Reducing or eliminating the use of oral corticosteroids (OCS) is a key goal in managing severe asthma due to the significant adverse events associated with long-term OCS use. Biologic therapies targeting thymic stromal lymphopoietin (TSLP), interleukin-4/13 (IL-4/13), interleukin-5 receptor (IL-5R), and interleukin-5 (IL-5) can improve lung function, lower the OCS dependence, and reduce exacerbation rates. Tezepelumab is a monoclonal antibody that blocks TSLP. It has shown more efficacy in reducing exacerbations and improving clinical outcomes in major clinical trials such as NAVIGATOR (NCT03347279) and DESTINATION (NCT03706079). However, the SOURCE (NCT03406078) study did not meet its primary outcome of OCS-reduction; benefits were mainly observed in patients with higher eosinophil counts, with additional support from long-term clinical studies.
The WAYFINDER study (NCT05274815), published in The Lancet Respiratory Medicine, aimed to assess the safety and efficacy of tezepelumab in reducing the use of OCS in adult patients with uncontrolled, severe, OCS-dependent asthma. WAYFINDER clinical trial was a multicentre (11 countries), open-label, and phase 3b design was conducted across 11 countries and enrolled 382 adults with severe asthma who had been receiving high doses of ICS/LABA for ≥6 months and a daily OCS dose of 5-40 mg for ≥3 months, with ≥1 exacerbation in the prior year. This study ran from May 17, 2022, to September 9, 2024.
A total of 298 patients (mean age = 54.4±12 years, male = 31%, female = 69%, mean asthma duration = 31.2±18.1 years, mean baseline OCS dose = 10.8±6.5 mg/day) were included in this study. Tezepelumab 210 mg was administered subcutaneously to participants once every 4 weeks for up to 52 weeks. The co-primary outcomes at weeks 52 and 28 were the proportions of patients who reduced OCS to ≤5 mg/day or fully discontinued OCS without loss of asthma control. Secondary outcomes were exacerbation rates, safety, lung function, and ≥50% OCS reduction as well as symptom and quality of life scores like St George’s respiratory questionnaire (SGRQ), asthma quality of life questionnaire (standardized) for patients aged ≥12 years ((AQLQ[S] + 12), and asthma control questionnaire 6 (ACQ-6) scores.
Results showed that the primary endpoint was achieved in 268/298 (89·9% [95% confidence interval {CI}: 85·9–93·1]) patients who had a maintenance dose of ≥5mg at week 52 and 265/298 (88.9% [84.8-92.3]) at week 28. A total of 150/298 (50·3% [44·5–56·2]) patients discontinued OCS at week 52, and 96/298 (32·2% [26·9–37·8]) at week 28.
OCS discontinuation and OCS reduction were observed across pre-specified subgroup patients based on allergy status, baseline OCS dose, fractional exhaled nitric oxide (FeNO) level, baseline blood eosinophil count (BEC), access to adrenocorticotropic hormone (ACTH) testing, and geographical region. The mean percentage reduction in daily dose of OCS from baseline increased over time by 72% (67·5–76·6) at week 52.
The annualized asthma exacerbation rate (AAER) was 0.57 at 52 weeks and 0.66 at 28 weeks. Post-bronchodilator forced expiratory volume in 1 second (FEV1 mean = 1.98±0.81 L) remained stable during the entire study. Improvements were also observed in ACQ-6, AQLQ(S) + 12, and SGRQ scores from baseline to week 28 and week 52. Furthermore, 9.4% of participants (28/298) reported serious adverse events (SAEs). Four patients experienced side effects that resulted in the discontinuation of tezepelumab. Two patients died during the research, although this death was not directly associated with tezepelumab therapy. The major limitation of this study was the lack of a control group.
In conclusion, the WAYFINDER study demonstrated that tezepelumab allows patients with severe OCS-dependent asthma to reduce OCS use across phenotypes meaningfully. Most patients achieved physiological OCS doses while maintaining asthma control, and half discontinued OCS by week 52. The study supports the use of personalized OCS-tapering with adrenal monitoring to guide safe OCS reduction in this population.
Reference: 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. 2025. Oral corticosteroid reduction and discontinuation in adults with corticosteroid-dependent, severe, uncontrolled asthma treated with tezepelumab (WAYFINDER): a multicentre, single-arm, phase 3b trial – The Lancet Respiratory Medicine
