Low-dose drug prevents diabetes progression in young people

Research presented at this year’s Annual Meeting of the European Association for the Study of Diabetes (EASD 2025), and published simultaneously in The Lancet, shows that a low dose of the immunomodulatory drug anti-thymocyte globulin (ATG) is safe and effective in preventing progression of type 1 diabetes (T1D) in young people. The authors say their trial findings open up the potential use of this affordable, repurposed agent in a low and safe dose, as a disease-modifying agent in children and adolescents with newly diagnosed clinical T1D.

Growing insight into T1D pathogenesis as an autoimmune disease, where destruction of pancreatic insulin-producing beta-cells leads to insulin dependence, has enabled the 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 — a well-known drug in transplantation immunology — 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. The study saw ATG given intravenously over two consecutive days in a double-blind manner, with a randomised, placebo-controlled design.

Participants aged between five and 25 years, diagnosed with clinical, stage 3 T1D 3–9 weeks before treatment, were recruited in 14 hospitals in eight European countries. The primary outcome of the trial surrounded 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, with a median age of 13 years and a median duration of diabetes of 51 days.

Participants were treated with a placebo, 2.5 mg/kg ATG and 0.5 mg/kg ATG, with progressive dropping of 0.1 mg/kg and 1.5 mg/kg ATG, according to the adaptive trial design. The difference between the AUC result for placebo and the 2.5 mg/kg dose was found to be similar to that for the 0.5 mg/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 33% and 24% of participants, and serum sickness in 82% and 32% of participants treated with 2.5 mg/kg or 0.5 mg/kg ATG, respectively, versus none in placebo-treated participants.

“The MELD-ATG trial … successfully identified a minimum effective dose of 0.5 mg/kg ATG,” the authors said. “In addition, it allowed confirmation of previous efficacy and safety findings of 2.5 mg/kg ATG, including in children as young as five years of age. Low-dose ATG is a safe and effective intervention for arresting or at least delaying progression of T1D.”

The authors said their results underscore the need to perform immune modulatory intervention studies directly in young individuals with T1D, in contrast to current drug development strategies that, driven by regulatory guidance, typically target adults first.

“Especially in the youngest age group, the 0.5 mg/kg dose was effective, with a good safety profile, and would be the recommended dose for treatment,” they said. “Of interest, being able to limit the administration of ATG to 0.5 mg/kg would also mean only needing one infusion on one day, instead of the two days of infusion with the previously studied 2.5 mg/kg.”

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