Tzield Drug Information

is indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adult and pediatric patients 1 year of age and older with Stage 2 type 1 diabetes . TZIELD is a CD3-directed antibody indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adult and pediatric patients 1 year of age and older with Stage 2 T1D.

Patient Selection Select adult and pediatric patients 1 year of age and

older with Stage 2 T1D for TZIELD treatment to delay the onset of Stage 3 T1D based on the confirmation of: At least two positive pancreatic islet cell autoantibodies, and 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 patient's diagnosis confirms an autoimmune origin and does not suggest type 2 diabetes or other forms of diabetes. These may include, but are not limited to, genetic forms of diabetes, maturity-onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), or diabetes secondary to medications or surgery.

Laboratory and Infection 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 : 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 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2 times the upper limit of normal (ULN) or bilirubin greater than 1.5 times ULN Active serious infection or chronic active infection other than localized skin infections. Prior to initiating treatment, evaluate patients for active EBV and CMV infection and confirm undetectable viral load.

Use of TZIELD is not recommended in patients with laboratory or clinical evidence of active infection with EBV or CMV . Administer all age-appropriate vaccinations prior to starting TZIELD : Administer live-attenuated (live) vaccines at least 8 weeks prior to TZIELD treatment. Administer inactivated (killed) vaccines or mRNA vaccines at least 2 weeks prior to treatment.

Important Premedication Instructions

Prior to each of the first 5 days of TZIELD infusion : Premedicate with a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen Premedicate with an antihistamine, and Consider premedication with an antiemetic If needed, administer additional premedication doses.

Recommended Dosage and

Administration Calculate the dosage using a body surface area (BSA) and administer TZIELD 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 Administer TZIELD by intravenous infusion over a minimum of: 30 minutes in adult and pediatric patients aged 8 years and older. 2 hours in pediatric patients aged 1 to less than 8 years .

Recommendations Regarding Missed Doses

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

Recommended Monitoring During Treatment with

TZIELD Monitor lymphocyte count regularly (every 2–3 days) during TZIELD infusion and monitor for lymphocyte recovery following completion of TZIELD. If prolonged severe lymphopenia (<500 cells per mcL lasting 1 week or longer) develops, permanently discontinue TZIELD. Monitor patients for signs and symptoms of viral reactivation during TZIELD treatment and for at least 2 months following the last infusion. If viral reactivation is suspected, discontinue TZIELD . Monitor liver enzymes and bilirubin 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 .

Preparation Instructions Using the dose calculated according to

BSA, dilute TZIELD prior to preparing the infusion according to the instructions below: TZIELD Dilution Preparation: Prior to dilution, 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. If the calculated dose is: 2,000 mcg or less, then prepare: One sterile glass vial with 18 mL of 0.9% Sodium Chloride Injection or One ≤50 mL polyvinylchloride (PVC) with di-(2-ethylhexyl)phthalate (DEHP) infusion bag with 18 mL of 0.9% Sodium Chloride Injection.

Greater than 2,000 mcg, then prepare: Two sterile glass vials with 18 mL of 0.9% Sodium Chloride Injection or Two ≤50 mL PVC with DEHP infusion bags with 18 mL of 0.9% Sodium Chloride Injection. Remove 2 mL of TZIELD from the single-dose vial and slowly add to the glass vial or PVC with DEHP infusion bag containing 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 TZIELD solution contains 100 mcg/mL of teplizumab-mzwv. If preparing a dose greater than 2,000 mcg, repeat the above process with second TZIELD vial and the glass vial, or PVC with DEHP infusion bag containing 18 mL of 0.9% Sodium Chloride Injection. TZIELD Infusion Solution Preparation: Using an appropriately sized syringe, withdraw the volume of diluted TZIELD solution required for that day's calculated dose from the 100 mcg/mL dilution ( for a calculated dose 2,000 mcg or less ) or from both prepared 100 mcg/mL dilutions ( for a calculated dose more than 2,000 mcg ). Discard unused portion of remaining diluted TZIELD solution in the glass vial or infusion bag.

