Open-label Study to Assess Reduction of Background Asthma Medication While Sustaining Asthma Control and Clinical Remission With Tezepelumab in Patients 12-80yrs With Severe Asthma.

Inclusion Criteria at Visit 1 (Screening):

Informed Consent

1. Provision of signed and dated written ICF prior to any mandatory study-specificprocedures, sampling, and analyses for patients who are at or over the age ofmajority (as per local law). For patients who are less than the age of majority, inaddition to providing their informed consent, the patients' legally authorisedrepresentative must also provide their informed assent (Appendix A 3). Age

2. Patients must be 12 to 80 years of age inclusive, at the time of signing the ICF. Type of Patient and Disease Characteristics

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

4. 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 thefollowing:

5. FEV1 > 12% reversibility, OR

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

7. 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

5. ACQ-5 ≥ 1.5 and < 3.

6. History of physician-diagnosed asthma that requires continuous treatment withhigh-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 LABAcan be contained within a combination product or given by separate inhalers. Note: Additional maintenance asthma controller medications (eg, LTRAs, tiotropium,cromone, theophylline) are allowed.

7. Pre-brochodilator FEV1 > 60% predicted and evidence of FEV1 reversibility of > 12%within 6 months prior to screening or at screening. Patients with normal lungfunction (FEV1 > 80%) need evidence of airflow variability as per inclusioncriterion 4.

8. Documented history of at least one asthma exacerbation requiring OCS bursts orrequiring hospitalization within 12 months prior to Visit 1. An asthma exacerbationwill be defined as a worsening of asthma symptoms that leads to any of thefollowing:

9. A temporary bolus/burst of systemic corticosteroids for at least 3 consecutivedays to treat symptoms of asthma worsening; a single depo-injectable dose ofcorticosteroids will be considered equivalent to a 3-day bolus/burst ofsystemic corticosteroids

10. Or, an ER visit (defined as evaluation and treatment for < 24 hours in ER) dueto asthma that required systemic corticosteroids (as per above)

11. Or, an in-patient hospitalisation (defined as admission to an inpatientfacility and/or evaluation and treatment in a healthcare facility for ≥ 24hours). Sex and Contraceptive/Barrier Requirements

12. Male or female. Female patients:

• Contraceptive use by women should be consistent with local regulationsregarding the methods of contraception for those participating in clinicalstudies. Women of nonchildbearing potential are defined as women who are eitherpermanently sterilised (hysterectomy, bilateral oophorectomy, or bilateralsalpingectomy) or who are postmenopausal. Women will be consideredpostmenopausal if they have been amenorrhoeic for 12 months prior to theplanned 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 beenamenorrhoeic for 12 months or more following cessation of exogenoushormonal treatment and follicle-stimulating hormone levels in thepostmenopausal range.

• Women ≥ 50 years old would be considered postmenopausal if they have beenamenorrhoeic for 12 months or more following cessation of all exogenoushormonal treatment.

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

10. WOCBP must be willing to use one of the methods of contraception describedhereafter, from the time of signing the ICF throughout the study and 16 weeks afterlast tezepelumab administration:

• Combined (oestrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation: oral, intravaginal, transdermal

• Progestogen-only hormonal contraception associated with inhibition ofovulation: oral, injectable, implantable

• Intrauterine device

• Intrauterine hormone-releasing system

• Bilateral tubal occlusion

• Vasectomised partner (vasectomised partner is a highly effective birth controlmethod provided that the partner is the sole sexual partner of the WOCBPpatient and that the vasectomised partner has received medical assessment ofthe surgical success)

• Sexual abstinence: it is considered a highly effective method only if definedas refraining from heterosexual intercourse during the entire period of riskassociated with the study treatments. The reliability of sexual abstinenceneeds to be evaluated in relation to the duration of the study and thepreferred and usual lifestyle of the patient.

• Cessation of contraception after this point should be discussed with aresponsible physician Inclusion Criteria 5.1.2 Treatment Induction Phase at Visit 2 (Week 0): Before dosing with tezepelumab at Week 0, patients should fulfil the followingcriteria:

11. ACQ-5 ≥ 1.5 and < 3.

12. Demonstrated proper inhaler technique (patients with improper technique at screeningmay be trained during screening, but must demonstrate proper technique beforeenrollment).

