Teplizumab

Abstract

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Generic Name: Teplizumab

Proprietary Name: Tzield (Provention Bio)

Approval Rating: 1P

Therapeutic Class: Anti-CD3 Monoclonal Antibody

Similar Drugs: None

Sound-/Look-Alike Names: Daclizumab, Tepezza, Tepotinib, Teprotumumab, Tocilizumab

Indications

Teplizumab-mzwv is Food and Drug Administration (FDA) approved to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older with stage 2 type 1 diabetes. ¹

Patients (adults and pediatric patients 8 years and older) should be selected based on diagnosis of stage 2 type 1 diabetes. Stage 2 type 1 diabetes can be confirmed by documentation of at least 2 positive pancreatic islet cell autoantibodies, and dysglycemia without overt hyperglycemia using an oral glucose tolerance test (OGTT) (if an OGTT is not available, an alternative method for diagnosing dysglycemia without overt hyperglycemia may be appropriate). Ensure the patient’s clinical history does not suggest type 2 diabetes. ¹

Teplizumab-mzwv treatment is not recommended in patients with the following ¹ :

• Lymphocyte count less than 1000 cells/µL

• Hemoglobin less than 10 g/dL

• Platelet count less than 150 000 cells/µL

• Absolute neutrophil count less than 1500 cells/µL

• Elevated ALT or AST greater than 2 times the upper limit of normal (ULN) or bilirubin greater than 1.5 times ULN

• Laboratory or clinical evidence of acute infection with Epstein-Barr virus or cytomegalovirus

• Active serious infection or chronic active infection other than localized skin infections

Clinical Pharmacology

Teplizumab-mzwv is a humanized, anti-CD3 monoclonal antibody (humanized IgG1 kappa) that is produced from a recombinant Chinese hamster ovary cell line. It binds to an epitope portion of the CD3-epsilon chain expressed by mature T cells^1,2 Its ability to delay the onset of diabetes may involve partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T lymphocytes. In addition, teplizumab-mzwv promotes CD8 T–cell exhaustion and subsequent loss of T-cell functions; this mechanism involves altering function of the T lymphocytes responsible for inducing destruction of insulin-producing beta cells of the islets of Langerhans in the pancreas. It is suggested that by preserving or protecting the remaining beta cells of the pancreas, teplizumab-mzwv prevents or delays the onset of type 1 diabetes.^{3 -14}

Teplizumab-mzwv may not be effective for every patient. The CD8 T–cell exhausted state is a complex phenotype, and different forms exist; the 3-step process (persistent antigen, negative costimulatory signals, and chronic inflammation) required for development of exhausted CD8 T cells may be influenced by epitope spreading, episodic as opposed to chronic antigen exposure, a proinflammatory cytokine environment, or enhanced costimulation, any of which may result in incomplete or unstable CD8 T–cell exhaustion in individuals prone to autoimmune-induced type 1 diabetes. ⁸ Development of type 1 diabetes involves progression through an asymptomatic stage prior to a symptomatic stage. The asymptomatic stage is characterized by the appearance of autoantibodies (stage 1) and then dysglycemia (stage 2). During stage 2, patient metabolic responses to glucose load become impaired but other metabolic indices (eg, glycosylated hemoglobin) remain normal and insulin treatment is not necessary; this process continues until enough beta cells have been injured or destroyed, with insulin treatment then required to manage blood glucose levels.^4,5,11,12,15

Pharmacokinetics

In a 60 kg subject, central volume of distribution of teplizumab-mzwv was 2.27 L, terminal half-life was 4.5 days, and clearance was 2.7 L/day. ¹

Teplizumab-mzwv is expected to be metabolized by catabolic pathways to small peptides. ¹

No clinically meaningful differences in the pharmacokinetics of teplizumab-mzwv were observed based on age (8to -35 years), biologic sex, or racial group (White, Asian). ¹

