Laurie Barclay, M.D.

Type 1 diabetes is an autoimmune disease in which the beta cells of the pancreas do not produce sufficient insulin, causing high blood glucose which must be treated with exogenous insulin. Unlike Type 2 diabetes, Type 1 diabetes, often termed juvenile or insulin-dependent diabetes, usually begins during childhood or early adulthood.

In the U.S., about 15.7 million people, or 5.9% of the population, have diabetes of either type. Although about 10.3 million have been diagnosed, about 5.4 million people are unaware that they have diabetes. The annual incidence of Type 1 diabetes, which affects more than 700,000 Americans, is 3.7 to 20 per 100,000. Health care costs and costs of lost productivity related to diabetes are between $98 billion and $138 billion annually.

Diabetes is the seventh leading cause of death in the U.S., the leading cause of new cases of blindness in adults 20 to 74 years of age, and the leading cause of end-stage renal disease, accounting for about 40% of new cases. Other complications include peripheral neuropathy, affecting about 60% to 70% of patients.

Diabetes is the most common cause of non-traumatic lower limb amputations, and it increases the risk of leg amputation 15- to 40-fold. Heart disease is present in 75% of diabetes-related deaths, and having diabetes doubles to quadruples the risk of heart disease. Most of these complications are related to changes in the microvasculature, with thickening of capillary walls resulting in local ischemia.

In type 1 diabetes, lack of insulin causes glucose to accumulate in the bloodstream instead of entering the cells. Because this glucose cannot be used for energy, symptoms include hunger, fatigue, and weight loss despite increased appetite. Hyperglycemia causes frequent urination and excessive thirst. Complete destruction of beta cells and cessation of insulin production typically occurs within five to 10 years. Other symptoms may include nausea, vomiting, abdominal pain, and amenorrhea.

Tests used to diagnose diabetes include fasting blood glucose of at least 126 mg/dL, urinalysis positive for glucose and ketone bodies, and low or undetectable level of insulin or C-peptide, a by-product of insulin production. Glycosylated hemoglobin (HbA1c) should be measured two to four times each year to evaluate overall glucose control.

Currently available treatment includes insulin, injected once to four times daily and adjusted based on self- testing of blood glucose; diet and weight control; exercise; and foot care. Insulin preparations differ in their onset and duration of action, and more than one type may be mixed together in an injection for optimal glucose control.

Complications include diabetic ketoacidosis, caused by breakdown of fat as an alternate fuel, and hypoglycemia related to excessive insulin use. Hypoglycemia usually responds to eating sugar, but in severe cases associated with confusion, seizures, or unconsciousness, an injection of glucagon may be needed. Diabetic ketoacidosis needs to be treated immediately, or coma and even death may ensue.

CenterWatch has identified a pipeline of 19 drugs in various stages of development for diabetes treatment and monitoring. Most of these are novel formulations of insulin.

Amylin Pharmaceuticals has submitted a new drug application for Symlin (pramlintide), a synthetic injectable analog of the human hormone amylin. This hormone is normally secreted by the beta cells and works synergistically with insulin and glucagon to maintain normal glucose concentrations.

In six Phase III clinical trials, Symlin has been associated with improved blood glucose control and reduced HbA1c levels in patients treated with insulin alone, or insulin plus one or more oral medications, without causing weight gain. More than 5,000 patients have been treated with Symlin in these studies, earlier trials, and long- term open-label safety trials.

During treatment for 26 or 52 weeks, there were no adverse effects on lipids or blood pressure. The most common adverse effects were nausea, anorexia and vomiting. These were generally mild to moderate, dose-related, and tended to resolve over time.

In collaboration with Aventis and Nektar Therapeutics, Pfizer has completed Phase III development of Exubera, an inhaled, short-acting, fine dry-powder insulin preparation with rapid onset of action. If approved, Exubera could eliminate the need for meal-time insulin injections and improve treatment compliance. However, concerns about long-term pulmonary safety have delayed filings for regulatory approval in Europe and the U.S., pending additional safety data.

More than 2,000 patients have been treated with Exubera in worldwide clinical trials to date, some for as long as five years. Phase III clinical trials suggest that Exubera may be as effective as injected insulin and better than oral hypoglycemic agents in lowering blood glucose. In a Phase III study of 328 patients, glucose control was similar in patients receiving Exubera before meals plus two daily insulin injections to that in patients receiving four daily insulin injections. Furthermore, the patients receiving Exubera had greater reductions in fasting plasma glucose levels and in two-hour post-prandial glucose. Compared with the insulin-only group, the Exubera group was more satisfied with overall treatment and had greater improvements in symptoms and in cognitive function.

