This study will evaluate the efficacy and safety of depemokimab (GSK3511294) without concomitant use of Intranasal corticosteroids (INCS) in participants with Chronic rhinosinusitis with nasal polyps (CRSwNP).

Inclusion Criteria:

• 18 years of age and older inclusive, at the time of signing the informed consent
• Endoscopic bilateral NP score of at least 5 out of a maximum score of 8 (with a minimum score of 2 in each nasal cavity) assessed by the investigator
• Participants who have had previous nasal surgery for the removal of nasal polyps, have used at least three consecutive days of systemic corticosteroids in the previous 2 years for the treatment of nasal polyps, or are medically unsuitable or intolerant to systemic corticosteroid
• Participants presenting with severe nasal polyp symptoms defined as symptoms of nasal congestion/blockade/obstruction with moderate or severe severity and loss of smell or rhinorrhoea (runny nose) based on clinical assessment by the investigator
• Presence of symptoms of chronic rhinosinusitis as described by at least 2 different symptoms for at least 12 weeks prior to Visit 1, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), or facial pain/pressure and/or reduction or loss of smell
• Male or eligible female participants

Exclusion Criteria:

• As a result of medical interview, physical examination, or screening investigation the physician responsible considers the participant unfit for the study
• Cystic fibrosis
• Antrochoanal polyps
• Nasal cavity tumor (malignant or benign)
• Fungal rhinosinusitis
• Severe nasal septal deviation occluding one nostril preventing full assessment of nasal polyps in both nostrils
• Participants who had a sino-nasal or sinus surgery changing the lateral wall structure of the nose making impossible the evaluation of nasal polyp score
• Acute sinusitis or URTI at screening or in 2 weeks prior to screening
• Ongoing rhinitis medicamentosa (rebound or chemical induced rhinitis)
• Participants who have had an asthma exacerbation requiring admission to hospital within 4 weeks of screening
• Participants who have undergone any intranasal and/or sinus surgery (for example polypectomy, balloon dilatation or nasal stent insertion) within 6 months prior to Visit 1; nasal biopsy prior to Visit 1 for diagnostic purposes only is excepted.
• Participants where NP surgery is contraindicated in the opinion of the Investigator
• Participants with other conditions that could lead to elevated eosinophils such as hyper-eosinophilic syndromes including (but not limited to) Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly known as Churg-Strauss Syndrome) or Eosinophilic Esophagitis
• Participants with a known, pre-existing parasitic infestation within 6 months prior to Visit 1
• A known immunodeficiency (e.g., human immunodeficiency virus - HIV), other than that explained by the use of corticosteroids (CSs) taken as therapy for asthma
• A current malignancy or previous history of cancer in remission for less than 12 months prior to screening.NOTE: Participants that had localised carcinoma of the skin which was resected for cure will not be excluded
• Participants who have known, pre-existing, clinically significant cardiac, endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, hematological or any other system abnormalities that are uncontrolled with standard treatment
• Participants with current diagnosis of vasculitis. Participants with high clinical suspicion of vasculitis at screening will be evaluated and current vasculitis must be excluded prior to enrolment
• Participants with allergy/intolerance to the excipients of depemokimab, a monoclonal antibody, or biologic
• Participants that have been exposed to ionizing radiation in excess of 10 millisievert (mSv) above background over the previous 3-year period as a result of occupational exposure or previous participation in research studies
• Participants using INCS (including intranasal liquid steroid wash/douching) for at least 8 weeks immediately prior to screening
• Participants on inhaled corticosteroids exhalation through nose (Inhaled corticosteroids exhalation through nose [ICS/ETN]) method of administration for their asthma and NP for at least the 8 weeks immediately prior to screening
• Participants who have received depemokimab (Exdensur), mepolizumab (Nucala), reslizumab (Cinqair/Cinqaero), or benralizumab (Fasenra) within 12 months prior to Visit 1 or experienced treatment failure with monoclonal antibodies targeting IL-5/5R
• Participants who have received omalizumab (Xolair), dupilumab (Dupixent) or Tezpelumab (Tezpire) within 130 days prior to Visit 1
• Previously participated in any study with depemokimab, mepolizumab, reslizumab, or benralizumab and received study intervention (including placebo) within 12 months prior to Visit 1
• Women who are pregnant or lactating or are planning on becoming pregnant during the study
• ALT >2* ULN
• Total bilirubin >1.5* ULN; For participants with Gilbert's syndrome can be included with total bilirubin >1.5* ULN if direct bilirubin is <=1.5* ULN
• Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice

Study Sponsor will assess requests from qualified researchers for anonymized individual patient-level data and related study documents. Data sharing is subject to certain criteria, conditions, and exceptions. For further information, refer to https://www.gsk-studyregister.com/gsk-patient-level-data-sharing-july2025.pdf

Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or asset(s) with development terminated across all indications.

Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months, but an extension may be granted, when justified, for up to 6 months.