Tezepelumab

TEZSPIRE is a thymic stromal lymphopoietin (TSLP) blocker, human monoclonal antibody (IgG2λ), indicated:

• for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with severe asthma. ( 1.1 ) Limitations of Use: Not for relief of acute bronchospasm or status asthmaticus. ( 1.1 )
• for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP). ( 1.2 )

1.1 Asthma TEZSPIRE is indicated for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with severe asthma. Limitations of Use: TEZSPIRE is not indicated for the relief of acute bronchospasm or status asthmaticus.

1.2 Chronic Rhinosinusitis with Nasal Polyps TEZSPIRE is indicated for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP).

Injection: a clear to opalescent, colorless to light yellow solution available as:

• 210 mg/1.91 mL (110 mg/mL) solution in a single-dose glass vial.
• 210 mg/1.91 mL (110 mg/mL) solution in a single-dose pre-filled syringe.
• 210 mg/1.91 mL (110 mg/mL) solution in a single‑dose pre‑filled pen. Injection:
• 210 mg/1.91 mL (110 mg/mL) solution in a single-dose glass vial. ( 3 )
• 210 mg/1.91 mL (110 mg/mL) solution in a single-dose pre-filled syringe. ( 3 )
• 210 mg/1.91 mL (110 mg/mL) solution in a single‑dose pre‑filled pen. ( 3 )

TEZSPIRE is contraindicated in patients who have known hypersensitivity to tezepelumab-ekko or any of its excipients [see Warnings and Precautions (5.1) ] . Known hypersensitivity to tezepelumab-ekko or excipients. ( 4 )

• Hypersensitivity Reactions: Hypersensitivity reactions have been observed in the clinical trials (e.g., rash, allergic conjunctivitis) following the administration of TEZSPIRE. Postmarketing cases of anaphylaxis have been reported. Initiate appropriate treatment as clinically indicated in the event of a hypersensitivity reaction. ( 5.1 )
• Risk Associated with Abrupt Reduction in Corticosteroid Dosage: Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with TEZSPIRE. Decrease corticosteroids gradually, if appropriate. ( 5.3 )
• Parasitic (Helminth) Infection: Treat patients with pre-existing helminth infections before therapy with TEZSPIRE. If patients become infected while receiving TEZSPIRE and do not respond to anti-helminth treatment, discontinue TEZSPIRE until the parasitic infection resolves. ( 5.4 )
• Vaccination: Avoid use of live attenuated vaccines. ( 5.5 )

5.1 Hypersensitivity Reactions Hypersensitivity reactions were observed in the clinical trials (e.g., rash and allergic conjunctivitis) following the administration of TEZSPIRE. Postmarketing cases of anaphylaxis have also been reported [see Contraindications (4) and Adverse Reactions (6.2) ] . These reactions can occur within hours of administration, but in some instances have a delayed onset (i.e., days). In the event of a hypersensitivity reaction, consider the benefits and risks for the individual patient to determine whether to continue or discontinue treatment with TEZSPIRE.

5.2 Acute Asthma Symptoms or Deteriorating Disease TEZSPIRE should not be used to treat acute asthma symptoms or acute exacerbations. Do not use TEZSPIRE to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with TEZSPIRE.

5.3 Risk Associated with Abrupt Reduction of Corticosteroid Dosage Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with TEZSPIRE. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

5.4 Parasitic (Helminth) Infection Thymic stromal lymphopoietin (TSLP) may be involved in the immunological response to some helminth infections. Patients with known helminth infections were excluded from participation in clinical trials. It is unknown if TEZSPIRE will influence a patient’s response against helminth infections. Treat patients with pre-existing helminth infections before initiating therapy with TEZSPIRE. If patients become infected while receiving treatment with TEZSPIRE and do not respond to anti-helminth treatment, discontinue treatment with TEZSPIRE until infection resolves.

