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In this installment of the How I Do It series on severe asthma, we tackle the clinical conundrum of choosing the right biologic for the right patient with severe asthma. With six biologics now approved for use in this area comprising four different targeting strategies (anti-Ig E: omalizumab; anti-IL-5 and anti-IL-5-receptor: mepolizumab, reslizumab, and benralizumab; anti-IL-4-receptor: dupilumab; anti-thymic stromal lymphopoietin: tezepelumab), this question is increasingly complex. Recognizing that no head-to-head trial has compared biologics, we based our review on the expected effects of inhibiting different aspects of type 2 airway inflammation, supported whenever possible by clinical trial and real-world data. We use four variations of a case of severe uncontrolled asthma to develop concepts and considerations introduced in the previous installment ("Workup of Severe Asthma") and discuss pregnancy-related, biomarker-related, comorbidity-related, and corticosteroid dependency-related considerations when choosing a biologic. The related questions of deciding when, why, and how to switch from one biologic to another also are discussed. Overall, we consider that the choice of biologics should be based on the available clinical trial data for the desired efficacy outcomes, the biomarker profile of the patient, safety profiles (eg, when pregnancy is considered), and opportunities to target two comorbidities with one biologic. Using systemic and airway biomarkers (blood eosinophils and exhaled nitric oxide [Feno]) and other phenotypic characteristics, we suggest a framework to facilitate therapeutic decision-making. Post hoc studies and new comparative studies are needed urgently to test this framework and to determine whether it allows us to make other clinically useful predictions., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: S. C. reports nonrestricted research grants from the NIHR Oxford BRC, the Quebec Respiratory Health Research Network, the Fondation Québécoise en Santé Respiratoire, AstraZeneca, bioMérieux, and Sanofi-Genyme-Regeneron; support as the Association Pulmonaire du Québec’s Research Chair in Respiratory Medicine and as a clinical research scholar of the Fonds de Recherche du Québec; speaker honoraria from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, and Valeo Pharma; consultancy fees from FirstThought, AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, Access Biotechnology, and Access Industries; and sponsorship to attend or speak at international scientific meetings by or for AstraZeneca and Sanofi-Regeneron. He is an advisory board member and will have stock options for Biometry, Inc., a company that is developing an Feno device (myBiometry). He advised the Institut National d’Excellence en Santé et Services Sociaux for an update of the asthma general practice information booklet for general practitioners. D. J. J. has received advisory board and speaker’s fees from AstraZeneca, Boehringer Ingelheim, Novartis, Teva, GSK, Sanofi/Regeneron, and Chiesi outside of the submitted work. I. D. P. has received speaker’s honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, Aerocrine AB, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini, and GSK in the last 5 years and has received payments for organizing educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Teva. He has received honoraria for attending advisory panels with Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi, and Knopp and has received payments to support Food and Drug Administration approval meetings from GSK. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, AstraZeneca, Teva, and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. He is copatent holder of the rights to the Leicester Cough Questionnaire and has received payments for its use in clinical trials from Merck, Bayer, and Insmed. In 2014-2015 he was an expert witness for a patent dispute involving AstraZeneca and Teva. M. E. W. reports grants and personal fees from Novartis, Sanofi, GSK, and Cohero Health; personal fees from Regeneron, Genentech, Sentien, Restorbio, Equillium, and Genzyme; grants, personal fees, and nonfinancial support from Teva; personal fees and nonfinancial support from Boehringer Ingelheim; and grants, personal fees, and nonfinancial support from AstraZeneca., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Uncontrolled asthma is associated with an increased risk of adverse perinatal outcomes. Asthma biologics reduce exacerbation frequency, are steroid sparing, and improve quality of life in people with severe asthma. However, evidence for the use and safety of asthma biologics during pregnancy is scarce, largely because pregnant women were excluded from clinical trials. To help to support clinical teams, we conducted an international modified Delphi study. 