (C. Newgard et al., Diabetologia, 40:S42-7, 1997). There are three avenues of research to create closed loop systems, all of which are invasive. One method is a pump implanted in the body and linked to a blood glucose detector. Developmental work is aimed at fitting the pump with a glucose sensor chip, essentially creating a mechanical pancreas. A second option is transplantation of the pancreas or pancreatic islet cells. "It used to be thought that islet cells would be less susceptible to rejection than a solid organ but that hasn't proven to be true," says David Sutherland, head of the transplant division in the University of Minnesota's department of surgery. "The only thing that currently works for transplantation is the whole pancreas." By 1996, almost 9,000 kidney transplants had been done worldwide, according to Sutherland. The operations usually are performed with a kidney transplant, because the need already exists in such patients for immunosuppression, which can cause serious side effects, including increased susceptibility to infection. Long-term insulin-independence is achieved in the majority of these cases. About 5,000 cadaver pancreases are available for transplantation annually in the U.S., yet just 1,000 transplants are now performed each year. "That means at least 4,000 pancreases are thrown away," Sutherland notes. "I think by the year 2000, at least 3,000 transplants per year will be done." He says a donor pancreas can be split, thus doubling the number of transplant possibilities. "It is possible to transplant from living donors," he adds. "We've done that with 100 patients." The third type of closed-loop technology, molecular engineering of cell lines that will secrete insulin, is still in animal testing phases, but some promising results have been achieved. In Dallas, BetaGene Inc. is engineering cell lines with regulated insulin secretion that could serve as surrogates for primary islets or pancreas tissue in transplants. Standardizing transplant material in this way could help to address the problem of donor tissue rejection. TESTS NEEDED: The time is nearing to test engineering cell lines in humans, states BetaGene's Karl Normington, left, with Chris Newgard, founding scientist and member of the company's board of directors. "A universally engineered cell line will give reproducibility in the transplant," explains Karl Normington, BetaGene's director of strategic alliance and cell biology. "We are curing diabetes in rats right now, for periods of time, but what's becoming more critical, I think, is just how well the cell lines will work in vivo." One challenge is to create a transplantation capsule that will protect the cell lines from the immune system. Normington says BetaGene's partner, diversified manufacturer W.L. Gore and Associates Inc. of Delaware, Md., is developing this "amino isolation device." Another hurdle is that the biochemical mechanism of glucose sensing, by which beta cells are stimulated to produce insulin, is not well understood. This makes it difficult to engineer cells that mimic the normal beta cell, especially because it responds not only to glucose but also to lipids, fatty acids, and other substances. Nevertheless, Normington is confident that the field will produce viable advances in insulin delivery. Other research also is galloping along. In April, Eli Lilly announced a licensing agreement with Eastern Virginia Medical School and McGill University of Montreal, the codiscoverers of a gene called INGAP (Islets Neogenesis Associated Protein) that is thought to convert dormant cells on the pancreas into insulin-producing beta cells. In July, researchers at Lilly and Washington University School of Medicine in St. Louis reported that supplements of the protein C-peptide-an insulin production byproduct with no known function-not only prevented damage to the blood vessels and nerve fibers of diabetic rats but also actually improved such functions in animals already damaged by the disease (Y. Ido et al., Science, 277:563-6, 1997). In August, an international team of virologists at the University of Geneva isolated a retrovirus-a virus that converts from RNA to DNA when it enters cells and incorporates itself into host genes-in the plasma of type 1 patients and concluded that the superantigen chemical it produces could activate the autoreactive T-cells that attack beta cells (B. Conrad et al., Cell, 90:303-13, 1997). If confirmed, this finding could have huge repercussions: it might mean that other autoimmune diseases also are sparked by a retrovirus. With so much happening, companies are looking for researchers in many disciplines. "We've had openings for 30 to 40 people for the last 11/2 years, so we're constantly hiring," remarks Inhale's Patton. He's looking for chemical engineers, protein chemists, and technicians adept in computerized architectural design for his R&D staff of 128. AutoImmune's Bishop says, "The kinds of people we employ are pharmaceutical developmental scientists and researchers who have expertise and technical skills in immunology." BetaGene's Normington comments, "We do a unique combination of molecular biology, cell biology. and animal work, so our people cross all worlds."

New Drugs, Devices Mount Assault On Diabetes

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