A course of Teplizumab (Tzield) may help preserve beta-cells when given early after a type 1 diabetes (T1D) diagnosis, similar to the anti-CD3 antibody’s delay on progression from preclinical disease, the randomized PROTECT trial showed.

Two 12-day courses of the drug resulted in 59.3% less loss of beta-cell function, with higher stimulated C-peptide levels at week 78 compared with placebo (least-squares mean difference 0.13 pmol/mL, 95% CI 0.09-0.17, P

Nearly all teplizumab recipients maintained peak C-peptide at 0.2 pmol/mL or above (94.9%), which was significantly greater compared with those on placebo (79.2%).

However, the drug didn’t reduce insulin dose requirements, improve glucose control, or reduce hypoglycemia events, Kevan C. Herold, MD, of Yale University in New Haven, Connecticut, and colleagues reported in the New England Journal of Medicine in conjunction with a presentation at the International Society for Pediatric and Adolescent Diabetes meeting in Rotterdam, the Netherlands.

Teplizumab was approved in 2022 for adults and children ages 8 years and older who have stage 2 (preclinical) T1D who want to delay the irreversible loss of insulin-producing beta-cell’s ability to maintain normal glycemic control (clinical, or stage 3 T1D).

While an FDA advisory panel had been tepid on the evidence base for that approval (a single 76-Patient trial), teplizumab represents the first win in a decades-long struggle to find a safe and effective way to temper the autoimmune attack on the beta-cells in T1D.

The drug is believed to work by binding to CD3 cell surface antigens on T lymphocytes that attack insulin-producing beta-cells and possibly by inducing regulatory T-cell activity to boost immune tolerance.

Unlike the single 14-day course of teplizumab used to delay preclinical progression, the phase III PROTECT trial included 328 patients ages 8 to 17 years who were randomly assigned to receive teplizumab or placebo for two 12-day courses 26 weeks apart (up to 52 weeks was allowed during the pandemic). These were administered on an inpatient or outpatient basis within 6 weeks of diagnosis with clinical, stage 3 T1D.

Key secondary endpoints included insulin doses required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events — none of which showed a significant difference between groups.

Adverse events occurred primarily at the time of administration of study drug. Consistent with the prior trial, most common among these events were headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome.

Adverse events leading to treatment discontinuation occurred in 6.9% of the teplizumab group and 2.7% of the placebo group. The only serious events were two cases of cytokine release syndrome with teplizumab that resolved within 7 days and one case of device-related bacteremia in the placebo group. Severe hypoglycemia occurred in 13.4% of teplizumab-treated patients and 16.2% of placebo patients.

“The long-term effects of teplizumab do not appear to entail chronic immunosuppression,” the researchers noted, pointing to resolution of Epstein-Barr virus reactivation without antiviral treatment in all eight cases and no higher rate of COVID-19 infection with teplizumab.

The pandemic complicated trial conduct, Herold’s group acknowledged, “including our having to account for missed patient visits and disrupted data collection. However, the dropout rate was not higher than anticipated and affected both treatment groups equally.”

While the patient population was similar to that of other T1D trials, most participants were white, “which is not representative of persons who report new-onset disease in the general population, and our trial showed lower rates of diabetic ketoacidosis than those seen in other new-onset cohorts,” the researchers noted.