What are the long-term effects of teplizumab on C-peptide response?
It is no surprise that patients with type 1 diabetes lose beta-cell function from destruction, leaving them to rely on insulin therapy. Various ways to preserve this function and slow beta-cell destruction have been explored. Previous studies have determined a short-term response, reducing the decline in C-peptide, by using teplizumab, but have not explored any long-term effects.
This study used previous participants from The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial to conduct their follow-up study to evaluate the “long-term effects of teplizumab on C-peptide response, clinical variables, immunological profiles and safety” succeeding the trial. The AbATE trial was a randomized, open-label study with a 2:1 ratio of drug versus control groups. Patients were newly diagnosed with type 1 diabetes (8 weeks), allotting 52 to the drug-treatment group, and 25 as the control group. The treatment was teplizumab IV as a 14-day course, with a median dose of 11.6 mg.
In the current study, at follow-up visit 1, 43 patients returned, those with a detectable C-peptide response at the year two follow-up of the AbATE trial: thirty-one patients from the drug-treated group and 12 from the control. They performed a four h mixed-meal tolerance test (MMTT), as previously done in the AbATE trial. If at visit 1, there were still detectable C-peptide levels, patients were to return for a follow-up visit 2, 1 year later, to perform another MMTT (n = 12). Throughout this time, autoantibodies, C-peptide and HbA1c levels were measured and recorded. Peripheral blood mononuclear cells (PBMCs) were collected for T cell phenotyping, marked as “exhausted” or “anergic” and then expressed as a percentage of CD4+ or CD8+ cells.
The trapezoidal rule was used to calculate the area under the C-peptide response curve (AUC) over the four h MMTT, diving by 240 minutes, converted to loge, represented as C-peptide AUC in ng/dL (nmol/L). C-peptide responses that were undetectable were assigned 0 for the AUC analysis. Data were presented as mean + SEM, considering a p-value < 0.05 as statistically significant.
At the follow-up visit, between the drug-treated and control groups, C-peptide responses were not significantly different. Yet, there was a greater C-peptide response in the drug-treated responders compared to the control group and drug-treated non-responders (p = 0.34, p = 0.01, p = 0.004). The researchers evaluated those who had a measure of clinically significant residual beta-cell function (stimulated C-peptide > 6 ng/dL [> 0.2 nmol/L]), and noted the frequency was highest in the drug-treated responders. However, between the three groups, the differences were not statistically significant. From the same data, they also assessed the change in C-peptide from baseline, with more than an 80% loss in both the drug-treated and controlled groups.
Conversely, there was a significantly less loss of C-peptide in the drug-treated responders. Lastly, a mixed model was used to evaluate changes in C-peptide over time. At all time points, drug-treated responders had greater C-peptide responses. In regards to age, the response was higher in older individuals in the control group (p = 0.0004), without finding any significant age interactions in the other groups.
In the AbATE, drug-treated responders were found to have significantly lower insulin use and HbA1c levels, but this was not seen at the follow-up. Between the C-peptide AUC and daily insulin use, there was a modest inverse relationship (p = 0.028), but not with HbA1c. Adverse effects were reported at the follow-up. In the control group and drug-targeted non-responders, reports of severe hypoglycemia, though few, were more frequently seen versus in the drug-targeted responders. However, in all three groups, respiratory and other infectious complications were comparable.
Throughout the study, while measuring for autoantibodies among the treatment groups, the antibody titers were not different. Looking at the metabolic and immunological predictors. In the control and non-responder groups, the C-peptide AUC projected the decline after 7 years (p = 0.005, p = 0.002), yet not in drug-treated responders (0.41). During the 2-year study, previously found, were changes in CD8+ T cells linked with clinical responses. At the follow-up visit, these markers were tested, and, in the drug-treated responders, PD-1 expression on CD8+ T cells was found to be significantly more frequent than in the other groups. Furthermore, at the follow-up visit, a direct relationship was seen between them and C-peptide responses.
Immune modulators have shown positive results, short-term, in C-peptide responses, but what about in terms of “lasting effects”? The data showed, at follow-up visits, patients treated with teplizumab who showed a positive response at one year retained detectable levels of C-peptide compared to the other groups in the long-term. While there were no differences among the groups in HbA1c levels or insulin use, the researchers noted in the treated group, there were fewer hypoglycemia events, though this wasn’t statistically significant. In terms of a potential biomarker of response, future trials should look further into the changes seen in CD8+ T cells. The authors acknowledged they had a smaller sample size due to circumstances and that future studies should be larger to have more robust results. They propose that there is potential for the preservation of immunological responses using immune or metabolic therapies to achieve better outcomes in patients with type 1 diabetes.
- Patients with type 1 diabetes will lose beta-cell function and rely on insulin.
- Studies have shown teplizumab to stimulate C-peptide response short-term.
- By using immune modulators, there is possible long-term preservation of beta-cell function.
Perdigoto, Ana Luisa, et al. Treatment of type 1 diabetes with teplizumab: clinical and immunological follow-up after seven years from diagnosis. 2018 December 19.
Emma Kammerer, L|E|C|O|M Bradenton School of Pharmacy, PharmD Candidate