Tzield Drug Information

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: 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.

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. 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).

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 the following conditions: 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, including assessment of viral load.

Consider expert consultation for appropriate laboratory and clinical evaluation to assess for active EBV or CMV infection. Use of TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection). 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 Body Surface Area Dosage Calculation The dosage of TZIELD is based on body surface (BSA) area, which is calculated using the Mosteller formula, below: Using the patient's BSA, calculate the dose based on treatment day: Dose (mcg) = Daily dosage (mcg/m 2 ) × BSA (m 2 ) Recommended Dosage and Administration in Patients with Stage 2 T1D Administer TZIELD once daily for 14 consecutive days using BSA-based dosing per the schedule below: 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. Recommended Dosage and Administration in Patients with Stage 3 T1D Initiate treatment as soon as possible following Stage 3 T1D diagnosis but no later than 8 weeks from diagnosis. If the second course is delayed, administer the second treatment course within 6 to 12 months after the first treatment course.

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Recommendations Regarding Missed Doses If a planned

TZIELD infusion is missed, administer the missed dose as soon as possible and all remaining doses on consecutive days to complete the 14 total dose regimen in patients with Stage 2 T1D or each of the two 12-day treatment courses in patients with Stage 3 T1D. 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 and Administration Instructions

Read this entire section carefully before preparing TZIELD. Must dilute TZIELD prior to use. This requires the preparation of 100 mcg/mL dilution followed by the preparation of an infusion solution.

Start the infusion after preparation is complete. If the TZIELD infusion solution is not used immediately, store as instructed per corresponding infusion preparation method. The following are preparation and administration instructions based on BSA dosing requirements: TZIELD 100 mcg/mL 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. Each vial is intended for one-time use only, discard any unused portion.

If the calculated dose is: 2,000 mcg or less, then prepare: One sterile syringe (polypropylene (PP), polycarbonate (PC) or glass) or 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. Remove the cap from the TZIELD vial – this is the preparation start time. Remove 2 mL of TZIELD from the single-dose vial and slowly add to the sterile syringes (PP, PC or glass), glass vial or PVC with DEHP infusion bag containing 18 mL of 0.9% Sodium Chloride Injection.

Mix gently by slowly swirling the vial or rocking the infusion bag or syringe. 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 or syringe (PP, PC or glass) containing 18 mL of 0.9% Sodium Chloride Injection.

TZIELD Infusion Solution Preparation: Calculate the volume of TZIELD 100 mcg/mL dilution needed for the infusion. Use the appropriate steps below depending on the selected method. Method 1: Infusion bag for intravenous administration: Using an appropriately sized syringe, withdraw the volume of TZIELD 100 mcg/mL dilution required for that day's calculated dose (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 TZIELD dilution in the syringe, sterile glass vial or PVC with DEHP infusion bag. Slowly add contents of the syringe containing the TZIELD dose to a 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. Infusion bag administration: Prime the 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 at room temperature between 15°C to 25°C (59°F to 77°F).

Discard if the infusion is unable to be completed within 6 hours of preparation. Method 2: Syringe for intravenous infusion via syringe pump: Requires an appropriately sized sterile syringe (up to 60 mL) which is compatible with available syringe pump. The syringe pump should support rates as low as 1 mL/hour.

The final concentration range is 15 mcg/mL to 60 mcg/mL with a maximum infusion volume of 60 mL. To fit technical constraints of syringe pump, a lower volume may be used as long as the concentration is between 15 mcg/mL and 60 mcg/mL. If the calculated dose is: 900 mcg or less: Calculate the maximum volume that can be administered for the calculated dose (based on treatment day, dose and patient BSA) using a minimum infusion concentration of 15 mcg/mL.

