Old drug, new purpose: Low-dose ATG may halt T1D progression in youths

The old immunomodulatory drug antithymocyte globulin (ATG), administered at a low dose, can safely reduce the loss of beta-cell function in young people with recent-onset type 1 diabetes (T1D), as shown in the phase II MELD-ATG trial.

At the 12-month follow-up, the area under the curve (AUC) of the stimulated C-peptide concentration, a marker of beta-cell function, during a 2-h mixed-meal tolerance test was significantly higher in the ATG arms than in the placebo arm. This was seen in both the 2.5-mg/kg ATG dose arm (0.535 vs 0.411 nmol/L per min; mean difference, 0.124 nmol/L per min, 95 percent confidence interval [CI], 0.043–0.205; p=0.0028) and the 0.5-mg/kg dose arm (0.513 vs 0.411 nmol/L; mean difference, 0.102 nmol/L per min, 95 percent CI, 0.021–0.183; p=0.014), with the low dose proving equally efficacious as the higher dose. [Lancet 2025;406:1375-1388]

However, typically ATG-associated adverse events (AEs) occurred more frequently with the 2.5-mg/kg dose than with the 0.5-mg/kg dose, including cytokine release syndrome (33 percent and 24 percent, respectively) and serum sickness (82 percent and 32 percent, respectively). None of the participants who received placebo experienced the said AEs. No AE-related deaths were documented.

“The findings suggest that low-dose ATG is an efficacious intervention for arresting or at least delaying progression of T1D, with mostly mild and moderate AEs,” in youths, including those as young as 5 years, according to the investigators. “This dose not only achieved the primary endpoint, reducing C-peptide decline compared with placebo at 12 months, but also resulted in lower HbA1c concentration.”

The adjusted mean difference in HbA1c was –0.36 percent (95 percent CI, –0.80 to 0.08; p=0.11) between the 2.5-mg/kg ATG arm and the placebo arm and –0.50 percent (–0.93 to –0.07; p=0.024) between the 0.5-mg/kg ATG arm and the placebo arm.

“Potential mechanisms explaining the beneficial effect of the 0.5-mg/kg dose could be sparing of regulatory T cells, exhausted signature of CD4 T cells, or other immunological changes,” the investigators noted.

“Future exploratory immunological analyses in our study population are needed to clarify the mechanism of action of the identified lower efficacious dose of ATG, understand dose-response differences in relation to immunological changes, and establish how these might vary across different age groups,” they said, emphasizing that such investigations could inform a dosing strategy tailored to the patient’s clinical or immunological characteristics.

MELD-ATG

Conducted at 14 centres across eight countries, MELD-ATG investigated the efficacy and safety of four different doses of ATG in young people aged 5–25 years with clinical, stage 3 T1D diagnosed within 3–9 weeks of enrolment. The trial had an adaptive design, allowing dropping (or restarting) doses based on prespecified criteria.

A total of 117 participants (54 percent female, 90.6 percent European) were included in the study, of which 21 were age 5–9 years, 76 were age 10–17 years, and 20 were age 18–25 years. They were randomly assigned to receive rabbit-derived ATG at 0.1 (n=6), 0.5 (n=35), 1.5 (n=12), or 2.5 mg/kg (n=33) or placebo (n=31).

Treatment was administered via intravenous infusion over 2 consecutive days. On day 1, the infusion lasted >12 h, with a maximal dose of 0.5 mg/kg. On day 2, the infusion lasted ≥8 h, with the remainder of the dose administered. The trial duration per participant was approximately 13 months, including a 2‒3-week screening period, 2 days of treatment, and 12 months of follow-up. The 0.1- and the 1.5-mg/kg doses were progressively dropped from the study.

The result for the primary outcome was similar across the 5–9-year, 10–17-year, and 18–25-year age cohorts (p=0.42 for age group by treatment by time interaction).

“Being able to limit the administration of ATG to 0.5 mg/kg would also mean only needing one infusion on 1 day, instead of the 2 days of infusion with 2.5 mg/kg. It should be noted that the ATG therapy at 0.5 mg/kg as a single day infusion is available in most countries worldwide at very affordable prices,” lead investigator Prof Chantal Mathieu from UZ Leuven in Leuven, Belgium, said in a press statement.

Mathieu also called for further research using redosing strategies with different forms of ATG once available to determine the optimal timing and duration of the immune system changes (CD4 to CD8 ratio) needed to prevent the decline of functional beta-cells in young people with T1D.