The study explores how chronic rhinosinusitis (CRS) and asthma share a common inflammatory process, particularly affecting patients with both conditions. Interaction between immune cells (Interleukins) and Th2 cytokines, such as TSLP, exacerbates asthma control in CRS patients, especially those with nasal polyps (CRSwNP). TSLP plays a pivotal role in initiating and maintaining airway inflammation in both diseases. Tezepelumab, a biologic therapy targeting TSLP, shows promise in reducing inflammation markers in severe asthma but its impact on CRSwNP and quality of life remains unclear. The study proposes investigating Tezepelumab's efficacy in treating CRSwNP and severe asthma to inform future biologic therapies.

The investigators hypothesize that TSLP blockade with Tezepelumab will a) reduce upper airway inflammation based on histological, inflammatory, and remodeling biomarkers, that are evident in the airway remodeling process and b) correlate to a positive clinical response. Thus, nasal samples from chronic rhinosinusitis with nasal polyps (CRSwNP) patients with Severe Asthma (SA) pre- and post-treatment will exhibit inflammatory biomarkers and histopathological evidence that could prove responsive to the Tezepelumab.

The overall research objectives are to evaluate the effect of study intervention (Tezepelumab) on CRSwNP-SA outcomes through a) evaluating the sinonasal inflammatory profile, histopathological features, and remodeling biomarkers and b) investigating the impact of Tezepelumab on the CRSwNP-related clinical outcomes in the treated study subjects.

Inclusion Criteria:

• Must be ≥19 of age at the time of signing the informed consent form

• Capable of giving signed informed consent.

• Having CRSwNP based on clinical symptoms and/or radiographic or endoscopic evidence of inflammation in their upper airways (Diagnosis consistent with EPOS 2020)(2)and severe asthma:

  • SA based on GINA criteria (37) and confirmed with spirometry and assessmenton the previous history of asthma (a pre-post bronchodilator spirometry ormethacholine challenge to document the positive or negative history of asthmawill be performed if there is no clinical record).
  • Nasal polyp score (NPS) of at least 2 on each side

• Females of childbearing potential must commit using an acceptable method of birthcontrol for the duration of the study and they must have a negative urine pregnancy test ateach study visit

• Not expecting to have surgery within the next 7 months

Exclusion Criteria:

• Have previously undergone sinus surgery or nasal polypectomy

• A history of organ transplantation such as lung transplantation

• Previously or currently using immunomodulator medications or antihistamines

• A history of auto-immune diseases

• Current or past sinonasal or bronchial tumors

• Currently using systemic or oral corticosteroids

• Women who are pregnant, plan to become pregnant, or breastfeed during the trial

• Current participation in any other interventional treatment trials

• Compliance: is unlikely to comply with study visits based on investigator judgment:

• Diagnosed or suspected malignant or premalignant nasal disease (e.g. SchniderianPapilloma, unilateral nasal polyposis)

• Fungal rhinosinusitis (CT/Histology), positive Aspergillus skin prick testing and/orpositive Aspergillus IgE RAST (Radioallergosorbent) testing

• Malignant neoplasm within 5 years (from screening) excluding basal cell or squamouscell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterinecervix treated locally and without metastatic disease for 3 years.

• Active bleeding disorders, and/or inability to support interruption to anticoagulant or anti-platelet therapies for nasal biopsy.

• Severe nasal deformity precluding endoscopic assessment/biopsy of postnasal space

• Have an acute or chronic infection (excluding that related to CRS) requiring managementas follows:

  • Currently on any treatment for a chronic infection such as pneumocystis,cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria
  • Hospitalisation solely for the treatment of proven infection requiring parenteral (IV orIM) antibiotics (antibacterial, antiviral, antifungal, or anti-parasitic agents) within 60days of Day 1
  • Proven severe infection requiring outpatient treatment with parenteral (IV or IM)antibiotics (antibacterial, antiviral, antifungal, or anti-parasitic agents) within 60 daysof Day 1. Prophylactic anti-infective treatment is allowed.

• Known positive human immunodeficiency virus (HIV) status

• Known positive Hepatitis B (HB) or Hepatitis C status

• Have clinical evidence of significant unstable or uncontrolled acute or chronic diseaseswhich, in the opinion of the principal investigator, could confound the results of the study orput the participant at undue risk

• Have a planned surgical procedure, laboratory abnormality, or condition that, in theopinion of the principal investigator, makes the participant unsuitable for the study.

• Have received any investigational agent (that is not approved for sale in Canada) within60 days of Day 1

• Smoking history; current or former smokers with a smoke history of packs year >15

• Subjects with parasitic (helminthic) infection

• Subjects with hypersensitivity; with allergy/intolerance to a monoclonal antibody or biologics

• Subjects allergic to Aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs)