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Phase 2CompletedNCT00505375

TN-09: Abatacept (CTLA4-Ig) in recent-onset type 1 diabetes

A randomized, double-blind, placebo-controlled Phase 2 trial (TrialNet TN-09) testing whether the T-cell co-stimulation modulator abatacept could slow the loss of insulin-producing beta cells in people recently diagnosed with type 1 diabetes. Two years of abatacept preserved C-peptide and delayed its decline by about 9.6 months, but the benefit plateaued after the first 6 months of dosing.

Primary endpoints

  • Baseline-adjusted geometric mean 2-hour area-under-the-curve (AUC) serum C-peptide after a mixed-meal tolerance test at 2 years

Results so far

Over 2 years, abatacept slowed the loss of beta-cell function: adjusted C-peptide was 59% higher than placebo (95% CI 6.1–112%; p=0.0029), equivalent to delaying C-peptide decline by about 9.6 months. Notably, the decline ran parallel to placebo after the first ~6 months, suggesting the drug acts mainly early. One year after infusions stopped (3 years from diagnosis), the gap persisted: C-peptide 0.217 vs 0.141 nmol/L (p=0.046), about a 9.5-month delay, with lower HbA1c (7.64% vs 8.55%; p<0.005). Insulin dose differences had evened out by year 3. Safety was reassuring, with no excess infections or neutropenia.

The full picture

What was tested and why it matters

Type 1 diabetes happens when the immune system's T cells mistakenly destroy the insulin-producing beta cells in the pancreas. For a T cell to switch fully "on," it needs two signals: it must see its target, and it must receive a second "co-stimulation" signal. Abatacept (CTLA4-Ig) is a fusion protein that blocks that second signal, so wandering T cells never become fully activated.1 This trial — TrialNet study TN-09 — asked a simple question: if you dampen T-cell activation soon after diagnosis, can you protect the beta cells that are still alive?1

This matters because people newly diagnosed with type 1 diabetes usually still make some of their own insulin, and holding onto even a little is linked to steadier glucose and fewer complications. A therapy that preserves that capacity could make the disease milder and easier to manage.2

Who it was for

The trial enrolled people aged 6–45 who had been diagnosed within the previous ~100 days, still had measurable insulin production, and carried at least one diabetes-related autoantibody.3

How it was designed

This was a multicenter, double-blind, randomized, placebo-controlled Phase 2 trial at sites across the United States and Canada.13 112 participants were randomly assigned 2:1 to abatacept (77 people) or placebo (35 people) and received 27 intravenous infusions over 2 years.1 Neither participants nor staff knew who got which.1 The main measure was how much insulin (gauged by C-peptide) people still made during a standardized meal test after 2 years.1

Key results

Abatacept clearly slowed beta-cell loss. At 2 years, C-peptide was 59% higher with abatacept than placebo (95% CI 6.1–112%; p=0.0029) — roughly a 9.6-month delay in the decline of insulin production.1 A striking detail: after the first ~6 months of treatment, beta-cell function fell at the same rate in both groups, hinting that the drug does most of its work early, when T-cell activation is most intense.1 Safety was reassuring — no excess infections or low white-blood-cell counts.1

A follow-up one year after infusions stopped (3 years from diagnosis) found the benefit endured rather than rebounding: C-peptide was 0.217 vs 0.141 nmol/L (p=0.046), about a 9.5-month delay, and HbA1c stayed lower with abatacept (7.64% vs 8.55%; p<0.005), though insulin doses had evened out.4

What it means and what's next

TN-09 was an early proof that the immune attack is still active and treatable around the time of diagnosis. But the plateau after 6 months suggests a single agent given continuously isn't enough — the benefit waned even while dosing continued.1 These findings point toward earlier intervention (before diagnosis) and combination strategies, and abatacept has since been carried into prevention trials in at-risk relatives.2

References

  1. Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet (2011);378(9789):412–419. https://pmc.ncbi.nlm.nih.gov/articles/PMC3462593/ ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8 ↩9 ↩10

  2. Rachid O, Osman A, Abdi R, Haik Y. CTLA4-Ig (abatacept): a promising investigational drug for use in type 1 diabetes. Expert Opinion on Investigational Drugs (2020);29(3):221–236. https://doi.org/10.1080/13543784.2020.1727885 ↩ ↩2

  3. U.S. National Library of Medicine. Intravenous CTLA4-Ig Treatment in Recent Onset Type 1 Diabetes Mellitus (NCT00505375). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT00505375 ↩ ↩2

  4. Orban T, Bundy B, Becker DJ, et al. Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment. Diabetes Care (2014);37(4):1069–1075. https://pmc.ncbi.nlm.nih.gov/articles/PMC3964491/ ↩