ESPEYB17 10. Type 1 Diabetes Mellitus (1) (14 abstracts)
10.8. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes
Herold KC , Bundy BN , Long SA , Bluestone JA , DiMeglio LA , Dufort MJ , Gitelman SE , Gottlieb PA , Krischer JP , Linsley PS , Marks JB , Moore W , Moran A , Rodriguez H , Russell WE , Schatz D , Skyler JS , Tsalikian E , Wherrett DK , Ziegler AG , Greenbaum CJ & Type 1 Diabetes TrialNet Study Group
To read the full abstract: N Engl J Med. 2019 Aug 15;381(7):603–613. doi: 10.1056/NEJMoa 1902226.
Type 1 diabetes (T1DM) is a chronic autoimmune disease that leads to destruction of insulin producing beta cells, which leaves the patient dependent on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in T1DM, but interventions to prevent clinical progression before T1DM onset are not yet available.
This phase 2, randomized, double-blind, placebo-controlled trial tested a single 14-day course of teplizumab (an Fc receptor–nonbinding anti-CD3 monoclonal antibody, over) in non-diabetic but high-risk relatives of patients with T1DM. Follow-up for progression to T1DM was performed with 6-monthly oral glucose-tolerance testing.
In total 76 participants (55 [72%] ≤18 years of age) underwent randomization, 44 to teplizumab, and 32 to placebo. The median time to T1DM diagnosis was 48.4 months with teplizumab versus 24.4 months with placebo; T1DM was diagnosed in 19 (43%) of the teplizumab group and in 23 (72%) of the placebo group (adjusted hazard ratio: 0.41, 95% CI, 0.22 to 0.78; P =0.006). The annualized incidence of T1DM was 14.9% per year with teplizumab and 35.9% with placebo. Rash and transient lymphopenia were expected adverse events on teplizumab. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group versus placebo. Among the participants who were HLA-DR3–negative, HLA-DR4–positive, or anti–zinc transporter 8 antibody–negative, fewer participants in the teplizumab group than in the placebo group developed T1DM. Despite the small size of the trial, it can be concluded that teplizumab delayed progression to T1DM in high-risk participants.
Teplizumab seems a hopeful candidate to reduce or prevent autoimmune beta cell destruction. The strongest effect in this high-risk population was seen in the first year after teplizumab administration. However, and sadly, not every person on the way to T1DM seemed to have benefited in the same way and many different factors may influence the progression of the disease. Especially persons with high anti-ZnT8 antibodies may be less responsive. This study tested a single course of teplizumab. A repeat application may further increase its efficacy. However, in other studies 55% of patients developed antibodies against teplizumab, which may limit repeat treatment cycles. The potential of teplizumab to prolong insulin secretion even after the T1DM onset in children and adolescents is also being explored currently. A trial in younger high-risk patients identified through screening programs should also be designed.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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