The primary purpose of the study is to evaluate the efficacy of brensocatib at 10 and 40 milligrams (mg) once daily (QD) compared with placebo in improving clinical symptoms of CRSsNP.

Inclusion Criteria:

• Participants who have at least a 12-week history before Screening Visit of CRSsNP and confirmed by endoscopy at Visit 1 (Screening).

• Participants must have a NCS of ≥2 at Visit 1 (Screening Visit) and Visit 2 (Baseline; average score in the week prior to randomization).

• Participants must have sTSS (nasal congestion [NC], anterior/posterior rhinorrhea, facial pain/pressure) ≥5 at Visit 1 (Screening) and at Visit 2 (Baseline; average score in the week prior to randomization).

• Participants who have at least 1 of the 3 following features:

  1. Previous sinonasal surgery for CRS, including but not limited to fenestrated endoscopic sinus surgery and balloon sinuplasty.
  2. Received medical treatment with systemic corticosteroids (SCS) to treat symptoms of CRS as defined by any dose and duration within 1 year of Screening Visit or intolerance/contraindication to SCS.
  3. Received a course of antibiotics to treat symptoms of CRS within 1 year before the Screening Visit.

• Participants who have a blood eosinophil count ≤750 cells/microliter (μL) at Visit 1 (Screening).

• Participants who have bilateral inflammation of paranasal sinuses in the CT scan performed during Screening and bilateral ethmoid and/or maxillary opacification before randomization as confirmed by the central reader.

• Participants who have a SNOT-22 score of ≥20 at Visit 1 (Screening) and Visit 2 (Baseline).

• Participants who have received a stable daily dose regimen of MFNS for at least 4 weeks before Visit 2 (Baseline).

Exclusion Criteria:

• Diagnosis of unilateral or bilateral chronic rhinosinusitis with nasal polyps (CRSwNP).
• Clinical diagnosis of cystic fibrosis (CF) or primary ciliary dyskinesia.
• Scheduled sinus surgery at any time during the study.
• Participants who have had nasal surgery within 4 weeks before Visit 1 (Screening) and during the Screening Period.
• Significant oral maxillofacial structural abnormalities or severe septal deviation.
• Participants with radiological suspicion or confirmed invasive fungal rhinosinusitis, odontogenic sinusitis, osteomas, or nasal tumors.
• Participants with acute change in symptoms consistent with acute rhinosinusitis.
• Participants with seasonal allergic rhinitis whose symptoms coincide with the treatment period of the study.
• Participants with moderate to severe atopic dermatitis requiring treatment with high potency topical steroids or topical calcineurin inhibitors or biologics.
• Clinical diagnosis of Papillon-Lefèvre syndrome.

Note: Other inclusion/exclusion criteria may apply.