Tezepelumab Reduces Oral Corticosteroid Use in Severe Asthma

Navigating Severe Asthma: The Quest for Oral Corticosteroid Reduction

Managing severe asthma frequently requires long-term oral corticosteroids (OCS) to maintain control, yet this strategy carries a substantial burden of systemic adverse effects, including metabolic dysfunction, bone density loss, and adrenal suppression [1, 2, 3]. This clinical reality has driven the search for effective OCS-sparing therapies. While biologic agents have demonstrated clear benefits in reducing exacerbations and improving lung function, particularly for patients with type 2 inflammation, their capacity to substantially lower OCS dependence remains a critical focus of investigation [4, 5, 6, 7]. For instance, a large meta-analysis of 48 studies involving 16,350 patients confirmed that biologics reduced annual asthma exacerbations by 44% (rate ratio 0.56, 95% CI 0.51-0.62) [4]. Building on this progress, a recent trial evaluated a specific biologic's ability to address the challenge of OCS reduction head-on.

Tezepelumab's Mechanism and Study Design

The SUNRISE trial focused on tezepelumab, a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP). TSLP is an epithelial-derived cytokine that acts as an upstream mediator in the inflammatory cascade, playing a role across multiple asthma phenotypes, not just those defined by type 2 inflammation. By targeting TSLP, tezepelumab intervenes earlier in the inflammatory process than agents targeting more downstream molecules. The phase 3, double-blind, placebo-controlled study was designed to rigorously assess the OCS-sparing effect of this mechanism in adults with severe, OCS-dependent asthma across 63 sites in 12 countries.

Investigators enrolled adults aged 18-80 years with physician-diagnosed asthma who were on medium-dose or high-dose inhaled corticosteroids for at least 12 months. After a period of OCS dose optimization, participants were randomly assigned in a 2:1 ratio to receive either subcutaneous tezepelumab 210 mg or placebo every 4 weeks for 28 weeks. To account for potential confounders, participants were stratified by geographic region and baseline blood eosinophil count. The trial was fully masked for participants, investigators, and site staff. The primary endpoint was the categorized percentage reduction in the daily maintenance OCS dose from baseline to week 28, contingent on maintaining asthma control. All outcomes were evaluated in the full analysis set, which included every participant who received at least one dose. The study, funded by AstraZeneca and Amgen, is registered with ClinicalTrials.gov (NCT05398263).

Trial Conduct and Participant Flow

The study began enrollment on August 9, 2022, but was terminated early on March 24, 2025, due to recruitment challenges. Consequently, 122 participants were treated out of a planned 207, with 83 individuals assigned to the tezepelumab group and 39 to the placebo group. Despite the premature end, a majority of participants, 90 (74%), completed the full 28-week treatment protocol. The early study termination was the primary reason for non-completion, accounting for 25 (20%) of the participants who did not finish the trial. This smaller-than-intended sample size is an important context for interpreting the study's findings.

Significant Oral Corticosteroid Reduction Achieved

Despite the smaller sample size resulting from early termination, the study met its primary endpoint. The analysis revealed that patients treated with tezepelumab were significantly more likely to achieve a greater reduction in their daily OCS dose by week 28 compared to those on placebo. The odds of reaching a higher category of OCS reduction were nearly three times greater with tezepelumab (odds ratio 2.93, 95% CI 1.43-6.03; p=0.0034). This statistically significant result demonstrates a clear OCS-sparing effect.

For clinicians managing patients with severe asthma, these findings indicate that tezepelumab can facilitate a meaningful reduction in chronic OCS exposure without sacrificing asthma control. This directly addresses a primary goal of severe asthma management: minimizing the cumulative toxicity associated with long-term systemic steroid use while maintaining disease stability.

Safety Profile and Exacerbation Rates

In addition to its OCS-sparing effect, tezepelumab demonstrated a benefit in reducing asthma exacerbations. Over the 28-week trial, fewer participants in the tezepelumab group experienced an exacerbation (25 of 83, or 30%) compared to the placebo group (23 of 39, or 59%). The overall safety profile also appeared favorable. Fewer participants receiving tezepelumab reported adverse events (47, or 57%) than those receiving placebo (28, or 72%). Serious adverse events were also less frequent in the tezepelumab arm, occurring in seven (8%) participants versus five (13%) in the placebo arm.

Three deaths were reported during the study: two in the tezepelumab group (during the post-treatment period) and one in the placebo group (during the treatment period). However, investigator assessment concluded that none of the deaths were causally related to the study treatment. Based on the totality of the data, the authors concluded that no new safety concerns for tezepelumab were identified, reinforcing its tolerability in this high-risk patient population.

References

1. Wechsler ME, Colice G, Griffiths JM, et al. SOURCE: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma. Respiratory Research. 2020. doi:10.1186/s12931-020-01503-z

2. Phinyo P, Krikeerati T, Vichara-Anont I, Thongngarm T. Efficacy and Safety of Biologics for Oral Corticosteroid-Dependent Asthma: A Systematic Review and Network Meta-Analysis.. The journal of allergy and clinical immunology. In practice. 2024. doi:10.1016/j.jaip.2023.11.007

3. Ma J, Ma Q, Yang J, et al. The clinical and pathological histology efficacy of biological therapy for severe asthma with a phenotype of type 2 inflammation - systematic review. Frontiers in Immunology. 2025. doi:10.3389/fimmu.2025.1531986

4. Kyriakopoulos C, Gogali A, Markozannes G, Κostikas Κ. Biologic agents licensed for severe asthma: a systematic review and meta-analysis of randomised controlled trials. European Respiratory Review. 2024. doi:10.1183/16000617.0238-2023

5. Lin F, Yu B, Deng B, He R. The efficacy and safety of tezepelumab in the treatment of uncontrolled asthma: A systematic review and meta-analysis of randomized controlled trials. Medicine. 2023. doi:10.1097/md.0000000000034746

6. Jackson DJ, Lugogo N, 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. The Lancet Respiratory Medicine. 2025. doi:10.1016/s2213-2600(25)00359-5

7. Corren J, Menzies‐Gow A, Chupp G, et al. Efficacy of Tezepelumab in Severe, Uncontrolled Asthma: Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials. American Journal of Respiratory and Critical Care Medicine. 2023. doi:10.1164/rccm.202210-2005oc