Reply to: Malik MMUD on Early and Sustained Improvements in Sense of Smell With Tezepelumab Treatment in Patients With Chronic Rhinosinusitis With Nasal Polyps (WAYPOINT)

1.

To the Editor:

We thank Professor MMUD Malik [1] for his interest in our recent publication describing the improvements in loss of smell symptoms with tezepelumab versus placebo in patients with uncontrolled chronic rhinosinusitis with nasal polyps in the WAYPOINT trial (NCT04851964) [2]. We appreciate Professor Malik's comments on the language used to describe the findings and the specific analyses presented as well as his note regarding the consistent improvements in sense of smell observed with tezepelumab treatment versus placebo, demonstrated by large effect sizes across three instruments.

Malik is correct that nominal, unadjusted p‐values are presented for nonprimary endpoint analyses. This approach is outlined in the methods section: “all p‐values reported for the secondary, exploratory, and post hoc endpoints in the present study are nominal and are not multiplicity protected.” The abstract also states that p‐values are nominal.

Regarding the anosmia prevalence analysis, this was a descriptive summary with no imputations involved. Malik is correct that the completer analysis was based on the subset of patients who had complete data at every time point. As Malik notes, the dropout and rescue therapy rates differed between treatment arms, with a greater dropout rate and missing data in the placebo arm. However, likely because of the increased dropout rate due to rescue therapy in the placebo arm, this completer analysis does not exaggerate the true between‐group contrast as Malik suggests: in fact, it may underestimate it. As a specific example, in the main completer analysis, 10.7% versus 2.3% of patients had normosmia at Week 52 in the tezepelumab and placebo groups, respectively (a 4.7‐fold relative difference), compared with 8.4% versus 1.5% for the full analysis set (a 5.6‐fold relative difference); this demonstrates a greater fold‐difference in the full analysis set than in the completer analysis. In this case, the completer analysis result is biased against tezepelumab. We selected the completer analysis for inclusion as a primary figure because it was felt to be more clinically relevant, and we included the full analysis set as a supplemental analysis for completeness. Both are available to enable readers to fully understand the analyses and results (refer to Figures 1 and S1 from Mullol et al. [2]). The most important result is that both analyses demonstrated consistent and similar findings that the proportion of patients with anosmia was lower in the tezepelumab group than in the placebo group, with differences starting at Week 4 and continuing through Week 52.

Finally, to Malik's point regarding the effect size at Day 7, the manuscript states that between‐group differences for post hoc endpoints are based on descriptive, nominal statistical significance, with specific reference to the minimal clinically important difference threshold of 1.0 point for the Nasal Polyposis Symptom Diary loss of smell item score in the methods section. The wording in the concluding section of “with improvements observed from as early as Day 7” does not suggest that this early statistical observation was clinically meaningful. This wording is similar to that used in the publication of the SINUS‐24 and SINUS‐25 trials, which similarly noted the first day in which a nominally statistically significant difference was observed [3].

In conclusion, we thank Professor Malik for his thoughtful commentary and emphasize that the early and sustained improvements in sense of smell with tezepelumab described in the manuscript are based on strong and consistent signals across three instruments interpreted within the outlined statistical approaches and limitations.

Funding

This study was funded by AstraZeneca and Amgen Inc.

Conflicts of Interest

Joaquim Mullol is or has been a member of national and international scientific advisory boards for, has consulted for, and has received fees for lectures and grants for research projects or clinical trials from Almirall, AstraZeneca, Genentech‐Roche, GSK, LETI Pharma, Lilly, Menarini Group, Mitsubishi Tanabe Pharma, MSD, Noucor/Uriach Group, Novartis, OptiNose, Procter & Gamble, Regeneron Pharmaceuticals, Sanofi Genzyme, UCB, and Viatris/MEDA Pharmaceuticals. Joseph K. Han has received consultancy fees from AstraZeneca, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, and Sanofi Genzyme. Tanya M. Laidlaw has served on scientific advisory boards for AstraZeneca, GSK, Lilly, Regeneron Pharmaceuticals, and Sanofi; and has received research support from Regeneron Pharmaceuticals and Sanofi. Claire Hopkins has participated in advisory boards for AstraZeneca, GSK, Lilly, and Sanofi Genzyme. Anju T. Peters has received fees for sponsored research from Areteia Therapeutics, AstraZeneca, Insmed, Lilly, and Sanofi Regeneron; and has received consultancy fees from AstraZeneca, Chiesi, Insmed, GSK, Lilly, Novartis, and Sanofi Regeneron. Oliver Pfaar has received grants from AstraZeneca for his institution as a trial site for the reported study; and he reports grants and/or personal fees and/or travel support from AEDA, Alfried Krupp Krankenhaus, ALK‐Abelló, Allergopharma, Almirall, Altamira Therapeutics, ASIT Biotech, AstraZeneca, Bencard Allergie GmbH/Allergy Therapeutics, Biologixpharma, Blueprint, Breazy Health, Cliantha, Deutsche AllergieLiga e.V., Cogitando GmbH/Medcram, Deutsche Forschungsgemeinschaft, Dustri‐Verlag, ECM Expro & Conference Management GmbH, Forum für Medizinische Fortbildung, Georg‐Thieme‐Verlag, GSK, HAL Allergy Holding B.V./HAL Allergie GmbH, Inmunotek, Ingress Health, Institut für Disease Management, IQVIA Commercial, Japanese Society of Allergology, Königlich Dänisches Generalkonsulat, Laboratorios LETI/LETI Pharma, Lilly, Lofarma, Medizinische Hochschule Hannover, med update europe GmbH, Meinhardt Congress GmbH, Novartis, Paul‐Ehrlich‐Institut, Paul‐Martini‐Stiftung, PneumoLive, Pohl‐Boskamp, Procter & Gamble, Red Maple Trials Inc., Regeneron Pharmaceuticals, RG Aerztefortbildung, ROXALL Medizin, Sanofi Aventis, Sanofi Genzyme, Springer Publisher, Stallergenes Greer, streamedup! GmbH, Technical University Dresden, John Wiley & Sons Publishers, Wort & Bild Verlag, Verlag ME, and the Gemeinnütziger Verein zur Förderung der Allergiefortbildung (VFAF), all outside the submitted work; Oliver Pfaar is a member of the external board of directors of the German Society of Allergy and Clinical Immunology (DGAKI); coordinator, main‐ or co‐author of different position papers and guidelines in rhinology, allergology, and allergen‐immunotherapy; and is Editor‐in‐Chief of Clinical Translational Allergy. Martin Desrosiers has received grants and speaker fees from AstraZeneca, GSK, Regeneron Pharmaceuticals, and Sanofi; has received consultancy fees from Boehringer Ingelheim and Insmed; and is an equity holder with Probionase Therapies Inc. Stella E. Lee has received fees for consultancy from AstraZeneca, Genentech, GSK, Lyra Therapeutics, Novartis, Regeneron Pharmaceuticals, and Sanofi Genzyme. Andrew P. Lane has served on scientific advisory boards for Regeneron Pharmaceuticals and Sanofi; and has served as a principal investigator for a study sponsored by Insmed. Claudia Chen, Sandhia S. Ponnarambil, Andrew Foster, and Christopher S. Ambrose are employees of AstraZeneca and may own stock or stock options in AstraZeneca. Yun Chon and Andrew W. Lindsley are employees of Amgen and own stock in Amgen.