Slowly add contents of the syringe containing the TZIELD dose to PVC with DEHP infusion bag containing 25 mL of 0.9% Sodium Chloride Injection ( for a calculated dose more than 2,000 mcg, add the cumulative volume for the calculated dose to a single infusion bag ). Gently rock the infusion bag to ensure that the solution mixes sufficiently. Do not shake. Prime the PVC with DEHP IV infusion set with the TZIELD infusion solution.

Do not waste any infusion solution during the priming process. After infusion, flush the IV set with a volume of 0.9% Sodium Chloride Injection greater than or equal to the priming volume, to ensure full dose is administered. Same infusion rate should be used for flushing.

If the TZIELD infusion solution is not used immediately, store the infusion at room temperature. Discard the TZIELD infusion solution if the infusion is unable to be completed within 4 hours of preparation. Use of in-line filter is not recommended.

If necessary, use a polyethylene sulfone (PES) filter. Do not use light protected (colored) infusion sets.

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 Adult and Pediatric Patients Aged 8 Years and Older with Stage 2 T1D The data in Table 1 are derived from the placebo-controlled study (Study TN-10) in adult and pediatric patients aged 8 years and older with Stage 2 T1D. 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 T1D and for an Unapproved Use 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 , 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 less than18 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 less than1% 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 T1D (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 . 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.

Open Label Study in Pediatric Patients Age 1 to Less Than 8 Years with Stage 2 T1D The safety of TZIELD was evaluated in a non-randomized, single arm, open-label, multicenter study in 23 pediatric patients age 1 to less than 8 years with Stage 2 T1D ( PETITE-T1D Study; NCT05757713). In this trial, 87% completed the full 14-day treatment course. The median age was 4.9 years (1 patient was less than 2 years old; 52% were 2 to less than 5 years old; 44% were 5 to less than 8 years old; range 1.7 to 6.8 years) and 52% were female. The majority of the population (96%) was White and one patient (4%) was Asian; 3 patients (13%) were Hispanic or Latino ethnicity.

At baseline, 87% of participants had a first-degree relative with T1D. The majority (87%) were positive for 3 or more diabetes-related autoantibodies. The most common autoantibodies were anti-insulin (87%), anti-ICA (85%), anti-GAD65 (83%), anti-ZnT8 (74%), and anti-IA2 (68%). The median HbA1c was 5.5%. Overall, the safety profile of TZIELD observed in pediatric patients less than 8 years of age with Stage 2 T1D was consistent with that observed in patients 8 years of age and older with Stage 2 T1D. The most common adverse reactions that occurred in patients less than 8 years of age were vomiting (52%) and diarrhea (30%). Other Adverse Reactions in Adult and Pediatric Patients Age 1 Year and Older with Stage 2 T1D 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. 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 these 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. Procedure-Related Venous Thrombosis Venous thrombus and thrombophlebitis have been reported in patients receiving teplizumab intravenously administered via peripherally inserted central catheter (PICC). In the pool of 5 clinical trials of patients, deep vein thrombus was reported in 0.4% of TZIELD-treated patients compared to 0 placebo-treated patients. One teplizumab-treated patient (4.3%) in the PETITE-T1D study experienced a deep vein thrombosis. 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.

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 in nonclinical studies, 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 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 or visit https://ae.reporting.sanofi. 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.

Pediatric Use The safety and effectiveness of TZIELD have been established to delay the onset of Stage 3 T1D in pediatric patients 1 year of age and older with Stage 2 T1D. Use of TZIELD for this indication is supported by evidence from an adequate and well-controlled study (Study TN-10) in adult and pediatric patients 8 years of age and older (including 29 pediatric patients) with Stage 2 T1D and from additional pharmacokinetic and safety data in 23 pediatric patients aged 1 to less than 8 years of age with Stage 2 T1D (PETITE T1D) . Adverse reactions observed in pediatric patients 1 year of age and older who received TZIELD were consistent with those reported in adults . The safety and effectiveness of TZIELD have not been established in pediatric patients younger than 1 year of age.