In patients treated with a single 14-course regimen of teplizumab, administered up to 1 year following diagnosis of type 1 diabetes, we observed a significant preservation of C-peptide loss after 1 year but this effect was not statistically significant after adjustment for chance imbalances in HbA1c at baseline. However, percentage change in C-peptide from baseline, as well as insulin requirements, were improved in those receiving teplizumab and a greater proportion of placebo-treated participants lost all detectable C-peptide responses. Our exploratory subgroup analyses suggest that younger age and near normal control of blood glucose improves responses to teplizumab.
The effect of the prior glucose control on responses to the drug was unexpected. The participants with lower HbA1c levels had higher baseline C-peptide responses, which may have been a factor in responsiveness to treatment, but younger participants also showed better response to the drug even though their baseline C-peptide levels were lower than in older participants.
Since teplizumab had no direct effect on HbA1c
, these findings suggest either an effect of prior glucose levels on beta, immune or other cells such as vascular cells during drug treatment [21
]. Glucose may stimulate increased levels of IL-1β by beta cells, which could affect responses to anti-CD3 mAb, as we have recently shown, and thus directly or indirectly cause beta cell toxicity [23
]. We have found a similar effect of baseline HbA1c
in a trial of teplizumab in patients with new-onset type 1 diabetes (K. Herold, unpublished data). Interestingly, in a recent trial of abatacept in type 1 diabetes that showed an effect of that drug on the decline of C-peptide, the drug-treated group had a significantly lower level of HbA1c
at randomisation (6.31±0.09% vs 6.74±0.16% [45.5 vs 50.2 mmol/mol], p
=0.01). These observations suggest that good glucose control prior to immune therapy is needed for the responses to immune therapies in patients with established disease but this hypothesis will need further evaluation in larger studies.
Our analysis did not identify differences in the efficacy of teplizumab between the duration strata. The differences that were seen reflected the decline in C-peptide in the two placebo groups and not the response to teplizumab. This may be explained by a slower rate of decline of C-peptide during the second year of disease, a finding recently reported [26
]. Therefore those in the longer duration stratum may lose C-peptide more slowly during the period on study. A longer follow-up time may be needed to detect differences in participants whose endpoint occurred after the first year of disease. In addition, participants who were recruited after 8 months may represent a ‘survivor’ group—by requiring the same level of C-peptide for enrolment in the 4-month as in the 9- to 12-month strata, we may have selected for individuals who have less aggressive disease: we do not know whether the same degree of preservation would be seen in those with lower stimulated levels at entry.
Based on data from other trials, it appears that the magnitude of the effects of the drug in this population who enrolled after 4 months following diagnosis, is less than in those studied within the first 100 days after diagnosis. In a previous trial recruiting participants of similar age with new-onset disease (i.e. within 100 days from diagnosis), there was an 84% increase in C-peptide in drug-treated vs control participants [18
] at 12 mos. In US participants in the Protégé trial, which also enrolled participants within 100 days from diagnosis (n
=95), there was a 33% increase in C-peptide at month 12. There are several potential reasons for the difference in the magnitude of response in patients with new-onset vs longer-duration diabetes, such as evolution of the immune response, inflammatory cells that are no longer active following presentation or the effects of an extended duration of damage to beta cells that may render them unrecoverable. The C-peptide responses at entry into new-onset trials has been higher than this study (e.g. 0.722±0.04 vs 0.575±0.030 nmol/l) despite our requirement for a stimulated level of at least 0.2 nmol/l. This might affect the responses to drug since we found that the baseline C-peptide responses were significantly higher in clinical responders, consistent with findings reported by Keymeulen et al [10
]. However, the response to drug treatment in our study was not restricted to those within the upper half of C-peptide responses at entry—individuals in the upper half of baseline C-peptide responses lost 19.9±8.8% (SEM) of baseline responses at month 12 whereas those in the lower half of baseline responses lost 18.2±5.2% (p
The effect of age in determining responses was previously identified in the Protégé trial [14
] and is confirmed by our findings. Although the baseline C-peptide responses were lower in younger participants, their baseline HbA1c
levels were not (6.82±0.17% [51±1.88 mmol/mol] [SEM] vs 6.51±0.24% [47.6±11.7 mmol/mol], p
=0.29). Since entry into the study required that participants meet a specific stimulated C-peptide level, there may have been a bias in the enrolment of younger participants with less aggressive disease since younger participants in general have lower levels of C-peptide than older participants [27
]. Caution is therefore needed in drawing conclusions from these findings.
In previous studies, we had identified an increase in the relative number of CD8+
T cells among clinical responders to anti-CD3 mAb and had shown that the CD8+
T cells from drug-treated participants had suppressor function ex vivo [18
]. In this trial we found that drug-treated responders could be distinguished from drug-treated non-responders by an increase in the number of CD8CM (CD45RO+
) T cells 3 months after treatment. A limitation of our finding is that it was restricted to a single time point and we did not perform corrections for multiple comparisons. We hypothesise that these CD8 T cells may be those associated with the functional responses we have previously identified but further studies will be needed to directly analyse the function of these cells at later time points, and to determine whether CD8CM cells respond differently in drug-treated responders and non-responders when they encounter antigen, analogous to adaptive Tr1 cells [31
]. We did not identify consistent changes in T cell subsets in young and older participants or in those with non-diabetic vs elevated HbA1c
levels although the differences in the CD4:CD8 T cell ratio and other immunological markers warrant further investigation.
In conclusion, our findings for the primary outcome did not conclusively demonstrate a significant benefit for teplizumab. Nevertheless, our secondary outcomes suggest that treatment with teplizumab may modulate the course and reduce the decline of C-peptide in patients with established disease of up to 1 year duration. The analyses we performed identified clinical (age) and laboratory (HbA1c) characteristics that may identify those participants most likely to respond to drug treatment and may serve as a guide to future studies with this or other immunological characteristics tested in this population. These characteristics of ‘responders’ may also provide insights into the mechanisms underlying drug efficacy. Specifically, the HbA1c findings emphasise the need to conduct studies to explore how glucose levels modulate responses to immunological treatments. We also identified immunological determinants of efficacy that may be useful in future trials in tracking responses or selecting those most likely to respond to therapy.