⁃ Informed Consent

• Provision of signed and dated written ICF prior to any mandatory study-specific procedures, sampling, and analyses for patients who are at or over the age of majority (as per local law). For patients who are less than the age of majority, in addition to providing their informed consent, the patients' legally authorised representative must also provide their informed assent (Appendix A 3).

• Age

• Patients must be 12 to 80 years of age inclusive, at the time of signing the ICF.

• Type of Patient and Disease Characteristics

• Documented medical record history for at least 12 months prior to Visit 1.

• Documented physician-diagnosed severe asthma within 10 years prior to Visit 1 (ie, severe asthma was not diagnosed more than 10 years prior) consisting of any of the following:

∙ FEV1 \> 12% reversibility, OR

‣ Evidence of airflow variability (to show that lung function is altered over time): FEV1 ≥ 400 mL variability over time, OR

‣ Challenge tests that are positive on one of the below:

• (i) Methacholine - PD20 ≤ 8 mg/mL (ii) Mannitol - PD15 15% drop on FEV1 out of dose \< than 635 mg of inhaled mannitol (iii) Exercise - 10% fall of FEV1

• ACQ-5 ≥ 1.5 and \< 3.

• History of physician-diagnosed asthma that requires continuous treatment with high-dose ICS (as defined by GINA or highest approved dose per posology per country) plus a LABA for at least 6 months prior to Visit 1 (Appendix I). The ICS and LABA can be contained within a combination product or given by separate inhalers.

• Note: Additional maintenance asthma controller medications (eg, LTRAs, tiotropium, cromone, theophylline) are allowed.

• Pre-brochodilator FEV1 \> 60% predicted and evidence of FEV1 reversibility of \> 12% within 6 months prior to screening or at screening. Patients with normal lung function (FEV1 \> 80%) need evidence of airflow variability as per inclusion criterion 4.

• Documented history of at least one asthma exacerbation requiring OCS bursts or requiring hospitalization within 12 months prior to Visit 1. An asthma exacerbation will be defined as a worsening of asthma symptoms that leads to any of the following:

∙ A temporary bolus/burst of systemic corticosteroids for at least 3 consecutive days to treat symptoms of asthma worsening; a single depo-injectable dose of corticosteroids will be considered equivalent to a 3-day bolus/burst of systemic corticosteroids

‣ Or, an ER visit (defined as evaluation and treatment for \< 24 hours in ER) due to asthma that required systemic corticosteroids (as per above)

‣ Or, an in-patient hospitalisation (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours).

• Sex and Contraceptive/Barrier Requirements

• Male or female.

• Female patients:

⁃ Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Women of nonchildbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned start date of the induction phase without an alternative medical cause.

⁃ The following age-specific requirements apply:

• Women \< 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle-stimulating hormone levels in the postmenopausal range.

∙ Women ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.

∙ Adolescents: if patient is female and has reached menarche or has reached Tanner stage 3 breast development (even if not having reached menarche), the patient will be considered a WOCBP.

⁃ WOCBP must be willing to use one of the methods of contraception described hereafter, from the time of signing the ICF throughout the study and 16 weeks after last tezepelumab administration:

∙ Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal

‣ Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable

‣ Intrauterine device

‣ Intrauterine hormone-releasing system

‣ Bilateral tubal occlusion

‣ Vasectomised partner (vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner of the WOCBP patient and that the vasectomised partner has received medical assessment of the surgical success)

‣ Sexual abstinence: it is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the patient.

‣ Cessation of contraception after this point should be discussed with a responsible physician

⁃ Before dosing with tezepelumab at Week 0, patients should fulfil the following criteria:

⁃ ACQ-5 ≥ 1.5 and \< 3.

⁃ Demonstrated proper inhaler technique (patients with improper technique at screening may be trained during screening, but must demonstrate proper technique before enrollment).

⁃ No excessive SABA use (should be \< 5 puffs/day) or for patients using SMART therapy outside the US, no excessive use of SYMBICORT (should be ≤ 8 inhalations/day) or for US patients, no excessive use of AIRSUPRA (should be ≤ 12 inhalations/day).