Are We Poised to Change the Trajectory of Maintenance Oral Corticosteroid Use in Severe Asthma in the Age of Biologics?

FOR RELATED ARTICLE, SEE PAGE 46Oral corticosteroids (OCS) have been used for decades to manage acute episodes of asthma and as maintenance therapy for severe uncontrolled asthma. The prevalence of OCS-dependent asthma is still relatively high in various populations, and there is regional variability.1Bleecker E.R. Gandhi H. Gilbert I. Murphy K.R. Chupp G.L. Mapping geographic variability of severe uncontrolled asthma in the United States: management implications.Ann allergy asthma immunol. 2022; 128: 78-88Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar OCS toxicity is well-characterized, and there is evidence that relatively low levels of exposure can have significant negative consequences.2Price D.B. Trudo F. Voorham J. et al.Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study.J Asthma Allergy. 2018; 11: 193-204Crossref PubMed Scopus (236) Google Scholar There has been a marked change in the therapeutic landscape for severe asthma with the approval of six biologics. Mepolizumab, benralizumab, and dupilumab demonstrated significant OCS-sparing effects with concomitant reductions in exacerbations providing hope that we may be on the precipice of a new era of OCS stewardship, with the opportunity to liberate patients from their reliance on oral steroids. All the phase 3 OCS-sparing trials included an optimization phase during which strict protocol-guided attempts at weaning were undertaken to ensure that patients were on the lowest possible dose of oral steroids.3Bel E.H. Wenzel S.E. Thompson P.J. et al.Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.N Engl J Med. 2014; 371: 1189-1197Crossref PubMed Scopus (1255) Google Scholar, 4Nair P. Wenzel S. Rabe K.F. et al.Oral glucocorticoid-sparing effect of benralizumab in severe asthma.N Engl J Med. 2017; 376: 2448-2458Crossref PubMed Scopus (710) Google Scholar, 5Rabe K.F. Nair P. Brusselle G. et al.Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.N Engl J Med. 2018; 378: 2475-2485Crossref PubMed Scopus (746) Google Scholar This was followed by an induction phase during which biologics were initiated followed by a protocol-driven down titration of oral steroids, often with a more rapid down titration than is performed clinically. The Long-Term Safety Evaluation of Dupilumab in Patients With Asthma (LIBERTY ASTHMA TRAVERSE) study6National Institutes of Health Clinical CenterLong-term safety evaluation of dupilumab in patients with asthma (LIBERTY ASTHMA TRAVERSE). NCT02134028. ClinicalTrials.gov. National Institutes of Health, 2014https://clinicaltrials.gov/ct2/show/NCT02134028Google Scholar (NCT2134928) is an open label extension trial that evaluates the long-term safety and efficacy of dupilumab in patients previously enrolled in dupilumab studies. This published analysis of the LIBERTY ASTHMA TRAVERSE study included 189 participants from the phase 3 Liberty Asthma VENTURE (Evaluation of Dupilumab in Patients with Severe Steroid Dependent Asthma) study7National Institutes of Health Clinical CenterEvaluation of dupilumab in patients with severe steroid dependent asthma (VENTURE). NCT02528214. ClinicalTrials.gov. National Institutes of Health, 2015https://clinicaltrials.gov/ct2/show/NCT02528214Google Scholar (NCT02528214) who were followed for up to 96 weeks.8Sher L.D. Wechsler M.E. Rabe K.F. et al.Dupilumab reduces oral corticosteroid use in patients with corticosteroid-dependent severe asthma: an analysis of the phase 3, open-label extension TRAVERSE trial.Chest. 2022; 162: 46-55Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar It assessed the OCS-sparing effect of add on dupilumab in patients with OCS-dependent asthma.5Rabe K.F. Nair P. Brusselle G. et al.Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.N Engl J Med. 2018; 378: 2475-2485Crossref PubMed Scopus (746) Google Scholar,9Wechsler M.E. Ford L.B. Maspero J.F. et al.Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study.Lancet Respir Med. 2022; 10: 11-25Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Dupilumab was highly effective in reducing maintenance OCS use in this patient population. The Evaluation of Dupilumab in Patients with Severe Steroid Dependent Asthma (VENTURE) study was a 28-week study; therefore, OCS down titration was limited by the study duration; however, patients were able to continue OCS weaning guided by their treating clinicians during the TRAVERSE study. The authors present compelling data to support durability of OCS-sparing effects of dupilumab, which further highlights the opportunity to use biologics as a game changer in OCS-dependent asthma. Furthermore, there was a concomitant 90% reduction in exacerbations in those patients who remained in the study. It is notable that there was a significant dropout rate with only 25% of the population remaining at study completion. This introduces potential biases because the patients who respond to therapy are likely to be the ones who remained in the trial. This limitation must be taken into consideration while interpreting the results. FOR RELATED ARTICLE, SEE PAGE 46 In this issue of CHEST, the analysis by Sher et al8Sher L.D. Wechsler M.E. Rabe K.F. et al.Dupilumab reduces oral corticosteroid use in patients with corticosteroid-dependent severe asthma: an analysis of the phase 3, open-label extension TRAVERSE trial.Chest. 2022; 162: 46-55Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar of the TRAVERSE study9Wechsler M.E. Ford L.B. Maspero J.F. et al.Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study.Lancet Respir Med. 2022; 10: 11-25Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar provides a crucial insight into the potential shortcoming of clinician-driven OCS reduction. The use of dupilumab in the placebo population reduced OCS dose over time; however, the trajectory of the reduction is slower, despite the rapid improvement in lung function and asthma control. It is notable that dupilumab has a rapid onset of action,5Rabe K.F. Nair P. Brusselle G. et al.Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.N Engl J Med. 2018; 378: 2475-2485Crossref PubMed Scopus (746) Google Scholar,10Pelaia C. Lombardo N. Busceti M.T. et al.Short-term evaluation of dupilumab effects in patients with severe asthma and nasal polyposis.J Asthma Allergy. 2021; 14: 1165-1172Crossref PubMed Scopus (24) Google Scholar and patients who transition to open label treatment should have had immediate effects of the drug, allowing for more rapid down titration. TRAVERSE did not require protocolized down titration, and OCS weaning was left to the discretion of the treating clinician. This study highlights the possibility that relying on a conventional way to reduce OCS is not as effective as approaching weaning in a structured manner. Indeed, this was noted in the Study to Evaluate Efficacy and Safety of Benralizumab in Reducing Oral Corticosteroid Use in Adult Patients With Severe Asthma (PONENTE) trial in which protocol-driven OCS weaning was highly successful at reducing OCS in a population of patients with severe asthma that was treated with benralizumab.11Menzies-Gow A. Gurnell M. Heaney L.G. et al.Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study.Lancet Respir Med. 2022; 10: 47-58Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar It was also noted in the VENTURE study,5Rabe K.F. Nair P. Brusselle G. et al.Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.N Engl J Med. 2018; 378: 2475-2485Crossref PubMed Scopus (746) Google Scholar wherein, although dupilumab achieved a 68% reduction in OCS dose, the placebo-treated patients achieved a remarkable 41% reduction, presumably as a result of the study protocol. Hence, the use of a protocolized OCS down titration has proved to be a highly effective and superior way to liberate patients from high doses of OCS. Although the asthma guidelines recommend OCS sparing strategies, there are no specific recommendations regarding how this goal should be achieved.12Reddel H.K. Global Initiative For Asthma (GINA): Global Strategy for Asthma Managment and Prevention.2021: 2021Google Scholar,13Clouthier M.M. Baptist A.P. Blake K.V. et al.2020 Focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program (NAEPP) Coordinating Committee Expert Panel Working Group.J Allergy Clin Immunol. 2020; 146: 1217-1270Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar There is an urgent need for standardized guidelines on the management of OCS-dependent asthma and implementation of OCS weaning protocols following biologic initiation. OCS weaning is a very nuanced and challenging issue in clinical practice. Clinicians are often hesitant to wean OCS rapidly because of safety concerns such as inciting worsening asthma control and acute exacerbations. Weaning OCS is a complex process, and patients can be hesitant to reduce OCS dose for a variety of reasons. Frequent clinical trial visits, remote monitoring with diaries and peak flowmeters, and use of objective measures to guide OCS weaning results in assuaging of safety concerns. The intensity with which these weaning protocols are executed results in rapid and significant reductions in OCS dose, and clinical practice should be informed by these successes. Indeed, similar patterns have emerged from both optimization and postinduction weaning in other OCS-sparing trials in asthma.3Bel E.H. Wenzel S.E. Thompson P.J. et al.Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.N Engl J Med. 2014; 371: 1189-1197Crossref PubMed Scopus (1255) Google Scholar, 4Nair P. Wenzel S. Rabe K.F. et al.Oral glucocorticoid-sparing effect of benralizumab in severe asthma.N Engl J Med. 2017; 376: 2448-2458Crossref PubMed Scopus (710) Google Scholar, 5Rabe K.F. Nair P. Brusselle G. et al.Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.N Engl J Med. 2018; 378: 2475-2485Crossref PubMed Scopus (746) Google Scholar Given these experiences, it is time to change how we manage severe OCS-dependent asthma. OC- dependent asthma should be treated with urgency, and OCS stewardship should be a goal for all clinicians who manage asthma. Best practices for OCS weaning should be standardized and must include an assessment for adrenal insufficiency, a common and critical complication of chronic OCS exposure.11Menzies-Gow A. Gurnell M. Heaney L.G. et al.Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study.Lancet Respir Med. 2022; 10: 47-58Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Clinicians should be reassured that OCS reduction can be achieved in a safe and effective manner with durable long-term effects. Last, maintenance OCS initiation should be avoided, and biologics should be initiated earlier in the course of disease. With the advent of highly effective biologics for asthma, clinicians should identify those who are at risk for rapid escalation and significant OCS exposure and introduce biologics early. The use of biologics in rheumatoid arthritis and its impact on OCS use underscores the possibilities for clinicians to spare asthma patients the harms of OCS use and should serve as an example of what can be accomplished in the next decade. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: N. L. received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva; honoraria for nonspeakers bureau presentations from GSK and Astra Zeneca; and travel support from Astra Zeneca; her institution received research support from Amgen, AstraZeneca, Avillion, Evidera, Janssen, Gossamer Bio, Genentech, GSK, Regeneron, Sanofi, Novartis and Teva; she is an honorary faculty member of Observational and Pragmatic Research Institute (OPRI) but does not receive compensation for this role. None declared (A. M.). Dupilumab Reduces Oral Corticosteroid Use in Patients With Corticosteroid-Dependent Severe Asthma: An Analysis of the Phase 3, Open-Label Extension TRAVERSE TrialCHESTVol. 162Issue 1PreviewIn the open-label TRAVERSE study, dupilumab demonstrated the ability to sustain the OCS dosage reduction from the parent OCS-sparing study, while maintaining a low exacerbation rate and improved lung function. 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