Brand Name
Tzield
Generic Name
Teplizumab-Mzwv
View Brand Information FDA approval date: November 17, 2022
Classification: CD3-directed Antibody
Form: Injection
What is Tzield (Teplizumab-Mzwv)?
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 [see Dosage and Administration.
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An Observational, Long-term Safety Study of TZIELD® (Teplizumab-mzwv) in Patients With Stage 2 Type 1 Diabetes
Summary: Stage 2 Type 1 Diabates (T1D) is an early stage of T1D characterized by dysglycemia but not yet leading to clinical symptoms. Progression of the disease to Stage 3 (clinical T1D), leads to overt hyperglycemia requiring eventually exogenous insulin. TZIELD® (teplizumab-mzwv) has been approved to delay onset of stage 3 T1D, by the United States (US) Food and Drug Administration (FDA) for adults and ...
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Brand Information
TZIELD (teplizumab-mzwv)
1INDICATIONS AND USAGE
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
2DOSAGE FORMS AND STRENGTHS
Injection: 2 mg per 2 mL (1 mg/mL) clear and colorless solution in a single-dose vial.
3CONTRAINDICATIONS
None.
4ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the Prescribing Information:
- Cytokine Release Syndrome
- Serious Infections
- Lymphopenia
- Hypersensitivity Reactions
4.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Placebo-Controlled Study in Patients with Stage 2 Type 1 Diabetes
The data in Table 1 are derived from the placebo-controlled study (Study TN-10) in patients aged 8 years and older with Stage 2 type 1 diabetes (T1D) [see Clinical Studies (. These data reflect exposure of 44 patients of whom 93% completed the full 14-day treatment course.
The data in Table 1 are derived from the placebo-controlled study (Study TN-10) in patients aged 8 years and older with Stage 2 type 1 diabetes (T1D) [see Clinical Studies (. These data reflect exposure of 44 patients of whom 93% completed the full 14-day treatment course.
Pool of Five Controlled Clinical Studies in Stage 2 Type 1 Diabetes and in an Unapproved Population
Adverse reactions in TZIELD-treated patients were also evaluated in a larger pool of adult and pediatric patients who participated in five controlled clinical studies (including Study TN-10 described above):
Adverse reactions in TZIELD-treated patients were also evaluated in a larger pool of adult and pediatric patients who participated in five controlled clinical studies (including Study TN-10 described above):
- One study in patients with Stage 2 T1D (Study TN-10)
- Three placebo-controlled studies in an unapproved population,
- One open-label standard-of-care controlled study of TZIELD in an unapproved population.
In this pool:
- 773 patients received TZIELD (44 patients with Stage 2 TID and 729 patients from an unapproved population), and
- 245 patients received either placebo or standard of care control (32 patients with Stage 2 T1D and 213 patients from an unapproved population).
In these studies, 436 patients received a 14-day dosing regimen of TZIELD with a total drug exposure that was comparable to the total drug exposure achieved with the recommended dosage
Common Adverse Reactions
Table 1 presents common (≥ 5%) adverse reactions that occurred during treatment and through 28 days after the last study drug administration in Study TN-10. Adverse reactions observed in pediatric patients 8 years and older who received TZIELD were consistent with those reported in adult patients in this study.
Table 1 presents common (≥ 5%) adverse reactions that occurred during treatment and through 28 days after the last study drug administration in Study TN-10. Adverse reactions observed in pediatric patients 8 years and older who received TZIELD were consistent with those reported in adult patients in this study.
Cytokine Release Syndrome (CRS)
In Study TN-10, CRS was reported in 2% of TZIELD-treated patients compared to 0% of placebo-treated patients.
In Study TN-10, CRS was reported in 2% of TZIELD-treated patients compared to 0% of placebo-treated patients.
Of the 39 TZIELD-treated patients that developed CRS (5% of all TZIELD-treated patients) in the pool of 5 clinical trials, 13% of the CRS cases were serious adverse reactions
Serious Infections
In Study TN-10, serious infections (cellulitis, gastroenteritis, pneumonia, wound infection) were reported in 9% (4/44) of TZIELD-treated patients compared to 0% (0/32) of placebo-treated patients any time during or after the first dose of study treatment.
