An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes

Abstract

Background: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.

Methods: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.

Results: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. 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; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+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.

Conclusions: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).

Figure 1.. Effects of Teplizumab on Development of Type 1 Diabetes.

Shown are Kaplan–Meier estimates of the proportions of participants in whom clinical diabetes was not diagnosed. The overall hazard ratio was 0.41 (95% confidence interval [CI], 0.22 to 0.78; two-sided P = 0.006 by adjusted Cox proportional-hazards model). The median time to diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The numbers of participants with or without a diagnosis of clinical type 1 diabetes (upper right) represent data at the conclusion of the trial. Tick marks indicate censored data.

Figure 2.. Changes in T-Cell Subsets in the Treatment Groups.

Panel A shows the absolute lymphocyte counts in the treatment groups over the first 7 weeks after enrollment. Panel B shows the frequency of KLRG1+TIGIT+CD8+ T cells as a percentage of total CD3+ T cells in the teplizumab and placebo groups. The estimates of the percentage differences between the teplizumab group and the placebo group are 46.5% at 3 months (95% CI, 8.23 to 98.4), 49% at 6 months (95% CI, 4.13 to 113), and 15.9% at 18 months (95% CI, −14.2 to 56.4). The analysis was performed with log-transformed values by analysis of covariance and corrected for the baseline values. In both panels, means and 95% confidence intervals are shown.

Figure 3.. Subgroup Analysis of Responses to Teplizumab.

The forest plot shows the hazard ratios and 95% confidence intervals for a diagnosis of type 1 diabetes in the teplizumab group as compared with the placebo group for the two categories of each baseline feature. The Cox model was adjusted for age, with the exception of the interaction test for age (<18 years vs. ≥18 years), but was not adjusted for multiple testing. BMI denotes body-mass index, GAD65 glutamic acid decarboxylase 65, IA-2 islet antigen 2, ICA islet-cell autoantibody, and ZnT8 zinc transporter 8.