Comparative Efficacy

Indication: Prevention of Type 1 Diabetes

Guidelines

• Guideline: Standards of medical care in diabetes—2022

• Reference: Draznin et al, 2022 ¹⁶

• Comments: The guidelines state that while various pharmacologic agents have been evaluated for diabetes prevention, there are no drugs approved or recommended by the FDA for the prevention of type 1 diabetes. The standards do not address how to predict who might develop type 1 diabetes. Criteria for testing for diabetes or prediabetes in asymptomatic adults include the following: first-degree relative with diabetes; high-risk race/ethnicity (eg, African American, Latino, Native American, Asian American, Pacific Islander); history of cardiovascular disease; lipid disorders; polycystic ovary syndrome (in females); physical inactivity; and other clinical conditions associated with insulin resistance (eg, severe obesity, acanthosis nigricans). Teplizumab-mzwv is not mentioned in the ADA 2022 recommendations but was approved by the FDA several months after its publication.

Studies

• Drug: Teplizumab-mzwv vs Placebo

• Reference: Herold KC, et al, 2019 (Study TN-10; NCT01030861)^1,15

• Study Design: Phase 2, randomized, double-blind, placebo-controlled, multicenter, international study

• Study Funding: National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Center for Research Resources; Juvenile Diabetes Research Foundation; American Diabetes Association

• Patients: 76 participants (8 -49 years of age) at high risk for developing clinical diabetes (ie, patients were nondiabetic relatives [eg, sibling, child, parent, or second- or third-degree relative] of patients with type 1 diabetes). Participants also had to have 2 or more diabetes-related autoantibodies detected in 2 samples obtained within 6 months prior to randomization. Patients also had to have evidence of dysglycemia during an OGTT, with dysglycemia defined as a fasting glucose level of 110 to 125 mg/dL, a 2-hour postprandial plasma glucose level of at least 140 mg/dL and less than 200 mg/dL, or an intervening postprandial glucose level at 30, 60, or 90 minutes of greater than 200 mg/dL on 2 occasions within 52 days before enrollment. The protocol was amended 3 years after initiation to allow enrollment of participants younger than 18 years who had a single abnormal OGTT result. The majority of participants were younger than 18 years (66% in the teplizumab-mzwv group and 81% in the placebo group), White (100% in the teplizumab-mzwv group and 93.8% in the placebo group), and siblings of patients with type 1 diabetes (64% in the teplizumab-mzwv group and 50% in the placebo group). HLA type was available for 43 patients in the teplizumab-mzwv group, of whom 49% had HLA-DR3 and 65% had HLA-DR4 major histocompatibility complex molecules. Duration of follow-up was longer than 3 years in 75% of participants.

• Intervention: Subjects were randomized (1:1) to receive teplizumab-mzwv (n = 44) or placebo (n = 32). All received a 14-day outpatient treatment course of teplizumab-mzwv or placebo (ie, saline) by intravenous (IV) administration at a clinical research center. Teplizumab-mzwv was administered as 51 µg/m² of body surface area given on day 0, then 103 µg/m² given on day 1, then 207 µg/m² given on day 2, then 413 µg/m² given on day 3, and 826 µg/m² given on days 4 through 13. Mean total dose of teplizumab-mzwv was 9.14 mg/m². Ibuprofen and diphenhydramine were given prior to infusions on the first 5 days; thereafter, ibuprofen, diphenhydramine, and/or acetaminophen were allowed as needed for symptomatic relief. Prednisone, other immunosuppressive agents, and long-term inhaled or nasal corticosteroids were not allowed during the trial; however, participants who used any of these medications were not withdrawn from analysis. Live vaccines were to be avoided during the first year after dosing, and killed-virus vaccines were to be avoided for the first 4 weeks after treatment.

Results

Primary End Point(s):

• Median time to diagnosis of stage 3 type 1 diabetes was 50 months in the teplizumab-mzwv group and 25 months in the placebo group (hazard ratio [HR], 0.41 for not being diagnosed with diabetes; 95% CI, 0.22-0.78; 2-sided P = .006); median follow-up was 51 months.