Volume Infusion (mL) = Dose (mcg) Minimum infusion concentration 15 mcg/mL Calculate the volume of 0.9% Sodium Chloride Injection to be added to the infusion syringe: Volume 0.9% Sodium Chloride Injection (mL) = Volume Infusion (mL) - Volume 100 mcg/mL dilution (mL) Greater than 900 mcg: the maximum infusion volume is capped at 60 mL. Volume 0.9% Sodium Chloride Injection (mL) = 60 mL - Volume 100 mcg/mL dilution (mL) For all doses: Measure the appropriate volume of 0.9% Sodium Chloride Injection from above calculation into the infusion syringe. Using an appropriately sized syringe, withdraw the volume of TZIELD 100 mcg/mL dilution required for that day's calculated dose (for a calculated dose 2,000 mcg or less) and add it to the infusion syringe.

For a calculated dose more than 2,000 mcg, add the cumulative volume from both prepared 100 mcg/mL dilutions to a single infusion syringe. Do not shake. Attach infusion syringe to a syringe pump.

Infusion administration rate may be slowed for patient's tolerability.

Compatible Materials for Administration Compatibility has been demonstrated with the materials listed in Table 1. Other materials should not be used. Table 1.

Compatible Materials for TZIELD Administration 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 (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. These data reflect exposure of 44 patients of whom 93% completed the full 14-day treatment course.

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 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.

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) 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 described above): One study in patients with Stage 2 T1D (Study TN-10), Three placebo-controlled studies in patients with Stage 3 T1D, One open-label standard-of-care controlled study of TZIELD in patients with Stage 3 T1D. 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.

Common Adverse Reactions Cytokine Release Syndrome (CRS) In Study TN-10, CRS was reported in 2% of TZIELD-treated patients compared to 0% of placebo-treated patients. In the PROTECT Study, CRS was reported in 9% of TZIELD-treated patients compared to 1% of placebo-treated patients. 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.

In clinical trials, serious infections were reported in 3.5% of TZIELD-treated patients compared to 2% of control-treated patients any time during or after the first dose of study treatment. Rash and Hypersensitivity Reactions Hypersensitivity reactions were reported with TZIELD treatment in Study TN-10. 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 PROTECT Study, hypersensitivity reactions were reported in 1% of TZIELD-treated patients and 0% in the placebo group. One patient in the TZIELD group experienced delayed hypersensitivity. The patient had a prior history of allergic rhinitis and presented with symptoms of rash and arthralgia 16 days after completing Course 1.

The event resolved with antihistamine treatment. In the pool of 5 clinical trials of patients with Stage 2 or Stage 3 T1D: 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. The majority of events of rash 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. In the PROTECT Study, rash occurred in 30% of TZIELD-treated patients who developed anti-teplizumab-mzwv antibodies and in 17% of TZIELD-treated patients who did not develop anti-teplizumab-mzwv antibodies. In this trial, 87% completed the full 14-day treatment course.

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 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 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. In the PROTECT Study, lymphopenia was reported in 51% of TZIELD-treated patients compared to 3% of placebo-treated patients. Lymphocyte count nadir occurred at approximately Day 4 of treatment, with recovery and return to baseline by Week 4.

Neutropenia In Study TN-10, neutropenia was observed in 7% of TZIELD-treated patients compared to 3% of placebo-treated patients. In the PROTECT Study, neutropenia was observed in 23% of TZIELD-treated patients compared to 5% of placebo-treated patients. Liver Enzyme Elevations Liver enzyme and bilirubin 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, ALT increased was 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 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 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 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). Delay the decline in endogenous insulin production in pediatric patients aged 8 to 17 years recently diagnosed with Stage 3 T1D.

Use of TZIELD for this indication is supported by an adequate and well-controlled study (PROTECT Study) in pediatric patients recently diagnosed with Stage 3 T1D. Adverse reactions observed in pediatric patients 1 year of age and older who received TZIELD were consistent with those reported in adults.

TZIELD is contraindicated in patients who are immunocompromised or have active viral infection (such as EBV or CMV infection).