Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial

Abstract

Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8-17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.

FIG. 1.

Adjusted mean changes in AUC mean C-peptide from baseline over time in the 14-day full-dose and placebo groups. Bars indicate standard errors; numbers of patients are above (teplizumab) or below (placebo). P values are indicated where significant. Changes in AUC mean C-peptide from baseline were calculated using [ln(AUC mean C-peptide_{Day x} + 1) − ln(AUC mean C-peptide_Baseline + 1)]. A: All patients. B: Patients in the U.S. C: Patients randomized ≤6 weeks after diagnosis. D: Subjects 8–17 years of age.

FIG. 2.

Adjusted mean difference is shown in AUC mean C-peptide change from baseline at 2 years among subsets at study entry in the 4-day full-dose group vs. placebo. The ♦ indicate least squares means; bars indicate 95% CIs. AUC mean C-peptide change from baseline was calculated using [ln(AUC mean C-peptide_{Day x} + 1) − ln(AUC mean C-peptide_Baseline + 1)].

FIG. 3.

Flow cytometry for CD4⁺ (left) and CD8⁺ T cells (right). A: Cell counts. B: CD3 occupancy/cell. C: CD3/TCR (T-cell receptor) modulation on cells. D: Percentage of cells positive for Foxp3 marker. Symbols indicate means, and bars indicate standard errors. A and C: Number of patients is above (placebo) or below (teplizumab). B and D: Number of patients is above (teplizumab) or below (placebo).