Tezepelumab Enables Oral Corticosteroid Reduction in Severe Asthma Patients, WAYFINDER Trial Shows
核心洞察
Nearly 90% of patients with oral corticosteroid-dependent severe asthma (搜索) achieved maintenance doses of 5 mg per day or less after 52 weeks of tezepelumab treatment.
Half of the 298 participants completely discontinued oral corticosteroids (搜索) while maintaining asthma control by week 52 in the open-label WAYFINDER trial.
Mean Asthma Control Questionnaire-6 scores improved from 2.6 at baseline to 1.4 at week 52, with 47.3% achieving partially or well-controlled asthma.
Patients with severe, oral corticosteroid-dependent asthma experienced dramatic reductions in steroid use while maintaining disease control after treatment with tezepelumab, according to results from the phase 3 WAYFINDER trial published in The Lancet Respiratory Medicine.
The multicenter, single-arm study enrolled 298 adults with severe, uncontrolled asthma who were receiving maintenance oral corticosteroid (OCS) doses of 5-40 mg per day. After 52 weeks of treatment with tezepelumab 210 mg subcutaneously every four weeks, 89.9% of participants achieved maintenance OCS doses of 5 mg per day or less without loss of asthma control, while 50.3% completely discontinued OCS use.
Significant Improvements in Asthma Control
Beyond steroid reduction, patients demonstrated clinically meaningful improvements in asthma control measures. Mean Asthma Control Questionnaire-6 (ACQ-6) scores fell from 2.6 at baseline to 1.4 at week 52, representing an adjusted mean change of -1.15 (95% CI, -1.3 to -1).
The proportion of patients with well-controlled asthma (ACQ-6 score ≤0.75) increased dramatically from 3% at baseline to 26.9% at week 52. Additionally, patients with partially controlled asthma (ACQ-6 score >0.75 to <1.5) grew from 5.7% to 20.5%. Overall, 47.3% of patients achieved partially or well-controlled asthma by week 52, compared to just 8.7% at baseline.
"Improvements in asthma therapies in recent years, including the advent of personalised, potentially disease-modifying biologic therapies, have resulted in the evolution of treatment goals from short-term control of symptoms and exacerbations to long-term disease remission," wrote study investigator David J. Jackson, MBBS, MSc, PhD, Professor at Guy's Severe Asthma (搜索) Centre, King's College London, and colleagues.
Targeting TSLP at the Top of Inflammatory Cascade
Tezepelumab represents the first-in-class human monoclonal antibody targeting thymic stromal lymphopoietin (搜索) (TSLP (搜索)), a key epithelial cytokine that sits at the top of multiple inflammatory cascades. According to study presenter Sandeep Bansal, MD, FCCP, FACP, medical director at The Lung Center and Interventional Pulmonology at Penn Highlands Healthcare (搜索), TSLP "is critical in the initiation and persistence of allergic, eosinophilic and other types of epithelial inflammation associated with severe asthma (搜索)."
The WAYFINDER trial was conducted between May 17, 2022, and September 9, 2024, across 68 clinical centers in 11 countries. Participants had a mean baseline maintenance OCS dose of 10.8 mg per day (SD, 6.5). The study population was 69.1% female, and 80% had blood eosinophil counts of 150 cells/μL or higher at screening.
Consistent Benefits Across Patient Subgroups
OCS reduction and discontinuation outcomes remained consistent across prespecified subgroups defined by baseline blood eosinophil count, fractional exhaled nitric oxide, and allergy status. This suggests tezepelumab's effectiveness is independent of typical type-2 inflammation biomarkers.
"By targeting TSLP (搜索) at the top of the inflammatory cascade and controlling asthma effectively with tezepelumab, we may be able to reduce these risks from OCS and significantly improve control for patients living with severe asthma (搜索)," Bansal explained.
Safety Profile and Limitations
The safety profile was favorable, with serious adverse events occurring in 9.4% of participants, most commonly asthma (13 cases) and pneumonia (3 cases). Only 1.3% experienced adverse events leading to tezepelumab discontinuation. Two deaths occurred during the study but were not considered related to treatment.
However, the open-label, non-randomized design has drawn criticism. In a related editorial, Paola Rogliani, MD, and Luigino Calzetta, PhD, from University of Rome (搜索) "Tor Vergata" compared WAYFINDER's positive findings to the previously negative SOURCE trial results. They noted that "methodological limitations, baseline imbalances, and the influence of the placebo effect indicate that these findings are not definitive."
The editorialists emphasized that "well-designed randomized, placebo-controlled trials or high-quality pooled analyses are needed to confirm the OCS-sparing effect of tezepelumab."
Clinical Implications
For patients with severe asthma (搜索), prolonged OCS use carries significant risks including bone loss, cardiovascular issues, metabolic disturbances, gastrointestinal problems, psychiatric effects, and adrenal insufficiency. The ability to reduce or eliminate OCS dependence while maintaining asthma control represents a major therapeutic advance.
"That durability of control is clinically meaningful for this population, which has historically struggled to maintain stability during OCS reduction," Bansal noted. The findings suggest tezepelumab may help patients achieve clinical remission, defined as the absence of systemic corticosteroid use and asthma exacerbations together with very mild or no asthma symptoms.