5.5 Live Attenuated Vaccines The concomitant use of TEZSPIRE and live attenuated vaccines has not been evaluated. The use of live attenuated vaccines should be avoided in patients receiving TEZSPIRE.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Most common adverse reactions (incidence ≥ 3%) are:
• Asthma: pharyngitis, arthralgia, and back pain. ( 6.1 )
• Chronic rhinosinusitis with nasal polyps: nasopharyngitis, upper respiratory tract infection, epistaxis, pharyngitis, back pain, influenza, injection site reaction and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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. Adverse Reactions in Adult and Pediatric Patients 12 Years of Age and Older with Asthma The safety of TEZSPIRE in asthma was based on the pooled safety population from PATHWAY and NAVIGATOR, which consists of 665 adult and pediatric patients 12 years of age and older with severe asthma who received at least one dose of TEZSPIRE 210 mg subcutaneously once every 4 weeks. The two placebo-controlled clinical trials were of 52 weeks duration. In addition, a similar safety profile was seen in a trial that enrolled 150 adult patients with severe asthma who required treatment with daily oral corticosteroids [see Clinical Studies (14.1) ] . Adverse reactions that occurred at an incidence greater than or equal to 3% and more common than in the placebo group from the pooled safety population (PATHWAY and NAVIGATOR) are shown in Table 1. Table 1 Adverse Reactions with TEZSPIRE with Incidence Greater than or Equal to 3% and More Common than Placebo in Patients with Severe Asthma in the Pooled Safety Population (PATHWAY and NAVIGATOR) Adverse Reaction TEZSPIRE N=665 % Placebo N=669 % Pharyngitis Pharyngitis (including Pharyngitis, Pharyngitis bacterial, Pharyngitis streptococcal and Viral pharyngitis) 4 3 Arthralgia 4 3 Back pain 4 3 Specific Adverse Reactions Cardiovascular Events In a randomized, double-blind, long term extension trial, patients 12 years and older with severe asthma from trials NAVIGATOR and the additional trial [see Clinical Studies (14.1) ] received TEZSPIRE 210 mg subcutaneously every 4 weeks or placebo for up to 104 weeks. In the trial, the incidence rates (IR) per 100 patient-years (PY) for serious cardiac adverse events in patients treated with TEZSPIRE or placebo were 1.08 and 0.21, respectively, with an incidence rate difference (IRD) of 0.88 (95% CI: 0.24, 1.53). The types of serious cardiac adverse events were heterogeneous. In the trial, the IR per 100 PY for adjudicated major adverse cardiovascular events (MACE, defined as cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with TEZSPIRE or placebo were 0.60 and 0.42, respectively, with an IRD of 0.18 (95% CI: -0.51, 0.75). Injection Site Reactions In the pooled safety population (PATHWAY and NAVIGATOR), in which TEZSPIRE or placebo was administered using the vial by a healthcare provider, injection site reactions (e.g., injection site erythema, injection site swelling, injection site pain) occurred at a rate of 3.3% in patients treated with TEZSPIRE compared with 2.7% in patients treated with placebo. In an open-label trial of 216 patients with asthma in which TEZSPIRE was administered by healthcare providers and patients or caregivers using either the pre-filled pen or pre-filled syringe, injection site reactions (e.g., injection site erythema, injection site swelling, injection site pain) were observed in 5.7% patients using the pre-filled pen and 0% using the pre-filled syringe. However, the trial was not designed to compare injection site reactions between patients who received TEZSPIRE by the pre-filled pen versus pre-filled syringe. Adverse Reactions in Adult Patients with Chronic Rhinosinusitis with Nasal Polyps The safety of TEZSPIRE in CRSwNP was based on WAYPOINT, a randomized, double-blind, parallel group, multicenter, placebo-controlled trial of 52 weeks duration, which consisted of 203 adult patients aged 18 years and older on standard of care treatment for CRSwNP who received at least one dose of TEZSPIRE 210 mg subcutaneously once every 4 weeks [see Clinical Studies (14.2) ] . Adverse reactions that occurred at an incidence greater than or equal to 3% and more common than in the placebo group from the safety population (WAYPOINT) are shown in Table 2. Table 2 Adverse Reactions with TEZSPIRE with Incidence Greater than or Equal to 3% and More Common than Placebo in Patients with CRSwNP (WAYPOINT) Adverse Reaction TEZSPIRE N=203 % Placebo N=205 % Nasopharyngitis 18 10 Upper respiratory tract infection Upper respiratory tract infection (including Upper respiratory tract infection and Viral upper respiratory tract infection) 12 8 Epistaxis 6 3 Pharyngitis Pharyngitis (including Pharyngitis, Pharyngitis bacterial, Pharyngitis streptococcal and Viral pharyngitis) 5 1 Back pain 5 2 Influenza 4 1 Injection site reaction Injection site reaction (e.g., Injection site erythema, Injection site swelling and Injection site pain) 4 2 Arthralgia 3 2

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TEZSPIRE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions : anaphylaxis

No formal drug interaction studies have been performed with TEZSPIRE.

8.1 Pregnancy Risk Summary There are no available data on TEZSPIRE use in pregnant women to evaluate for any drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Placental transfer of monoclonal antibodies such as tezepelumab-ekko is greater during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. In an enhanced pre- and post-natal development (ePPND) study conducted in cynomolgus monkeys, placental transport of tezepelumab-ekko was observed but there was no evidence of fetal harm following intravenous administration of tezepelumab-ekko throughout pregnancy at doses that produced maternal exposures up to 168 times the exposure at the maximum recommended human dose (MRHD) of 210 mg administered subcutaneously (see Data) . The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk: In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control. Data Animal Data In the ePPND study, pregnant cynomolgus monkeys received tezepelumab-ekko from GD20 to GD22 (dependent on pregnancy determination), at the beginning of organogenesis, and once every 7 days until the end of gestation at doses that produced exposures up to 168 times that achieved with the MRHD (on an AUC basis with maternal intravenous doses up to 300 mg/kg/week). There were no tezepelumab-ekko related adverse effects on maternal health, pregnancy outcome, embryo-fetal development, or neonatal growth and development up to 6.5 months of age. Tezepelumab-ekko crossed the placenta in cynomolgus monkeys and tezepelumab-ekko serum concentrations were 0.5- to 6.7-fold higher in infants relative to maternal animals.

