Introduction

Type 1 diabetes is an endocrine disorder characterized by a T cell–mediated autoimmune response that leads to pancreatic beta cell destruction. This results in a decrease in insulin production, impaired glycemic control, and complete reliance on exogenous insulin products. This chronic disease can develop at any age, but more commonly presents during childhood and the adolescent years. Symptoms include polyuria, polydipsia, polyphagia, and sudden weight loss.¹

According to the CDC, around 244,000 children and adolescents were diagnosed with type 1 diabetes in 2019.² In addition, around 1.6 million adults reported having type 1 diabetes and using insulin the same year.² The clinical progression of type 1 diabetes has been categorized into three sequential and predictable stages. Presymptomatic type 1 diabetes can be classified as stage 1, which represents individuals who have B-cell autoimmunity but are normoglycemic, and stage 2, which represents those who have B-cell autoimmunity but have developed glucose intolerance. Those who are categorized with stage 3 represent individuals who have symptomatic type 1 diabetes.³ Studies have shown that the lifetime risk of progression from stage 1 and stage 2 to stage 3 is almost 100%. Despite improvements in medicine, type 1 diabetes continues to cause substantial patient and family burden because of the lack of disease-modifying agents. However, on November 17, 2022, the FDA approved the Tzield injection to help delay the onset of stage 3 type 1 diabetes in patients 8 years and older.⁴

Mechanism of Action

Tzield is a monoclonal antibody that works by binding to the CD3 molecules present on the cell surfaces of T lymphocytes such as CD4 and CD8 cells, which are involved in the autoimmune-mediated insulin deficiency that occurs in type 1 diabetes. This mechanism is thought to involve partial agonistic signaling that ultimately deactivates autoreactive T lymphocytes that destroy pancreatic beta cells. In addition, this anti-CD3 therapy was specifically designed to be an FC-nonbinding antibody to help decrease the incidence of cytokine release syndrome often associated with this class of medications.⁵

Clinical Trial: TN-10 Study

The safety and efficacy of Tzield was evaluated in a randomized, placebo-controlled, double-blind clinical trial conducted from July 2011 through November 2018 at sites in the United States, Canada, Australia, and Germany. Eligible participants were nondiabetic relatives of patients with type 1 diabetes who were 8 years and older, who had tested positive for two or more type 1 diabetes-related autoantibodies, and who had dysglycemia present. The primary end point investigated was elapsed time from randomization until diagnosis of stage 3 type 1 diabetes. A total of 76 patients with stage 2 type 1 diabetes were randomized to receive a once-daily intravenous infusion of either Tzield or placebo (saline) for 14 days. Tzield was given at a dose of 51 micrograms per square meter of body area (mcg/m²) on day 0, 207 mcg/m² on day 2, and 413 mcg/m² on day 3, followed by a daily dose of 826 mcg/m² from days 4 through 13.⁶

Results of TN-10 Study

Of the 112 patients screened for eligibility, 76 with stage 2 type 1 diabetes were randomized to receive a 14-day outpatient course of teplizumab or saline to be administered intravenously in a clinical research center. The Tzield group had 44 participants, and 32 patients were randomized to the control group. Most participants were younger than 18 years (73%) and male (55%) and had a median glycated hemoglobin percentage of 5.2%. The primary end point, which was diagnosis of stage 3 type 1 diabetes, occurred in 43% in the Tzield group and 72% in the control group (HR 0.41; 95% CI, 0.22–0.78; p=0.006). In addition, the median time to diagnosis was around 48.4 months in the Tzield group and 24.4 months in the placebo group (see Figure 1). These data suggest that a 14-day course of Tzield effectively and significantly delays the progression to clinical type 1 diabetes for up to 24 months in patients at high risk.⁶

Figure 1. Kaplan-Meier curve that shows effects of teplizumab on development of type 1 diabetes.

Adverse Events

In clinical trials, adverse events of any grade were more common in the Tzield group. Seventy-five percent of the participants in this group experienced lymphopenia during the first 30 days after administration. However, this adverse event was resolved in all participants except for one by day 45. In addition, 36% of participants in the Tzield group reported developing a rash that spontaneously resolved. Infection rate was similar between the treatment and control groups. Other adverse events reported included leukopenia (Tzield 21% vs. placebo 0%) and headache (Tzield 11% vs. placebo 6%).⁶

Use in Special Populations

According to the full prescribing information, use of this medication in pregnancy may cause fetal harm. In addition, it is recommended that women who are lactating should consider pumping and discarding breast milk while receiving therapy and for up to 20 days after administration of teplizumab to minimize exposure to a breastfed infant.⁷ Because type 1 diabetes commonly presents in childhood and the adolescent years, Tzield is approved for use in patients 8 years and older.⁶ Studies do not elaborate on the use of this medication in patients with renal or liver impairment.

Patient Education

Tzield is the first disease-modifying therapy for type 1 diabetes, which is used in people with stage 2 type 1 diabetes to delay progression to stage 3. Before starting therapy, have your laboratory test results checked to ensure you have no contraindications to therapy. Make sure you are up to date with all your vaccines before treatment with this drug. This medication is given as an infusion into a vein over a minimum of 30 minutes once daily for 14 days, usually at a clinic. It is recommended to premedicate with an NSAID or acetaminophen, an antihistamine, and/or an antiemetic before each dose for at least the first 5 days of the treatment course. The most common adverse reactions reported were low WBC, rash, and headache. If serious infection, severe hypersensitivity reactions, or persistent low WBCs occur, discontinue Tzield and talk to your doctor.

References

1. Centers for Disease Control and Prevention (CDC). What Is Type 1 Diabetes? Published March 11, 2022. Available at https://www.cdc.gov/diabetes/basics/what-is-type-1-diabetes.html.
2. Centers for Disease Control and Prevention (CDC). Prevalence of Diagnosed Diabetes. Published September 21, 2022. Available at https://www.cdc.gov/diabetes/data/statistics-report/diagnosed-diabetes.html.
3. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015;38:1964-74.
4. U.S. Food and Drug Administration (FDA). FDA Approves First Drug That Can Delay Onset of Type 1 Diabetes. Published November 18, 2022. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes.
5. TZIELD^TM (teplizumab-mzwv) Approved by FDA as the First and Only Treatment Indicated to Delay the Onset of Stage 3 Type 1 Diabetes (T1D) in Adult and Pediatric Patients Aged 8 Years and Older with Stage 2 T1D. November 17, 2022. Available at https://investors.proventionbio.com/2022-11-17-TZIELD-TM-teplizumab-mzwv-approved-by-FDA-as-the-first-and-only-treatment-indicated-to-delay-the-onset-of-Stage-3-type-1-diabetes-T1D-in-adult-and-pediatric-patients-aged-8-years-and-older-with-Stage-2-T1D.
6. 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;381:603-13.
7. Lexicomp: Teplizumab [registration required]. Available at https://online-lexi-com.eu1.proxy.openathens.net/lco/action/doc/retrieve/docid/patch_f/7289485#monograph-tab-content.