Submitted by aml95 on Tue, 23/09/2025 - 12:26
New research presented at this year's Annual Meeting of the European Association for the Study of Diabetes (EASD) in Vienna, Austria (15-19 September) and published simultaneously in The Lancet shows that a much lower dose than previously thought of a well-known drug used in transplantation immunology, anti-thymocyte globulin (ATG), is safe and effective in preventing progression of type 1 diabetes (T1D) in young people.
The authors, led by EASD President Professor Chantal Mathieu (Belgium) and including Professor Mark Evans from the IMS-MRL, say that the MELD-ATG trial findings open up the potential use of this affordable, repurposed agent, ATG, in a low and safe dose, as a disease-modifying agent in children and adolescents with newly diagnosed clinical T1D.
Professor Evans said:
“One of the most exciting concepts to emerge in last decade in type 1 diabetes (T1D) is the realisation that using targeted immune therapies can alter the natural history and progression of the disease. The MELD ATG study performed with colleagues in Paediatrics and collaborators across Europe builds on previous work, now showing that immune therapy with a low dose of ATG (anti thymocyte globulin) can help preserve insulin-producing beta cells in early stage T1D. This is now starting to translate into clinical practice with the first approved therapy getting marketing authorisation in UK in last few weeks and with the very real likelihood of more agents being approved in near future, changing the clinical landscape of T1D.”
14 hospitals in 8 European countries who are all part of the INNODIA IHI consortium, were involved in the study including Cambridge University Hospitals NHS Foundation Trust (Dr Emile Henricks and Dr Loredana Marcovecchio).
Background
T1D is a chronic disease affecting approximately 9·5 million people worldwide. T1D affects both adults and children, but particularly in children and adolescents incidence rates have been rising by more than 2% per year in the last 20 years. Growing insight into T1D pathogenesis as an autoimmune disease where destruction of pancreatic insulin-producing beta-cells leads to insulin dependence, has allowed identification of promising disease-modifying interventions. Several interventions have been tested in people with recent-onset clinical T1D (stage 3), and demonstrated relative therapeutic success, with preservation of stimulated C-peptide (a biomarker of beta cell viability) in the first year after diagnosis.
ATG is a well-known drug in transplantation immunology with over 35 years of use. It is an immunomodulatory drug made of antibodies that target T lymphocytes, which are cells of the immune system that can attack the body's own tissues (as happens in T1D). It is produced by immunising rabbits with human T cells and then collecting and purifying the antibodies from the animals' blood.
Study details
In this study, ATG was given intravenously over 2 consecutive days in a double-blind manner, with a randomised design, placebo controlled. Participants aged between 5-25 years diagnosed with clinical, stage 3 T1D between 3-9 weeks before treatment, having random C-peptide levels 0.2 nmol/L or above and at least one diabetes-related autoantibody (GADA, IA-2A or ZnT8) (confirming presence of T1D) were recruited. A novel, adaptive trial design was used, to allow testing of multiple doses of ATG in a single trial.
The primary outcome of the trial was each patient's C-peptide level (and thus beta cell function) during a 2-hour mixed meal tolerance test, conducted 12 months after treatment, assessed by a statistical method called area under the curve (AUC).
Participants were mainly European Caucasian, had a median age of 13·0 years, a median duration of diabetes of 51 days, a mean HbA1c (glycated haemoglobin) of 7.79 % and a median AUC of the stimulated C-peptide of 0·82 nmol/L/min. They were treated with placebo (n=30 of whom 10 females), 2·5mg/kg (n=33 of whom 20 females), and 0·5mg/kg (n=34 of whom 22 females) ATG, with progressive dropping of 0·1mg/kg (n=6 of whom 3 females) and 1·5mg/kg (n=11 of whom 7 females) ATG according to the adaptive trial design.
The difference between the AUC result for placebo and the 2.5mg/kg dose was similar to that for the 0.5mg/kg dose, showing that the lower dose was similarly effective. However, previously documented side effects were more common with the higher dose - cytokine release syndrome occurred in 11 (33%) and 8 (24%) participants, and serum sickness in 27 (82%) and 11 (32%) participants treated with 2·5mg/kg or 0·5mg/kg ATG, respectively, versus none in placebo-treated participants.
Reference: Minimum effective low dose of antithymocyte globulin in people aged 5–25 years with recent-onset stage 3 type 1 diabetes (MELD-ATG): a phase 2, multicentre, double-blind, randomised, placebo-controlled, adaptive dose-ranging trial. Mathieu, Chantal et al. The Lancet, https://doi.org/10.1016/S0140-6736(25)01674-5
