Tezepelumab blocks thymic stromal lymphopoietin (TSLP), an epithelial upstream cytokine, and in PATHWAY and NAVIGATOR reduced exacerbations, improved lung function, and lowered biomarkers across phenotypes, including patients with low blood eosinophils [1–3].

Because trial populations may not fully reflect routine-care severe asthma—particularly patients with prior biologic failure and mixed inflammatory profiles—this nationwide multicentre study provides 12-month real-world effectiveness data for tezepelumab across clinical, exacerbation and OCS outcomes, lung function and biomarkers, stratified by T2 status and prior biologic exposure

In this multicentre real-world cohort of 304 adults with severe asthma treated across 17 Spanish tertiary hospitals, tezepelumab was associated with clinically meaningful improvements after 12 months of follow-up. Asthma control improved, the annualised exacerbation rate decreased from 2.9 to 0.8 events/year, 47% of patients remained exacerbation-free, and oral corticosteroid (OCS) exposure was reduced. Lung function gains were statistically significant but modest, whereas blood eosinophil counts and FeNO levels decreased during follow-up. These findings were observed in a clinically complex population, including a high proportion of patients previously exposed to other biologics and a subgroup with low T2 biomarker expression.

Overall, our results are consistent with the mechanism of action of tezepelumab as an upstream epithelial cytokine blocker and with pivotal clinical evidence demonstrating reductions in exacerbations, improvements in lung function, and biomarker reductions across severe asthma phenotypes, including patients with low blood eosinophil counts [1–11]. They are also broadly consistent with emerging real-world studies reporting clinical and biological improvement with tezepelumab in heterogeneous severe asthma populations, including multicentre and nationwide cohorts, patients with previous biologic failure, and cohorts assessing multidomain remission or small-airway outcomes [2,12–22].

In particular, our findings align with the recently published Spanish prospective multicentre real-world study, which reported clinically relevant 12-month improvements with tezepelumab across multidomain clinical and biological outcomes [15]. However, the magnitude of response in our cohort appears more modest than that reported in some real-world series and in studies of other biologics, particularly in highly selected T2 populations. This may be explained by the high proportion of biologic-experienced patients, many of whom had previously shown suboptimal responses to 1 or more targeted therapies and may therefore represent a more treatment-refractory population with less residual potential for improvement [2,6,16,20,22,23].

Regarding individual response domains, the most clinically relevant findings were the marked reduction in exacerbations and the OCS-sparing effect. The annualised exacerbation rate decreased from 2.9 to 0.8events/year, and 47% of patients remained exacerbation-free, outcomes that are particularly important in severe asthma because exacerbations are associated with morbidity, healthcare utilisation, and cumulative corticosteroid exposure.

OCS outcomes also support a clinically relevant steroid-sparing effect, with fewer patients requiring >5mg/day prednisone and lower cumulative OCS exposure. Although OCS tapering was not protocolised, it was generally undertaken gradually in accordance with Spanish expert-consensus recommendations, which advocate minimising systemic glucocorticoid exposure and tapering cautiously in long-term users [24].

ACT score also improved by more than the minimal clinically important difference; however, as a patient-reported outcome, it is inherently influenced by symptom perception, comorbidities, and individual variability. Moreover, the mean ACT score at 12 months remained below 20, indicating that many patients were not fully symptomatically controlled. Therefore, in this severe and clinically complex cohort, ACT score should be interpreted as a complementary measure of response rather than the primary marker of therapeutic benefit.

Lung function gains were statistically significant but modest, with a mean FEV1 improvement of approximately 80mL, which may reflect long-standing disease, fixed airway remodelling, prior biologic exposure, and a ceiling effect among patients with preserved baseline lung function. Radiological markers of remodelling, mucus plugging, and small-airway dysfunction were not assessed and should be explored in future studies, particularly given emerging evidence suggesting that tezepelumab may improve small-airway dysfunction in real-world settings [10,16,19,20].

Composite response frameworks, including clinical remission, FEOS, and EXACTO, provided an integrated assessment of multidomain response beyond individual endpoints [4–6,23,24]. Clinical remission was defined according to a 4-domain framework including absence of OCS use, ACT score>20, absence of exacerbations, and stable lung function, in line with recent proposals for standardising remission assessment in severe asthma.4 FEOS and EXACTO further allowed response to be characterised across exacerbations, symptoms, OCS exposure, and airflow obstruction, domains that are particularly relevant when evaluating biologic therapy in heterogeneous real-world populations [5,6,23,24]. These tools showed that a substantial proportion of patients achieved good or super-response, whereas a meaningful minority derived limited benefit. In this context, composite response tools may complement clinical judgement, particularly when improvements in symptoms, exacerbations, OCS exposure, and lung function do not occur in parallel.