Secondary End Point(s):

• Development of type 1 diabetes occurred in 43% of the teplizumab-mzwv group and in 72% of the placebo group; treatment difference was 29%. The largest effect occurred during the first year, when 7% of the teplizumab-mzwv group and 44% of the placebo group were diagnosed with type 1 diabetes (unadjusted HR, 0.13; 95% CI, 0.05-0.34). The prescribing information reports development of stage 3 type 1 diabetes occurred in 45% and 72%, respectively.

• Annualized rates of diagnosis of type 1 diabetes were 14.9% per year in the teplizumab-mzwv group and 35.9% per year in the placebo group. The percentage of participants with progression to clinical type 1 diabetes was greater in the first year (40%) compared to the second year (24%), third year (14%), and fourth year (12%).

• C-peptide AUC increased after teplizumab-mzwv treatment, while the placebo group experienced a decline over the 6 months after study entry. Also, insulin secretion during the first hour of OGTT at 6 months declined in the placebo group and increased in the teplizumab-mzwv group. ¹⁷

• Subgroup analysis showed participants with presence of HLA-DR4 and absence of HLA-DR3 had more robust responses to teplizumab-mzwv (HR, 0.2 [95% CI, 0.09-0.45] and 0.18 [95% CI, 0.07-0.45], respectively, without adjustment for multiplicity). Response to teplizumab-mzwv was also greater in participants without anti–zinc transporter 8 antibodies than in those with these antibodies (HR, 0.07; 95% CI, 0.02-0.26), and in participants whose C-peptide responses to OGTT at baseline were below the median (1.75 nmol/L).

Comments: The study was conducted in the United States, Canada, Australia, and Germany; the prescribing information states 95% were from the United States. Randomization was stratified by age (younger than 18 years or 18 years and older) and second OGTT results before treatment (impaired, normal, or diabetes). The treatment period was completed by 93% in the teplizumab-mzwv group and 88% in the placebo group. Seven participants did not complete the treatment period because of laboratory abnormalities (n = 4), inability to establish IV access (n = 2), or rash (n=1). ¹⁵ Due to slower than anticipated enrollment, the original protocol was changed from requiring 144 participants to detect a 50% lower risk with teplizumab-mzwv versus placebo to requiring 71 participants to detect a 60% lower risk (HR, 0.4), with 80% statistical power at an alpha level of 0.025 (one-sided). Participants were followed until 40 were diagnosed with type 1 diabetes. These results support observations of the earlier phase 3 Protégé study. ¹² The extended follow-up period (median of 923 days) showed median times to diagnosis of 59.6 months in the teplizumab-mzwv group and 27.1 months in the placebo group; HR was 0.457 (P = .01). The percentage of patients who remained diabetes free was 50% in the teplizumab-mzwv group and 22% in the placebo group. ¹³

Limitations: The study included a small sample size, and the protocol was amended to allow for an even smaller sample size after slow enrollment during the first 4 years. The estimated power was limited. Participants were relatives of patients with type 1 diabetes, making it difficult to determine whether findings will be generally applicable to individuals at risk for type 1 diabetes without first-degree relatives with diabetes. The trial population consisted of mostly non-Hispanic White participants. Because the study used only one treatment period, it is unknown whether multiple treatments would produce a greater response. Potential for development of antibodies to teplizumab-mzwv has not been fully assessed.

Drug: Teplizumab-mzwv vs Conventional Therapy

Reference: Perdigoto AL, et al, 2019 (AbATE follow-up) ¹¹

Study Design: 7-year follow-up study of AbATE trial

Study Funding: Juvenile Diabetes Research Foundation; National Institutes of Health

Patients: 43 patients (31 from the teplizumab-mzwv group and 12 from the conventional therapy [control] group) with detectable C-peptide at year 2 of the original AbATE study, which had enrolled 77 patients 8 to 30 years of age who were autoantibody positive (anti-GAD65, anti-ICA512, or islet cell autoantibodies) and newly diagnosed with type 1 diabetes (within 8 weeks of enrollment). Participants had last received treatment 6.03 ± 0.2 years prior to the AbATE follow-up study.

