Trial of new drug that may halt progression of Type I Diabetes

Mar 30 2004

The results of a long-term clinical trial on a new drug designed to inhibit the progression of type I diabetes was announced at the International Diabetes Society meeting in Cambridge, England, March 29. The findings of the 18-month long clinical trial confirm the drug's efficacy in improving a diabetic's ability to produce insulin.

In addition, researchers have identified a particular type of immune cell that appears to be involved in the drug's protective mechanism. The extent to which the drug boosted production of these immune cells correlated with the extent to which the patient's insulin production was preserved over a long period. The results may lead to a new treatment to prevent type I diabetes — currently there is no cure.

The new drug to prevent type I diabetes arose from research at UCLA with diabetes‑prone mice that were protected from developing the disease by treating them with a protein called "GAD" taken from insulin-producing cells.

"We are very pleased to see our work at UCLA go from the lab to a clinical application with the potential to help so many people" said professor Daniel Kaufman, UCLA Department of Molecular and Medical Pharmacology, whose research team first developed and tested the drug in diabetes-prone mice.

In type I diabetes (also known as juvenile diabetes), the immune system mistakenly destroys the insulin-producing cells in the pancreas. Over time, this attack leads to a lack of insulin, the hormone that controls blood sugar levels. People with type I diabetes must inject insulin daily. The prevention of type I diabetes is critical since although affected individuals can lead active lives by injecting insulin daily, long-term complications frequently occur including kidney and heart disease, nervous system damage, and blindness.

Diamyd Medical (Stockholm, Sweden) conducted the phase II clinical trial by treating adults who had recently been diagnosed with diabetes. The company previously had reported promising results six months after treatment with the new drug containing the GAD protein. Diamyd's latest findings show that this drug improved the patients' ability to make insulin over an 18-month period, compared with patients who received a placebo.

"Such long-term improvement in insulin production after the diagnosis of diabetes is quite remarkable," Kaufman said.

The Swedish team also found that the drug boosted the number of immune cells — called CD4+CD25+ — which are very potent at suppressing autoreactive immune responses. Individuals who had the greatest increases in CD4+CD25+ after treatment also showed the most improvement in long-term insulin production.

"This provides important new insights into how to control the autoimmune responses that cause type I diabetes," said Anders Essen-Moller, president and CEO of Diamyd Medical. "The study also shows that the drug is safe and that it is possible to inhibit the autoimmune attack on the cells that make insulin, thereby slowing the progression of the disease.

 "Since the drug is effective when given to people with very advanced disease, we are hopeful that it will be highly effective when given at earlier stages of the disease process — we now know that type I diabetes takes years to develop and that we can identify people who are at early stages of the disease process by testing for autoantibodies in their blood," Essen-Moller said.

Diamyd Medical's phase II trial was conducted on 47 adult patients who were recently diagnosed with type I diabetes at the UMAS hospital in Malmoe and St. Gorans Hospital in Stockholm. The patients were randomly divided into four groups with 12 patients in each group. Each patient received one first injection of Diamyd, followed by at least one boost injection four weeks after. Nine patients in every group received active drug; three received placebo. The groups received different doses of the drug ranging from 4 to 500 micrograms per dose. All patients visited the hospitals 10 times during the six-month study, and detailed clinical, immunological as well as neurological investigations showed no safety concerns at the administered dose levels.

The study results show that the drug could protect significantly the patient's ability to secrete insulin both when fasting and after meals. No side effects were reported and the patients have now been continuously followed for the past 18 months.

UCLA's lab work leads to drug development

The GAD therapeutic originated at UCLA from an unexpected convergence of studies in neurobiology and immunology. In the late 1980s, the laboratory of Dr. Allan Tobin, who is now director of UCLA's Brain Research Institute and Eleanor Leslie Chair in Neuroscience, was involved in isolating genes that were thought to be important in brain development and neurological diseases.

Graduate students Daniel Kaufman and Mark Erlander, working with Tobin, isolated the gene that makes GAD, which creates an important neurotransmitter in the brain. At that time, it was known that although GAD was primarily made in the brain, it was also made in the pancreas cells that secreted insulin.

Several years later, Kaufman came to the realization that the autoimmune response that causes type I diabetes may be due to the immune system attacking the GAD protein in the insulin-producing cells in the pancreas. With this knowledge, he and Tobin developed a GAD diagnostic test to identify individuals who were developing type I diabetes based on antibodies in their blood that recognized GAD.

Later, Kaufman, then in his own laboratory at the UCLA Department of Molecular and Medical Pharmacology, along with Dr. Jide Tian, searched for ways to help the immune system tolerate the GAD protein, which would circumvent or inhibit the autoimmune attack. The team reported in the journal Nature in 1993 that by treating young diabetes-prone mice with a small amount of the GAD protein, the immune system learned to tolerate the protein, and the autoimmune response that leads to type I diabetes never developed in these mice as they grew older.

In another study published by Nature-Medicine in 1996, the UCLA team developed a GAD-based drug to inhibit the autoimmune response after it had already begun to attack the insulin-producing cells. Kaufman and Tian showed that even after the type I diabetes disease process had started in diabetes-prone mice, its progression could be inhibited by treatment with GAD.

With this proof-of-principle in mice, UCLA licensed the technology to Diamyd Medical for clinical development. UCLA recently was issued the patent on the GAD gene.