U.S. Food and Drug Administration (FDA)-Approved Indications

Tzield is indicated to delay the onset of Stage 3 type 1 diabetes in adults and pediatric patients 8 years of age and older with Stage 2 type 1 diabetes.

Teplizumab-mzwv, available as Tzield (Provention Bio, Inc.), is a CD3-directed antibody that binds to certain immune system cells (i.e., CD3, which is a cell surface antigen present on T lymphocytes) and delays progression to Stage 3 type 1 diabetes in patients aged 8 years and older with Stage 2 type 1 diabetes. Teplizumab-mzwv may deactivate the immune cells that attack insulin-producing cells, while increasing the proportion of cells that help moderate the immune response. Specifically, the mechanism may involve partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T lymphocytes, and leads to an increase in the proportion of regulatory T cells and of exhausted CD8+ T cells in peripheral blood. Tzield is administered by intravenous infusion once daily for 14 consecutive days (FDA, 2022; Provention Bio, 2022).

Although teplizumab-mzwv does not have any specified contraindications, the label does include the following warnings and precautions: cytokine release syndrome (CRS), serious infections, lymphopenia, and hypersensitivity reactions. In clinical trials, CRS was reported in 5 percent of teplizumab-treated patients compared to 0.8 percent of control-treated patients during the treatment period and through 28 days after the last study drug administration. Teplizumab-treated patients had a higher rate of serious infections (3.5 percent) than control-treated patients (2 percent), including gastroenteritis, cellulitis, pneumonia, abscess, and sepsis. Seventy-eight percent of teplizumab-treated patients developed lymphopenia compared to 11 percent of control-treated patients. Acute hypersensitivity reactions including serum sickness, angioedema, urticaria, rash, vomiting and bronchospasm occurred in teplizumab-treated patients.

The safety of immunization with live-attenuated vaccines in teplizumab-treated patients has not been studied. Additionally, teplizumab may interfere with the immune response to vaccination and decrease vaccine efficacy. It is recommended that all age-appropriate vaccinations be administered prior to starting Tzield.

Available case reports from clinical trials are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Although there are no data on teplizumab-mzwv, monoclonal antibodies can be actively transported across the placenta, and may cause immunosuppression in the utero-exposed infant. To minimize exposure to a fetus, avoid use of teplizumab-mzwv during pregnancy and at least 30 days prior to planned pregnancy. There are no data on the presence of teplizumab-mzwv in either human or animal milk, the effects on the breastfed child, or the effects on milk production. A lactating woman may consider pumping and discarding breast milk during and for 20 days after Tzield administration.

Clinical studies of teplizumab-mzwv to delay the onset of Stage 3 type 1 diabetes did not include patients 65 years of age and older.

The most common adverse reactions (greater than 10 percent) include lymphopenia, rash, leukopenia and headache.

Type 1 Diabetes

Type 1 diabetes (T1D), or type 1 diabetes mellitus (T1DM), is a chronic autoimmune disease in which there is an immune-mediated loss of functional pancreatic beta cells resulting in symptomatic diabetes and lifelong dependence on exogenous insulin for survival (Insel et al, 2015). Although it can appear at any age, T1D diabetes is usually diagnosed in children and young adults. There is no cure and current treatment has been directed towards glucose management via insulin, diet and lifestyle measures to prevent complications.

Beta cells are a type of islet of Langerhan cell in the pancreas that produce the hormone insulin, which the body uses to facilitate glucose to enter cells for energy production. In T1D, the pancreas will produce little or no insulin, and represents a disease continuum that begins prior to its symptomatic manifestations. T1D is characterized by four stages (Couper et al, 2018, Insel et al, 2015, Levitsky and Misra, 2022):

In genetically susceptible persons, T1D progresses through asymptomatic stages before the development of overt hyperglycemia (Herold et al, 2019). Insel and colleagues (2015) state that "Stage 2, like stage 1, includes individuals with two or more islet autoantibodies but whose disease has now progressed to the development of glucose intolerance, or dysglycemia, from loss of functional β-cell mass. The 5-year risk of symptomatic disease at this stage is approximately 75%, and the lifetime risk approaches 100%. Stage 3 represents manifestations of the typical clinical symptoms and signs of diabetes, which may include polyuria, polydipsia, weight loss, fatigue, diabetic ketoacidosis (DKA), and others". Couper et al (2018) state, "The majority of children at risk of type 1 diabetes with multiple islet antibodies progress to diabetes within the next 15 years, compared to ~10% who have a single islet antibody".

Herold et al (2019) state that Fc receptor–nonbinding anti-CD3 monoclonal antibodies, such as teplizumab, reduces the loss of (delaying the decline in) beta cell function in patients diagnosed with recent-onset clinical T1D. The authors conducted a phase 2, randomized, placebo-controlled, double-blind trial (NCT01030861) of teplizumab involving relatives of patients with T1D who did not have diabetes but were at high risk for development of clinical disease. Patients (n=76; ages 8 to 49 years) were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical T1D was performed with the use of oral glucose-tolerance tests (OGTT) at 6-month intervals. Of the total participants (55 of whom were 18 years of age or younger), 44 were randomized to the teplizumab group and 32 to the placebo group. The authors found that the median time to the diagnosis of T1D 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 (p= 0.006). 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. The authors concluded that teplizumab delayed progression to clinical T1D in high-risk participants. The authors point out certain study limitations such as the cohort was relatively small, and the estimated power was limited. The trial population was overwhelmingly made up of non-Hispanic white participants. The drug was given for only one course, and although repeated dosing may provide additional benefits and capture more persons with active disease or prolong the therapeutic effect, this strategy was not tested in this trial.

In November 2022, the FDA announced the approval of the first drug that can delay the onset of T1D. The FDA approved Tzield (teplizumab-mzwv) injection to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes. The approval is based on the safety and efficacy that was evaluated in the

study (NCT01030861). Stage 2 type 1 diabetes was defined as having both of the following:

Two or more of the following pancreatic islet autoantibodies:

Dysglycemia on oral glucose tolerance testing (OGTT)

The trial results showed that over a median follow-up of 51 months, 45% of the 44 patients who received Tzield were later diagnosed with stage 3 type 1 diabetes, compared to 72% of the 32 patients who received a placebo. The mid-range time from randomization to stage 3 type 1 diabetes diagnosis was 50 months for the patients who received Tzield and 25 months for those who received a placebo. Per the FDA, this represents a statistically significant delay in the development of stage 3 type 1 diabetes. Thus, Tzield received Priority Review and Breakthrough Therapy designations for this indication.

: Requires Precertification:

Precertification of teplizumab-mzwv (Tzield) is required of all Aetna participating providers and members in applicable plan designs. For precertification of teplizumab-mzwv (Tzield),

Prescriber Specialties

This medication must be prescribed by or in consultation with an endocrinologist.

Criteria for Initial Approval

Aetna considers teplizumab-mzwv (Tzield) medically necessary for members with Stage 2 type 1 diabetes to delay the onset of Stage 3 type 1 diabetes when

of the following criteria are met:

Member has an abnormal oral glucose tolerance test (OGTT) confirming dysglycemia within the past 2 months when

of the following are met:

Aetna considers all other indications as experimental and investigational.