2.1 Patient Selection

Select adult patients and pediatric patients 8 years of age and older for TZIELD treatment who have a diagnosis of Stage 2 type 1 diabetes.

• Confirm Stage 2 type 1 diabetes by documenting:
  • At least two positive pancreatic islet cell autoantibodies
  • Dysglycemia without overt hyperglycemia using an oral glucose tolerance test (if an oral glucose tolerance test is not available, an alternative method for diagnosing dysglycemia without overt hyperglycemia may be appropriate)
• Ensure the clinical history of the patient does not suggest type 2 diabetes.

2.2 Laboratory Evaluation and Vaccination Prior to Initiation

• Prior to initiating TZIELD, obtain a complete blood count and liver enzyme tests.
• Use of TZIELD is not recommended in patients with [see Warnings and Precautions (5)]:
  • Lymphocyte count less than 1,000 lymphocytes/mcL
  • Hemoglobin less than 10 g/dL
  • Platelet count less than 150,000 platelets/mcL
  • Absolute neutrophil count less than 1,500 neutrophils/mcL
  • 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 (EBV) or cytomegalovirus (CMV)
  • Active serious infection or chronic active infection other than localized skin infections
• Administer all age-appropriate vaccinations prior to starting TZIELD [see Warnings and Precautions (5.5)]:
  • Administer live-attenuated (live) vaccines at least 8 weeks prior to treatment.
  • Administer inactivated (killed) vaccines or mRNA vaccines at least 2 weeks prior to treatment.

2.3 Important Preparation and Premedication Instructions

The following are important preparation and premedication instructions:

• Must dilute TZIELD prior to use [see Dosage and Administration (2.5)].
• Premedicate prior to TZIELD infusion for the first 5 days of dosing with: (1) a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, (2) an antihistamine, and/or (3) an antiemetic [see Warnings and Precautions (5.1)]. Administer additional doses of premedication if needed.

2.4 Recommended Dosage and Administration

Administer TZIELD by intravenous infusion (over a minimum of 30 minutes), using a body surface area-based dosing, once daily for 14 consecutive days as follows:

• Day 1: 65 mcg/m2
• Day 2: 125 mcg/m2
• Day 3: 250 mcg/m2
• Day 4: 500 mcg/m2
• Days 5 through 14: 1,030 mcg/m2

Do not administer two doses on the same day.

Recommendations Regarding Missed Dose(s)
If a planned TZIELD infusion is missed, resume dosing by administering all remaining doses on consecutive days to complete the 14-day treatment course.

2.5 Additional Preparation and Administration Instructions

The following are additional preparation and administration instructions [see Dosage and Administration (2.2, 2.3, 2.4)]:

• Inspect TZIELD visually before use (the supplied solution is clear and colorless). Do not use TZIELD if particulate matter or coloration is seen.
• Prepare TZIELD using aseptic technique. Each vial is intended for single dose only.
• Prepare a:
  • Sterile glass vial with 18 mL of 0.9% Sodium Chloride Injection or
  • Polyvinylchloride (PVC) infusion bag with 18 mL of 0.9% Sodium Chloride Injection.
• Remove 2 mL of TZIELD from the vial and slowly add to the 18 mL of 0.9% Sodium Chloride Injection. Mix gently by slowly inverting the vial or rocking the infusion bag. The resulting 20 mL diluted solution contains 100 mcg/mL of teplizumab-mzwv.
• Using an appropriately sized syringe (e.g., 5 mL), withdraw the volume of diluted TZIELD solution required for that day's calculated dose from the 100 mcg/mL solution.
• Slowly add contents of the syringe containing the TZIELD dose to a 25 mL 0.9% Sodium Chloride Injection PVC infusion bag. Gently rock the infusion bag to ensure that the solution mixes sufficiently. Do not shake.
• Discard unused portion of remaining diluted TZIELD solution in the sterile glass vial or PVC infusion bag.
• Start the TZIELD infusion within 2 hours of preparation. If not used immediately, store the infusion 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 infusion solution if not administered within 4 hours of preparation.

5.1 Cytokine Release Syndrome

Cytokine release syndrome (CRS) has been observed in TZIELD-treated patients. In clinical trials, CRS was reported in 5% of TZIELD-treated patients compared to 0.8% of control-treated patients during the treatment period and through 28 days after the last study drug administration. CRS manifestations in TZIELD-treated patients included fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), and increased total bilirubin. These manifestations typically occurred during the first 5 days of TZIELD treatment [see Adverse Reactions (6.1)]. To mitigate CRS:

• Premedicate with antipyretics, antihistamines and/or antiemetics prior to TZIELD treatment [see Dosage and Administration (2.3)].
• Monitor liver enzymes during treatment. Discontinue TZIELD treatment in patients who develop elevated ALT or AST more than 5 times the upper limit of normal (ULN) or bilirubin more than 3 times ULN.
• Treat symptoms of CRS with antipyretics, antihistamines and/or antiemetics. If severe CRS develops, consider temporarily pausing dosing for 1-2 days (and administer the remaining doses to complete the full 14-day course on consecutive days) or discontinuing treatment.

