The results of this study demonstrate that over two years co-stimulation modulation with abatacept slows the decline of beta cell function in recent-onset T1DM by 9·6 months. The early beneficial effect suggests that T-lymphocyte activation still occurs around the time of clinical diagnosis of T1DM, even though the disease course has presumably been going on for several years 1
. However, despite continued administration of abatacept over 24 months, the decline in beta cell function in the abatacept group parallels that in the placebo group based on the mixed model results that included the time interval from 6 to 24 months. This subsequent decline in beta cell function causes us to speculate that continuing T-lymphocyte activation may subside as the clinical course of the disease progresses. Nevertheless, the difference from the placebo group is mantained during the drug administration. Further observation will determine whether the beneficial effect continues after cessation of monthly abatacept infusions.
It is important to note that abatacept was well tolerated, with no difference between the two groups in adverse events. However, a potential limitation to clinical applicability is that live vaccines cannot be used within 3 months of abatacept therapy. This may be important in view of the young age of the target population.
The main effect appears to be early after initiation of treatment with subsequent resumption of decline in beta cell function. This is reminiscent of the effects of anti-CD3 5,6
, anti-CD20 7
and a GAD-65 vaccine 8
, all of which showed some efficacy followed later by a decline in beta cell function parallel to that in the control group. This is consistent with our notion that there is an early window of opportunity after diagnosis in which T-lymphocyte activation is prominent. The 59% (0·378/0·238) higher mean AUC C-peptide than placebo at 24 months in our study is similar to that seen with those other interventions, although it is difficult to make direct comparisons of different studies. This is because the studies have differed in important baseline characteristics, including age, disease duration at time of randomisation, and baseline HbA1c. Moreover, our study differs from those studies in that abatacept was administered continuously throughout the study, whereas in the case of anti-CD3, anti-CD20, and GAD-65 vaccine, administration of drug was completed within 2–4 weeks after randomization.
It is crucial to note that our study was not designed to answer the questions whether a shorter treatment protocol would be sufficient to maintain improved C-peptide secretion over two years or whether a continuation of therapy is needed beyond two years. With all patients having completed their course of abatacept, the ongoing follow-up phase of the study will investigate whether the improved C-peptide secretion is sustained after discontinuation of abatacept. Long term follow up of patients in one anti-CD3 trial showed diminishing difference in C-peptide secretion between the treated and the placebo group after 3 years 24
In the abatacept group mean HbA1c was lower than the placebo group throughout the trial, although it was also lower at baseline. The maintenance of HbA1c below 7% for 18 months in the abatacept treated group is noteworthy as 96 (86%) study participants were 18 years or younger. The clinical importance of HbA1c at this level has been well documented 25
. Insulin usage was similar in the two groups, and thus did not contribute to the difference in HbA1c.
In this phase II clinical trial, abatacept treated patients with recent-onset T1DM had more endogenous insulin production, measured by C-peptide, during the two years of study drug administration. The duration of these effects after discontinuation of abatacept is being tested in ongoing follow up of these patients.
Abatacept administered over two years showed an excellent safety profile in patients with T1DM. Its main effect seems to be early after the initiation of treatment. TrialNet uses the paradigm of studying interventions in recently diagnosed T1DM not only to evaluate its safety and effectiveness in that setting but also to qualify interventions that might be useful to evaluate in a prevention study in individuals at-risk for T1DM, or to be used in combination with other agents. In this regard, abatacept has characteristics to support it as a potential candidate to be tested in a prevention trial. Abatacept would also seem to be a candidate as a useful component of a combination therapy protocol in recent-onset T1DM 26
. These approaches might be more easily tested using a subcutaneous version of abatacept, which is currently in development.
Panel: Research in context
We searched the PubMed database for articles published up to March 31, 2011, with the search terms “immune intervention” AND “type 1 diabetes”. A comprehensive review by Luo et al summarised immune intervention studies performed in people with type 1 diabetes 27. There have been four recent randomised trials 5–8 with adequate sample size that have demonstrated some preservation of beta cell function in T1DM as evidenced by stimulated C-peptide secretion. These trials used anti-CD3 5,6, anti-CD20 7, and a GAD-65 antigen vaccine 8. Our trial is the first trial in which patients were randomised to abatacept or any co-stimulation modulating agent.
In this study, abatacept was superior to placebo with respect to the preservation of beta cell function in T1DM as evidenced by stimulated C-peptide secretion, with minimal adverse events. However, the effect diminished with time. Abatacept has characteristics to support it as a potential candidate to be tested in a prevention trial, or to be a candidate as a useful component of a combination therapy protocol in recent-onset T1DM. Until further studies are conducted, it is not appropriate to use abatacept in T1DM in clinical practice.