TZIELD

1 INDICATIONS AND USAGE TZIELD 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 [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 adult and pediatric patients 1 year of age 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 patient's diagnosis confirms an autoimmune origin and does not suggest type 2 diabetes ( 2.1 ). Prior to initiating TZIELD, obtain a complete blood count and liver enzyme tests. Evaluate patients for active EBV and CMV infection and confirm undetectable viral load (e.g., polymerase chain reaction testing). Use of TZIELD is not recommended in patients with certain laboratory abnormalities or patients with laboratory or clinical evidence of active infection with EBV or CMV ( 2.2 ). Premedicate with: (1) a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, (2) an antihistamine, and (3) consider use of 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 once daily for 14 days. See full prescribing information for the dosing schedule, minimum infusion duration according to age, and recommendations regarding missed doses ( 2.4 , 2.5 ). See full prescribing information for recommendations on monitoring for changes in lymphocyte counts, liver enzymes, bilirubin, and symptoms of viral reactivation and discontinuing treatment ( 2.6 ). Must dilute TZIELD in 0.9% Sodium Chloride Injection, USP. See full prescribing information for detailed preparation and administration instructions ( 2.7 ). 2.1 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. 2.2 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 [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ] : 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 [see Warnings and Precautions (5.3) ]. Prior to initiating treatment, evaluate patients for active EBV and CMV infection and confirm undetectable viral load [e.g., polymerase chain reaction (PCR) testing]. Use of TZIELD is not recommended in patients with laboratory or clinical evidence of active infection with EBV or CMV [see Warnings and Precautions (5.1) ] . Administer all age-appropriate vaccinations prior to starting TZIELD [see Warnings and Precautions (5.6) ] : 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. 2.3 Important Premedication Instructions Prior to each of the first 5 days of TZIELD infusion [see Warnings and Precautions (5.2) ] …

5 WARNINGS AND PRECAUTIONS Cytokine Release Syndrome (CRS): Premedicate, monitor liver enzymes, discontinue in those that develop elevated ALT or AST more than 5 times the upper limit of normal, and if severe CRS develops consider temporarily pausing dosing ( 5.2 ). Serious Infections: Use of TZIELD is not recommended in patients with active serious infection or chronic infection. Monitor for signs and symptoms of infection during and after TZIELD treatment. If a serious infection develops, discontinue TZIELD ( 5.3 ). Lymphopenia: 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: If severe hypersensitivity reactions occur, discontinue TZIELD and treat promptly ( 5.5 ). Vaccinations: Administer all age-appropriate vaccinations prior to starting TZIELD. See recommendations regarding live-attenuated, inactivated, and mRNA vaccines ( 5.6 ). 5.1 Viral Reactivation Serious, life-threatening cases of viral reactivation, including EBV and CMV have been reported with TZIELD. During and within 2 months of TZIELD treatment, if primary infection or reactivation of EBV or CMV occurs, it may present with increased severity, including EBV-associated lymphoproliferative disease and organ failure. Patients who are immunocompromised, including patients with Down syndrome, may be at increased risk. The majority of serious viral reactivation cases occurred in patients who continued TZIELD despite persistent, severe lymphopenia [see Warnings and Precautions 5.4 ]. Prior to initiating treatment with TZIELD, evaluate patients for active EBV and CMV infection and confirm undetectable viral load (e.g., PCR testing). TZIELD is not recommended in patients with laboratory or clinical evidence of active EBV or CMV infection [see Dosage and Administration (2.2) ]. During treatment with TZIELD, regularly monitor lymphocyte counts [see Dosage and Administration (2.6) , Warnings and Precautions (5.4) ] and monitor patients for signs and symptoms of viral reactivation during treatment and for at least 2 months following the last infusion. If viral reactivation is suspected, discontinue TZIELD and obtain viral load (e.g., PCR) promptly. Consider appropriate expert consultation for diagnostic testing recommendations as some diagnostic tests may give inaccurate results in immunosuppressed patients. If viral reactivation is confirmed, permanently discontinue TZIELD [see Dosage and Administration (2.6) ]. Consider appropriate expert consultation for the management of severe viral reactivation. 5.2 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 (with or without vomiting), fatigue, headache, myalgia, arthralgia, increased ALT, increased 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 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. Treat symptoms of CRS in TZIELD-treated patients with antipyretics, antihistamines and/or antiemetics. If severe CRS develops, consider: Temporarily pausing TZIELD dosing for 1–2 days and if symptoms have resolved or significantly improved, subsequently administering the remaining doses on consecutive days to complete the full 14-day course or Discontinu…

4 CONTRAINDICATIONS None. None. ( 4 ).

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 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the Prescribing Information: Viral Reactivation [see Warnings and Precautions (5.1) ] Cytokine Release Syndrome [see Warnings and Precautions (5.2) ] Serious Infections [see Warnings and Precautions (5.3) ] Lymphopenia [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions were lymphopenia, vomiting, rash, leukopenia, diarrhea 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 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 [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 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) [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 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 pa…