Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals

Abstract

We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457, P = 0.01). Fifty percent of teplizumab-treated but only 22% of the placebo-treated remained diabetes-free. Glucose tolerance, C-peptide area under the curve (AUC), and insulin secretory rates were calculated, and relationships to T cell subsets and function were analyzed. Teplizumab treatment improved beta cell function, reflected by average on-study C-peptide AUC (1.94 versus 1.72 pmol/ml; P = 0.006). Drug treatment reversed a decline in insulin secretion before enrollment, followed by stabilization of the declining C-peptide AUC seen with placebo treatment. Proinsulin:C-peptide ratios after drug treatment were similar between the treatment groups. The changes in C-peptide with teplizumab treatment were associated with increases in partially exhausted memory KLRG1⁺TIGIT⁺CD8⁺ T cells (r = 0.44, P = 0.014) that showed reduced secretion of IFNγ and TNFα. A single course of teplizumab had lasting effects on delay of T1D diagnosis and improved beta cell function in high-risk individuals. Changes in CD8⁺ T cell subsets indicated that partially exhausted effector cells were associated with clinical response. Thus, this trial showed improvement in metabolic responses and delay of diabetes with immune therapy.

Figure 1.. Teplizumab Treatment is Associated with a Sustained Effect on Type 1 Diabetes Progression Over 923 Days of Follow-up.

Updated Kaplan-Meier Curve based on 923 days of follow up (range 74-3,119 days). Hazard ratio for development of type 1 diabetes in teplizumab-treated participants vs. placebo was 0.457; p=0.01. The median time to diabetes was 27.1 and 59.6 months in the placebo and teplizumab treatment groups respectively. At the conclusion of this period, 7 (22%) and 22 (50%) respectively were not diagnosed with T1D.

Figure 2.. Improved glycemia in teplizumab treated participants is associated with maintenance of dysglycemic status.

A. OGTT classifications for participants in each group over 36 months of follow-up. The data are shown to 36 months because of loss of placebo treated participants because of the clinical diagnosis of T1D (for individual participants see Supplemental Figure 2). B. Boxplot displaying median and interquartile ranges for on-study OGTT glucose AUC mean for participants from placebo and teplizumab treated groups. ANCOVA model incorporating baseline value, age, and treatment group showed that treatment group had a significant effect to decrease average on-study glucose AUC (ANCOVA teplizumab effect: 92.8%, p=0.03).

Figure 3.. Teplizumab treatment was associated with increased average on-study C-peptide AUC.

Boxplot displaying median and interquartile ranges for average on-study OGTT C-peptide AUC mean for participants from placebo and teplizumab treated groups. An ANCOVA model including baseline C-peptide AUC and age showed that treatment was associated with higher average on-study C-peptide AUC (p=0.009).

Figure 4.. C-peptide over time in the two treatment arms over the first year.

The log-transformed mean C-peptide AUC is shown. Arrows indicate individual drop out from OGTT monitoring due to diabetes development at each timepoint. Median value for “pre-baseline” timepoint was 24. Months prior to randomization and median value for “baseline” timepoint was 0.85 months prior to randomization. *P<0.05 for comparisons of 6-month on-treatment C-peptide AUC values to baseline in the teplizumab group and 6-month C-peptide AUC values in the teplizumab group to 6-month C-peptide AUC values in the placebo group.

Figure 5.. Insulin secretion after treatment with teplizumab or placebo.

Estimated slopes for the insulin secreted (pmol) during the total (A), first hour (B), and second hour (C) of the OGTT at the visits before enrollment and over the first 6 months after study drug treatment. Median values (and 95% confidence intervals in shaded colors) are shown. Significance for Wilcoxon signed-rank test for comparison of posttreatment slopes between treatment groups are shown in each panel. Please refer to Table 1 for full statistical analyses. (D and E) Representative insulin secretion rates during serial OGTTs for two teplizumab-treated participants who were not diagnosed with T1D (aged 11 and 12 years) and (F and G) two placebo-treated individuals (both aged 13 years) who were diagnosed with T1D. The colored lines indicate the time of the visits in relationship to study drug administration. tx, treatment. **P < 0.01 and ***P < 0.001.

Figure 6.. Teplizumab preserves C-peptide over the course of the study until the period surrounding diagnosis.

For all panels, data from teplizumab-treated participants are shown in blue, and placebo-treated participants are shown in maroon. A,B. Regression lines for C-peptide AUC values over the study period of OGTT monitoring from baseline study visit until diagnosis (teplizumab n=44, placebo n=32). C,D. Regression lines for C-peptide AUC values over 6 month period before diabetes diagnosis (placebo n=23, teplizumab n=22). E. Slopes of C-peptide AUC for 6-month period before diagnosis in those that developed T1D, and the last 6 months of study in individuals remaining T1D-free.

Figure 7.. Functional changes in T cells are associated with improvements in metabolic function.

A. The changes in TIGIT+KLRG1+CD45RO+CD8+ T cells between baseline and 3 months and the change in the C-peptide AUC between the baseline and 6 months are shown. There was a significant correlation between the changes in this cell subset and C-peptide in the teplizumab (Pearson r=0.44, p=0.014, n=31) but not the placebo treated (r=0.28, p=0.25, n=18) participants. B, C. The frequency of double positive (DP) CD8+ memory cells that produce IFNγ or TNFα are shown for the placebo treated (●, n=16) and drug treated (●, n=24) participants at baseline and month 3. The frequency of the IFNγ and TNFα producing cells were reduced in the teplizumab treated participants (paired T-test, ***p<0.0001).