Type 1 diabetes is a chronic autoimmune disorder that results in destruction of the insulin-producing beta islet cell of the pancreas leading to insulin deficiency and hyperglycemia. In 2016, approximately 1.3 million adults in the United States were reported to have type 1 diabetes¹. Our understanding of the pathophysiology of the disease is largely based on Dr. George S. Eisenbarth’s model proposed in 1986. In this model, a person with genetic susceptibility to type 1 diabetes is exposed to a triggering environmental factor that incites an autoimmune reaction involving antigen-presenting cell recruitment. During the early stages, patients have normal glucose tolerance with detectable diabetes autoantibodies. They eventually progress to overt diabetes when 80-90% of beta cells are destroyed². Autoreactive T cells are the key mediators in beta cell destruction. The latest International Society for Pediatric and Adolescent Diabetes (ISPAD) 2018 guideline on type 1 diabetes characterized the condition as having four stages. Stages 1 and 2 are presymptomatic with multiple antibodies but with normal blood glucose in stage 1, while stage 2 has abnormal blood glucose. Patients with stage 3 type 1 diabetes have multiple autoantibodies with raised blood glucose and are symptomatic, while those with stage 4 have long-standing diabetes³. Studies on interventions at various stages of type 1 diabetes have focused not only on delaying beta cell loss in individuals with recent onset diabetes (stage 3,) but also on delaying the onset of clinical disease in early stages of the disease (stage 1 and 2).

Immunotherapies such as anti-CD3 monoclonal antibodies targeting T cells, anti-CD20 monoclonal antibodies targeting B cells, and costimulation blockade are among some of the promising therapies being investigated⁴. Preclinical animal model studies have found that antibodies targeting anti-CD3 were able to prevent or reverse the development of type 1 diabetes. These antibodies are able to induce apoptosis of activated T cells while enhancing regulatory T cells⁵.

Teplizumab is a non-activating, Fc-modified anti-CD3 monoclonal antibody. Due to the alterations in the Fc region, the drug is able to maintain its immunomodulatory effects with reduced cytokine release potential. Previous studies in patients with newly diagnosed type 1 diabetes showed preservation of C-peptide, despite not meeting the primary outcome of insulin and glycated hemoglobin reduction⁶.

Study Summary

This year, exciting data emerged on the use of teplizumab in the prevention of type 1 diabetes. The Trialnet Teplizumab Prevention Study is a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab in relatives of patients with type 1 diabetes. To be eligible for inclusion, participants had to have two or more diabetes-related autoantibodies with evidence of dysglycemia during an oral glucose-tolerance test. Individuals were randomly assigned to a single 14-day course of teplizumab or placebo. Progression to clinical type 1 diabetes was monitored by performing oral glucose tolerance tests at six-month intervals. The primary end point researchers looked at was duration of time from randomization to the clinical diagnosis of diabetes.

A total of 76 patients were enrolled in the trial, with an age range of 8.5 to 49.5 years. The seven-year study found that a single course of teplizumab reduced the risk of developing type 1 diabetes by 59% (adjusted HR 0.41, p=0.006) in high-risk autoantibody positive relatives who did not have diabetes. The median duration to the delay of diagnosis was two years. The rate of diagnosis of type 1 diabetes was 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. Development of type 1 diabetes was highest in the first year of trial entry (40%), with diminishing rates in year two (24%) and year three (14%). The greatest effect of the drug was seen in the first year of treatment with diabetes being diagnosed in seven percent in the teplizumab group compared to forty-four percent in the placebo group (unadjusted hazard ratio, 0.13; 95% CI, 0.05 to 0.34). Subgroup analysis found that the presence of human leukocyte antigen (HLA)-DR4, absence of HLA-DR3, and the absence of anti–zinc transporter-8 (ZnT8) antibodies were associated with better response to teplizumab. In terms of the safety profile of the drug, 75% of participants developed a transient lymphopenia while a spontaneously resolving rash occurred in 36% of participants⁷.

This study is the first to show that immune modulation with teplizumab can delay the clinical onset of type 1 diabetes. Questions remain regarding the effect of repeat dosing, long-term side effects, effects of antibody development, and identifying responders from non-responders before treatment. For now, the results of this study further support the concept that type 1 diabetes is a chronic T-cell mediated disease and that there is potential for immune modulation to alter the course of type 1 diabetes.

Full text link:

https://www.nejm.org/doi/full/10.1056/NEJMoa1902226?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

Reference:

1. Bullard KM, Cowie CC, Lessem SE, et al. Prevalence of Diagnosed Diabetes in Adults by Diabetes Type – United States. 2018;67(12):359-361.
2. Atkinson MA. The pathogenesis and natural history of type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2(11):a007641.
3. Couper JJ, Haller MJ, Greenbaum CJ, et al. ISPAD clinical practice consensus guidelines 2018: Stages of type 1 diabetes in children and adolescents. Pediatr Diabetes. 2018;19(27):20-27.
4. Skyler JS. The compelling case for anti-CD3 in type 1 diabetes. Diabetes. 2013;62(11):3656–3657.
5. Vudattu NK, Herold KC. Treatment of new onset type 1 diabetes with teplizumab: successes and pitfalls in development. Expert Opin Biol Ther. 2014;14(3):377–385.
6. Sherry N, Hagopian W, Ludvigsson J, et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet. 2011;378(9790):487–497.
7. Herold KC, Bundy BN, Long SA, et al.  An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med. 2019;381(7):603-613.

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