Inclusion Criteria:
* Age
1\. Participant must be 18 years of age or older, at the time of signing the informed consent.
* Type of Participant and Disease Characteristics 2. Participants who are with physician-diagnosed CRSwNP for at least 12 months prior to Visit 1 who have all of the following:
* Severity consistent with the need for surgery as defined by total NPS ≥ 4 (at least 2 for each nostril) at screening, as determined by the central reader
* Mean NCS ≥ 2 in the 2 weeks prior to Visit 2
* Ongoing documented NP symptoms for \> 8 weeks prior to screening such as rhinorrhoea, reduction or loss of smell and/or poor quality/loss of sleep
* SNOT-22 total score ≥ 30 as assessed at screening. 3. Any standard of care for treatment of CRSwNP, which must include treatment with intranasal corticosteroids, provided the participant is stable on that treatment for at least 30 days prior to Visit 1. Investigators should also ensure that participants are compliant and on a stable dose of the background INCS during study period.
4\. Either 1) documented treatment of NP exacerbation with SCS for at least 3 consecutive days or one IM depo-injectable dose (or contraindications/intolerance or intolerance to surgery) within the past 12 months prior to Visit 1 but not within the last 3 months prior to Visit 1 OR 2) any history of NP surgery (or contraindications/intolerance or intolerance to surgery).
5\. Participants with JESREC score of ≥ 11.
* Weight 6. Body weight of ≥ 40 kg at Visit 1.
* Sex and Contraceptive/Barrier Requirements 7. Male and/or female
Female participants:
* Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Women of non-childbearing 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 first tezepelumab administration 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 FSH levels within 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.
* 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 participant 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 participant.
* Cessation of contraception after this point should be discussed with a responsible physician.
* Informed Consent 8. Provision of signed and dated written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:
-Medical Conditions
1. Participants with documented allergic fungal rhinosinusitis and/or central compartment atopic disease.
2. Any clinically important pulmonary disease other than asthma (eg, active lung infection, bronchiectasis, pulmonary fibrosis, cystic fibrosis, primary ciliary dyskinesia, allergic bronchopulmonary mycosis, hypereosinophilic syndromes, etc) that could confound interpretation of clinical CRSwNP endpoints results.
3. 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 the opinion of the investigator and could:
* Affect the safety of the participant throughout the study
* Influence the findings of the study or the interpretation
* Impede the participant's ability to complete the entire duration of study
4. Sinus surgery within 6 months of screening visit OR any sinus surgery in the past which changed the lateral wall of the nose making NPS evaluation impossible.
5. Participants with conditions or concomitant disease that makes them non-evaluable for the primary CRSwNP endpoints such as:
* Antrochoanal polyps
* Nasal septal deviation that occludes at least one nostril
* Acute sinusitis, nasal infection, asthma exacerbation or upper respiratory infection at screening or in the two weeks before screening, or Churg-Strauss syndrome (also known as eosinophilic granulomatosis with polyangiitis), Young's syndrome or Kartagener's syndrome
6. History of cancer:
* Participants who have had basal cell carcinoma, localised squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible to participate in the study provided that curative therapy was completed at least 12 months prior to Visit 1
* Participants who have had other malignancies are eligible provided that curative therapy was completed at least 5 years prior to Visit 1
7. Uncontrolled epistaxis within 2 months of Visit 1.
8. A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that has not been treated with, or has failed to respond to, standard of care therapy.
9. For participants with comorbid asthma: Current smokers or participants with a smoking history \> 10 packs per year and participants using vaping products, including electronic cigarettes. Former smokers with a smoking history of \< 10 packs per year and users of vaping or e-cigarette products must have stopped for at least 6 months prior to Visit 1 to be eligible.
10. History of chronic alcohol or drug abuse within 12 months prior to Visit 1.
11. Tuberculosis requiring treatment within the 12 months prior to Visit 1. Particpiants who in the opinion of the investigator have evidence of active tuberculosis (TB), either treated or untreated, or latent TB without completion of an appropriate course of treatment or appropriate ongoing prophylactic treatment. Evaluation will be according to the local standard of care as determined by local guidelines and may consist of medical history and physical examinations, chest x-ray, sputum stain and/or culture, and/or TB test (eg, purified protein derivative or QuantiFeron test).
12. Major surgery within 8 weeks prior to Visit 1 or planned NP surgery or planned surgical procedures requiring general anaesthesia or inpatient status for more than 1 day during the conduct of the study.
13. History of known immunodeficiency disorder including a positive HIV test at Visit 1, or the participant taking antiretroviral medications as determined by medical history and/or participant's verbal report.
14. Infection requiring systemic antibiotics within 14 days prior to Visit 1. Note: Participants with respiratory infections requiring antibiotics within 14 days prior to Visit 1 may extend their screening period to allow recovery and return no sooner than 14 days after completion of therapy.
-Prior/Concomitant Therapy
15. Receipt of any marketed or investigational biologic agent within 4 months or 5 half-lives (whichever is longer) prior to Visit 1 or receipt of any investigational non-biologic agent within 30 days or 5 half-lives (whichever is longer) prior to Visit 1.
16. Treatment with systemic immunosuppressive/immunomodulating drugs (eg, methotrexate, cyclosporine, etc.), except for SCS used in the treatment of asthma/asthma exacerbations, within the last 12 weeks or 5 half-lives (whichever is longer) prior to Visit 1.
17. Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.
18. Receipt of live attenuated vaccines 30 days prior to the date of Visit 1 and during the study including the follow-up period.
19. Known history of sensitivity to any component of the tezepelumab formulation or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.
20. History of anaphylaxis or documented immune complex disease (Type III hypersensitivity reactions) following any biologic therapy.
21. Regular use of decongestants (topical or systemic) from Visit 1 onward is not allowed unless used for endoscopic procedure.
22. Use of corticosteroid-eluting intranasal stents within 6 months prior to Visit 1 and during the study period.
23. Recent aspirin desensitisation within 6 months of enrolment.
-Prior/Concurrent Clinical Study Experience
24. Concurrent enrolment in another clinical study involving a study intervention.
-Diagnostic Assessments
25. Any clinically meaningful abnormal finding in physical examination, haematology, or clinical chemistry at Visit 1 which, in the opinion of the investigator, may put the participant at risk because of his/her participation in the study, or may influence the results of the study, or the participant's ability to complete the entire duration of the study.
26. Evidence of active liver disease, including jaundice or AST, ALT, or ALP \> 2 times ULN at Visit 1.
27. Positive hepatitis B surface antigen, or hepatitis C antibody serology at screening, or a positive medical history for hepatitis B or C. Participants with a history of hepatitis B vaccination without a history of hepatitis B are allowed to participate.
-Other Exclusions
28. Participants with JESREC score of \<11
29. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site), or participants employed by or relatives of the relatives of the employees of the site or sponsor.
30. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
31. For women only: Pregnant, breastfeeding, or lactating women. A serum β-HCG pregnancy test 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 tezepelumab, a participant may be enrolled on the basis of a negative urine pregnancy test, though serum β-HCG must still be obtained. If either test is positive, the participant should be excluded. Since urine and serum tests may miss a pregnancy in the first days after conception, relevant menstrual history and sexual history, including methods of contraception, should be considered. Any participant whose menstrual and/or sexual history suggests the possibility of early pregnancy should be excluded.
