Teplizumab: The First Treatment to Delay the Progression of Type 1 Diabetes

Type 1 diabetes is caused by autoimmune β-cell destruction leading to the need for management with life-sustaining insulin. Typically, people are diagnosed with type 1 diabetes based on clinical symptoms. Glucose and A1C levels, as well as autoantibodies, may rise well before clinical symptoms are seen.

Three stages of type 1 diabetes have been identified. Until recently, these stages were primarily used for research purposes. Stage 1 is presymptomatic, and people in this stage have normoglycemia and the presence of two or more islet autoantibodies. Stage 2 is the presence of two or more autoantibodies with dysglycemia. Individuals in this stage are still presymptomatic. Stage 3 is the onset of symptomatic disease and is usually when diagnosis occurs. Although there is no cure for type 1 diabetes, there is now a treatment to delay the progression from stage 2 to stage 3 of the disease (1,2).

The American Diabetes Association’s Standards of Care in Diabetes—2023 recommends screening for presymptomatic type 1 diabetes in the research setting and in people with first-degree relatives who have the disease. The recommendation is to use a screening test that detects autoantibodies to insulin, GAD, IA-2, or zinc transporter 8. The development and persistence of multiple antibodies is a risk factor for the development of clinical type 1 diabetes and can serve as an indication for intervention (1,2).

Early onset of type 1 diabetes has been shown to be associated with increased loss of life years and cardiovascular morbidity and mortality. In a nationwide cohort study, individuals with type 1 diabetes with onset before the age of 10 years experienced a 16 life-year loss and up to a 30-fold increased risk of severe cardiovascular events in early adulthood. Early onset of type 1 diabetes before the age of 10 years was also associated with a 12-fold increased risk of heart failure and mortality (3). Thus, early screening and intervention to delay the progression of type 1 diabetes can be crucial to reduce morbidity and mortality in individuals with the disease.

The U.S. Food and Drug Administration (FDA) approved the pharmacotherapy teplizumab on 17 November 2022 after a priority review and granted a breakthrough therapy designation for its use (4). Relatives of people with type 1 diabetes are the target population for this therapy because these individuals have a 15-fold increased risk of developing the disease compared with individuals who do not have a relative with type 1 diabetes. However, 85% of individuals who are newly diagnosed with type 1 diabetes do not have a positive family history of the disease (5).

This review summarizes the indications and pharmacology of this first treatment to delay the progression of type 1 diabetes.

Indications

Teplizumab is indicated for adult and pediatric patients ≥8 years of age with stage 2 type 1 diabetes to delay progression to stage 3 of the disease. Stage 2 type 1 diabetes should be confirmed by the presence of at least two pancreatic islet autoantibodies in individuals with dysglycemia without symptoms, as determined with an oral glucose tolerance test (OGTT) or an alternative assessment of glycemic status if an OGTT is not available. Baseline complete blood count and liver enzyme tests should be obtained.

Premedication should be given during the first 5 days of dosing with a nonsteroidal anti-inflammatory drug or acetaminophen, an antihistamine, and/or an antiemetic, with additional doses of these agents given as needed. Teplizumab must be diluted before administration, and it is delivered via intravenous infusion over a minimum of 30 minutes once daily for 14 days. The dosages are 65 μg/m² on day 1, 125 μg/m² on day 2, 250 μg/m² on day 3, 500 μg/m² on day 4, and 1,030 μg/m² on days 5–14 (6).

Mechanism of Action

Teplizumab is a monoclonal antibody that binds to CD3, a cell surface antigen on T lymphocytes. In type 1 diabetes, infiltration of T lymphocytes—specifically CD8+—leads to the destruction of pancreatic β-cells. Through its partial agonistic signaling, teplizumab increases the proportion of regulatory T cells and exhausts CD8+ T cells in peripheral blood, leading to deactivation of autoreactive T lymphocytes, which in turn moderates the immune response and slows down the progression from stage 2 to stage 3 type 1 diabetes (6,7).