141 panellists from 32 countries who were involved in the care of people with severe asthma completed two rounds of online surveys covering key areas surrounding the use of asthma biologics in pregnancy. The results from this international Delphi study emphasise risk versus benefit discussions and shared clinical decision making, with consensus among panellists that asthma biologics can be used during conception and throughout pregnancy, initiated during pregnancy in line with prescribing criteria for non-pregnant people, and initiated or continued during breastfeeding. Collating data through international registries remains essential to inform clinical guidelines., Competing Interests: Declaration of interests JN and MC declare no competing interests. DJJ has received advisory board and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi and research grant funding to his institution from AstraZeneca. GdA has received grants from AstraZeneca, GSK, and Chiesi; consulting fees and payment for educational events from AstraZeneca, GSK, Sanofi, and Chiesi; and support to attend meetings from Chiesi and Sanofi. LGH has received research grant funding to his institution from GSK, AstraZeneca, and Roche/Genentech; lectures fees from AstraZeneca, Novartis, Roche, Genentech, Sanofi, Circassia, GSK, Chiesi, and Teva; and travel funding from AstraZeneca and GSK. LGH has sat on Novartis, Roche/Genentech, GSK, Teva, and Celltrion monitoring and advisory boards. PD has received advisory board fees, speaker fees, and congress travel support from AstraZeneca, GSK, Chiesi, and Sanofi. AB has received research grant funding to his institution from AstraZeneca and lecture fees from Chiesi. HR has received advisory board and speaker fees from GSK, Chiesi, AstraZeneca, Sanofi, and Boehringer Ingelheim; conference support from AstraZeneca; and grant funding to her institution from AstraZeneca and GSK., (Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Depemokimab is an ultra-long-acting biologic therapy with enhanced binding affinity for interleukin-5 that may enable effective 6-month dosing intervals., Methods: In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the efficacy and safety of depemokimab in patients with severe asthma and an eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per microliter in the previous 12 months or ≥150 cells per microliter at screening) and a history of exacerbations despite the receipt of medium- or high-dose inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus standard care. The primary end point was the annualized rate of exacerbations at 52 weeks. Secondary end points, which were analyzed in a hierarchical manner to adjust for multiplicity, included the change from baseline in the score on the St. George's Respiratory Questionnaire (SGRQ), the forced expiratory volume in 1 second, and asthma symptom reports at 52 weeks., Results: Across the two trials, 792 patients underwent randomization and 762 were included in the full analysis; 502 were assigned to receive depemokimab and 260 to receive placebo. The annualized rate of exacerbations was 0.46 (95% confidence interval [CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and 0.56 (95% CI, 0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41) with placebo (rate ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2. No significant between-group difference in the change from baseline in the SGRQ score was observed in either trial, so no statistical inference was drawn on subsequent secondary end points. The proportion of patients with any adverse event was similar in the two groups in both trials., Conclusions: Depemokimab reduced the annualized rate of exacerbations among patients with severe asthma with an eosinophilic phenotype. (Funded by GSK; SWIFT-1 and SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and NCT04718103.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: In asthma, clinical response is characterised by disease improvement with treatment, whereas clinical remission is characterised by long-term disease stabilisation with or without ongoing treatment. The proportions of patients receiving tezepelumab who responded to treatment and who achieved on-treatment clinical remission were assessed in the NAVIGATOR (ClinicalTrials.gov identifier NCT03347279) and DESTINATION (ClinicalTrials.gov identifier NCT03706079) studies of severe, uncontrolled asthma., Methods: NAVIGATOR and DESTINATION were phase 3, randomised, double-blind, placebo-controlled studies; DESTINATION was an extension of NAVIGATOR. Complete clinical response was defined as achieving all of