Promising Drug for Juvenile Diabetes Developed at UCSF

May 29, 2002
News Office: Wallace Ravven (415) 502-6397

The course of early stage Type 1 (juvenile) diabetes has been halted for a year by treating patients for two weeks with a new immune-suppressive drug which had only minor side effects, according to researchers at UCSF Medical Center and Columbia University.

The year-long clinical trial is the first to stop the progression of Type 1 diabetes using a short-term therapy that specifically targets disease-causing T-cells of the immune system, the scientists report.

Patients taking the drug continued to produce their own insulin and needed less supplemental hormone to maintain their blood sugar than those who did not take the drug, according to the results of the study published in the May 30 issue of The New England Journal of Medicine.

The phase I/II clinical trial, which measured dosages and effectiveness of the drug, treated 12 patients, ages 7 to 27, within six weeks of being diagnosed with Type 1 diabetes, a disease in which the body's own immune system destroys the insulin-secreting islet cells of the pancreas.

For two weeks, they received daily injections of a new-generation immunosuppressive drug designed to disable the T cells that orchestrate destruction of insulin-producing islet cells (known as beta cells), the process responsible for the progression of diabetes.

Twelve other patients, who also were recently diagnosed with Type 1 diabetes and did not receive the drug, served as controls.

Patients were followed for a year. Nine of the 12 in the treated group had little, if any, loss in their ability to secrete insulin compared with 10 of the 12 controls who had a significant decrease, the study showed. Treated patients also showed improvements in other clinical signs and symptoms of diabetes.

The ability to continue secreting insulin is an important marker of healthier prognosis for Type 1 diabetics. Earlier studies have shown that retaining insulin secretion, rather than relying solely on insulin injections, allows better metabolic control of diabetes. Strict metabolic control of the disease leads to fewer complications such as vascular, eye and kidney disease.

The clinical trials were directed by Dr. Kevan Herold, associate professor at the Naomi Berrie Diabetes Center at the Columbia University College of Physicians & Surgeons and lead author and principal investigator on the study. The new immunosuppressive drug was developed by Jeffrey Bluestone, director of the Diabetes Center at UCSF Medical Center, senior author on the NEJM paper and co-principal investigator on the study.

"The remarkable results reported in this study provide enormous hope for finding a cure for people with Type 1 diabetes," says Robert Goldstein, chief scientific officer of the Juvenile Diabetes Research Foundation (JDRF), which partially funded the research. "For the first time it has been shown that progression of the destructive autoimmune response can be stopped with few side effects and islet function preserved.

"Furthermore this provides the basis for expanded clinical studies that may extend the range of individuals who can be helped, including use before onset of disease as well as in individuals whose disease is more chronic in nature."

The study also was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID) and the National Center for Research Resources (NCRR).

"Preserving insulin production is a very important finding of this trial since patients taking the new drug would not be entirely dependent on exogenous insulin for metabolic control," says Columbia's Kevan Herold. "People with diabetes who make some insulin have a much easier time in controlling their disease than those who do not."

Although diabetes has been arrested in its early stages before, these previous successes have come at a cost. In the mid-1980s, protracted therapy with the immunosuppressive drugs cyclosporine and azathioprine were shown to preserve remaining beta cell function in newly diagnosed patients. But because patients in these trials generally suffered serious side effects from the drugs, such as increased infection risk, kidney disease and certain types of cancer, most of these studies were abandoned.

The new drug, a "humanized" monoclonal antibody known as hOKT3g1 (ala-ala), acts far more selectively and requires only a short treatment period compared with the earlier immunosuppressive drugs. The selectivity and shorter use are intended to minimize toxicity, and hOKT3g1 (ala-ala) caused few side effects, the study showed.

The drug was designed to prevent "activation" of T cells that have already identified their target -- in this case, the insulin producing beta cells in the pancreas. In effect, hOKT3g1 (ala-ala) disarms the T cells once they are poised to attack their target, says UCSF's Bluestone.

Bluestone developed the monoclonal antibody drug in the late 1980s in collaboration with Johnson & Johnson. He designed it to target activated T cells. In addition, the monoclonal antibody was humanized to avoid provoking an immune response in the host against the drug.

Diabetes, with its many long-term complications, ranks fourth among diseases in its cost to society. One million people in the U.S. have Type 1 diabetes, also known as juvenile diabetes, in which the immune system destroys the body's natural insulin-secreting islet cells. Another 15 million people have Type 2 diabetes in which obesity, inactivity and other conditions interfere with the body's insulin control.

The two-week administration of the new drug is not expected to forestall Type 1 diabetes indefinitely, but it significantly extends the period during which patients continue to produce their own insulin, which is likely to reduce complications and improve their overall prognosis.

Further testing and development of the new therapy is planned in a multi-center clinical trial of more than 80 patients to be conducted by the international Immune Tolerance Network (ITN), funded by the NIAID, NIDDK and the JDRF. The ITN aims to accelerate clinical trials of innovative immune therapies in autoimmune diseases, allergy and transplantation. The expanded study will evaluate a multiple dose regimen designed to amplify the effects of the drug, in a fashion analogous to the repeated administration of vaccines.

The results of the NEJM trial establish the effectiveness of managing early stage Type 1 diabetes and possibly other immune diseases with the drug administered over the short-term to provide benefits over the long-term, the researchers say. Ultimately, they say, the best way to deal with diabetes will be to prevent the disease entirely or to restore insulin-secretion in Type 1 diabetics through islet transplantation.

The ITN already is investigating hOKT3g1 (ala-ala) in clinical trials of islet transplantation for Type 1 diabetes and for treatment of psoriatic arthritis, a type of arthritis that develops in about a quarter of people who have psoriasis.

Co-authors on the paper and colleagues in the research are: Dr. William Hagopian, Pacific Northwest Research Institute, Seattle; Julie A. Auger, the University of Chicago; Ena Poumian-Ruiz and Lesley Taylor, the Naomi Berrie Diabetes Center, Columbia University College of Physicians & Surgeons; Dr. David Donaldson, the University of Utah, Salt Lake City; Dr. Stephen E. Gitelman, UCSF Medical Center; Dr. David M. Harlan, the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md.; Danlin Xu and Robert A. Zivin, the R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J.

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