Teplizumab

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.

1 INDICATIONS 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 [see Dosage and Administration ( 2.1 )] . TZIELD is a CD3-directed antibody indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with Stage 2 T1D ( 1 ).

2 DOSAGE AND ADMINISTRATION Confirm Stage 2 T1D by documenting at least two positive pancreatic islet autoantibodies in those who have dysglycemia without overt hyperglycemia using an oral glucose tolerance test (OGTT) or alternative method if appropriate and OGTT is not available ( 2.1 ). In patients who meet criteria for a diagnosis of Stage 2 type 1 diabetes, ensure the clinical history of the patient does not suggest type 2 diabetes ( 2.1 ). Prior to initiating TZIELD, obtain a complete blood count and liver enzyme tests. Use of TZIELD is not recommended in patients with certain laboratory abnormalities ( 2.2 ). Must dilute TZIELD in 0.9% Sodium Chloride Injection, USP. See full prescribing information for detailed preparation and administration instructions ( 2.3 , 2.4 , 2.5 ). Premedicate with: (1) a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, (2) an antihistamine, and/or (3) an antiemetic before each TZIELD dose for at least the first 5 days of the 14-day treatment course ( 2.3 ). Administer TZIELD by intravenous infusion (over a minimum of 30 minutes) once daily for 14 days. See full prescribing information for the dosing schedule ( 2.4 ). 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/m 2 Day 2: 125 mcg/m 2 Day 3: 250 mcg/m 2 Day 4: 500 mcg/m 2 Days 5 through 14: 1,030 mcg/m 2 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

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the Prescribing Information: Cytokine Release Syndrome [see Warnings and Precautions ( 5.1 )] Serious Infections [see Warnings and Precautions ( 5.2 )] Lymphopenia [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (>10%) were lymphopenia, rash, leukopenia and headache ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Provention Bio at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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. Table 1. Common Adverse Reactions That occurred during treatment and through 28 days after the last study drug administration in Adult and Pediatric Patients Aged 8 Years and Older with Stage 2 Type 1 Diabetes (Study TN-10) Adverse reactions that occurred in 2 or more TZIELD-treated patients Adverse Reaction Placebo N=32 TZIELD N=44 Lymphopenia 6% 73% Rash Composite of rash-related terms including rash erythematous, rash macular, rash papular, rash maculo-papular, rash pruritic 0% 36% Leukopenia 0% 21% Headache 6% 11% Neutropenia 3% 5% Increased alanine aminotransferase 3% 5% Nausea 3% 5% Diarrhea 0% 5% Nasopharyngitis 0% 5% 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 aft