Reply to “Have we reached our final destination with biologics in severe uncontrolled asthma?”

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We thank Lipworth and Chan1Lipworth B. Chan R. Have we reached our final destination with biologics in severe uncontrolled asthma?.J Allergy Clin Immunol Pract. 2023; 11: 1575-1576Abstract Full Text Full Text PDF Scopus (1) Google Scholar for their thoughtful comments on our rostrum article “Super-responders to biologic treatment in type 2-high severe asthma: passing fad or a meaningful phenotype?”2Portacci A. Dragonieri S. Carpagnano G.E. Super-responders to biologic treatment in type 2-high severe asthma: passing fad or a meaningful phenotype?.J Allergy Clin Immunol Pract. 2023; 11: 1417-1420Abstract Full Text Full Text PDF Scopus (2) Google Scholar Results from the DESTINATION trial3Menzies-Gow A. Wechsler M.E. Brightling C.E. Korn S. Corren J. Israel E. et al.Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study.Lancet Respir Med. Published online January. 2023; 23https://doi.org/10.1016/s2213-2600(22)00492-1Abstract Full Text Full Text PDF Google Scholar on the reduction of the annualized exacerbation rates in patients with T2-high severe asthma confirm how effective a strategy based on the block of upstream alarmins could be. What would be interesting to assess in real-life prospective studies is the number of patients with super-response (SR) and clinical remission after tezepelumab administration. Following the findings from the SOURCE study,4Wechsler M.E. Menzies-Gow A. Brightling C.E. Kuna P. Korn S. Welte T. et al.Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study.Lancet Respir Med. 2022; 10: 650-660Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar only patients with blood eosinophils ≥150 cells/μL experienced a significant reduction of oral corticosteroid (OCS) use, which is unsurprising considering the impact of tezepelumab on T2 biomarker reduction.5Diver S. Khalfaoui L. Emson C. Wenzel S.E. Menzies-Gow A. Wechsler M.E. et al.Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial.Lancet Respir Med. 2021; 9: 1299-1312Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Accordingly, the OCS cessation criterion should be carefully evaluated in SR/remission classifications because patients with a T2-low endotype treated with tezepelumab could not fulfill this point despite a significant clinical and functional improvement. Moreover, considering the lack of specific non-T2 biomarkers to assess tezepelumab response, some useful clues could arise from airway hyper-responsiveness (AHR) assessment. As shown in the CASCADE trial,5Diver S. Khalfaoui L. Emson C. Wenzel S.E. Menzies-Gow A. Wechsler M.E. et al.Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial.Lancet Respir Med. 2021; 9: 1299-1312Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar AHR is markedly decreased in the tezepelumab arm, suggesting that the block of thymic stromal lymphopoietin can improve this feature with mechanism independent from eosinophilic inflammation. Although this last statement needs further compelling evidence to be proven, it would be fascinating to understand whether the AHR decrease after tezepelumab administration could be a reliable biomarker to assess SR in patients with T2-low severe asthma. Finally, DESTINATION results revealed a significant reduction of exacerbation rates in patients with concomitant severe asthma and chronic rhinosinusitis with nasal polyposis (CRwNP). Despite the large confidence interval due to the small sample size, these data confirm how a good control over upper airways inflammation can significantly affect severe asthma outcomes. Future studies should translate this concept into the specific SR/remission criterion, considering the importance of CRwNP in severe asthma response to biologics. Have we reached our final destination with biologics in severe uncontrolled asthma?The Journal of Allergy and Clinical Immunology: In PracticeVol. 11Issue 5PreviewPortacci et al1 eloquently proposed a comprehensive assessment model for defining super-responders to biologics in patients with type 2 (T2)-high severe uncontrolled asthma (SUA). This in turn begs the pertinent question as to whether it is preferable to block upstream epithelial alarmins such as thymic stromal lymphopoietin (TSLP) or downstream cytokines such as IL4, IL5, and IL13 (Figure 1) in order to achieve the best response in a given patient.2 Full-Text PDF