Intervention: The original intention-to-treat analysis consisted of 52 patients receiving teplizumab-mzwv and 25 receiving control. The treatment group received daily IV infusions of teplizumab-mzwv for 14 days (median cumulative dose, 11.6 mg). Forty of the 52 teplizumab-mzwv–treated patients received a second teplizumab-mzwv treatment cycle at year 1 (median cumulative dose, 12.4 mg). Patients with a detectable C-peptide response according to 4-hour mixed-meal tolerance test at year 2 of AbATE were asked to return to the clinic for another 4-hour mixed-meal tolerance test approximately 7 years after diagnosis (follow-up visit 1, occurring a mean of 7.02 years after baseline [median, 6.7 years; range, 5.32-9.22 years]). If patients had detectable levels of C-peptide at that visit, they returned approximately 1 year later for repeat testing (follow-up visit 2, occurring a mean of 7.35 years from baseline [median, 7.3 years; range, 6.33 to 8.8 years]).

Results

End Point(s):

• C-peptide response to a mixed-meal tolerance test was similar overall between the teplizumab-mzwv and control groups at follow-up; however, response was significantly greater in those who had been classified as drug-treated responders at year 1 compared to the control group and drug-treated nonresponders (P = .34, P = .01, and P = .004; mixed model corrected for duration).

• Percentage of participants with detectable levels of C-peptide at follow-up was higher among drug-treated responders versus nonresponders or control patients (P = .009).

• Frequency of individuals with stimulated C-peptide greater than 0.2 nmol/L, indicating clinically significant residual beta-cell function, was highest in drug-treated responders (40% vs 14.3% in the teplizumab-mzwv nonresponder group and 16.7% in the control group); however, these differences were not statistically significant.

• Hemoglobin A_1c level and insulin use improvements observed during the first 2 years were not maintained at follow-up, with no significant differences among groups.

• There was an increased frequency of programed cell death protein 1–positive central memory and anergic CD8+ T cells in teplizumab-mzwv–treated responders at follow-up.

Comments: The AbATE follow-up study was conducted to determine the long-term effects of teplizumab-mzwv, particularly in teplizumab-mzwv–treated responders who had shown robust response during the original 2-year study period. Of the original participants, 56% returned for the 7-year follow-up. The frequency of drug-treated responders was similar in those who did (23%) and did not return (30%) for the follow-up visit. While AbATE enrolled both children and adults, PROTECT is a phase 3, randomized, double-blind, placebo-controlled, multinational, multicenter study evaluating efficacy and safety of teplizumab-mzwv in children and adolescents 8 through 17 years of age and recently diagnosed with type 1 diabetes (within 6 weeks of diagnosis). Patients will receive 2 courses of teplizumab-mzwv, or placebo 6 months apart, and then be followed for 78 weeks. The study is still active, with an anticipated completion date of May 2023. ¹⁸

The manufacturer is required to complete an observational registry study to assess the long-term safety of teplizumab-mzwv in patients with stage 2 type 1 diabetes. This study will evaluate cytokine-release syndrome (CRS), serious infections, hypersensitivity reactions, lymphoproliferative disorders, and malignancy. The registry will also collect information on females exposed during pregnancy to assess for adverse events from pregnancy through the first year postpartum, and regarding birth and developmental outcomes through the infant’s first year of life. The study design should include a comparator group, and patients should be monitored for at least 10 years after their first course of treatment. The study should enroll at least 150 subjects exposed to teplizumab-mzwv and collect sufficient clinical information to assess for sources of confounding for the target outcomes. A draft protocol needs to be submitted to the FDA by March 2023, with annual reports submitted through January 2037 and a final report due by September 2037. ¹⁹

The manufacturer is required to complete the PRV-031-001 (PROTECT) study by May 2023 and submit a final report by November 2023. The 42 months long-term safety extension phase of the PROTECT study (PRV-031-003, PROTECT Extension) needs to be completed by November 2026, with the final report due by May 2027. ¹⁹

Limitations: Follow-up data were not available for all original participants of the AbATE trial; a larger number of follow-up participants would have provided greater power to detect differences between groups. The T-cell analysis was based on previous studies of the mechanisms of action of teplizumab-mzwv; use of an unsupervised approach might identify additional markers associated with clinical responses in the long-term.

