Efficacy of Tezepelumab on Upper and Lower Airway Outcomes in Adults With Severe, Uncontrolled Chronic Rhinosinusitis With Nasal Polyps in Patients With and Without Comorbid Asthma: Results from the Phase 3 Waypoint Study

Abstract Rationale: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with a high symptom burden and poor health-related quality of life. Comorbid respiratory diseases are common and contribute to disease severity in patients with CRSwNP. Tezepelumab, a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP), significantly reduced NP size and improved patient-reported sino-nasal symptoms versus placebo in adults with CRSwNP in the WAYPOINT study (NCT04851964). This analysis evaluated the efficacy of tezepelumab in patients with severe, uncontrolled CRSwNP and comorbid asthma. Methods: WAYPOINT was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible adults (aged ≥18 years) with severe CRSwNP were randomized (1:1) to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Randomization was monitored to ensure that 50-70% of patients had comorbid asthma based on medical history; asthma diagnosis was not confirmed through study procedures. The co-primary endpoints were changes from baseline in total nasal polyp score (NPS) and biweekly mean nasal congestion score (NCS) at week 52. Prespecified subgroup analyses in patients with comorbid asthma assessed NPS and NCS, pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1; key secondary endpoint) and Asthma Control Questionnaire-6 (ACQ-6) score (secondary endpoint) at week 52. Results: Patients received tezepelumab (n=203) or placebo (n=205). Among patients with comorbid asthma (tezepelumab, n=122; placebo, n=126), at baseline, the mean (SD) pre-BD FEV1 was 2.89 (0.89) L, equating to 85.8% (16.4) of the predicted normal value, and the mean (SD) ACQ-6 score was 1.82 (1.16). At week 52, tezepelumab improved the total NPS in patients with comorbid asthma (LS mean difference versus placebo [95% CI]: −2.21 [−2.63, −1.80]) and without comorbid asthma (−1.84 [−2.35, −1.33]). Tezepelumab improved NCS at week 52 in patients with comorbid asthma (LS mean difference versus placebo [95% CI]: −1.13 [−1.35, −0.91]) and in those without (−0.87 [−1.15, −0.59]) comorbid asthma. Among patients with comorbid asthma, pre-BD FEV1 remained stable to week 52, with no significant differences between groups at week 52, and ACQ-6 score improved with tezepelumab versus placebo at week 52 (Table). In the overall population, asthma exacerbations were more frequently reported with placebo than tezepelumab (5.9% vs 0.5%). Conclusions: Tezepelumab significantly reduced upper airway symptoms, including NP size, and improved patient-reported nasal congestion versus placebo in adults with severe CRSwNP with and without comorbid asthma. Among those with comorbid asthma, tezepelumab simultaneously improved asthma control, which indicates an effect on lower airway symptoms.