Intra-lymphatic administration of GAD-alum in type 1 diabetes: long-term follow-up and effect of a late booster dose (the DIAGNODE Extension trial)

Rosaura Casas,Fabrícia Dietrich,Jeannette Wahlberg,Hugo Barcenilla,Johnny Ludvigsson,Beatriz Tavira,Sara Puente-Marin,Peter Achenbach

doi:10.1007/s00592-022-01852-9

Rosaura Casas, Fabrícia Dietrich + Show 6 more

Open Access

https://doi.org/10.1007/s00592-022-01852-9

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Abstract

AimTo evaluate the long-term effect of intra-lymphatic administration of GAD-alum and a booster dose 2.5 years after the first intervention (DIAGNODE Extension study) in patients with recent-onset type 1 diabetes.MethodsDIAGNODE-1: Samples were collected from 12 patients after 30 months who had received 3 injections of 4 μg GAD-alum into a lymph node with one-month interval. DIAGNODE Extension study: First in human, a fourth booster dose of autoantigen (GAD-alum) was given to 3 patients at 31.5 months, who were followed for another 12 months. C-peptide was measured during mixed meal tolerance tests (MMTTs). GADA, IA-2A, GADA subclasses, GAD65-induced cytokines, PBMCs proliferation and T cells markers were analyzed.ResultsAfter 30-month treatment, efficacy was still seen in 8/12 patients (good responders, GR). Partial remission (IDAA1c < 9) had decreased compared to 15 months, but did not differ from baseline, and HbA1c remained stable. GAD65-specific immune responses induced by the treatment started to wane after 30 months, and most changes observed at 15 months were undetectable. GADA subclasses IgG2, IgG3 and IgG4 were predominant in the GR along with IgG1. A fourth intra-lymphatic GAD-alum dose to three patients after 31.5 months gave no adverse events. In all three patients, C-peptide seemed to increase the first 6 months, and thereafter, C-peptide, HbA1c, insulin requirement and IDAA1c remained stable.ConclusionThe effect of intra-lymphatic injections of GAD-alum had decreased after 30 months. Good responders showed a specific immune response. Administration of a fourth booster dose after 31.5 months was safe, and there was no decline in C-peptide observed during the 12-month follow-up.

Highlights

Despite the use of modern devices and drugs, treatment of type 1 diabetes is heavy and the disease cause complications and increased mortality [1, 2]
Fasting and stimulated C-peptide (AUC) were significantly higher in good responders (GR) patients (n = 8), who had lower insulin requirement and IDAA1c compared to poor responders (PR) patients (n = 4) (Fig. 1B, Supplementary Table S1)
Analysis of GAD65 antibody levels (GADA) IgG subclasses showed that the levels of IgG1, IgG2, IgG3 and IgG4 remained higher at 30 months than baseline

Summary

Introduction

Despite the use of modern devices and drugs, treatment of type 1 diabetes is heavy and the disease cause complications and increased mortality [1, 2]. Results from the 6 and 15-month follow-up showed that the treatment was safe, seemed to preserve C-peptide and induced several immunological reactions (19–21). These encouraging results gave rise to a randomized double-blind placebo-controlled Phase II trial, DIAGNODE-2. When this was ongoing, a meta-analyses of the previous studies with sc GAD-alum treatment showed that the efficacy was mainly restricted to patients with HLDR3DQ2 [22], and efficacy in this subgroup of patients was added in an amendment of the DIAGNODE-2 protocol. There was a significant efficacy to preserve C-peptide with associated clinical benefit (increased proportion of patients in so-called partial remission (insulin dose-adjusted A1c; IDAA1c < 9) [23, 24]

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