From Pages to Practice

By Clement Lee, MD, MSc

Published January 26, 2024


Type 1 diabetes mellitus (T1DM) is a chronic disease that is primarily diagnosed in childhood and marked by the autoimmune destruction of pancreatic insulin-producing β-cells. Histopathologic studies in the 1960s showed that by the time the disease becomes clinically apparent, fewer than 10% of β-cells remain. One third of pediatric patients with T1DM first present with diabetic ketoacidosis, which can be life-threatening. Diagnosis and treatment of T1DM before the pancreas accrues major damage might mitigate some of the complications described.

Teplizumab is an anti-CD3 monoclonal antibody that has the potential to modulate the CD8+ T cells that induce β-cell destruction. In the randomized, placebo-controlled TN10 trial published in NEJM in 2019, 14 daily infusions of teplizumab delayed the time to diagnosis of diabetes by a median of 24 months in children aged 8 years and older with stage 2 diabetes (defined as the presence of ≥2 autoantibodies and evidence of dysglycemia but not yet meeting diagnostic criteria for diabetes mellitus). If teplizumab delayed the progression of prediabetic dysglycemia in the TN10 trial, could it also delay the progression of diabetes after diagnosis?

Investigators examined this question in the international, phase 3, randomized, placebo-controlled PROTECT study in 328 predominantly white children aged 8–17 years with a recent (mean, 5.3 weeks) diagnosis of overt (stage 3) T1DM. The children had relatively nascent disease marked by robust stimulated C-peptide levels and a mean glycated hemoglobin of 9.00%. Participants were randomized to receive two 12-day courses of daily teplizumab or placebo infusions 26 weeks apart. The teplizumab protocol was modified from the single 14-day course in the TN-10 trial based on the observation that teplizumab’s effect on immune cells was short-lived.

Teplizumab was efficacious in preserving β-cell function at week 78 (the primary endpoint), as measured by the mean change from baseline in C-peptide area under the concentration-time curve (AUC) in children with newly diagnosed T1DM. Secondary endpoints, including required insulin doses, glycated hemoglobin levels, time in target glucose range, and hypoglycemic events did not differ significantly between groups. The safety data were reassuring; two episodes of cytokine release syndrome in the treatment group and one case of Epstein-Barr virus infection in each group.

Although questions remain about the clinical utility of teplizumab in patients with newly diagnosed T1DM, let us hope that we are turning the page to a new chapter in T1DM care and not just entering a “honeymoon” period of drug development that will rapidly fade.

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Clement Lee, MD, MSc, was a 2021–2022 NEJM Editorial Fellow and a 2022–2023 Senior Editorial Fellow. He is currently a Guest Editor for NEJM, an internal medicine hospitalist at Newton-Wellesley Hospital, and a pediatric hospitalist at Boston Children's Hospital. He completed his internal medicine-pediatrics residency at Penn-CHOP.
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