the following: ≥50% reduction in exacerbations versus the previous year, improvements in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV 1 ) of ≥100 mL or ≥5%, improvements in Asthma Control Questionnaire (ACQ)-6 score of ≥0.5 and physician's assessment of asthma improvement. On-treatment clinical remission was defined as an ACQ-6 total score ≤1.5, stable lung function (pre-BD FEV 1 >95% of baseline) and no exacerbations or use of oral corticosteroids during the time periods assessed., Results: Higher proportions of tezepelumab than placebo recipients achieved complete clinical response over weeks 0-52 (46% versus 24%; OR 2.83, 95% CI 2.10-3.82) and on-treatment clinical remission over weeks 0-52 (28.5% versus 21.9%; OR 1.44, 95% CI 0.95-2.19) and weeks >52-104 (33.5% versus 26.7%; OR 1.44, 95% CI 0.97-2.14). Tezepelumab recipients who achieved on-treatment clinical remission versus complete clinical response at week 52 had better preserved lung function and lower inflammatory biomarker levels at baseline, and fewer exacerbations in the 12 months before the study., Conclusions: Among patients with severe, uncontrolled asthma, tezepelumab treatment was associated with an increased likelihood of achieving complete clinical response and on-treatment clinical remission compared with placebo. Both are clinically important outcomes, but may be driven by different patient characteristics., Competing Interests: Conflict of interest: M.E. Wechsler is an employee of National Jewish Health and has received consultancy fees from AstraZeneca, Equillium, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, resTORbio, Sanofi and Teva Pharmaceuticals. G. Brusselle has received fees for participation in advisory boards and/or speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MSD, Novartis and Sanofi. J.C. Virchow has received grants for research or clinical trials from the German Research Foundation, GSK and MSD, has received consulting fees from Avontec, Boehringer Ingelheim, Chiesi, Essex Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron Pharmaceuticals, Revotar, Roche, Sandoz-Hexal, Sanofi-Aventis, Teva Pharmaceuticals and UCB Schwarz-Pharma, has received fees for lectures from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Essex Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed Altana, Pfizer, Revotar, Sandoz-Hexal, Stallergenes Greer, Teva Pharmaceuticals, UCB Schwarz-Pharma and Zydus Cadila, has received fees for data safety-monitoring board participation from Chiesi, and has received travel support from Boehringer Ingelheim and Sanofi. A. Bourdin has received grants from AstraZeneca, Boehringer Ingelheim, Cephalon/Teva Pharmaceuticals, GSK, Novartis and Sanofi-Regeneron, has provided consultancy for Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MedinCell, Merck, Novartis, Roche and Sanofi-Regeneron, and has acted as an investigator or co-investigator for trials sponsored by Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, Galapagos, GSK, Merck, Novartis, Roche, Sanofi-Regeneron and Vertex Pharmaceuticals. K. Kostikas has received fees for presentations and/or consultancy fees from Alector Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, ELPEN, Gilead, GSK, Menarini, Novartis, Pfizer, Sanofi, Specialty Therapeutics and WebMD, and his department has received funding and/or grants from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Innovis, Menarini, Novartis and NuvoAir. J-P. Llanos is an employee of Amgen and owns stock in Amgen. S.L. Roseti, C.S. Ambrose, G. Hunter and N. Martin are employees of AstraZeneca and may own stock or stock options in AstraZeneca. D.J. Jackson has received consultancy fees and speaker fees from AstraZeneca, GSK, Novartis, Sanofi and Teva Pharmaceuticals. M. Castro reports grants/research support from ALA, AstraZeneca, Gala Therapeutics, Genentech, GSK, Novartis, Patient-Centered Outcomes Research Institute, Pulmatrix, Sanofi-Aventis, Shionogi Theravance and the US National Institutes of Health, consulting fees from Allakos, Amgen, Arrowhead, AstraZeneca, Genentech, Merck, Novartis, OM Pharma, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and has received royalties from Aer Therapeutics and Elsevier. N. Lugogo has received consultancy fees for participation in advisory boards from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received fees for non-speaker bureau presentations from AstraZeneca and GSK, has received travel support from AstraZeneca, and her institution has received research support from Amgen, AstraZeneca, Avillion, Genentech, Gossamer Bio, GSK, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals. I.D. Pavord has received speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received payments for organisation of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough and Teva Pharmaceuticals, has received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and has received a research grant from Chiesi. C.E. Brightling has received grants and consultancy fees from 4D Pharma, AstraZeneca, Chiesi, Genentech, Global Access Diagnostics (formerly Mologic), GSK, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi., (Copyright ©The authors 2024.)

