Pulmonology · Medical Literature
Efficacy and safety of tezepelumab versus placebo in reducing oral corticosteroid use in adults with severe, oral corticosteroid-dependent asthma (SUNRISE): a multicentre, placebo-controlled, double-blind, phase 3 trial.
Abstract
Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This study aimed to evaluate the oral corticosteroid-sparing effect of tezepelumab in adults with severe, oral corticosteroid-dependent asthma. SUNRISE was a phase 3, double-blind, placebo-controlled trial conducted across 63 sites in 12 countries. After oral corticosteroid optimisation, participants aged 18-80 years with physician-diagnosed asthma who were receiving medium-dose or high-dose inhaled corticosteroids for at least 12 months before screening were randomly assigned (2:1) to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 28 weeks. Participants were stratified by region and blood eosinophil count. Participants, investigators, and site staff were masked to treatment assignment. The primary outcome was the categorised percentage reduction from baseline in the daily maintenance oral corticosteroid dose at week 28 while maintaining asthma control. The primary outcome and safety outcomes were evaluated in all randomly assigned participants who received at least one dose of tezepelumab or placebo (ie, the full analysis set). This study is registered with ClinicalTrials.gov (NCT05398263). Between Aug 9, 2022, and March 24, 2025, when the study was terminated, 122 of 207 planned participants received tezepelumab (n=83) or placebo (n=39). 90 (74%) participants completed treatment. Of 122 participants, 25 (20%) did not complete the study owing to early study termination due to recruitment challenges. The odds of reaching a category of greater percentage oral corticosteroid reduction at week 28 were significantly higher with tezepelumab than placebo (odds ratio 2·93 [95% CI 1·43-6·03]; p=0·0034). Overall, 25 (30%) participants in the tezepelumab group and 23 (59%) participants in the placebo group had at least one asthma exacerbation over 28 weeks. Adverse events occurred in 47 (57%) participants in the tezepelumab group and 28 (72%) participants in the placebo group. Serious adverse events occurred in seven (8%) participants in the tezepelumab group and five (13%) participants in the placebo group. Three deaths occurred (two in the tezepelumab group during the post-treatment period and one in the placebo group during the treatment period); none were considered causally related to study treatment based on investigator assessment. In this study, tezepelumab treatment led to greater reductions from baseline in daily oral corticosteroid dose than placebo at week 28 despite early study termination. No safety concerns were identified for tezepelumab. These findings show that patients receiving tezepelumab can reduce maintenance oral corticosteroid use while maintaining asthma control and without compromising efficacy. AstraZeneca and Amgen.
Clinical relevance
In adults with severe, oral corticosteroid-dependent asthma receiving medium- or high-dose inhaled corticosteroids, does tezepelumab 210 mg subcutaneously every 4 weeks produce greater reductions in daily maintenance oral corticosteroid dose than placebo while maintaining asthma control over 28 weeks? __SNAPSHOT__ {"studyDesign":"Phase 3, multicentre, randomized, double-blind, parallel-group, placebo-controlled trial (SUNRISE; NCT05398263)","setting":"63 sites in 12 countries (international; countries include South Korea, Thailand, Türkiye, USA, and others); conducted August 9, 2022 – March 24, 2025","sampleSize":"n=122 enrolled and analysed (tezepelumab: n=83, placebo: n=39); planned enrolment was 207 — trial was terminated early due to recruitment challenges","population":"Adults aged 18–80 years with physician-diagnosed asthma; receiving medium- or high-dose ICS (≥500 µg fluticasone propionate equivalent) plus LABA for ≥12 months; on stable daily maintenance OCS 7.5–30 mg prednisone/prednisolone equivalent for ≥1 month; pre-bronchodilator FEV1 0% to <50%; no change or any increase)","followUp":"28 weeks of treatment; follow-up period post-treatment not reported for secondary outcomes","fundingSource":"Industry (AstraZeneca and Amgen); the study sponsor (AstraZeneca) conducted the study, coordinated data management, and performed the statistical analysis; medical writing was funded by AstraZeneca and Amgen"}
Key findings