In Study TN-10, serious infections (cellulitis, gastroenteritis, pneumonia, wound infection) were reported in 9% (4/44) of TZIELD-treated patients compared to 0% (0/32) of placebo-treated patients any time during or after the first dose of study treatment.
Rash and Hypersensitivity Reactions
Hypersensitivity reactions were reported with TZIELD in Study TN-10. Serum sickness was observed in 2% (1/44) of TZIELD-treated patients compared to 0% (0/32) of placebo-treated patients. The patient who developed serum sickness had a prior history of positive anti-nuclear antibody and presented with arthralgias and elevated c-reactive protein and low C4 complement five days after completing their course of TZIELD; illness resolved in 2.5 months.
Hypersensitivity reactions were reported with TZIELD in Study TN-10. Serum sickness was observed in 2% (1/44) of TZIELD-treated patients compared to 0% (0/32) of placebo-treated patients. The patient who developed serum sickness had a prior history of positive anti-nuclear antibody and presented with arthralgias and elevated c-reactive protein and low C4 complement five days after completing their course of TZIELD; illness resolved in 2.5 months.
In the pool of 5 clinical trials of patients:
- Anaphylaxis (with hypoxia and bronchospasm) was observed in one TZIELD-treated patient who was hospitalized.
- Angioedema (periorbital and facial) was observed in 0.3% TZIELD-treated patients, compared to 0% in control-treated patients. Peripheral and generalized edema was reported in 1.6% of TZIELD-treated patients and 0% of control-treated patients.
- Rash was observed in 48% of TZIELD-treated patients compared to 15% in control-treated patients, with 33 excess cases of rash per 100 patients. The majority of rashes observed with TZIELD treatment were not serious and resolved without intervention; although 0.3% (2/773) of TZIELD-treated patients had a serious rash compared to 0% (0/245) of placebo- treated patients.
- Urticaria was reported in 1.9% of TZIELD-treated patients and in 1.2% of control-treated patients.
Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions
In Study TN-10, rash occurred in 39% of TZIELD-treated patients who developed anti- teplizumab-mzwv antibodies and in 33% of TZIELD-treated patients who did not develop anti- teplizumab-mzwv antibodies [see Clinical Pharmacology (.
In Study TN-10, rash occurred in 39% of TZIELD-treated patients who developed anti- teplizumab-mzwv antibodies and in 33% of TZIELD-treated patients who did not develop anti- teplizumab-mzwv antibodies [see Clinical Pharmacology (.
Other Adverse Reactions
Lymphopenia
In Study TN-10, lymphopenia was reported in 73% of TZIELD-treated patients compared to 6% of placebo-treated patients. The average lymphocyte count nadir occurred at Day 5 of treatment, with recovery and return to baseline by Week 6 [see Warnings and Precautions (.
Lymphopenia
In Study TN-10, lymphopenia was reported in 73% of TZIELD-treated patients compared to 6% of placebo-treated patients. The average lymphocyte count nadir occurred at Day 5 of treatment, with recovery and return to baseline by Week 6 [see Warnings and Precautions (.
Neutropenia
In Study TN-10, neutropenia was observed in 7% of TZIELD-treated patients compared to 3% of placebo-treated patients.
In Study TN-10, neutropenia was observed in 7% of TZIELD-treated patients compared to 3% of placebo-treated patients.
Anemia and Thrombocytopenia
In the pool of 5 clinical trials of patients, anemia was reported in 27% of TZIELD-treated patients compared to 21% of placebo-treated patients, and thrombocytopenia was reported in 13% of TZIELD-treated patients compared to 5% of placebo-treated patients during the 14-day treatment course; recovery occurred within 2 to 4 weeks of treatment. In clinical trials, 1.8% of TZIELD-treated patients discontinued treatment due to hemoglobin less than 8.5 g/dL (or a decrease of more than 2 g/dL to a value less than 10 g/dL), and 1% discontinued TZIELD due to platelet count less than 50,000 platelets/mcL.
In the pool of 5 clinical trials of patients, anemia was reported in 27% of TZIELD-treated patients compared to 21% of placebo-treated patients, and thrombocytopenia was reported in 13% of TZIELD-treated patients compared to 5% of placebo-treated patients during the 14-day treatment course; recovery occurred within 2 to 4 weeks of treatment. In clinical trials, 1.8% of TZIELD-treated patients discontinued treatment due to hemoglobin less than 8.5 g/dL (or a decrease of more than 2 g/dL to a value less than 10 g/dL), and 1% discontinued TZIELD due to platelet count less than 50,000 platelets/mcL.