Although the frequency and nature of adverse events were similar in the Exubera and insulin-only groups, mild to moderate cough was more common early in Exubera treatment, and there was a small, non-progressive reduction in pulmonary function.

Another pulmonary delivery system for insulin is the AERx diabetes management system, in Phase III development by Aradigm and Novo Nordisk. The AERx Strip dosage form contains a disposable nozzle allowing superior aerosol performance with each inhalation, as well as adjustment for various treatment requirements to regulate the particle size and thus the primary deposition area of the medication.

Alkermes is also developing an inhaled insulin formulation, AIR-insulin, now in Phase II testing. Based on positive results in preliminary trials, Alkermes is developing short-acting formulations for mealtime, and long-acting formulations to be administered once to twice daily administered from small, simple inhalers. The company’s proprietary AIR pulmonary drug delivery technology is based on the concept that relatively large, low-density drug particles can be inhaled into the lungs with high efficiency from simple inhaler devices.

Emisphere Technologies has completed Phase II testing of Eligen, an oral formulation using a carrier" molecule to keep insulin in a fat-soluble state. In a rat model where diabetes was induced with streptozotocin to destroy beta cells, Eligen reversed hyperglycemia, polydipsia (increased water consumption), weight loss and autonomic dysfunction. In primates, Eligen rapidly and significantly increased insulin levels and prolonged reduction of blood glucose.

Oralin is an oral liquid form of insulin in Phase II development by Generex Biotechnology. Using a RapidMist device, this unique formulation is delivered directly into the mouth where it is rapidly absorbed into the bloodstream through the buccal mucosa. In clinical trials involving more than 250 people, insulin and blood glucose levels after Oralin administration were consistent with levels achieved by injected insulin.

An alternate approach to novel insulin formulations is encapsulated pancreatic islet cell implants, in Phase II testing by Amcyte/Mylan. These proliferated insulin-secreting cells resemble islets of Langerhans, and are designed to reduce the need for supplemental insulin.

Once fully developed and approved, these proliferated islets could theoretically treat patients with a simple infusion into the abdominal cavity, without the need for life-long immune suppression. A clinical safety trial showed that blood sugar control was achievable following intraperitoneal transplantation.

An approach based on the autoimmune etiology of type 1 diabetes is Diamys rhGAD65, in Phase II testing by Diamyd Medical. This recombinant human glutamic acid decarboxylase (GAD65) is designed to prevent and treat insulin-dependent diabetes in patients with GAD antibodies. In a Phase I trial, no safety concerns were defined, and there was a positive outcome at one of the dose levels in a Phase II trial.

Another approach targeting the immune system is TRX4, an anti-CD3 monoclonal antibody in Phase II development by TolerRx. This humanized monoclonal antibody binds to the CD3 receptor found on all T cells to regulate normal T cell signaling. TRX4 is designed to block the function of T-effector cells that cause autoimmune disease, promoting immunological tolerance. Based on the results of a Phase II clinical trial in Europe, TolerRx is planning further clinical trials in patients with new-onset Type I diabetes after discussions with the FDA in 2005.

Insmed is in Phase II development of SomatoKine (mecasermin rinfabate), a novel recombinant insulin-like growth factor (IGF-BP3) complex. In a double-blind, randomized, placebo- controlled trial, SomatoKine was safe and well tolerated, with mild, dose-dependent hypoglycemia. It improved insulin sensitivity and glycemic control, with decrease in requirements for insulin dosage by 49% (P < .01), in mean blood glucose by 23% (P < .03), in plasma insulin levels by 47%, and in mean growth hormone by 72%.

Neurocrine Biosciences is in Phase II testing of NBI-6024, a peptide based on insulin B chain amino acid residues 9 to 23. Safety data show that this compound is safe and well tolerated.

Also in Phase II testing is AS-3201, an aldose reductase inhibitor being developed by Dainippon Pharmaceutical for diabetic complications such as cataract, neuropathy, retinopathy and nephropathy. Results of a double-blind, randomized trial published in 2004 in Diabetes Care suggest that S-3201 penetrates the sural nerve and inhibits sorbitol accumulation in patients with diabetic sensorimotor polyneuropathy. Sensory nerve conduction velocities also improved by 1 m/s (P < .05). However, additional studies are needed to determine whether AS-3201 delays progression or leads to regression of polyneuropathy.

Novel formulations of insulin by the inhaled or oral route may allow greater patient convenience and compliance. Approaches targeting the immune basis of diabetes may theoretically allow earlier intervention in the course of this disease, while drugs correcting defects in the microvasculature may help to address neuropathy, retinopathy, and other chronic complications.