Teplizumab

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.

Injection: 2 mg/2 mL (1 mg/mL) clear and colorless solution in a single-dose vial. Injection: 2 mg/2 mL (1 mg/mL) single-dose vial ( 3 ).

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 ).

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 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 treatment course in patients with Stage 2 T1D or each of the two 12-day courses in patients with Stage 3 T1D, or Discontinuing TZIELD treatment .

5.3 Serious Infections Bacterial and viral infections have occurred in TZIELD-treated patients. In a pool of clinical trials, TZIELD-treated patients had a higher rate of serious infections (3.5%) than control-treated patients (2%), including gastroenteritis, cellulitis, pneumonia, abscess, sepsis [see Adverse Reactions (6.1) ]. Adults may have a longer duration of severe lymphopenia following TZIELD treatment, which may increase the risk for serious infections. Use of TZIELD is not recommended in patients with active serious infection, or chronic infection other than localized skin infections. Monitor patients for signs and symptoms of infection during and after TZIELD treatment. If serious infection develops, treat appropriately, and discontinue TZIELD.

5.4 Lymphopenia In a pool of clinical trials, 78% of TZIELD-treated patients developed lymphopenia compared to 11% of control-treated patients. For most TZIELD-treated patients who experienced lymphopenia, lymphocyte levels began to recover after the fifth day of treatment and returned to pre-treatment values within two weeks after treatment completion and without dose interruption. Severe lymphopenia (<500 cells per mcL) lasting 1 week or longer occurred in 0.9% of TZIELD-treated patients, 0.5% of TZIELD-treated patients permanently discontinued TZIELD because of lymphopenia [see Adverse Reactions (6.1) ]. In the PROTECT study, 51% of TZIELD-treated patients developed lymphopenia compared to 3% of placebo-treated patients. Severe lymphopenia lasting 1 week or longer occurred in 1.4% of TZIELD-treated patients [see Adverse Reactions (6.1) ]. Severe lymphopenia following TZIELD treatment may be more prolonged in adults. Obtain a CBC prior to starting TZIELD and monitor lymphocyte counts during TZIELD treatment. If prolonged severe lymphopenia (<500 cells per mcL lasting 1 week or longer) develops, permanently discontinue TZIELD.

5.5 Hypersensitivity Reactions Acute hypersensitivity reactions including serum sickness, angioedema, urticaria, rash, vomiting and bronchospasm occurred in TZIELD-treated patients [see Adverse Reactions (6.1) ]. If severe hypersensitivity reactions occur, discontinue use of TZIELD and treat promptly.

5.6 Vaccinations The safety of immunization with live-attenuated vaccines in TZIELD-treated patients has not been studied. Additionally, TZIELD may interfere with the immune response to vaccination and decrease vaccine efficacy. Administer all age-appropriate vaccinations prior to starting TZIELD [see Dosage and Administration (2.2) ]. Inactivated or mRNA vaccinations are not recommended within the 2 weeks prior to any TZIELD treatment course, during treatment, or up to 6 weeks after completion of any treatment course. Live-attenuated vaccinations are not recommended within the 8 weeks prior to starting TZIELD treatment, during treatment, between treatment courses, or up to 52 weeks after completion of final treatment course.

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 described above): One study in patients with Stage 2 T1D (Study TN-10) [see Clinical Studies (14.1) ] , 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 this pool: 773 patients received TZIELD (44 patients with Stage 2 T1D and 729 patients with Stage 3 T1D), and 245 patients received either placebo or standard of care control (32 patients with Stage 2 T1D and 213 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 [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 than 18 years old (40% age 12 to 17; 21% age 8 to 11), 38% were 18 years and older (36% age 18 to 34; 2% age ≥35), and 64% were male. The population was 72% White, 26% Asian, 1% Black or African American, 1% were multiple or unknown race, and less than 1% American Indian or Alaska Native; 5% were Hispanic or Latino ethnicity. 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. Of the 39 TZIELD-treated patients 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 (5.2) ] . 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 greater than 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. 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. 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 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. 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. […]

Pregnancy: May cause fetal harm. To minimize exposure to a fetus, avoid use of TZIELD during pregnancy and at least 30 days prior to planned pregnancy ( 8.1 ). Lactation: A lactating woman may consider pumping and discarding breast milk during and for 20 days after TZIELD administration ( 8.2 ).

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.

8.2 Lactation Risk Summary There are no data on the presence of teplizumab-mzwv in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Endogenous maternal IgG and monoclonal antibodies are transferred into human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to teplizumab-mzwv are unknown. Although the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TZIELD and any potential adverse effects on the breastfed child from TZIELD or from the underlying maternal condition, a lactating woman may interrupt breastfeeding and pump and discard breast milk during treatment and for 20 days after TZIELD administration to minimize drug exposure to a breastfed child.

8.4 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) [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.1) ] . 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 [see Clinical Studies (14.2) ] . Adverse reactions observed in pediatric patients 1 year of age and older who received TZIELD were consistent with those reported in adults [see Adverse Reactions (6.1) ] . The safety and effectiveness of TZIELD have not been established to delay the onset of Stage 3 T1D in pediatric patients younger than 1 year of age with Stage 2 T1D. The safety and effectiveness of TZIELD have not been established to delay the decline in endogenous insulin production in pediatric patients less than 8 years of age years recently diagnosed with Stage 3 T1D.

8.5 Geriatric Use Stage 2 T1D is largely a condition that occurs in pediatric and younger adult patients. Clinical studies of TZIELD to delay the onset of Stage 3 T1D did not include patients 65 years of age and older.

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.