Potential Advantages

In a phase 2, randomized, placebo-controlled, double-blind trial, teplizumab delayed progression to clinical type 1 diabetes in people without diabetes who were considered to be at high risk because they had relatives with the disease. A total of 76 participants ≥8 years of age were randomized to either a single 14-day course of teplizumab or placebo. Fifty-five participants (72%) were ≤18 years of age. Glucose tolerance tests were performed at 6-month intervals for follow-up to monitor progression to type 1 diabetes.

Over a median follow-up of 51 months, 43% of those who received teplizumab progressed to stage 3 type 1 diabetes compared with 72% of those who received placebo. The median time to diagnosis was statistically significantly different: 48.4 months in the teplizumab group and 24.4 months in the placebo group (hazard ratio 0.41, 95% CI 0.22–0.78, P = 0.006). The greatest effect of teplizumab was found to occur in the first year, during which 7% of the intervention group was diagnosed with type 1 diabetes compared with 44% in the placebo group (7). In an extension trial with median follow-up of 76.9 months, median time to diagnosis was 59.6 months with teplizumab and 27.1 months with placebo. Fifty percent of participants who received teplizumab remained diabetes free, compared with 22% of those who received placebo (8).

Potential Disadvantages

The most common adverse effects occurring in >10% of study participants were lymphopenia (73%), rash (36%), leukopenia (21%), and headache (11%) (7). There are precautions and warnings for the use of teplizumab, including the previously mentioned premedication and monitoring for symptoms of cytokine release syndrome (CRS). CRS typically occurred during the first 5 days of administration and was observed in 5% of people who received teplizumab compared with 0.8% of people in the placebo group. CRS manifestations included fever, nausea, fatigue, headache, myalgia, arthralgia, increased ALT, increased AST, and increased total bilirubin.

Teplizumab should be discontinued if ALT or AST is more than five times the upper limit of normal, and if severe CRS develops, temporarily pausing teplizumab dosing should be considered. The therapy should not be given to anyone with an active serious infection and should be stopped if such an infection develops. White blood cells should be monitored for the development of lymphopenia; if it develops and is prolonged and severe (<500 cells per μL lasting ≥7 days), teplizumab should be discontinued (6).

Cost

Each vial of teplizumab 1 mg/1 mL in 2-mL vials costs $13,850, and a 14-day supply of teplizumab costs $193,900 (9). Insurance companies are covering the infusions with various required copayments. Programs are available to lower out-of-pocket costs to as low as $0.

Commentary

One small study was conducted in individuals with stage 2 type 1 diabetes and a first-degree relative with type 1 diabetes. The study showed a statistically significant delay of a median of 2 years in the diagnosis of stage 3 type 1 diabetes, with the largest effect found in the first year of treatment. Whether this delay can be translated into clinical outcomes such as increased life expectancy and decreased cardiovascular morbidity and mortality will require further and longer studies.

The one completed study only screened individuals with a first-degree relative with type 1 diabetes, although most newly diagnosed individuals with type 1 diabetes do not have a positive family history of the disease. Therefore, further screening programs to target wider populations are needed. Before mass screenings can take place, infusion centers or home-infusion opportunities will need to be elucidated to ensure that all people who are eligible for treatment have appropriate and convenient access with qualified personnel.

Bottom Line

Teplizumab is the first pharmacotherapy approved by the FDA to delay clinical type 1 diabetes. It is a monoclonal antibody that binds and modifies T lymphocytes, which delays their destruction of pancreatic β-cells. One clinical trial has shown a significant delay in the onset of clinical type 1 diabetes in patients who received a 14-day course of teplizumab. However, the treatment is costly, and it can cause CRS and lymphopenia and increase the risk of serious infections. Despite the challenges ahead, teplizumab addresses an important and unmet need: the delay or prevention of the lifelong burden of type 1 diabetes.