Early and Sustained Improvements in Sense of Smell with Tezepelumab Treatment in Patients with CRSwNP (WAYPOINT)

CLINICAL QUESTION

Does tezepelumab improve loss of smell in adults with uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP)?

BOTTOM LINE

In WAYPOINT, tezepelumab produced early and sustained improvements in patient-reported and objective smell outcomes compared with placebo, with differences evident by day seven on daily symptom diary scores and maintained through 52 weeks. Tezepelumab also markedly reduced the proportion of patients with UPSIT-defined anosmia.

BACKGROUND: Loss of smell is a major symptom of CRSwNP and affects quality of life, food enjoyment, social functioning, and safety. Type 2 inflammation contributes to olfactory dysfunction in CRSwNP. Tezepelumab blocks thymic stromal lymphopoietin (TSLP), an upstream epithelial cytokine involved in multiple inflammatory pathways relevant to CRSwNP.

STUDY DESIGN: Phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Adults with uncontrolled CRSwNP were randomized one-to-one to tezepelumab 210 mg or placebo subcutaneously every four weeks for 52 weeks. Smell outcomes included the Nasal Polyposis Symptom Diary (NPSD) loss-of-smell item, University of Pennsylvania Smell Identification Test (UPSIT), Sino-Nasal Outcome Test (SNOT-22) loss-of-smell/taste item, and UPSIT-defined anosmia prevalence.

SETTING: International multicenter clinical trial of adults with uncontrolled CRSwNP

SYNOPSIS: The analysis included 408 patients: 203 assigned to tezepelumab and 205 to placebo. Baseline smell impairment was severe, with mean NPSD loss-of-smell scores of 2.9 in both groups, mean UPSIT scores of 13.1 with tezepelumab and 11.9 with placebo, and mean SNOT-22 smell/taste item scores of 4.7 in both groups.

Tezepelumab improved daily NPSD loss-of-smell scores versus placebo beginning on day seven (least-squares mean difference, −0.08; nominal P<0.01). By week four, tezepelumab showed greater improvement than placebo in biweekly NPSD loss-of-smell score (difference, −0.36), UPSIT score (difference, 6.03), and SNOT-22 smell/taste item score (difference, −1.01). These effects persisted through week 52, with treatment differences of −1.01 for NPSD, 9.50 for UPSIT, and −1.90 for SNOT-22 smell/taste score; all reported P-values were nominal.

Among patients with complete UPSIT data, anosmia prevalence was lower with tezepelumab than placebo at week four (43.0% versus 80.3%) and week 52 (31.5% versus 75.8%). Normosmia increased from 0% at baseline to 10.7% through week 52 in the tezepelumab group, compared with 2.3% in the placebo group.

Benefits were observed across prespecified subgroups, including sex, prior nasal polyp surgery, disease duration, geographic region, asthma/aspirin-exacerbated respiratory disease status, and allergic rhinitis. Limitations include post hoc analyses, nominal testing for many endpoints, and use of UPSIT, which assesses odor identification but not olfactory threshold or discrimination.

CITATION: Mullol J, et al. Early and sustained improvements in sense of smell with tezepelumab treatment in patients with chronic rhinosinusitis with nasal polyps (WAYPOINT). Int Forum Allergy Rhinol. 2026;16:484-494. doi:10.1002/alr.70090.

COMMENT: Loss of olfaction is one of the most troubling symptoms for patients suffering from CRSwNP. This is thought to occur not only due to the obstruction caused by the presence of polyps but also due to inflammation in the epithelium itself. Before the approval of tezepelumab for CRSwNP, dupilumab appeared to provide the greatest benefit for improvement in olfaction for patients with CRSwNP, rivaling surgery. Tezepelumab is a relatively new agent targeting TSLP. This study evaluated olfactory outcomes in the pivotal WAYPOINT trial and similarly found significant improvements in olfaction for patients on tezepelumab, offering another option in the armamentarium to improve this critical sense for these patients with severe inflammatory disease.—Ashoke Khanwalkar, MD