New Haven, CT—Could progression to type 1 diabetes in high-risk relatives be slowed with immunotherapy? A new study suggests that could be the case.

The Type 1 Diabetes TrialNet Study Group was seeking interventions to affect clinical progression of type 1 diabetes, a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and subsequent dependence on exogenous insulin for survival.

While some interventions have delayed the loss of insulin production in those patients, prediagnosis options are needed, the authors said in a presentation at the American Diabetes Association Scientific Sessions in San Francisco, which was simultaneously published in The New England Journal of Medicine.

A phase ll, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor–nonbinding anti-CD3 monoclonal antibody) was conducted with relatives of patients with type 1 diabetes; participants did not have diabetes but were at high risk for development of clinical disease. Yale University–led researchers randomly assigned patients to a single 14-day course of teplizumab or placebo. They then used oral glucose-tolerance tests at 6-month intervals to follow up for progression to clinical type 1 diabetes.

Most, 72%, of the participants were aged 18 years and younger, with all undergoing randomization—44 to the teplizumab group and 32 to the placebo group. Results indicate that the median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group.

Overall, type 1 diabetes was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo.

That meant the hazard ratio for the diagnosis of type 1 diabetes—teplizumab versus placebo—was 0.41 (95% CI, 0.22-0.78; P = 0.006 by adjusted Cox proportional-hazards model). In addition, the annualized rates of diagnosis of diabetes were calculated as 14.9% per year in the teplizumab group and 35.9% per year in the placebo group.

Adverse events of rash and transient lymphopenia, which were expected, occurred in some patients. Researchers also determined that TIGIT+KLRG1+CD8+ T cells were more common in the teplizumab group than in the placebo group.

“Among the participants who were HLA-DR3–negative, HLA-DR4–positive, or anti–zinc transporter 8 antibody–negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed,” they report, adding, “Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants.”

“The difference in outcomes was striking. This discovery is the first evidence we’ve seen that clinical type 1 diabetes can be delayed with early preventive treatment,” said Lisa Spain, PhD, project scientist from the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), sponsor of TrialNet. “The results have important implications for people, particularly youth, who have relatives with the disease, as these individuals may be at high risk and benefit from early screening and treatment.”

The study points out that teplizumab targets T cells to lessen the destruction of beta cells.

“Previous clinical research funded by the NIH found that teplizumab effectively slows the loss of beta cells in people with recent onset clinical type 1 diabetes, but the drug had never been tested in people who did not have clinical disease,” explained lead author Kevan C. Herold, MD, of Yale University. “We wanted to see whether early intervention would have a benefit for people who are at high risk but do not yet have symptoms of type 1 diabetes.”

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