Contraindications Precautions and Precautions

Contraindications

The teplizumab-mzwv prescribing information states there are no contraindications to its use. ¹ Though not stated in the product labeling, a potential contraindication is hypersensitivity to teplizumab-mzwv or any of its inactive ingredients (ie, dibasic sodium phosphate, monobasic sodium phosphate, polysorbate 80, sodium chloride).

Warnings and Precautions

CRS (eg, fever, nausea, fatigue, headache, myalgia, arthralgia, increased ALT, increased AST, increased total bilirubin) may occur after IV administration of teplizumab-mzwv. In clinical trials, CRS was reported in 5% of patients treated with teplizumab-mzwv versus 0.8% with control during treatment and up to 28 days after the last dose. However, CRS generally occurs within the first 5 days of treatment. To decrease the risk of CRS, patients should receive premedication with antipyretics, antihistamines, and/or an antiemetics. In addition, patient liver enzymes should be monitored; if ALT or AST more than 5 times the ULN or bilirubin more than 3 times the ULN develops, treatment should be discontinued. CRS symptoms should also be treated with antipyretics, antihistamines, and or antiemetics. If severe CRS develops, teplizumab-mzwv should be paused for 1 to 2 days (and the remaining doses administered to complete the full 14-day course on consecutive days) or discontinued. ¹

Serious infections (eg, gastroenteritis, cellulitis, pneumonia, abscess, sepsis) have occurred during treatment with teplizumab-mzwv (3.5% of teplizumab-mzwv–treated patients vs 2% of control patients). Use of teplizumab-mzwv is not recommended in patients with active infection or chronic infection other than localized skin infections. Monitor for signs and symptoms of infection during or after teplizumab-mzwv treatment. If serious infection develops, it should be treated appropriately and teplizumab-mzwv therapy should be discontinued. ¹

Lymphopenia has occurred in clinical trials (78% with teplizumab-mzwv and 11% with control). Patient white blood cell counts should be monitored during the treatment period. If prolonged severe lymphopenia (less than 500 cells/µL lasting 1 week or longer) develops, teplizumab-mzwv treatment should be discontinued. In clinical trials, most patients’ lymphocyte levels improved after the fifth day of treatment and returned to pretreatment levels within 2 weeks after treatment completion and without dose interruption. ¹

Immunogenicity is a potential problem with teplizumab-mzwv because it is a biologically active compound. In Study TN-10, approximately 57% of teplizumab-mzwv–treated patients developed anti–teplizumab-mzwv antibodies, 46% of whom developed neutralizing antibodies. There is insufficient information to characterize the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, or effectiveness of teplizumab-mzwv. There was a higher incidence of rash in teplizumab-mzwv–treated patients who developed anti–teplizumab-mzwv antibodies. ¹

Acute hypersensitivity reactions have occurred in patients treated with teplizumab-mzwv. If a hypersensitivity reaction (eg, serum sickness, angioedema, urticaria, rash, vomiting, bronchospasm) occurs, treatment should be discontinued and appropriate treatment initiated. ¹

All age-appropriate vaccinations should be administered prior to starting teplizumab-mzwv; live-attenuated (live) vaccines should be given at least 8 weeks prior to treatment and inactivated (killed) vaccines or mRNA vaccines given at least 2 weeks prior to treatment. Vaccinations are not recommended during treatment; in addition, live-attenuated vaccines are not recommended for up to 52 weeks after teplizumab-mzwv treatment and inactivated or mRNA vaccinations are not recommended for 6 weeks after completion of treatment. ¹

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 teplizumab-mzwv may cause immunosuppression in the utero-exposed infant. To minimize exposure to a fetus, use of teplizumab-mzwv should be avoided during pregnancy and for at least 30 days prior to planned pregnancy. ¹

There are no data on the presence of teplizumab-mzwv in human milk, or its effects on the breastfeeding child or milk production. Endogenous maternal IgG and monoclonal antibodies are transferred into human milk. Effects of local GI exposure and limited systemic exposure to teplizumab-mzwv on the breastfeeding infant are unknown. To minimize drug exposure in the breastfeeding child, patients should interrupt breastfeeding and pump and discard breast milk during treatment and for 20 days after teplizumab-mzwv treatment. ¹