5.2 Serious Infections

Bacterial and viral infections have occurred in TZIELD-treated patients. In clinical trials, TZIELD-treated patients had a higher rate of serious infections (3.5%) than control-treated patients (2%), including gastroenteritis, cellulitis, pneumonia, abscess, sepsis [see Adverse Reactions (6.1)]. Use of TZIELD is not recommended in patients with active serious infection or chronic infection other than localized skin infections. Monitor patients for signs and symptoms of infection during and after TZIELD treatment. If serious infection develops, treat appropriately, and discontinue TZIELD.

5.3 Lymphopenia

In clinical trials, 78% of TZIELD-treated patients developed lymphopenia compared to 11% of control-treated patients. For most TZIELD-treated patients who experienced lymphopenia, lymphocyte levels began to recover after the fifth day of treatment and returned to pre-treatment values within two weeks after treatment completion and without dose interruption. Severe lymphopenia (<500 cells per mcL) lasting 1 week or longer occurred in 0.9% of TZIELD-treated patients, and 0.5% of TZIELD-treated patients permanently discontinued TZIELD because of lymphopenia [see Adverse Reactions (6.1)].

Monitor white blood cell counts during the treatment period. If prolonged severe lymphopenia (<500 cells per mcL lasting 1 week or longer) develops, discontinue TZIELD.

5.4 Hypersensitivity Reactions

Acute hypersensitivity reactions including serum sickness, angioedema, urticaria, rash, vomiting and bronchospasm occurred in TZIELD-treated patients [see Adverse Reactions (6.1)]. If severe hypersensitivity reactions occur, discontinue use of TZIELD and treat promptly.

5.5 Vaccinations

The safety of immunization with live-attenuated vaccines in TZIELD-treated patients has not been studied. Additionally, TZIELD may interfere with the immune response to vaccination and decrease vaccine efficacy.

• Administer all age-appropriate vaccinations prior to starting TZIELD [see Dosage and Administration (2.2)].
• Inactivated or mRNA vaccinations are not recommended within the 2 weeks prior to TZIELD treatment, during treatment, or 6 weeks after completion of treatment.
• Live-attenuated vaccinations are not recommended within the 8 weeks prior to TZIELD treatment, during treatment, or up to 52 weeks after treatment.

6.1 Clinical 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 (14)]. 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):

• One study in patients with Stage 2 T1D (Study TN-10) [see Clinical Studies (14)],
• 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 [see Dosage and Administration (2.4)], 168 patients received a 14-day course of TZIELD with a lower total TZIELD drug exposure, and 169 patients received a 6-day course of TZIELD with a lower total TZIELD drug exposure. The mean age of TZIELD-treated patients was 17.6 years (median 15 years), 62% were <18 years old (40% age 12 to 17; 21% age 8 to 11), and 64% were male. The population was 72% White, 26% Asian, 1% Black or African American, 1% were multiple or unknown race, and <1% American Indian or Alaska Native; 5% were Hispanic or Latino ethnicity.

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.

Cytokine Release Syndrome (CRS)
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 [see Warnings and Precautions (5.1)]. Liver transaminase elevations were observed in 56% of TZIELD-treated patients who experienced CRS: 64% were up to 2.5 times ULN, 32% were more than 2.5 to 5 times ULN, and 4.5% were 5-10 times ULN.

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.

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.

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 (12.6)].

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 (5.3)].

Neutropenia
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.

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.

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.

8.1 Pregnancy

Risk Summary
Available case reports from clinical trials with TZIELD 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 TZIELD may cause immunosuppression in the utero- exposed infant (see Clinical Considerations). To minimize exposure to a fetus, avoid use of TZIELD during pregnancy and at least 30 days (6 half-lives) prior to planned pregnancy.

TZIELD is not active in rodents. In animal reproduction studies, mice were given a surrogate anti-mouse CD3 antibody subcutaneously during organogenesis through lactation. Pups born to dams administered the murine surrogate antibody during pregnancy showed a reduction in the adaptive immune response consistent with the expected pharmacology (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Report pregnancies to Provention Bio, Inc.'s Adverse Event reporting line at 1-800-633-1610.

Clinical Considerations
Fetal/Neonatal Adverse Reactions
Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Because teplizumab-mzwv may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants exposed to teplizumab-mzwv in utero. There are insufficient data regarding infant serum levels of teplizumab-mzwv at birth and the duration of persistence of teplizumab- mzwv in infant serum after birth to identify a specific timeframe to delay live virus immunizations in infants exposed in utero.

Data
Animal Data
In an embryo-fetal developmental toxicity study, pregnant mice were administered a murine surrogate anti-mouse CD3 antibody by subcutaneous injection at dose levels of 0, 0.03, 0.3, or 20 mg/kg on Gestation Days 6, 10, and 14. Increase in post-implantation loss occurred in the 20 mg/kg group, in the presence of maternal toxicity.

