Low-dose anti-thymocyte globulin (ATG)

Screening: finding T1D before it strikes

Like every prevention therapy, low-dose ATG only helps people who are found in time — and that depends on screening. Type 1 diabetes develops along a defined three-stage path. Stage 1 is two or more islet autoantibodies (against insulin, GAD, IA-2, or ZnT8) with normal blood glucose and no symptoms; stage 2 adds abnormal glucose (dysglycemia) but still no symptoms; stage 3 is clinical disease, when insulin becomes necessary.¹ These autoantibodies are powerful predictors: in genetically at-risk children with two or more, symptomatic diabetes develops in roughly 44% by 5 years, 70% by 10 years, and 84% by 15 years, with lifetime risk approaching 100% — so the staging model is reliable enough to build prevention trials on.¹

Screening is often offered to relatives of someone with T1D, but about 90% of new cases have no family history — so finding most at-risk people requires general-population autoantibody (and sometimes genetic-risk) testing.² Early detection matters even without treatment: people identified through screening are monitored, so when they reach stage 3 they are far less likely to arrive in diabetic ketoacidosis (DKA), a dangerous and sometimes fatal emergency.² Capillary and home-collected blood-spot methods are lowering the cost and burden that long blocked wide screening.²

Therapy: an old transplant drug, repurposed and shrunk

Anti-thymocyte globulin is a polyclonal antibody (rabbit-derived Thymoglobulin, from Sanofi/Genzyme) that has been used for decades to deplete T cells in organ-transplant patients. The repurposing idea is simple: T1D is driven by T cells destroying insulin-producing cells, so depleting those T cells should slow the attack.³ The breakthrough was dose. A high-dose course (6.5 mg/kg) tested in new-onset T1D failed to preserve insulin-producing function and caused serum sickness and cytokine-release syndrome in nearly every patient.⁴ Counter-intuitively, a much lower dose works better — it shifts the balance toward protective regulatory T cells (raising the Treg-to-effector ratio) rather than just blunt depletion.³

The pivotal evidence is the TrialNet phase 2b trial (NCT02215200): 89 people aged 12–45, within 100 days of diagnosis, randomized to low-dose ATG (2.5 mg/kg), ATG plus GCSF, or placebo. At one year, stimulated C-peptide (a direct readout of surviving insulin-producing cells) was 0.646 nmol/L with ATG versus 0.406 with placebo (p=0.0003), and HbA1c was significantly lower.⁵ At two years the benefit held (C-peptide p=0.00005; HbA1c still lower), with the decline in C-peptide roughly halved versus placebo — durable for an immunotherapy and from a single course.³ Adding GCSF gave no extra benefit.

The decisive follow-up is the 2025 MELD-ATG trial (NCT04509791), an INNODIA dose-ranging study of 117 people aged 5–25 with recent-onset (stage 3) T1D across eight European countries.⁶ It found that an even lower 0.5 mg/kg dose preserved C-peptide about as well as 2.5 mg/kg — and far more safely: serum sickness fell from 82% to 32%, and cytokine-release from 33% to 24%.⁶ That makes ATG a rare thing in T1D: an affordable, off-patent, globally stocked disease-modifying drug.⁶

Safety: the main effects are serum sickness and cytokine-release symptoms in the days after infusion — uncomfortable but predictable and short-lived, with no deaths and no long-term safety signals in these trials.³ The lower dose meaningfully shrinks this burden.

Access: ATG is widely available and cheap, but it is not approved for T1D anywhere — use is investigational or off-label, given as a brief IV infusion over two days, and (like all prevention therapy) depends on screening to find candidates.⁵

What's coming

The trials so far treat people already diagnosed (stage 3). The stated next step, voiced by the investigators themselves, is to move earlier — into stage 1/2 to delay or prevent clinical onset, the same territory where teplizumab is already approved.³ With the safe minimum dose now defined by MELD-ATG, a low-cost repurposed agent is positioned for prevention trials in screened, autoantibody-positive children — potentially reaching far more people than an expensive new biologic could.⁶

References

1. Insel RA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care (2015). https://doi.org/10.2337/dc15-1419 ↩ ↩²

2. Sims EK, et al. Screening for Type 1 Diabetes in the General Population: A Status Report and Perspective. Diabetes (2022). https://doi.org/10.2337/dbi20-0054 ↩ ↩² ↩³

3. Haller MJ, et al. Low-Dose Anti-Thymocyte Globulin Preserves C-Peptide, Reduces HbA1c, and Increases Regulatory to Conventional T-Cell Ratios in New-Onset Type 1 Diabetes: Two-Year Clinical Trial Data. Diabetes (2019). https://doi.org/10.2337/db19-0057 ↩ ↩² ↩³ ↩⁴ ↩⁵

4. Gitelman SE, et al. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol (2013). https://doi.org/10.1016/S2213-8587%2813%2970065-2 ↩

5. Haller MJ, et al. Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. Diabetes Care (2018). https://doi.org/10.2337/dc18-0494 ↩ ↩²

6. Mathieu C, et al. 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. Lancet (2025). https://doi.org/10.1016/S0140-6736%2825%2901674-5 ↩ ↩² ↩³ ↩⁴