Ulf Hannelius, Sweden
Diamyd Medical AB ManagementPresenter of 1 Presentation
NOVEL TREATMENT OF TYPE 1 DIABETES - THE INFLUENCE OF HLA, NUMBER OF DOSES AND ADMINISTRATION ROUTE ON THE EFFECT OF GAD-SPECIFIC IMMUNOTHERAPY
Abstract
Background and Aims
We have previously shown an association between the HLA haplotype DR3-DQ2 and a positive treatment effect of GAD-alum in individuals recently diagnosed with type 1 diabetes. In this study we sought to further investigate the influence of HLA, number of injections and administration route on the clinical effect of GAD/alum treatment.
Methods
We combined individual-level data (n=627) from four placebo controlled randomized clinical trials of both subcutaneous and intralymphatic GAD-alum immunotherapy. We estimated the treatment effect at 15 months from baseline on C-peptide retention, HbA1c, insulin dose and insulin adjusted HbA1c (IDAA1c) using a mixed model repeated measures model including terms for HLA subgroup and number of doses. The effect of administration route was evaluated using a Bayesian model.
Results
A significant treatment effect was seen in individuals carrying HLA DR3-DQ2 (n=313), with the best effect seen in those receiving three-four doses showing an effect ratio of 1.48 (adjusted P<0.0001) on preserving C-peptide compared to 1.21 (p=0.092) for those receiving two doses. A lower HbA1c was also seen in the three-four dose group compared to placebo (-4.74mmol/mol, adjusted P<0.01). Despite using only 1/5 of the dose, there was a 98%, 99%, 71% and 97% probability that three intralymphatic injections were superior to three subcutaneous injections for C-peptide retention, HbA1c, insulin dose and IDAA1c, and safety profiles were comparable.
Conclusions
These analyses highlight the importance of genetics, dosing regimen, and administration route in immunotherapeutic treatment of type 1 diabetes and a clinically relevant potential for intralymphatic GAD-alum.