Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders

Abstract

Trials of immune therapies in new-onset type 1 diabetes (T1D) have shown success, but not all subjects respond, and the duration of response is limited. Our aim was to determine whether two courses of teplizumab, an Fc receptor-nonbinding anti-CD3 monoclonal antibody, reduces the decline in C-peptide levels in patients with T1D 2 years after disease onset. We also set out to identify characteristics of responders. We treated 52 subjects with new-onset T1D with teplizumab for 2 weeks at diagnosis and after 1 year in an open-label, randomized, controlled trial. In the intent to treat analysis of the primary end point, patients treated with teplizumab had a reduced decline in C-peptide at 2 years (mean -0.28 nmol/L [95% CI -0.36 to -0.20]) versus control (mean -0.46 nmol/L [95% CI -0.57 to -0.35]; P = 0.002), a 75% improvement. The most common adverse events were rash, transient upper respiratory infections, headache, and nausea. In a post hoc analysis we characterized clinical responders and found that metabolic (HbA1c and insulin use) and immunologic features distinguished this group from those who did not respond to teplizumab. We conclude that teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D. Metabolic and immunologic features at baseline can identify a subgroup with robust responses to immune therapy.

Trial registration: ClinicalTrials.gov NCT00129259.

Figures

FIG. 1.

Enrollment, randomization, and participation. Subjects (n = 125) were screened and 83 were eligible for enrollment. The majority of subjects who were excluded failed to meet entry criteria. Of 83 subjects randomized, 25 in the control group and 52 in the teplizumab group underwent an MMTT at baseline, received the first dose of study drug (teplizumab group), and are included in the ITT analysis. Of the subjects randomized to the teplizumab group, 12 did not receive the second course of drug because of AEs leading to discontinuation during cycle 1 (n = 6), had predefined laboratory abnormalities that precluded readministration (n = 4), or were withdrawn (n = 2). In addition, 3 of 40 subjects who started cycle 2 discontinued treatment because of AEs. The reasons for drug discontinuation are listed in Supplementary Table 1.

FIG. 2.

C-peptide (C-pep) responses in drug-treated and control subjects. A: The mean ± 25th and 75th percentiles of the C-pep AUC (nanomoles per liter) are shown for the drug and control groups (***P = 0.002; **P < 0.02, ANCOVA for each time point). B: Estimates and 95% CIs from a mixed effects model, with fixed effects for treatment group and linear and quadratic trends over time and random subject-level effects for intercepts and linear trends over time. Drug-treated subjects are estimated to have a delay of decline in C-pep by 15.9 months (i.e., would reach control 6-month values 21.9 months after study entry). C: Proportion of subjects with detectable C-pep (i.e., >0.05 nmol/L). The actual study dates when the MMTTs were performed are shown. There was a significantly greater loss of detectable C-pep secretion in the control group at month 24 (P = 0.002, χ2 test).

FIG. 3.

Insulin use and HbA1c in drug and control groups. A: HbA1c levels in the drug and control groups (means ± 25th and 75th percentiles are shown; *P < 0.05). B: Average insulin use in the 3 days before the visit was calculated (group means ± 25th and 75th percentiles; *P < 0.05, ***P < 0.005; P < 0.001 for overall trend at month 12, and P = 0.022 at month 18 using ANCOVA).

FIG. 4.

Identification of clinical responders to teplizumab. A: The cumulative frequency of subjects and distribution of percentage decrease from baseline C-peptide AUC at month 24. The arrow shows the smallest percentage loss of C-peptide AUC in the control group. B: The C-peptide AUC at each time point (means ± 25th and 75th percentiles) is shown for the responders (red line) and nonresponders (green line) in the drug-treated group and for the control subjects (blue line). ***P < 0.001 between responders and nonresponders at each time point based on ANCOVAs.

FIG. 5.

Baseline clinical characteristics in responders versus nonresponders. A: Ladder plot of covariates and clinical response. The effects of the indicated covariates on the ratio of log odds of responder status and 95% CIs are shown. The baseline HbA1c (P = 0.011) and insulin use (P = 0.004) were inversely associated with response. Baseline insulin use (B) and HbA1c (C) in the drug-treated responders (red) and nonresponders (green) (**P = 0.004, *P = 0.011).