The safety and effectiveness of teplizumab-mzwv have not been established in pediatric patients younger than 8 years of age. ¹ The manufacturer is required to conduct a 12-month, single-arm, open-label study to assess the safety and pharmacokinetics of teplizumab-mzwv in pediatric patients 0 to younger than 8 years with 2 type 1 diabetes–related autoantibodies and dysglycemia (stage 2 type 1 diabetes) [part A], followed by a 12-month, open-label extension [part B]; part A is scheduled to be completed by October 2025 with the final report submitted by April 2026, and part B is scheduled to be completed in October 2026 with the final report submitted by April 2027. ¹⁹

Adverse Reactions

The most common adverse reactions (incidence 10% or greater) associated with teplizumab-mzwv treatment include lymphopenia, rash, leukopenia, and headache (see Table 1). ¹

Table 1.

Common Adverse Reactions ^a (Incidence ≥5%) With Teplizumab-mzwv in Adult and Pediatric Patients ≥8 Years With Stage 2 Type 1 Diabetes (Study TN-10). ^{b 1}

Adverse reaction	Teplizumab-mzwv (n = 44)	Placebo (n = 32)
Lymphopenia	73%	6%
Rash c	36%	0%
Leukopenia	21%	0%
Headache	11%	6%
Neutropenia	5%	3%
Increased ALT	5%	3%
Nausea	5%	3%
Diarrhea	5%	0%
Nasopharyngitis	5%	0%

^aOccurring during treatment and through 28 days after the last study drug administration.

^bAdverse reactions that occurred in 2 or more teplizumab-mzwv–treated patients.

^cComposite of rash-related terms including rash erythematous, rash macular, rash maculopapular, rash pruritic.

In Study TN-10, 9% (4 of 44) of teplizumab-mzwv–treated patients experienced serious infections (cellulitis, gastroenteritis, pneumonia, wound infection) during or after the first dose, compared to 0% (0 of 32) of placebo-treated patients. ¹

Drug Interactions

No drug interaction studies have been conducted.

Recommended Monitoring

Monitor complete blood cell count and liver chemistries (eg, AST, ALT, total bilirubin) prior to initiating therapy and during treatment as necessary. Monitor liver chemistries, lymphocytes, and signs/symptoms of CRS, infection, or hypersensitivity daily throughout therapy. ¹

Dosing

Note: The FDA-approved dose does not reflect the dose used in the premarket clinical trial due to pharmacokinetic differences between the product used in the clinical trial and the product that was FDA approved; therefore, doses used in the clinical trial should not be used. ²⁰

Teplizumab-mzwv is only for use in patients with stage 2 type 1 diabetes mellitus. Prior to initiating teplizumab-mzwv, confirm stage 2 type 1 diabetes diagnosis (ie, at least 2 positive pancreatic islet cell autoantibodies, dysglycemia without overt hyperglycemia following an OGGT, and clinical history not suggestive of type 2 diabetes mellitus). ¹

Prior to initiating teplizumab-mzwv, a complete blood count and liver enzyme tests should be obtained. All age-appropriate vaccinations should be administered prior to starting teplizumab-mzwv; these include live-attenuated (live) vaccines administered at least 8 weeks prior to treatment and inactivated (killed) vaccines or mRNA vaccines administered at least 2 weeks prior to treatment. ¹

Premedicate with a nonsteroidal anti-inflammatory drug or acetaminophen, an antihistamine, and/or an antiemetic for the first 5 days of teplizumab-mzwv infusions to mitigate risk of CRS; administer additional doses of premedication, if needed. ¹

In adults and children 8 years and older, teplizumab-mzwv should be administered IV once daily for 14 consecutive days using BSA. ¹ See Table 2 for teplizumab-mzwv dosing recommendations.

Table 2.

