London, UK – [Insert Date] – A pivotal Phase 3 clinical trial, known as WAYPOINT, has demonstrated that tezepelumab, a novel biologic therapy, significantly improves the sense of smell in adults suffering from uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP). The study, published in the International Forum of Allergy & Rhinology, provides compelling evidence of both early and sustained olfactory recovery, offering a new therapeutic avenue for a debilitating symptom that profoundly impacts patients’ quality of life.

The clinical question at the heart of the WAYPOINT trial was direct: Does tezepelumab improve the loss of smell experienced by adults with uncontrolled CRSwNP? The results emphatically indicate that it does. The study found that tezepelumab not only restored a sense of smell but did so with remarkable speed, with improvements noted as early as seven days into treatment. These gains were not fleeting; they were maintained consistently throughout the 52-week treatment period. Furthermore, the therapy markedly reduced the proportion of patients experiencing anosmia, the complete absence of smell, as defined by objective testing.

Understanding the Devastating Impact of Olfactory Loss in CRSwNP

Loss of smell, medically termed hyposmia or anosmia, is far more than an inconvenience for individuals with CRSwNP. It is a major, often distressing, symptom that erodes fundamental aspects of daily living. The ability to perceive odors is intrinsically linked to the enjoyment of food, a crucial component of social interaction and cultural experience. Its absence can lead to a diminished appetite, weight loss, and a sense of isolation. Beyond gastronomy, smell plays a vital role in safety, alerting individuals to hazards such as gas leaks, spoiled food, or smoke. In the context of CRSwNP, the persistent inflammation and physical obstruction caused by nasal polyps create a challenging environment for olfactory neurons, leading to this significant symptom burden.

The underlying pathophysiology of CRSwNP is complex, but Type 2 inflammation is recognized as a key driver, contributing significantly to olfactory dysfunction. This inflammatory cascade involves various signaling molecules, and it is this upstream pathway that tezepelumab targets. By blocking thymic stromal lymphopoietin (TSLP), an epithelial cytokine that sits at the apex of multiple inflammatory pathways relevant to CRSwNP, tezepelumab aims to dampen the inflammatory response that underlies the disease and its associated symptoms, including the loss of smell.

WAYPOINT Trial: Design and Methodology

The WAYPOINT trial was a rigorously designed Phase 3, multicenter, randomized, double-blind, placebo-controlled study, considered the gold standard for evaluating therapeutic efficacy. The trial enrolled adults diagnosed with uncontrolled CRSwNP, a condition characterized by persistent inflammation in the nasal passages and sinuses, leading to the formation of nasal polyps. These participants were then randomly assigned, in a one-to-one ratio, to receive either tezepelumab at a dose of 210 mg administered subcutaneously every four weeks, or a placebo, for a full year.

The assessment of olfactory function was comprehensive, employing a suite of validated instruments to capture both patient-reported experiences and objective measures. These included:

  • Nasal Polyposis Symptom Diary (NPSD): This daily diary allowed patients to track specific symptoms, including a dedicated item assessing loss of smell. The promptness of symptom changes could be readily identified through daily reporting.
  • University of Pennsylvania Smell Identification Test (UPSIT): A widely recognized psychophysical test designed to assess a patient’s ability to identify common odors. This provided an objective measure of olfactory performance.
  • Sino-Nasal Outcome Test (SNOT-22): A comprehensive quality-of-life questionnaire that includes items specifically addressing loss of smell and taste, providing a broader patient-reported perspective on the impact of the condition.
  • UPSIT-defined anosmia prevalence: This metric specifically tracked the proportion of patients who met the criteria for complete loss of smell based on their UPSIT scores.

The study was conducted across multiple international sites, ensuring a diverse patient population and generalizability of the findings.

Key Findings: A Rapid and Enduring Return of Smell

The analysis of the WAYPOINT trial data encompassed 408 patients, with 203 receiving tezepelumab and 205 receiving placebo. At the commencement of the study, patients presented with severe baseline smell impairment, underscoring the significant unmet need. Mean NPSD loss-of-smell scores were 2.9 in both groups, indicating a substantial deficit. Similarly, baseline UPSIT scores averaged 13.1 for the tezepelumab group and 11.9 for the placebo group, well below the scores indicative of normal olfactory function. Mean SNOT-22 smell/taste item scores also reflected this impairment, standing at 4.7 in both treatment arms.

The impact of tezepelumab on olfactory function became evident remarkably quickly. Improvements in daily NPSD loss-of-smell scores were observed versus placebo beginning as early as day seven, with a least-squares mean difference of -0.08 (nominal P<0.01). This indicates that patients receiving tezepelumab started to report a reduction in their perceived smell loss within the first week of treatment.

