Highlights
The WAYFINDER trial provides critical evidence for the use of tezepelumab in reducing systemic steroid exposure in patients with severe asthma. Key findings include:
- Approximately 90% of patients achieved a maintenance oral corticosteroid (OCS) dose of 5 mg per day or less by week 52.
- Complete OCS discontinuation was achieved by 50.3% of participants at one year, representing a significant milestone in asthma management.
- Efficacy in OCS reduction was observed across all patient subgroups, independent of baseline blood eosinophil counts (BEC), fractional exhaled nitric oxide (FeNO), or allergy status.
- The safety profile remained consistent with previous tezepelumab trials, with no new safety signals identified despite the tapering of systemic steroids.
The Clinical Challenge of OCS-Dependent Asthma
For decades, oral corticosteroids (OCS) have served as a cornerstone for managing severe, uncontrolled asthma. However, this reliance comes at a high price. Chronic systemic glucocorticoid exposure is associated with a litany of iatrogenic morbidities, including adrenal insufficiency, osteoporosis, Type 2 diabetes, cardiovascular disease, and psychiatric disturbances. Despite the advent of several biologic therapies targeting Type 2 (T2) inflammation, a substantial cohort of patients remains “steroid-dependent” to maintain symptom control and prevent life-threatening exacerbations.
The challenge for clinicians has been identifying a therapeutic intervention that allows for aggressive OCS tapering without compromising asthma control. Previous studies, such as the SOURCE trial, suggested that tezepelumab—a human monoclonal antibody that inhibits thymic stromal lymphopoietin (TSLP)—could facilitate OCS reduction. However, the SOURCE trial highlighted the need for larger, real-world-representative cohorts to confirm whether these effects were sustained and broad-based across different inflammatory phenotypes.
The WAYFINDER Trial: Study Design and Objectives
WAYFINDER was a phase 3b, multicentre, single-arm, open-label study designed to evaluate the OCS-sparing potential of tezepelumab in a pragmatic clinical setting. The trial enrolled 298 adults (mean age 53.6 years) with severe, uncontrolled asthma who were receiving a maintenance OCS dose of 5–40 mg per day of prednisone or equivalent.
The methodology was rigorous regarding OCS tapering. Participants received 210 mg of tezepelumab subcutaneously every four weeks. The OCS dose was systematically reduced according to a predefined schedule, provided asthma control was maintained. Crucially, for participants to reduce their dose below 5 mg per day, preserved adrenal function had to be demonstrated through biochemical testing, ensuring patient safety during the transition away from exogenous steroids.
The primary endpoints were the proportion of patients achieving an OCS dose of 5 mg/day or less and the proportion achieving complete discontinuation at weeks 28 and 52.
Primary Outcomes: Achieving the Impossible in OCS Reduction
The results of the WAYFINDER trial suggest a shift in the treatment paradigm for steroid-dependent asthma. At the 28-week mark, 88.9% of participants had successfully reduced their OCS dose to 5 mg per day or less. This success rate was maintained through week 52, where 89.9% (268 of 298) met this threshold.
Even more striking was the rate of complete OCS discontinuation. At week 28, 32.2% of patients were OCS-free. By week 52, this figure rose to 50.3%. This time-dependent improvement suggests that the clinical benefits of TSLP inhibition may accrue over time, allowing for more profound physiological recovery and steroid withdrawal as the underlying airway inflammation is stabilized.
Secondary Insights: Biomarker Independence and Sustained Control
One of the most significant aspects of the WAYFINDER data is the consistency of response across various biological phenotypes. Traditionally, biologics targeting IL-5 or IL-4/IL-13 have shown the greatest efficacy in patients with high T2 biomarkers (e.g., elevated BEC or FeNO). However, because TSLP sits at the very top of the inflammatory cascade—released by the airway epithelium in response to multiple triggers—its inhibition has a broader impact.
The study found that OCS reduction and discontinuation were achieved regardless of baseline BEC, FeNO levels, or the presence of perennial aeroallergen sensitivity. This supports the use of tezepelumab as a versatile option for clinicians managing heterogeneous severe asthma populations where specific T2-high biomarkers may be suppressed by ongoing OCS use or are simply not the primary drivers of the disease.
Safety Profile and Tolerability
Transitioning patients off long-term OCS is a high-risk period, primarily due to the risk of asthma exacerbation and the unmasking of adrenal insufficiency. In WAYFINDER, the safety profile of tezepelumab was favorable. Serious adverse events (SAEs) occurred in 9.4% of participants. The most common SAEs were asthma-related (13 participants) and pneumonia (three participants). Importantly, only 1.3% of the cohort discontinued tezepelumab due to adverse events. Two deaths occurred during the study, but investigators determined neither was related to the study drug. These results provide reassurance that aggressive OCS tapering under the cover of TSLP inhibition is clinically manageable.
Expert Commentary: Shifting the Treatment Paradigm
The findings from WAYFINDER represent a significant advancement in evidence-based respiratory medicine. By targeting TSLP, tezepelumab addresses the “upstream” epithelial signaling that initiates multiple downstream inflammatory pathways. This mechanism likely explains why the drug remains effective even as “downstream” biomarkers are suppressed by steroids.
Clinicians should note that the success of OCS withdrawal in this study was facilitated by a structured tapering protocol and adrenal function monitoring. In clinical practice, the 50% discontinuation rate should be viewed as a goal that requires patient education and close physiological monitoring. The study’s open-label, single-arm design is a limitation; however, the magnitude of the OCS reduction observed—from a mean baseline of 10.8 mg to zero in half the patients—is clinically profound and unlikely to be a placebo effect alone.
Conclusion and Summary
The WAYFINDER trial confirms that tezepelumab is a potent OCS-sparing agent for adults with severe, uncontrolled asthma. With 90% of patients reaching a minimal dose and 50% achieving complete cessation, the study offers hope for mitigating the long-term burden of steroid-induced morbidity. As healthcare systems look to reduce the total cost of care associated with asthma complications, the broad applicability of tezepelumab across various phenotypes makes it a vital tool in the modern respiratory armamentarium.
Funding and clinicaltrials.gov
The WAYFINDER study was funded by AstraZeneca and Amgen. The trial is registered with ClinicalTrials.gov under the identifier NCT05274815.
References
Jackson DJ, Lugogo NL, Gurnell M, et al. Oral corticosteroid reduction and discontinuation in adults with corticosteroid-dependent, severe, uncontrolled asthma treated with tezepelumab (WAYFINDER): a multicentre, single-arm, phase 3b trial. Lancet Respir Med. 2026 Feb;14(2):129-140. doi: 10.1016/S2213-2600(25)00359-5. Epub 2025 Nov 26. PMID: 41317738.