Liver Enzyme Elevations
Liver enzyme elevations were observed in TZIELD-treated patients, both in the context of CRS and in patients without CRS. In the pool of 5 clinical trials, elevated aminotransferases were reported in 25% of TZIELD-treated patients compared to 11% of placebo-treated patients during the 14-day treatment course. On laboratory analysis, 5.1% of TZIELD-treated patients experienced a peak ALT more than 3 times the ULN compared to 0.8% of control-treated patients. Most liver enzyme elevations were transient and resolved 1-2 weeks after treatment; 98% resolved by follow-up week 14.
Liver enzyme elevations were observed in TZIELD-treated patients, both in the context of CRS and in patients without CRS. In the pool of 5 clinical trials, elevated aminotransferases were reported in 25% of TZIELD-treated patients compared to 11% of placebo-treated patients during the 14-day treatment course. On laboratory analysis, 5.1% of TZIELD-treated patients experienced a peak ALT more than 3 times the ULN compared to 0.8% of control-treated patients. Most liver enzyme elevations were transient and resolved 1-2 weeks after treatment; 98% resolved by follow-up week 14.
Other Laboratory Abnormalities
In the pool of 5 clinical trials, other laboratory abnormalities including decreased bicarbonate (15% in TZIELD-treated patients, compared to 7% in placebo-treated patients) and decreased blood calcium (19% in TZIELD-treated patients, compared to 13% in placebo-treated patients) were noted.
In the pool of 5 clinical trials, other laboratory abnormalities including decreased bicarbonate (15% in TZIELD-treated patients, compared to 7% in placebo-treated patients) and decreased blood calcium (19% in TZIELD-treated patients, compared to 13% in placebo-treated patients) were noted.
5DESCRIPTION
Teplizumab-mzwv is a CD3-directed monoclonal antibody (humanized IgG1 kappa) that has a molecular weight of approximately 150 kilodalton (kDa) and is expressed from a recombinant Chinese hamster ovary (CHO) cell line.
TZIELD (teplizumab-mzwv) injection is supplied as a sterile, preservative-free, clear and colorless solution in a 2 mg/2 mL (1 mg/mL) single-dose vial for intravenous use. Each mL contains 1 mg of teplizumab-mzwv, dibasic sodium phosphate (0.26 mg), monobasic sodium phosphate (0.98 mg), polysorbate 80 (0.05 mg), sodium chloride (8.78 mg), and water for injection. The pH is 6.1.
6CLINICAL STUDIES
The effectiveness of TZIELD was investigated in a randomized, double-blind, event-driven, placebo-controlled study (Study TN-10; NCT01030861) in 76 patients, 8 to 49 years of age with Stage 2 type 1 diabetes. 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
In this study, patients were randomized to receive TZIELD or placebo once daily by intravenous infusion for 14 days. Patients in the TZIELD group had a total drug exposure that was comparable to the total drug exposure achieved with the recommended total TZIELD dosage
Baseline Patient Characteristics
In this study, 45% were female; 97% White, 1% Asian, and 1% reported multiracial background; 3% were Hispanic or Latino ethnicity; and 95% were from the United States. The median age was 14 years (72% were <18 years old) (Table 2).
In this study, 45% were female; 97% White, 1% Asian, and 1% reported multiracial background; 3% were Hispanic or Latino ethnicity; and 95% were from the United States. The median age was 14 years (72% were <18 years old) (Table 2).
Baseline Disease Characteristics
Table 3 displays the baseline disease characteristics in Study TN-10.
Table 3 displays the baseline disease characteristics in Study TN-10.
Efficacy Results
In Study TN-10, Stage 3 type 1 diabetes was diagnosed in 20 (45%) of the TZIELD-treated patients and in 23 (72%) of the placebo-treated patients. A Cox proportional hazards model, stratified by age and oral glucose tolerance test status at randomization, demonstrated that the median time from randomization to Stage 3 type 1 diabetes diagnosis was 50 months in the TZIELD group and 25 months in the placebo group, for a difference of 25 months. With a median follow-up time of 51 months, therapy with TZIELD resulted in a statistically significant delay in the development of Stage 3 type 1 diabetes, hazard ratio 0.41 (95% CI: 0.22 to 0.78; p=0.0066) (Figure 1).
