Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial

Abstract

Background Type 1 diabetes (T1DM) is an autoimmune disease leading to destruction of insulin producing beta cells and life-long requirement for insulin therapy. Glutamic acid decarboxylase (GAD) is a major target of this immune response. Studies in animal models of autoimmunity have shown that treatment with a target antigen can modulate aggressive autoimmunity. We evaluated immunization with GAD formulated in aluminum hydroxide (alum) as an adjuvant in recent onset T1DM. Methods In this multicentre, double-masked, randomised controlled trial, 145 subjects (ages 3-45) with T1DM for less than 3 months received 3 injections of 20 μg GAD-alum (48 subjects), 2 injections of GAD-alum and one of alum alone (49 subjects) or 3 injections of alum (48 subjects) subcutaneously at baseline, 4 weeks later and 8 weeks after the second injection. Primary outcome was baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide following a mixed meal tolerance test at one year. Secondary outcomes included changes in HbA1c and insulin dose, and safety. This trial is registered in ClinicalTrials.gov (NCT00529399). Findings The ratio (experimental to control) of the adjusted population mean of C-peptide for the GAD-alum ×3 and GAD-alum ×2/alum ×1 groups is 0.998 (95% CI: [0.779, 1.22], p = 0.98) and 0.926 (95% CI: [0.720, 1.13], p = 0.50), respectively. HbA1c and insulin use did not differ between groups. There was no difference in rate or severity of adverse events between groups. Interpretation Antigen-based immunotherapy therapy using GAD-alum given subcutaneously in two or three doses over 4 to 12 weeks does not alter the course of loss of insulin secretion over one year in subjects with recently diagnosed T1DM. While antigen-based therapy is a highly desireable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. Funding National Institutes of Health.

Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Nonobese Diabetic Mice

“…There are currently no effective treatments for type 1 diabetes. Anti-B-cell antibodies (rituximab), anti-CD3 antibodies (otelixizumab and teplizumab) targeting T cells and the Diamyd vaccine (GAD immunotherapy) have all failed to meet endpoints in recent clinical trials (24)(25)(26)(27)(28)(29)(30).…”

Antigen-based vs. systemic immunomodulation in type 1 diabetes

“…108 However, this study failed to demonstrate efficacy as measured by stimulated C-peptide secretion. 108 Even in the subgroup aged 10-18 y no effect was achieved, in contrast to the results obtained by Ludvigsson et al Also the EU Diamyd phase III study using four doses of 20 μg GAD-Alum did not achieve its endpoints. 109 Heat shock protein 60 (HSP60).…”

Immune therapy in type 1 diabetes mellitus

“…GAD-alum tested in Phase II clinical trials with some effect on preserving residual cpeptide 39,40 was tested in an additional phase II trial with a dose-regiment that differed from previous trials 53 . Two or three doses of subcutaneous GAD-alum across 4-12 weeks did not alter the c-peptide disappearance rate during 12 month in newly diagnosed T1D patients (NCT00529399).…”

“…The different approaches of autoantigen administration have revealed effects on secondary end-point measures such as increased numbers of Treg cells. Although β-cell function has not been fully preserved 40 and reproducible 53,54 these high safety studies makes it possible to design trials to evaluate dose and exposure dependent parameters. Recent advances in flow cytometry, immunogenetics in combination with β-cell function tests such as the MMTT should make it possible to dissect the impact of autoantigen immunomodulation on the immune response in relation to β-cell function.…”