Type 1 Diabetes Safely Arrested With Short-Term Use Of New Drug

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Type 1 Diabetes Safely Arrested With Short-Term Use Of New Drug

Researchers at Columbia University and the University of California, San

Francisco have halted the course of early stage Type 1 diabetes for a year

by treating patients for just two weeks with a new immune-suppressive drug,

which only had minor side effects.

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 which are 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 were recently diagnosed with Type 1 diabetes and

did not receive the drug, served as controls.

Patients were followed for a year and 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, endocrinologist at

the Naomi Berrie Diabetes Center at Columbia Presbyterian Medical Center,

associate professor of clinical medicine at Columbia University College of

Physicians & Surgeons, and lead author and principal investigator on the

study. The new immunosuppressive drug was developed by Dr.

Bluestone, director of the UCSF Diabetes Center, senior author on the NEJM

paper and co-principal investigator on the study.

The research work was funded by the National Institute of Diabetes and

Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and

Infectious Diseases (NIAID), the Juvenile Diabetes Research Foundation

(JDRF), and the National Center for Research Resources.

" The remarkable results reported in this study provide enormous hope for

finding a cure for people with Type 1 diabetes,² says Goldstein,

chief scientific officer of the JDRF. ³For 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.

³Furthermore 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. "

³Preserving 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,² says Columbia¹s Kevan Herold.

³People with diabetes who make some insulin have a much easier time in

controlling their disease than those who do not.²

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 ³humanized² 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 ³activation² 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 UCSF¹s Bluestone.

Dr. Bluestone developed the monoclonal antibody drug in the late 1980s in

collaboration with & . 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

body¹s natural insulin-secreting islet cells. Another 15 million people have

Type 2 diabetes in which obesity, inactivity and other conditions interfere

with the body¹s 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 trial published in the NEJM establish the effectiveness

of managing early state 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 Hagopian,

M.D., Ph.D., Pacific Northwest Research Institute, Seattle; A. Auger,

University of Chicago; Ena Poumian-Ruiz and Lesley , Naomi Berrie

Diabetes Center, Columbia University College of Physicians & Surgeons;

son, M.D., University of Utah, Salt Lake City; E. Gitelman,

M.D., University of California at San Francisco; M. Harlan, M.D.,

National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda,

Md.; Danlin Xu, Ph.D., and A. Zivin, Ph.D., R. W.

Pharmaceutical Research Institute, Raritan, N.J.

NOTES The new drug offers significant advantages in several important ways:

· It is ³humanized² by fusing certain parts of a mouse antibody with that of

a human antibody to retain the desired binding specificity without provoking

an immune response as a mouse antibody would.

· It is less toxic than cyclosporine and other earlier immunosuppressive

drugs because it is administered for only two weeks. Briefer

immunosuppression prevents the side effects which were severe in some cases

with the earlier drugs ­ including infections and cancer. Moreover, the drug

is more specific and does not cause other organ toxicity such as kidney

disease.

· It is less toxic than other OKT3 monoclonal antibody drugs because it

doesn¹t activate aggressive inflammatory cytokines of the immune system,

which have led to fever, nausea, headache, hypertension and even cardiac

problems. This drug was developed by mutating a portion of the antibody so

that it does not activate T cells thus avoiding the release of the

cytokines.