By week four, the benefits of tezepelumab were amplified across all measured olfactory endpoints. The drug demonstrated greater improvement than placebo in biweekly NPSD loss-of-smell scores (difference of -0.36), UPSIT scores (a significant difference of 6.03), and SNOT-22 smell/taste item scores (a difference of -1.01). These results point to a tangible restoration of olfactory capacity, both from the patient’s perspective and in objective testing.

Crucially, these improvements were not transient. The positive effects of tezepelumab persisted through the entire 52-week treatment period. At week 52, the treatment differences remained substantial, with -1.01 for NPSD, an impressive 9.50 for UPSIT, and -1.90 for SNOT-22 smell/taste score. While nominal P-values were reported for many of these endpoints, the consistency and magnitude of the differences strongly suggest a clinically meaningful effect.

Perhaps one of the most striking findings was the reduction in anosmia. Among patients with complete UPSIT data, the prevalence of anosmia was dramatically lower in the tezepelumab group compared to the placebo group. At week four, only 43.0% of patients on tezepelumab experienced anosmia, a stark contrast to the 80.3% in the placebo group. This trend continued through week 52, with 31.5% of the tezepelumab group affected by anosmia versus 75.8% in the placebo arm.

Furthermore, the trial observed a notable increase in the proportion of patients achieving normosmia (normal sense of smell). In the tezepelumab group, normosmia increased from 0% at baseline to 10.7% by week 52. While a smaller percentage (2.3%) in the placebo group also regained normal smell, the difference highlights the therapeutic impact of tezepelumab.

Broad Efficacy Across Patient Subgroups

The positive effects of tezepelumab on smell were not confined to a specific segment of the CRSwNP population. The benefits were observed across a range of prespecified subgroups, indicating a robust and consistent therapeutic profile. These subgroups included variations in sex, history of prior nasal polyp surgery, duration of disease, geographic region of treatment, and the presence of comorbidities such as asthma or aspirin-exacerbated respiratory disease (AERD), as well as allergic rhinitis. This broad applicability suggests that tezepelumab could be a valuable treatment option for a wide spectrum of patients with CRSwNP who experience olfactory dysfunction.

Limitations and Future Directions

While the WAYPOINT trial presents highly encouraging results, the researchers acknowledge certain limitations. Some analyses were post hoc, meaning they were conducted after the primary endpoints were determined. Additionally, nominal testing was employed for many of the endpoints, which can increase the chance of false positives. The use of the UPSIT, while a standard tool, primarily assesses odor identification and does not fully capture other aspects of olfactory function, such as olfactory threshold (the minimum concentration of an odor that can be detected) or olfactory discrimination (the ability to distinguish between different odors). Future research may benefit from incorporating a wider array of olfactory assessment tools to provide an even more nuanced understanding of tezepelumab’s effects.

The Evolving Landscape of CRSwNP Treatment

The findings from the WAYPOINT trial are particularly significant in the context of existing treatments for CRSwNP. Loss of olfaction is consistently reported by patients as one of the most distressing and impactful symptoms of their condition. Before the advent of advanced biologic therapies, surgical intervention was often the primary recourse for improving severe olfactory dysfunction, albeit with its own set of risks and limitations.

In recent years, biologic agents targeting Type 2 inflammation have revolutionized CRSwNP management. Dupilumab, another biologic that targets the interleukin-4 receptor alpha (IL-4Rα) subunit, has previously demonstrated significant benefits in improving olfaction in CRSwNP patients, often rivaling the outcomes seen with surgery. Tezepelumab, by targeting the upstream cytokine TSLP, represents a distinct mechanism of action within the Type 2 inflammatory pathway.

The introduction of tezepelumab offers a new and valuable option in the armamentarium available to clinicians treating severe inflammatory sinonasal disease. Its ability to achieve early and sustained improvements in smell, as evidenced by the WAYPOINT trial, addresses a critical unmet need for patients whose quality of life is severely compromised by anosmia.

Broader Implications for Patient Care

The success of tezepelumab in restoring olfactory function has profound implications for the overall management of CRSwNP. Beyond the direct impact on quality of life, improved smell can lead to better nutritional intake, enhanced safety, and a greater sense of normalcy. For patients who have lived with the burden of a diminished or absent sense of smell for years, the prospect of regaining this vital sense can be life-changing.

The data suggests that tezepelumab’s mechanism of action, by targeting TSLP, effectively modulates the inflammatory processes that contribute to olfactory dysfunction in CRSwNP. This provides further validation for a targeted approach to managing this complex disease. As research continues, understanding the specific patient profiles that respond best to tezepelumab, and how it compares in the long term to other available biologic therapies, will be crucial in optimizing treatment strategies.

In conclusion, the WAYPOINT trial marks a significant advancement in the understanding and treatment of olfactory dysfunction in CRSwNP. The early, sustained, and broad-ranging improvements in sense of smell observed with tezepelumab offer renewed hope for patients living with this challenging condition, highlighting the growing power of targeted biologic therapies in restoring vital sensory function and improving overall well-being.

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.