Clinical bottom line
Anti-TSLP (thymic stromal lymphopoietin) therapies, exemplified by tezepelumab, represent a promising biologic approach for patients with moderate-to-severe asthma, particularly those with a broad inflammatory phenotype including non-eosinophilic asthma. Current evidence suggests these agents can reduce exacerbation rates and improve lung function and asthma control across diverse patient subgroups. However, long-term safety data and comparative effectiveness versus established biologics remain limited, warranting cautious integration into clinical practice pending further validation (Yao et al., 2021).
What the evidence shows
TSLP is an epithelial-cell–derived cytokine that initiates type 2 and non-type 2 airway inflammation by activating dendritic cells and innate lymphoid cells, positioning it as an upstream regulator in asthma pathobiology. Tezepelumab, a human monoclonal antibody targeting TSLP, has been evaluated in phase 2 and phase 3 trials demonstrating significant reductions in annualized asthma exacerbation rates compared to placebo in patients with severe asthma irrespective of baseline eosinophil counts (Yao et al., 2021).
Notably, tezepelumab’s efficacy extends to patients with low eosinophil levels, a subgroup often less responsive to anti-IL-5 or anti-IL-4/13 therapies. Improvements in lung function (FEV1), asthma control questionnaire scores, and quality of life metrics have also been reported. The broad anti-inflammatory effect of anti-TSLP therapy suggests potential utility in heterogeneous asthma phenotypes, including those with mixed or non-type 2 inflammation (Yao et al., 2021).
Comparative data with other biologics remain sparse. Existing biologics targeting IL-5, IL-4Rα, or IgE have defined roles but are limited by phenotype-specific efficacy and failure in some patients (Papale et al., 2012; Chung et al., 2020). Anti-TSLP therapy may fill an unmet need for patients who do not meet criteria for or respond inadequately to current biologics (Yao et al., 2021).
Caveats and uncertainty
While the clinical trials of tezepelumab provide encouraging results, several uncertainties remain. The long-term safety profile beyond trial durations is not fully characterized. Real-world effectiveness and adherence patterns require further study. The optimal patient selection criteria, including biomarkers predictive of response, are not yet established, limiting precision in clinical application (Yao et al., 2021).
Moreover, head-to-head trials comparing anti-TSLP agents with other biologics are lacking, making it difficult to define their relative positioning in treatment algorithms. Cost-effectiveness analyses and impact on healthcare utilization have not been comprehensively reported. Finally, the durability of response and potential immunogenicity with prolonged use warrant ongoing surveillance.
How this may change practice
Anti-TSLP therapies may expand the therapeutic arsenal for moderate-to-severe asthma by offering a treatment option with broader applicability across inflammatory phenotypes, including patients with low eosinophil counts who currently have fewer biologic options. Clinicians should consider anti-TSLP agents for patients with uncontrolled asthma despite optimized standard therapy, especially when other biologics are contraindicated or ineffective.
Integration into practice will require careful patient selection, monitoring for efficacy and adverse effects, and alignment with evolving guideline recommendations as more data emerge. Anti-TSLP therapy may also stimulate biomarker research to refine phenotype-driven treatment strategies. Ultimately, these agents could shift the paradigm toward targeting upstream inflammatory pathways to achieve better asthma control.