Introduction: Tezepelumab significantly reduced nasal polyp size and improved nasal congestion severity and other sino-nasal symptoms versus placebo in adults with severe, uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) after 52 weeks in the WAYPOINT study (NCT04851964). This prespecified secondary analysis evaluated the onset of action and duration of the treatment response in WAYPOINT. Methods: Eligible adults were randomised (1:1) to tezepelumab 210 mg or placebo subcutaneously every 4 weeks (Q4W) for 52 weeks. Endoscopic total nasal polyp score (NPS) was assessed post-baseline at weeks 4, 12, 24, 36 and 52. Biweekly mean nasal congestion score (NCS), loss of smell score and total symptom score (TSS) were calculated using daily entries from the patient-reported Nasal Polyposis Symptom Diary (NPSD); scores assessed post-baseline at weeks 2 and 4, then Q2W. Sino-Nasal Outcome Test (SNOT)-22 total score was assessed post-baseline Q4W. Smell was evaluated post-baseline using the University of Pennsylvania Smell Identification Test (UPSIT) at weeks 4, 12, 24, 36 and 52. Results: Patients received tezepelumab (n=203) or placebo (n=205). Improvements from baseline in NPS, NCS, NPSD scores, SNOT-22 total score and UPSIT score were observed with tezepelumab versus placebo from the first post-baseline assessment after initiation of tezepelumab (at week 2 or week 4) and were sustained until the end-of-study treatment (week 52). Conclusions: Rapid improvements versus placebo in nasal polyp size, nasal congestion severity, loss of smell and other sino-nasal symptoms were observed within the first 2–4 weeks of tezepelumab treatment (after one dose) and continuously improved throughout treatment. *This abstract was previously presented at European Rhinologic Society (ERS), 22–25 June 2025.