Recommended Dosage for Teplizumab-mzwv in Patients ≥8 Years With Stage 2 Type 1 Diabetes Mellitus. ¹

Day(s)	Dosage
1	65 µg/m2
2	125 µg/m2
3	250 µg/m2
4	500 µg/m2
5-14	1030 µg/m2

If a planned dose is missed, resume dosing by administering all remaining doses on consecutive days to complete the 14-day treatment course. Do not administer 2 doses on the same day. ¹

There are no dosage adjustments provided in the manufacturer’s labeling for altered kidney function or altered hepatic impairment. Avoid use in patients with ALT or AST greater than 2 times ULN or bilirubin greater than 1.5 times ULN; discontinue teplizumab-mzwv for AST or ALT greater than 5 times ULN or for bilirubin greater than 3 times ULN. ¹

Treat symptoms of CRS with antipyretics, antihistamines, and/or antiemetics; if severe CRS occurs, consider temporarily pausing dosing for 1 to 2 days or discontinuing treatment. ¹

In most patients, lymphocyte levels began to recover after the fifth day of treatment and returned to pretreatment values within 2 weeks after treatment completion and without dose interruption; however, discontinue therapy if prolonged severe lymphopenia (ie, less than 500 cells/µL lasting 1 week or more) occurs. ¹

Prior to administration, teplizumab-mzwv should be diluted. The infusion should begin within 2 hours of preparation. It should be administered over at least 30 minutes, with complete infusion occurring within 4 hours after the start of preparation. ¹

The supplied undiluted solution should be clear and colorless; do not use if particulate matter or discoloration is seen. Remove 2 mL of teplizumab-mzwv from the vial and slowly add to 18 mL of normal saline (contained in a sterile glass vial or PVC infusion bag) to make a 100 µg/mL diluted teplizumab-mzwv solution; mix gently by slowly inverting the vial or rocking the infusion bag. Withdraw the volume of diluted solution required for that day’s calculated dose and slowly add to a 25 mL normal saline PVC infusion bag and gently rock to mix (do not shake); discard unused portion of the remaining 100 µg/mL diluted solution. Begin infusion within 2 hours of preparation. ¹

If not used immediately, the diluted solution may be stored at room temperature (15°C-30°C [59°F-86°F]) and the infusion completed within 4 hours of the start of preparation; discard prepared infusion solution if not administered within 4 hours of the start of preparation. ¹

Product Availability and Storage

The FDA designated teplizumab-mzwv a “breakthrough therapy” in August 2019. ²¹ Teplizumab-mzwv was approved by the FDA on November 17, 2022. ¹⁹

Teplizumab-mzwv injection is available as a sterile, preservative-free solution for IV administration in a single-dose vial containing 2 mg per 2 mL (1 mg/mL), with a pH of 6.1. It is supplied in cartons containing 1 single-dose vial, 10 single-dose vials, or 14 single-dose vials. ¹

Teplizumab-mzwv should be stored refrigerated (2°C-8°C [36°F-46°F]) in the original carton to protect it from light. It should be stored upright, and the vials should not be shaken or frozen. ¹

If not used immediately, the diluted solution may be stored at room temperature (15°C-30°C [59°F-86°F]) and the infusion completed within 4 hours of the start of preparation; discard prepared infusion solution if not administered within 4 hours of the start of preparation. ¹

Drug Safety/REMS

A medication guide that explains the risk of CRS, serious infections, lymphopenia, hypersensitivity reactions, vaccinations, pregnancy, and lactation is required.^1,19

Conclusion

Teplizumab-mzwv. a humanized anti-CD3 monoclonal antibody, is FDA approved to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older with stage 2 type 1 diabetes. The FDA-approved dose does not reflect the dose used in the premarket clinical trial due to pharmacokinetic differences between the product used in the clinical trial and the product that was FDA approved; therefore, doses used in the clinical trial should not be used. Additionally, several issues require clarification, including regarding the best candidates for teplizumab-mzwv therapy, varying efficacy among individuals, stage at which therapy should be initiated, optimal dosage, and whether changes in HbA_1c C-peptide levels are adequate end points or markers to assess the efficacy of this type of therapy.