Anti-CD3 monoclonal antibody teplizumab can delay the onset of type 1 diabetes
Anti-CD3 monoclonal antibody teplizumab can delay the onset of type 1 diabetes
Take-home messages
- Teplizumab delayed the onset of T1D by 2 years compared with placebo in individuals identified as high risk
- The trial subjects were between 11 and 22 years old, were positive for auto-antibodies and had a close relative with T1D
- The response to teplizumab varied for certain subpopulations
Professor Kevan Herold, CNH Long Professor of Immunobiology and of Medicine (endocrinology), Yale University, US
Teplizumab, a non-Fc receptor binding anti-CD3 monoclonal antibody, has been shown to reduce the autoimmune-driven loss of beta cells in patients with type 1 diabetes (T1D), and can slow the progression of the disease in those recently diagnosed. A phase II clinical trial has now shown that teplizumab can delay the onset of T1D in individuals at high risk. The study results were presented by Professor Kevan Herold, CNH Long Professor of Immunobiology and of Medicine (endocrinology), Yale University, US at the 2019 EASD annual meeting.
Study design
This was a multicentre, randomised, double-blinded, placebo-controlled trial designed to determine whether the administration of teplizumab prevents or delays the development of T1D in high-risk non-diabetic individuals. To be included, the subjects needed to have tested positive for auto-antibodies and be a first-degree relative of a patient with confirmed T1D. 76 subjects were selected and randomised to receive teplizumab, which was given intravenously over 14 days, or placebo. 41 out of 44 subjects in the teplizumab group and 28 out of 32 in the placebo group completed the full period of therapy. The median age of the participants in the teplizumab group was 14 years (range: 12-22 years) and in the placebo group was 13 years (range: 11-16 years).Primary outcome:
- Time from randomisation to diagnosis of T1D for teplizumab group compared with placebo group
Secondary outcomes:
- Assessment of the safety of teplizumab
- Assessment of the mode of action of teplizumab
- Determination of whether responses varied across subgroups
- Analysis of the effect of teplizumab on metabolic responses
Main outcomes
The number of patients diagnosed with T1D was significantly lower for individuals treated with teplizumab compared with control, and the time to diagnosis significantly longer:- T1D diagnosed in 19 (43%) subjects treated with teplizumab group and 23 (72%) treated with placebo (intention-to-treat analysis; HR 0.41; 95% CI 0.22-0.78)
- Annualised rates of diabetes were 14.9% for teplizumab group and 35.9% for placebo group
- Median time to diagnosis was 48.4 months for teplizumab group and 24.4 months for placebo group (during the follow-up period)
It is unknown whether participants who were not diagnosed with T1D during the trial will develop the disease in the future (follow-up will continue for these individuals).
The impact of teplizumab was seen to be greatest in the first year. 14 (43.8%) of placebo-treated subjects were diagnosed with T1D within 1 year of randomisation, compared with 3 (6.8%) treated with teplizumab (HR 0.129; 95% CI 0.048-0.343).
The median follow-up time was 2.0 years (range: 2.4 months - 7.3 years), with follow-up being over 3 years in 75% of subjects.
Safety outcomes
There was a total of 112 adverse events affecting 44 (100%) subjects in the teplizumab group, compared with 23 adverse events affecting 32 (100%) of the control subjects. The adverse event categories, which occurred more frequently in the teplizumab group than the placebo group, were blood/ bone marrow events (reduction in number of circulating lymphocytes) and dermatology/ skin events (rash). Lymphocyte count in teplizumab-treated patients dropped significantly during the first few days of treatment, but had recovered to baseline levels after 6 weeks.There was no evidence of persistent EBV or CMV viraemia.
Subpopulations
The subpopulations with the following characteristics responded better to teplizumab:- Negative for ZnT8 autoantibodies (compared with positive)
- Negative for HLA-DR3 (compared with positive)
- Positive for HLA-DR4 (compared with negative)
Conclusions
This was the first trial to show that immunotherapy can be used to delay the onset of T1D. The delay, found from this trial, was at least 2 years, although when or if patients who were non-diabetic at trial end might develop the disease in the future is unknown.Treating patients at risk provides a more robust response than treating patients with new onset T1D (AbATE study) or those who have been diagnosed 4-12 months previously.
The data suggest it may be possible to identify certain subgroups of the population at high risk of T1D who will have a more robust and prolonged response to anti-CD3 therapy.
Based on Herold K C. Clinical data from the trial including the background, results, features of the participants associated with clinical responses; conclusions and significance (OP SO8.1). Presented in the session "Results from the anti-CD3 mAb (teplizumab) prevention trial" held on Tuesday 17 September 2019 at the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD), Barcelona, Spain, 16-20 September 2019.
EBV: Epstein-Barr virus; CI: confidence interval; CMV: cytomegalovirus; HR: hazard ratio; T1D: type 1 diabetes.
Top image: @ iStockPhoto: Kwangmoozaa
Article image: Kwangmoozaa
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