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An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes
Kevan C Herold1, Brian N Bundy1, S Alice Long1
1From the Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT (K.C.H.); the Departments of Epidemiology and Pediatrics, University of South Florida, Tampa (B.N.B., J.P.K., H.R.), the Department of Medicine, University of Miami, Miami (J.B.M., J.S.S.), and the Department of Pediatrics, University of Florida, Gainesville (D.S.) - all in Florida; Benaroya Research Institute, Seattle (S.A.L., M.J.D., P.S.L., C.J.G.); the Diabetes Center, University of California at San Francisco, San Francisco (J.A.B., S.E.G.); the Department of Pediatrics, Indiana University, Indianapolis (L.A.D.); the Barbara Davis Diabetes Center, University of Colorado, Anschultz (P.A.G.); Children's Mercy Hospital, Kansas City, MO (W.M.); the Department of Pediatrics, University of Minnesota, Minneapolis (A.M.); the Department of Pediatrics and Cell and Developmental Biology, Vanderbilt University, Nashville (W.E.R.); the Department of Pediatrics, University of Iowa, Iowa City (E.T.); the Hospital for Sick Children, University of Toronto, Toronto (D.K.W.); and Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany (A.-G.Z.).
Background:
Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed.
Methods:
We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals.
Results:
A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. 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 had diabetes diagnosed.
Conclusions:
Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).
Insights
Teplizumab significantly delayed the onset of clinical type 1 diabetes in high-risk individuals. This immunotherapy offers a potential new strategy for preventing type 1 diabetes progression.
Area of Science:
- Immunology
- Endocrinology
- Clinical Trials
Background:
- Type 1 diabetes is an autoimmune disease causing beta cell destruction.
- Current treatments focus on managing insulin deficiency post-diagnosis.
- There is a need for interventions to slow disease progression before clinical onset.
Purpose of the Study:
- To evaluate the efficacy of teplizumab in delaying the progression to clinical type 1 diabetes.
- To assess the safety and tolerability of teplizumab in high-risk individuals.
Main Methods:
- Phase 2, randomized, placebo-controlled, double-blind trial of teplizumab.
- Participants were relatives of type 1 diabetes patients at high risk but without the disease.
- Single 14-day course of teplizumab or placebo, with 6-month oral glucose-tolerance test follow-ups.
Main Results:
- Teplizumab delayed type 1 diabetes diagnosis; median time to diagnosis was 48.4 months vs. 24.4 months (placebo).
- Diagnosis occurred in 43% of the teplizumab group vs. 72% of the placebo group (hazard ratio 0.41, P=0.006).
- Annualized diagnosis rates were 14.9% (teplizumab) vs. 35.9% (placebo); rash and lymphopenia were expected adverse events.
Conclusions:
- Teplizumab demonstrated a significant delay in the progression to clinical type 1 diabetes in high-risk participants.
- The findings support teplizumab as a potential disease-modifying therapy for type 1 diabetes prevention.
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