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By Karen Pihl-Carey
Senior Staff Writer
In the early part of the 20th century, before the Depression and World War II, dozens of children lay comatose in hospital wards where hopeless families gathered awaiting their inevitable deaths.
This was not cancer before chemotherapy, or tuberculosis before antibiotics. This was Type I diabetes before insulin.
That was prior to 1922 when Frederick Banting and Charles Best began the first insulin injections, moving from bed to bed at a Toronto hospital, causing a wave of awakenings - a powerful illustration of how funded research can culminate into the difference between life and death.
Today, researchers are working equally as hard to stop the disease in its tracks, preserve beta cell function and reduce serious complications that include diabetic retinopathy, foot ulcers, end-stage renal disease, heart attack and stroke. Areas of research include the transplantation of insulin-producing cells, the development of an artificial pancreas and the search for drugs to tackle autoimmunity.
While there have been improvements in insulin delivery over the years, there have been no new drugs to reverse the disease process or to treat its complications.
"Nothing has worked in Type I diabetes. Many people have tried to modulate the immune response" with common immunosuppressants, such as cyclosporine and azathioprine, said Doug Ringler, CEO of Tolerx Inc. "They've all essentially failed because upon the discontinuation of therapy, the disease returns."
Immunosuppressant therapies are believed to have serious side effects upon chronic use, making patients vulnerable to infections and malignancies.
Investors tend to gravitate toward research in the Type II diabetes space because that billion dollar market is growing exponentially, partially due to the obesity epidemic. The American Diabetes Association estimates there are 23.6 million people, or 8 percent of the U.S. population, with diabetes. Type I, however, makes up a small portion of that amount and is still considered an orphan indication that may not bring hefty returns.
But researchers stress that if they can find a way to alter the autoimmune process in which the body's own defense system kills off the beta cells needed to make insulin, then those methods could be carried over to other autoimmune diseases with more sizeable markets.
"In the years prior to today, I think there was a misconception that the market was very small," said Ringler, who estimates that a drug able to modulate the immune response has a "multibillion dollar peak annual sales" potential. In addition to Type I diabetes, his company's drug otelixizumab could have applications in rheumatoid arthritis, psoriasis and inflammatory bowel disease, among others.
Scott Koenig, president and CEO of MacroGenics Inc., said his company's drug teplizumab initially is targeting Type I diabetes but might work in rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease as well. "This is a first step in understanding how this drug works," he said, "and if successful, our plan is to expand this into other diseases."
Type I diabetes researchers have depended on foundation money and big pharmaceutical support to conduct their work. Last year, the Juvenile Diabetes Research Foundation (JDRF) doled out $137 million to companies, and the American Diabetes Association gave out $42 million for both Type I and Type II research.
According to Leslie Schwartz, a spokeswoman for JDRF, about 3 million people in the U.S. have Type I diabetes. Patients are often diagnosed as children, although 40 percent are found to have the disease after age 18. Insulin through daily injections or an insulin pump is necessary for survival since their immune systems destroy insulin-producing beta cells found in the pancreas. In contrast, Type II diabetes is not considered autoimmune because the body still makes insulin, but the cells are resistant to the insulin uptake.
Patients of both types must manage the disease with diet and exercise, but they are still susceptible to serious complications that can reduce their life spans by up to 15 years.
Advances such as continuous glucose monitoring devices and blood tests to evaluate a sibling's risk of disease have helped to minimize complications. Scientists now know of certain genes that predispose people to Type I and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established the Type I Diabetes Genetics Consortium to collect genetic material from 2,800 families that have at least two siblings with the disease. The NIDDK, which asked for an extra $150 million in their next budget for Type I diabetes research, also is tracking newborns through adolescents who are susceptible to Type I diabetes to find environmental factors that could trigger the disease.
Another place companies have found research support is through big pharmaceutical firms. Eli Lilly & Co. signed a $1 billion deal with MacroGenics Inc. last October for teplizumab, while GlaxoSmithKline plc signed a $760 million deal with Tolerx for otelixizumab.
Tolerx, of Cambridge, Mass., is enrolling patients in a Phase III trial of otelixizumab (TRX4), a monoclonal antibody that binds to CD3, a T lymphocyte receptor involved in normal cell signaling. Studies have shown that daily injections for about a week result in roughly a 250 percent increase of T regulatory cells two weeks after dosing.
"Most of us do not get autoimmune disease because T regulatory cells keep those cells (T effector cells) at bay," Ringler said. "We reasoned that in autoimmune disease, such as Type I diabetes, there were likely not enough T regulatory cells to keep the immune system at bay." That led his team to ask whether they could "generate therapies that increase T regulatory activity."
A study published in the New England Journal of Medicine in 2005 showed that a six-day regimen of otelixizumab helped to preserve the function of beta cells in the pancreas, thereby reducing the amount of insulin needed to control blood glucose levels, for 18 months. Animal studies indicated that the response could be permanent.
A patient recently diagnosed with Type I diabetes still has about 30 percent of beta cells functioning, Ringler said. "If a patient is able to preserve just some of their beta cell capacity, whether it be 30 percent or 20 percent or 10 percent, then that patient will do better throughout the course of their disease."
Early clinical development was completed with experts from the Immune Tolerance Network, part of the National Institute of Allergy and Infectious Disease, on MacroGenics' anti-CD3 humanized monoclonal antibody teplizumab, which is constructed so it does not bind to Fc receptors. As was the case with Tolerx's drug, evidence has shown that teplizumab "will expand a population of regulatory T cells, which control the autoimmune process," Koenig said.
MacroGenics is enrolling patients worldwide between the ages of 8 and 35 years within the first three months of diagnosis. Koenig expects it will fully enroll sometime in 2009.
"The goal is really to stop the progression of this disease," he said. "In the patients, we're looking for improvement both in metabolic control, marked improvements in HbAC1 level, as well as reduced requirements for insulin."
The ITN also is conducting studies in patients diagnosed within four to 12 months in order to find a therapeutic window for teplizumab, and NIDDK plans to start a trial this year with the drug treating the relatives of Type I diabetes patients who are at high risk for developing the disease themselves.
"If we intervene early enough in the course of this disease," there's a chance, Koenig said, of stopping Type I diabetes before it manifests, before a patient is sentenced to a lifelong dependence on exogenous insulin.
"Some of these patients may be able to completely stop insulin treatment," he said. "We don't know yet. We'll have to see."
Other drugs in development for Type I diabetes include Andromeda Biotech Ltd.'s DiaPep 277, a peptide fragment derived from heat-shock protein 60, which is in Phase III; Diamyd Medical AB's Phase III vaccine Diamyd; Living Cell Technologies Ltd's DiabeCell, a porcine pancreatic cell product in Phase I; Bayhill Therapeutics Inc.'s BHT-3021, a plasmid encoding proinsulin in Phase I/II; improved forms of injectable and inhalable insulin; and the mesenchymal stem cell therapy Prochymal, from Osiris Therapeutics Inc, which is in Phase II. (For more, see The Diabetes Report 2008: Developments and Opportunities in Drugs and Devices, from BioWorld.) | 
