Teplizumab

1 INDICATIONS AND USAGE TZIELD is indicated to [see Dosage and Administration (2.1) ]: 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. Delay the decline in endogenous insulin production in pediatric patients aged 8 to 17 years recently diagnosed with Stage 3 T1D. This indication is approved under accelerated approval based on evidence of reduced C-peptide decline [see Clinical Studies (14.2) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Limitations of Use: There is limited evidence of safety and effectiveness in patients aged 45 years and older with Stage 2 T1D. TZIELD is not effective as a disease modifying therapy in non-autoimmune dysglycemic conditions . TZIELD is a CD3-directed antibody indicated to: ( 1 ) 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. Delay the decline in endogenous insulin production in pediatric patients aged 8 to 17 years recently diagnosed with Stage 3 T1D. This indication is approved under accelerated approval based on evidence of reduced C-peptide decline. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Limitations of Use : ( 1 ) There is limited evidence of safety and effectiveness in patients aged 45 years and older with Stage 2 T1D. TZIELD is not effective as a disease modifying therapy in non-autoimmune dysglycemic conditions.

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 T1D in adult and pediatric patients aged 1 year and older with Stage 2 T1D and delays the decline in endogenous insulin production in patients aged 8 to 17 years recently diagnosed with Stage 3 T1D. 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.

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 T1D ensure the patient's diagnosis confirms an autoimmune origin and does not suggest insulin resistance due to obesity, type 2 diabetes (T2D) or dysglycemia due to other forms of diabetes. Confirm Stage 3 T1D by documenting at least one positive pancreatic islet cell autoantibody and peak C-peptide ≥0.2 pmol/mL on a mixed-meal tolerance test (MMTT) or alternative method if appropriate and MMTT is not available ( 2.1 ). Prior to initiating TZIELD, obtain a complete blood count and liver enzyme tests and evaluate patients for active EBV and CMV infection, including assessment of viral load (e.g., polymerase chain reaction testing). Consider expert consultation for appropriate laboratory and clinical evaluation to assess for active EBV or CMV infection. Use of TZIELD is not recommended in patients with certain laboratory abnormalities. TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection) ( 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 treatment course ( 2.3 ). Administer TZIELD by intravenous infusion once daily for 14 days (Stage 2) or 12 days (Stage 3). See full prescribing information for the recommended dosage, 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 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 Patients with Stage 2 T1D 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 (OGTT): If an OGTT is not available, an alternative method for diagnosing dysglycemia without overt hyperglycemia may be appropriate. In adults aged 18 years or older , recommend following the definition of dysglycemia used in clinical trials to diagnose dysglycemia prior to use of TZIELD due to the lack of specificity of other measures [see Clinical Studies (14.1) ] . Ensure the patient's diagnosis confirms an autoimmune origin and does not suggest insulin resistance due to obesity, type 2 diabetes (T2D) or dysglycemia due to 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. Patients with Stage 3 T1D Select pediatric patients aged 8 to 17 years recently diagnosed (within the last 8 weeks) with Stage 3 T1D for TZIELD treatment to delay the decline in endogenous insulin production based on confirmation of both of the following: At least one positive pancreatic islet cell autoantibody Peak C-peptide ≥0.2 pmol/mL on a mixed-meal tolerance test (if a mixed meal tolerance test is not available, an alternative method for measuring peak C-peptide ≥0.2 pmol/mL may be appropriate). 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

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, neutropenia, increased liver transaminase and headache ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Provention Bio, Inc. 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 (TN-10) The data in Table 2 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 (14.1) ]. These data reflect exposure of 44 patients of whom 93% completed the full 14-day treatment course. Table 2 presents common (≥5%) adverse reactions that occurred during treatment and through 28 days after the last study drug administration in patients with Stage 2 T1D 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 2. 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 TZIELD N=44 Placebo N=32 Lymphopenia Grouped term includes other related terms 73% 6% Rash 36% 0% Leukopenia 21% 0% Headache 11% 6% Neutropenia 5% 3% Increased alanine aminotransferase 5% 3% Nausea 5% 3% Diarrhea 5% 0% Nasopharyngitis 5% 0% Placebo-Controlled Trial in Pediatric Patients Aged 8 to 17 Years with Stage 3 T1D In a 78-week placebo-controlled trial (PROTECT) in patients aged 8 to 17 years recently diagnosed with Stage 3 T1D, 328 patients were randomized to TZIELD or placebo daily by intravenous infusion for a 12-day course followed by another 12-day course 6 months later [see Clinical Studies (14.2) ]. Table 3 presents common adverse reactions (≥5%) that occurred during either of the two 12-day treatment courses and through 28 days after the last dose of study drug administration in the PROTECT trial. Table 3. Common Adverse Reactions Adverse reactions occurring in equal or more than 5% of participants in the TZIELD group, higher in TZIELD compared to placebo, in treatment course 1 through 28 days after the last dose. in Pediatric Patients Aged 8 to 17 Years with Stage 3 T1D (PROTECT Study) Adverse Reaction TZIELD n=217 Placebo n=111 Course 1 Lymphopenia Grouped term includes other related terms. 51% 3% Rash 51% 9% Leukopenia 34% 3% Nausea 34% 12% Headache 29% 16% Vomiting 26% 5% Neutropenia 23% 5% Abdominal pain 18% 11% Pyrexia 16% 3% Alanine aminotransferase increased 11% 0% Diarrhea 10% 6% Cytokine release syndrome 7% 1% Hypotension 7% 6% Aspartate aminotransferase increased 7% 1% Hemoglobin decreased 5% 4% Chills 5% 0% No new adverse reactions were observed with the second course of TZIELD treatment. Incidence rates were similar than those reported during the first treatment course. Pool of Five Controlled Clinical Studies in Stage 2 or Stage 3 T1D 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

5 WARNINGS AND PRECAUTIONS Cytokine Release Syndrome (CRS): Premedicate, monitor liver enzymes and bilirubin during treatment, and discontinue in those that develop elevated ALT or AST more than 5 times the upper limit of normal (ULN) or bilirubin more than 3 times ULN. If severe CRS develops, consider temporarily pausing or discontinuing TZIELD. ( 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 lymphocyte 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 the full PI for 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 infections, 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. TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection). The majority of serious viral reactivation cases occurred in patients who continued TZIELD despite persistent, severe lymphopenia. The duration of severe lymphopenia following TZIELD treatment may be prolonged in adults [see Warnings and Precautions (5.4) ]. Serious cases have also been reported in adults with higher body surface area or comorbid conditions, such as adrenal insufficiency or cardiovascular disease. Prior to initiating treatment with TZIELD, evaluate patients for active EBV and CMV infection and confirm absence of active infection on assessment of viral load (e.g., PCR). TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as 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 following treatment with TZIELD, including rapid heterophile antibody testing. 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 a pool of clinical trials, CRS was reported in 5% of TZIELD-treated patients compared to 0.8% of control-treated patients. In the PROTECT study, CRS was reported in 9% of TZIELD-treated patients compared to 1% of placebo-treated patients during the treatment period and through 28 days after the last study drug administration. Manifestations of CRS 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 m

4 CONTRAINDICATIONS TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection) [see Warnings and Precautions (5.1) ]. TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection) ( 4 ).