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

Exclusion Criteria:

Medical Conditions

1. Any clinically important pulmonary disease other than asthma (eg, active lunginfection, chronic obstructive pulmonary disease, bronchiectasis, pulmonaryfibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lungcancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) orpulmonary or systemic diseases, other than asthma, that are associated with elevatedperipheral EOS counts (eg, allergic bronchopulmonary aspergillosis/mycosis,Churg-Strauss syndrome, hypereosinophilic syndrome).

2. Any disorder, including, but not limited to, cardiovascular, gastrointestinal,hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic,haematological, psychiatric, or major physical impairment that is not stable in theopinion of the investigator and could:

• Affect the safety of the patient throughout the study

• Influence the findings of the study or the interpretation

• Impede the patient's ability to complete the entire duration of study.

3. A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that hasnot been treated with, or has failed to respond to, standard of care therapy.

4. Current smokers or patients with smoking history ≥ 10 pack-years and patients usingvaping products, including electronic cigarettes. Former smokers with a smokinghistory of < 10 pack-years and users of vaping or e-cigarette products must havestopped for at least 6 months prior to Visit 1 to be eligible.

5. History of chronic alcohol or drug abuse within 12 months prior to Visit 1.

6. Tuberculosis requiring treatment within the 12 months prior to Visit 1.

7. History of known immunodeficiency disorder including a positive humanimmunodeficiency virus test at Visit 1, or the patient taking antiretroviralmedications as determined by medical history and/or patient's verbal report.

8. Major surgery within 8 weeks prior to Visit 1 or planned surgical proceduresrequiring general anaesthesia or inpatient status for > 1 day during the conduct ofthe study.

9. Evidence of COVID-19 within 4 weeks prior to screening or ongoing clinicallysignificant COVID-19 sequelae. Prior/Concomitant Therapy

10. Receipt of any marketed or investigational biologic agent within 4 months or 5half-lives (whichever is longer) prior to Visit 1 or receipt of any investigationalnonbiologic agent within 30 days or 5 half-lives (whichever is longest) prior toVisit 1.

11. OCS-dependent patients (received chronic OCS therapy [prednisone ≥ 5 mg/day orequivalent]) for at least 3 months preceding Visit 1.

12. Daily use of maintenance corticosteroids for any reason.

13. Treatment with systemic immunosuppressive/immunomodulating drugs (eg, methotrexate,cyclosporine, etc.), except for OCS used in the treatment of asthma/asthmaexacerbations, within the last 12 weeks or 5 half-lives (whichever is longer) priorto Visit 1.

14. Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.

15. Receipt of live attenuated vaccines 30 days prior to the date of Visit 1 and duringthe study.

16. Patients that have been treated with bronchial thermoplasty in the last 12 monthsprior to Visit 1. Prior/Concurrent Clinical Study Experience

17. Known history of sensitivity to any component of the tezepelumab formulation or ahistory of drug or other allergy that, in the opinion of the investigator or medicalmonitor, contraindicates their participation.

18. History of anaphylaxis or documented immune complex disease (Type IIIhypersensitivity reactions) following any biologic therapy.

19. Concurrent enrolment in another clinical study involving an IMP. Diagnostic Assessments

20. Any clinically meaningful abnormal finding in physical examination, haematology,clinical chemistry at Visit 1 which, in the opinion of the investigator, may put thepatient at risk because of his/her participation in the study, or may influence theresults of the study, or the patient's ability to complete the entire duration ofthe study.

21. Evidence of active liver disease, including jaundice or AST, ALT, or ALP > 2 timesthe ULN at Visit 1.

22. Positive hepatitis B surface antigen, hepatitis C virus antibody serology atscreening, or a positive medical history for hepatitis B or C. Patients with ahistory of hepatitis B vaccination without a history of hepatitis B are allowed toparticipate. Other Exclusions

23. Involvement in the planning and/or conduct of the study (applies to AstraZenecastaff and/or site staff), or patients employed by or relatives of the employees ofthe site or AstraZeneca.

24. Judgement by the investigator that the patient should not participate in the studyif the patient is unlikely to comply with study procedures, restrictions, andrequirements.

25. For women only: Pregnant, breastfeeding, or lactating women. A serum β-HCG pregnancytest must be drawn for WOCBP at the screening visit. If the results of the serum β-HCG cannot be obtained prior to dosing of the IMP, a patient may be enrolled onthe basis of a negative urine pregnancy test, though serum β-HCG must still beobtained. If either test is positive, the patient should be excluded. Since urineand serum tests may miss a pregnancy in the first days after conception, relevantmenstrual history and sexual history, including methods of contraception, should beconsidered. Any patient whose menstrual and/or sexual history suggests thepossibility of early pregnancy should be excluded.