PRIMARY OUTCOME: The trial met its primary endpoint. The cumulative odds of achieving a category of greater percentage OCS reduction at week 28 were significantly higher with tezepelumab than placebo (OR 2.93 [95% CI 1.43–6.03]; p=0.0034). SECONDARY OCS OUTCOMES: 69% of tezepelumab-treated participants achieved ≥50% reduction in OCS dose versus 44% in the placebo group (absolute difference: 25 percentage points [calculated]). Complete OCS discontinuation (100% reduction) was achieved in 35% of the tezepelumab group versus 21% with placebo (absolute difference: 14 percentage points [calculated]). NNT for ≥50% OCS reduction ≈ 4 (calculated); NNT for complete OCS discontinuation ≈ 7 (calculated). EXACERBATIONS: Annualised asthma exacerbation rate (AAER) was 0.64 (95% CI 0.44–0.93) with tezepelumab versus 2.04 (95% CI 1.47–2.83) with placebo (rate ratio 0.31 [95% CI 0.19–0.51]; p<0.001), representing a 69% relative reduction. Participants experiencing ≥1 exacerbation: 30% (n=25) tezepelumab versus 59% (n=23) placebo. Rate of exacerbations requiring emergency department visit or hospitalisation: 0.09 versus 0.67, respectively. The benefit in OCS reduction was observed across blood eosinophil count subgroups (≥150 and <150 cells/µL), though baseline eosinophil imbalance limits subgroup interpretation. SAFETY: Adverse events occurred in 57% of tezepelumab-treated and 72% of placebo-treated participants. The most common adverse event was nasopharyngitis (13% tezepelumab, 18% placebo). Two treatment discontinuations occurred in the tezepelumab arm due to serious adverse events (prostate cancer and plasma cell myeloma); causality was not established. No additional safety concerns beyond the known tezepelumab profile were identified. FEV1 and other secondary outcomes (ACQ-6, AQLQ[S]+12, HRQoL): improvements were reported in favour of tezepelumab; specific values from the SUNRISE abstract are not fully reported—see full publication for quantitative secondary results.
Practice implications
SUNRISE is the first phase 3 RCT to demonstrate a statistically significant OCS-sparing effect for tezepelumab in severe OCS-dependent asthma using a prospective, double-blind design. The study established that, over 28 weeks, tezepelumab increased the probability of achieving meaningful OCS dose reduction—including complete discontinuation—while maintaining asthma control and reducing exacerbations. These findings are consistent with, and strengthen, earlier signals from the single-arm WAYFINDER study. Importantly, the trial was terminated early at 59% of planned enrolment (122 of 207 participants), driven by declining availability of eligible patients as clinical practice shifted away from chronic OCS use in severe asthma. The smaller-than-planned sample size reduces statistical power and the reliability of subgroup analyses (including eosinophil-stratified results). Notable baseline imbalances existed between arms: the tezepelumab group had a lower proportion of patients with BEC 10 mg/day (55% vs 33%), which could bias efficacy estimates in either direction and cannot be fully adjusted for in a small trial. The 28-week duration is insufficient to assess long-term OCS-sparing durability, effects on OCS-related comorbidities (diabetes, osteoporosis, cardiovascular disease), or long-term safety. Patients who required OCS doses >20 mg/day at baseline may have been structurally prevented from reaching complete discontinuation within the protocol timeframe. Results most reliably apply to adults with severe OCS-dependent asthma on maximal ICS/LABA therapy with blood eosinophil counts ≥150 cells/µL. Patients with very low eosinophil counts ( 20 mg/day at baseline were mathematically unable to achieve complete OCS discontinuation within the OCS reduction phase duration, artificially constraining the 100% reduction endpoint in the tezepelumab group (which had 55% on >10 mg/day vs 33% in placebo),No data safety monitoring board: justified by investigators based on tezepelumab's known profile, but this represents a potential oversight limitation for a novel indication,Exclusively industry-sponsored: AstraZeneca conducted the study, managed data, performed statistical analyses, approved the manuscript — the highest category of industry involvement,All p-values described as nominal: formal alpha-control for multiple secondary comparisons was not reported, increasing risk of Type I error for secondary outcomes,Subgroup analyses (eosinophil strata) are unreliable given small cell sizes resulting from early termination and baseline imbalances,Study enrolment challenges reflect a secular trend away from chronic OCS use, meaning this specific patient population may be increasingly rare and the enrolled sample may not represent contemporary practice patterns,No direct active comparator: results cannot establish superiority or equivalence versus other approved biologics (dupilumab, benralizumab, mepolizumab) for OCS sparing in this indication __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ The SUNRISE trial demonstrated that tezepelumab 210 mg SC every 4 weeks significantly increased the odds of achieving greater OCS dose reductions versus placebo (OR 2.93; p=0.0034), with 69% of tezepelumab-treated patients achieving ≥50% OCS reduction and 35% achieving complete discontinuation over 28 weeks. These results are clinically meaningful for a population at high risk of OCS-related morbidity, and no new safety signals were identified. However, early termination, significant baseline imbalances, a 28-week observation window, and complete industry sponsorship of data analysis warrant cautious interpretation; these findings are best viewed as strong supportive evidence for an already-approved agent rather than a practice-changing paradigm shift.