8.2 Lactation Risk Summary There is no information regarding the presence of tezepelumab-ekko in human milk, its effects on the breastfed infant, or its effects on milk production. However, tezepelumab-ekko is a human monoclonal antibody immunoglobulin G2λ (IgG2λ), and immunoglobulin G (IgG) is present in human milk in small amounts. Tezepelumab‑ekko was present in the milk of cynomolgus monkeys postpartum following dosing during pregnancy (see Data) . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TEZSPIRE and any potential adverse effects on the breastfed infant from TEZSPIRE or from the underlying maternal condition. Data Animal Data In a prenatal and postnatal development study in cynomolgus monkeys, tezepelumab-ekko concentrations in milk were up to 0.5% of the maternal serum concentrations after intravenous administration of tezepelumab-ekko up to 300 mg/kg/week (168 times the exposures based on AUC achieved at MRHD). The concentration of tezepelumab-ekko in animal milk does not necessarily predict the concentration of drug in human milk.

8.4 Pediatric Use Asthma The safety and effectiveness of TEZSPIRE for the add-on maintenance treatment of severe asthma have been established in pediatric patients aged 12 years and older [see Adverse Reactions (6.1) and Clinical Studies (14.1)] . Use of TEZSPIRE for this indication is supported by evidence from a total of 82 pediatric patients aged 12 to 17 years enrolled in NAVIGATOR and received treatment with TEZSPIRE 210 mg subcutaneously every 4 weeks (n=41) or placebo (n=41). Compared with placebo, improvements in annualized asthma exacerbation (rate ratio 0.70; 95% CI 0.34, 1.46) and FEV1 (LS mean change versus placebo 0.17 L; 95% CI -0.01, 0.35) were observed in pediatric patients treated with TEZSPIRE. The safety profile and pharmacodynamic responses in pediatric patients were generally similar to the overall study population. The safety and effectiveness of TEZSPIRE have not been established in patients younger than 12 years of age with asthma. CRSwNP The safety and effectiveness of TEZSPIRE for the add-on maintenance treatment of inadequately controlled CRSwNP have been established in pediatric patients aged 12 years and older. Use of TEZSPIRE for this indication is supported by evidence from the adequate and well-controlled study of TEZSPIRE in adults (WAYPOINT) [see Clinical Studies (14.2) ] with the following additional data:

• Pharmacokinetic (PK) data from adult and pediatric patients aged 12 years and older with severe asthma and adult patients with CRSwNP [see Clinical Pharmacology (12.3) ] .
• Safety data in pediatric patients aged 12 years and older with severe asthma [see Adverse Reactions (6.1) ] . The safety and effectiveness of TEZSPIRE have not been established in patients younger than 12 years of age with CRSwNP.

8.5 Geriatric Use Asthma Of the 665 patients with asthma treated with TEZSPIRE in clinical trials (PATHWAY and NAVIGATOR) for severe asthma, 119 patients (18%) were 65 years or older. No overall differences in safety or effectiveness of TEZSPIRE have been observed between patients 65 years of age and older and younger patients [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . CRSwNP Of the 203 patients with CRSwNP treated with TEZSPIRE in a clinical trial (WAYPOINT) for CRSwNP, 29 patients (14%) were 65 years or older. No overall differences in safety or effectiveness of TEZSPIRE have been observed between patients 65 years of age and older and younger adult patients [see Adverse Reactions (6.1) and Clinical Studies (14.2) ] .

Tezepelumab-ekko is a thymic stromal lymphopoietin (TSLP) blocker, human monoclonal antibody IgG2λ that binds to human TSLP with a dissociation constant of 15.8 pM and blocks its interaction with the heterodimeric TSLP receptor. TSLP is a cytokine mainly derived from epithelial cells and occupies an upstream position in inflammatory cascades. Airway and mucosal inflammation are important components of the pathogenesis of asthma and CRSwNP. Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes, ILC2 cells) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in airway and mucosal inflammation. Increased levels of TSLP mRNA and protein are found in the airways of patients with asthma as well as in nasal polyp tissue. Blocking TSLP with tezepelumab-ekko reduces biomarkers and cytokines associated with inflammation including blood eosinophils, airway submucosal eosinophils, IgE, FeNO, IL-5, and IL-13; however, the mechanism of tezepelumab-ekko action in asthma and CRSwNP has not been definitively established.