In Study TN-10, Stage 3 type 1 diabetes was diagnosed in 20 (45%) of the TZIELD-treated patients and in 23 (72%) of the placebo-treated patients. A Cox proportional hazards model, stratified by age and oral glucose tolerance test status at randomization, demonstrated that the median time from randomization to Stage 3 type 1 diabetes diagnosis was 50 months in the TZIELD group and 25 months in the placebo group, for a difference of 25 months. With a median follow-up time of 51 months, therapy with TZIELD resulted in a statistically significant delay in the development of Stage 3 type 1 diabetes, hazard ratio 0.41 (95% CI: 0.22 to 0.78; p=0.0066) (Figure 1).
Study TN-10 was not designed to assess whether there were differences in the effectiveness between subgroups based on demographic characteristics or baseline disease characteristics.
Figure 1: Kaplan-Meier Curve of Time to Diagnosis of Stage 3 Type 1 Diabetes in Adult and Pediatric Patients Aged 8 Years and Older with Stage 2 Type 1 Diabetes by Treatment Group (Study TN-10)ITT population
7HOW SUPPLIED / STORAGE AND HANDLING
TZIELD (teplizumab-mzwv) injection is a clear and colorless solution (2 mg/2 mL (1 mg/mL)) supplied in a single-dose vial as follows:
Refrigerate TZIELD vials at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Store upright. Do not freeze or shake the vials.
If not used immediately, store the diluted solution at room temperature [15°C to 30°C (59°F to 86°F)] and complete infusion within 4 hours of the start of preparation. Discard the diluted solution if not administered within 4 hours of preparation
8PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (
Cytokine Release Syndrome
Inform patients about the signs and symptoms of CRS [see Warnings and Precautions (.
Inform patients about the signs and symptoms of CRS [see Warnings and Precautions (.
Serious Infections
Inform patients that TZIELD may lower the ability of the immune system to fight infections. Instruct patients to contact their health care provider if they develop any symptoms of infection [see Warnings and Precautions (.
Inform patients that TZIELD may lower the ability of the immune system to fight infections. Instruct patients to contact their health care provider if they develop any symptoms of infection [see Warnings and Precautions (.
Lymphopenia
Inform patients that although most TZIELD-treated patients had mild lymphopenia; a few had severe lymphopenia that required stopping TZIELD [see Warnings and Precautions (.
Inform patients that although most TZIELD-treated patients had mild lymphopenia; a few had severe lymphopenia that required stopping TZIELD [see Warnings and Precautions (.
Hypersensitivity Reactions
Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking TZIELD and seek medical attention promptly if such symptoms occur [see Warnings and Precautions (.
Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking TZIELD and seek medical attention promptly if such symptoms occur [see Warnings and Precautions (.
Vaccinations
Advise patient to receive all age-appropriate vaccinations prior to starting TZIELD and avoid concurrent use of live, inactivated, and mRNA vaccines with TZIELD [see Warnings and Precautions (.
Advise patient to receive all age-appropriate vaccinations prior to starting TZIELD and avoid concurrent use of live, inactivated, and mRNA vaccines with TZIELD [see Warnings and Precautions (.
Pregnancy
Advise patients to inform their health care provider of a known or suspected pregnancy. Advise patients who are exposed to TZIELD during pregnancy to contact Provention Bio, Inc.'s Adverse Event reporting line at 1-800-633-1610 [see Use in Specific Populations (.
Advise patients to inform their health care provider of a known or suspected pregnancy. Advise patients who are exposed to TZIELD during pregnancy to contact Provention Bio, Inc.'s Adverse Event reporting line at 1-800-633-1610 [see Use in Specific Populations (.
Lactation
Advise a lactating woman that she may interrupt breastfeeding and pump and discard breast milk during treatment and for 20 days after TZIELD administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations (.
Advise a lactating woman that she may interrupt breastfeeding and pump and discard breast milk during treatment and for 20 days after TZIELD administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations (.
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U.S. License Number: 2170