Type 1 Diabetes Vaccine Can Preserve Insulin Production

Immunotherapy against a major autoantigen in type 1 diabetes may preserve beta-cell function early after disease onset but not reverse the process, researchers said.

Residual insulin secretion measured by fasting C-peptide levels declined significantly less over 30 months in children treated with an investigational vaccine of alum-formulated glutamic acid decarboxylase than with placebo (−0.21 versus −0.27 nmol/l, P=0.045), found Johnny Ludvigsson, M.D., Ph.D., of Linkoping University.

In the randomized trial, stimulated secretion also dropped less in the immunotherapy group (P=0.04), they reported online in the New England Journal of Medicine. The results will appear in the Oct. 30 print edition.

Although the trial missed its primary endpoint of improving C-peptide levels at 15 months and had no effect on insulin requirements or glucose levels, the results were promising compared with other type 1 diabetes prevention efforts, the researchers said.

"Even modest residual insulin secretion, with stimulated C-peptide levels above 0.2 nmol per liter, has been reported to provide clinically meaningful benefits in terms of reducing long-term complications," they wrote.

Most attempts at reversing type 1diabetes have failed, Dr. Ludvigsson’s group noted.

Early attempts found immunosuppressive agents were effective in reducing insulin requirements but caused kidney damage and even failure in children. More recent attempts have consistently found either minimal benefits or prohibitive adverse effects, they said.

The partial efficacy and low toxicity of the vaccine used in Dr. Ludvigsson’s trial was good news, commented Denise L. Faustman, M.D., Ph.D., of Massachusetts General Hospital and Harvard, in an accompanying editorial.

However, "it’s not quite where patients want to be," she said. "We still have a ways to go."

Many autoantigens are involved in the destructive immune responses of type 1 diabetes, Dr. Faustman noted, so improving efficacy may require a cocktail approach to generate immune tolerance to most or all of these self proteins. Starting earlier in the development of type 1 diabetes might help as well, she said.
"The future of these therapies might be detecting siblings of kids with diabetes to intervene with glutamic acid decarboxylase immunizations to try to better preserve the islet function," she said.

In Dr. Ludvigsson’s study, 70 children ages 10 to 18 years were given immunotherapy or placebo within 18 months of presentation with type 1 diabetes.
All had screened positive for the presence of autoantibodies to the 65-kD isoform of glutamic acid decarboxylase and had residual insulin production-indicated by fasting C-peptide levels above 0.1 nmol per liter.

These children were randomized to double-blind treatment at eight pediatric clinics in Sweden with two injections of either 20 μg of a vaccine formulated with recombinant glutamic acid decarboxylase and alum (Diamyd) or alum placebo.

Periodic mixed-meal tolerance tests to stimulate residual insulin secretion showed declining beta-cell function over time in both groups.

The vaccine did not significantly halt the decline in fasting C-peptide levels after 15 months, the primary endpoint, compared with baseline (−0.12 versus −0.17 nmol/l, P=0.28).

However, the difference in decline in fasting C-peptide levels reached significance by 30 months (−0.21 versus −0.27 nmol/l, P=0.045).
Other secondary measures showing subtle benefits with active vaccine included:

• Slower decline in stimulated secretion measured as the area under the curve at 15 months (−0.38 versus −0.75 nmol/l per two hours, P=0.01).
• Less decrease in stimulated secretion measured as the area under the curve at 30 months (−0.72 versus −1.02 nmol/l per two hours, P=0.04).
• Less change in the C-peptide:plasma glucose ratio at 30 months (P=0.02).

However, there were no advantages with the vaccine for glycosylated hemoglobin levels, glucose levels, or insulin requirements.

And although patients showed a glutamic acid decarboxylase-specific immune response, there was a protective effect only in patients treated six months or less after diagnosis.

Adverse events were mild and similar in frequency and pattern between treatment groups. None of the serious adverse events was considered treatment related.

The mechanism for the effects with the vaccine are unclear but could involve modulation of the general memory immune responses to the glutamic acid decarboxylase autoantigen, the researchers said.

These results provide the preliminary proof of concept for this immunotherapy treatment, they said, noting that large-scale confirmatory studies with the vaccine are under way in Europe and the United States.

About Diamyd(R) Type 1: Diamyd(R) Type 1 is the treatment of recently diagnosed patients with the Diamyd(R) diabetes vaccine. Diamyd(R) Type 1 is a simple treatment without any serious side effects. This treatment is now being tested in Phase III studies in Europe and the US. The company plans to complete the application for market approval in late 2010. The annual market for Diamyd(R) Type 1 is estimated at about one billion dollars.

About the mechanism of action: Type 1 diabetes is an autoimmune disease in which the body’s own immune system attacks the cells in the body that produce insulin. The active ingredient in Diamyd(R) is glutamic acid decarboxylase (GAD), which is a dominant antigen in type 1 diabetes. By treating with GAD formulated as a vaccine, the patient’s immune system is affected in such a way that it down regulates the attack on the insulin-producing cells. Stopping this autoimmune process is the cornerstone in curing type 1 diabetes.

Practice Pearls:

• Inform patients that type 1 diabetes causes the immune system to attack insulin and destroy insulin-producing beta-cells. Immunotherapy aims to prevent this kind of autoimmune response
• Caution to interested patients that the study showed better preservation of insulin production with the experimental vaccine, but clinical outcomes were unchanged.

Ludvigsson J, et al "GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes" N Engl J Med 2008; 359.

Faustman DL "Immunotherapy on Trial for New-Onset Type 1 Diabetes" N Engl J Med 2008; 359.

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