In a pre- and postnatal development toxicity study in pregnant mice, in which the murine surrogate antibody was administered every 3 days from gestation day 6 through lactation day 19 at doses of 0, 0.3, 3, or 20 mg/kg, no maternal toxicity or increased incidence of post- implantation loss was observed. Reductions in T cell populations and increases in B cells, and a reduction in the adaptive immune response to keyhole limpet hemocyanin (KLH) were observed in the offspring on postnatal days 35 and 84 at 20 mg/kg. The surrogate antibody was present in the offspring serum at level less than 1.5% that of maternal serum at the high dose. A trend towards reduction in fertility was observed in the offspring of dams administered the murine surrogate antibody at 20 mg/kg. The human relevance of this finding is unknown.

8.2 Lactation

Risk Summary
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. Endogenous maternal IgG and monoclonal antibodies are transferred into human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to teplizumab-mzwv are unknown.

Although the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TZIELD and any potential adverse effects on the breastfed child from TZIELD or from the underlying maternal condition, a lactating woman 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 child.

8.4 Pediatric Use

The safety and effectiveness of TZIELD to delay the onset of Stage 3 type 1 diabetes have been established in pediatric patients 8 years of age and older with Stage 2 type 1 diabetes. Use of TZIELD for this indication is supported by evidence from an adequate and well-controlled study (Study TN-10) in adults and pediatric patients 8 years of age and older (including 29 pediatric patients). Adverse reactions observed in pediatric patients 8 years of age and older who received TZIELD were consistent with those reported in adult patients [see Adverse Reactions (6.1)].

The safety and effectiveness of TZIELD have not been established in pediatric patients younger than 8 years of age.

8.5 Geriatric Use

Stage 2 type 1 diabetes is largely a condition that occurs in pediatric and younger adult patients. Clinical studies of TZIELD to delay the onset of Stage 3 T1D did not include patients 65 years of age and older.

12.1 Mechanism of Action

Teplizumab-mzwv binds to CD3 (a cell surface antigen present on T lymphocytes) and delays the onset of Stage 3 type 1 diabetes in adults and pediatric patients aged 8 years and older with Stage 2 type 1 diabetes. The mechanism may involve partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T lymphocytes. Teplizumab-mzwv leads to an increase in the proportion of regulatory T cells and of exhausted CD8+ T cells in peripheral blood.

12.2 Pharmacodynamics

Clinical studies have shown that teplizumab-mzwv binds to CD3 molecules on the surface of both CD4+ and CD8+ T cells during treatment, with internalization of the teplizumab- mzwv/CD3 complex from the surface of T cells. Pharmacodynamic effects include lymphopenia in the absence of depletion of T cells with a nadir on the 5th day of dosing, during a 14-day course of TZIELD treatment [see Warnings and Precautions (5.3)]. Teplizumab-mzwv exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of teplizumab-mzwv have not been fully characterized.

12.3 Pharmacokinetics

Steady state concentrations of teplizumab-mzwv are not expected to be achieved during the 14- day course of TZIELD.

Distribution
The central volume of distribution (Vd) of teplizumab-mzwv was 2.27 L in a 60 kg subject.

Elimination
Teplizumab-mzwv showed saturable binding and elimination. The mean (SD) terminal elimination half-life and clearance of teplizumab-mzwv are 4.5 (0.2) days and 2.7 (0.8) L/day in a 60 kg subject, respectively.

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

Specific Populations
No clinically significant differences in the pharmacokinetics of teplizumab-mzwv were observed based on age (8 to 35 years old), biologic sex, or racial groups (White, Asians).

BSA-based dosing normalizes the exposure to teplizumab-mzwv across body weight.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of teplizumab-mzwv or of other teplizumab products.

In the placebo-controlled study in patients aged 8 years of age and older with Stage 2 type 1 diabetes (Study TN-10) [see Clinical Studies (14)], approximately 57% of TZIELD-treated patients developed anti-teplizumab-mzwv antibodies, 46% of whom developed neutralizing antibodies. There is insufficient information to characterize the effects of ADA on pharmacokinetics, pharmacodynamics, or effectiveness of TZIELD. There was a higher incidence of rash in TZIELD-treated patients who developed anti-teplizumab-mzwv antibodies compared to those who did not develop anti-teplizumab-mzwv antibodies [see Adverse Reactions (6.1)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies have been performed to assess the carcinogenic potential of teplizumab- mzwv.

No studies have been performed to assess the mutagenic potential of teplizumab-mzwv. As an antibody, teplizumab-mzwv is not expected to interact directly with DNA.

Fertility and reproductive performance were unaffected in female and male mice that received a murine surrogate anti-mouse CD3 antibody administered by the subcutaneous route at doses up to 20 mg/kg.