The predictor analyses should be interpreted as exploratory. ACT improvement was positively associated with increasing age and negatively associated with female sex, findings that differ from several previous tezepelumab analyses in which response was generally consistent across demographic subgroups [3,11,19]. Previous biologic treatment was associated with a smaller reduction in exacerbations, supporting the hypothesis that biologic-experienced patients may have more refractory disease or a reduced margin for additional improvement, as suggested by other real-world cohorts including patients switched after prior biologic exposure [2,18,20–22].

Findings related to T2 status should be interpreted cautiously, as T2 and non-T2 classification was based on routinely available biomarkers that may fluctuate and can be suppressed by maintenance OCS therapy or prior biologic treatment. Therefore, the apparent benefit in patients with low T2 biomarker expression should be considered descriptive rather than definitive evidence of efficacy in biologically confirmed non-T2 asthma, despite the biological rationale and clinical trial evidence supporting tezepelumab activity across inflammatory phenotypes [1–3,8,10,11].

Tezepelumab was generally well tolerated in this cohort. Two patients experienced non-serious, non-treatment-related adverse events and continued treatment. No early discontinuations due to lack of effectiveness were recorded among patients with evaluable paired follow-up data. These findings are consistent with the favourable safety profile reported in clinical trials, meta-analyses, and real-world studies [1–3,10,12,16–18,20,22]. However, the retrospective design limits systematic ascertainment of adverse events.

The main strengths of this study include its multicentre design, inclusion of all tezepelumab initiators identified through pharmacy dispensing records during the study period, 12-month follow-up, and detailed assessment of clinical, functional, biomarker, and corticosteroid-related outcomes. Nevertheless, several limitations should be acknowledged. The retrospective uncontrolled pre-post design precludes causal inference, and improvements may partly reflect regression to the mean, optimisation of concomitant care, changes in adherence, or intensified specialist follow-up.

Missing data were handled using a complete-case approach, although baseline comparisons suggested that the complete-case subsets were broadly comparable with the overall cohort. OCS tapering was clinician-driven rather than protocolised, and cumulative OCS estimates may have been affected by incomplete documentation. Pharmacy records captured treatment initiators but not treatment persistence in detail; therefore, requiring paired 12-month data may have introduced survivorship or selection bias. However, only 3 of 307 initiators lacked paired baseline and 12-month data, making a material impact on the overall interpretation unlikely even under a conservative worst-case assumption.

Finally, residual confounding remains possible, and the predictor analyses should be considered hypothesis-generating. Prospective comparative studies, including matched-cohort designs and head-to-head analyses against other biologics, are needed to better define the positioning of tezepelumab within current severe asthma treatment algorithms [7,23,25–27].

In this large Spanish real-world cohort, tezepelumab was associated with clinically meaningful improvements in routine specialist care for severe asthma, including among biologic-experienced patients and those with low T2 biomarker expression. Treatment was associated primarily with marked reductions in exacerbations and OCS exposure, together with biomarker suppression, improved patient-reported asthma control, and modest lung function gains. However, the uncontrolled study design prevents attribution of these improvements exclusively to tezepelumab. Prospective comparative studies are needed to better define its positioning among biologic therapies and to identify patients most likely to benefit.

All authors (Villamañán E1,4,5, Carpio C2,4,5, Laorden D2,5, Domínguez-Ortega J3,5, Romero D2,5, De Las Vecillas LV3,5, Soto A1, Villaroya E1, Romero B2, Losantos I6, Sobrino C1,5, De Andrés S1,5, Herrero A1,5, Quirce S3,5, Álvarez-Sala R2,4,5) meet the four authorship criteria of the International Committee of Medical Journal Editors (ICMJE). All made substantial contributions to the conception and design of the study or to the acquisition, analysis, or interpretation of data; participated in drafting the Article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Each author has individually completed and submitted the ICMJE uniform disclosure form for potential conflicts of interest. There are no guest, honorary, or ghost authors. More than one author had full access to and verified the underlying data. All authors had access to all relevant data, approved the final version of the manuscript, and accept responsibility for the integrity, reliability, and completeness of the data and the analyses.

All authors confirm that the study protocol and the final version of the manuscript were reviewed and approved by all authors. The authors certify that this Article reports original work that has not been published previously and is not under consideration for publication elsewhere. The authors further declare that all required patient or participant consents and permissions were obtained and documented in accordance with applicable ethical and legal requirements.

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Hospital Universitario La Paz (PI-6401). All patient data were anonymised before analysis, and confidentiality was maintained in compliance with Spanish Organic Law 3/2018 on Personal Data Protection. Owing to the retrospective, observational design, written informed consent was not required.

Medical writing and English-language editing support, including refinement of scientific style, were provided in part by an artificial intelligence-based tool (ChatGPT 5.1, OpenAI) and were subsequently reviewed and approved by the authors.

There was no funding source in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit the manuscript for publication.

None declared.