Long-Term Effectiveness of Anti-IL-4R Therapy Following Suboptimal Response to Anti-IL-5/5R Therapy in Severe Eosinophilic Asthma

1. What is already known about this topic? A minority of patients with evidence of severe eosinophilic asthma do not respond adequately to eosinophil directed anti-IL5/5R therapies. In addition to targeting eosinophil chemotaxis, dupilumab targets other potentially relevant IL-13 pathways that may be clinically important in this subgroup. It is unclear whether a switch to dupilumab leads to improved clinical outcomes in this cohort. 2. What does this article add to our knowledge? This is the first report of the extended 2-year response to dupilumab in patients with SEA failing to respond adequately to anti-IL5/5R therapies. We report clinically significant improvements in the majority of patients including the ability to achieve clinical remission in over 40%. A higher pre-biologic FeNO was observed in the patients achieving clinical remission with dupilumab following a failure of anti-IL5/5R therapies, pointing to an IL-13 dominant sub-phenotype of T2-high asthma in which targeting the eosinophil appears less clinically relevant. 3. How does this study impact current management guidelines? This analysis highlights that many non-responders to anti-IL-5/5R treatment can go on to achieve clinical remission following a switch to dupilumab. Clinicians should be encouraged to assess FeNO when considering the likely benefit of switching from anti-IL5/5R therapies to dupilumab. Background Dupilumab is an anti-IL4R monoclonal antibody (mAb) with proven efficacy in severe eosinophilic asthma (SEA). A suboptimal response to anti-IL5/5R mAbs is seen in some patients with ongoing evidence of T2 inflammation. Objective To understand whether targeting IL-13 pathways with dupilumab in these patients may lead to better clinical outcomes. Methods We performed a retrospective analysis of the extended clinical effectiveness of dupilumab up to 2 years of treatment in patients with SEA who had not responded adequately to anti-IL5/5R biologics. Ability to achieve clinical remission and change in the remission domains of exacerbation rate (AER), maintenance oral corticosteroid dose (mOCS), lung function (FEV1) and asthma control (ACQ6) were recorded. Results Thirty-seven patients (mean age 41, 70% female) were included in the analysis. The mean (SD) AER fell by almost 90% from 3.16(1.28) at dupilumab initiation to 0.35(0.72) after 1 year. The median (IQR) mOCS dose (n=20) fell from 10(5-25) mg to 0 (0-5) mg at 1 year, with 14/20 (70%) able to stop prednisolone altogether. Clinical remission was achieved in 16/37 (43%). Patients who achieved remission had a higher pre-IL5/5R FeNO level (85ppb [39-198] vs 75ppb [42-96], p=0.03). Conclusion Significant improvements in clinical outcomes are possible following a switch to dupilumab in patients experiencing a suboptimal response to anti-IL5/5R therapies. A higher FeNO in poor responders to anti-IL5/5R who achieve remission with dupilumab is suggestive of an IL-13 driven sub-phenotype of T2-high asthma in which the eosinophil appears unlikely to play a key role in the disease pathogenesis. Dupilumab is an anti-IL4R monoclonal antibody (mAb) with proven efficacy in severe eosinophilic asthma (SEA). A suboptimal response to anti-IL5/5R mAbs is seen in some patients with ongoing evidence of T2 inflammation. To understand whether targeting IL-13 pathways with dupilumab in these patients may lead to better clinical outcomes. We performed a retrospective analysis of the extended clinical effectiveness of dupilumab up to 2 years of treatment in patients with SEA who had not responded adequately to anti-IL5/5R biologics. Ability to achieve clinical remission and change in the remission domains of exacerbation rate (AER), maintenance oral corticosteroid dose (mOCS), lung function (FEV1) and asthma control (ACQ6) were recorded. Thirty-seven patients (mean age 41, 70% female) were included in the analysis. The mean (SD) AER fell by almost 90% from 3.16(1.28) at dupilumab initiation to 0.35(0.72) after 1 year. The median (IQR) mOCS dose (n=20) fell from 10(5-25) mg to 0 (0-5) mg at 1 year, with 14/20 (70%) able to stop prednisolone altogether. Clinical remission was achieved in 16/37 (43%). Patients who achieved remission had a higher pre-IL5/5R FeNO level (85ppb [39-198] vs 75ppb [42-96], p=0.03). Significant improvements in clinical outcomes are possible following a switch to dupilumab in patients experiencing a suboptimal response to anti-IL5/5R therapies. A higher FeNO in poor responders to anti-IL5/5R who achieve remission with dupilumab is suggestive of an IL-13 driven sub-phenotype of T2-high asthma in which the eosinophil appears unlikely to play a key role in the disease pathogenesis.