Eosinophilic asthma is characterized by frequent exacerbations, poor symptom control and accelerated lung function decline. It is now recognized that the immune response underlying eosinophilic asthma involves a complex network of interconnected pathways from both the adaptive and innate immune systems. Within this response, interleukin-5 (IL-5) plays a central role in eosinophil differentiation, activation and survival and has emerged as a key target for therapies treating severe asthma. The monoclonal antibodies mepolizumab and reslizumab target the ligand IL-5, preventing its interaction with eosinophils; in contrast, benralizumab binds to the IL-5 receptor (IL-5R), preventing IL-5 from binding and leading to substantially greater eosinophil reduction by enhanced antibody-dependent cell-mediated cytotoxicity. Although no direct head-to-head clinical trials of asthma have been published to formally evaluate the clinical significance of these different therapeutic approaches, the potential benefits of partial versus complete eosinophil depletion continue to remain an important area of study and debate. Here, we review the existing real-world and clinical study data of anti-IL-5/anti-IL-5R therapies in severe eosinophilic asthma., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Benralizumab has been reported to lead to clinical remission of severe eosinophilic asthma (SEA) at 1 year in some patients. However, whether this is maintained over a longer term remains unclear. Additionally, the impact of pulmonary and extrapulmonary comorbidities on the ability to meet remission is poorly understood., Methods: Clinical outcomes including remission of SEA with benralizumab at 1 and 2 years were assessed retrospectively in a real-world UK multi-centre severe asthma cohort. The presence of clinically relevant pulmonary and extrapulmonary comorbidities associated with respiratory symptoms was recorded. Analyses to identify factors associated with the ability to meet remission were performed., Results: In total, 276 patients with SEA treated with benralizumab including 113 patients who had switched from a previous biologic to benralizumab were included. Overall, clinical remission was met in 17% (n = 31/186) and 32% (n = 43/133) of patients at 1 and 2 years, respectively. This increased to 28% at 1 year and 49% at 2 years once patients with pulmonary and/or extrapulmonary comorbidities were excluded. Body mass index (BMI) and maintenance OCS (mOCS) use demonstrated a negative association with clinical remission at 1 (BMI: OR: 0.89, 95% CI: 0.82-0.96, p < 0.01; mOCS: OR: 0.94, 95% CI: 0.89-0.99, p < 0.05) and 2 years (BMI: OR: 0.93, 95% CI: 0.87-0.99, p < 0.05; mOCS: OR: 0.95, 95% CI: 0.89-0.99, p < 0.05)., Conclusions: In this long-term, real-world study, patients with SEA demonstrated the ability to meet and sustain clinical remission when treated with benralizumab. The presence of comorbidities including obesity, which are known to be independently associated with respiratory symptoms, reduced the likelihood of meeting clinical remission., (© 2024 The Author(s). Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma., Methods: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV 1 ) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV 1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day., Results: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV 1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria., Conclusions: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Benralizumab and mepolizumab are interleukin (IL)-5Rα/interleukin-5-targeted monoclonal antibodies indicated as add-on treatments for patients with uncontrolled severe eosinophilic asthma (SEA)., Objective: To evaluate and compare the safety of benralizumab and mepolizumab among patients with SEA treated in MELTEMI and COLUMBA open-label, long-term extension studies, respectively., Methods: MELTEMI was an extension study of benralizumab every 4 weeks (q4w) or every 8 weeks (q8w) for adults (aged 18-75 y) with SEA. MELTEMI participants transitioned from the BORA extension, preceded by participation in 1 of 3 placebo-controlled studies (SIROCCO, CALIMA, or ZONDA). COLUMBA was an extension study of mepolizumab for patients (aged ≥ 12 y) with SEA who transitioned from the dose-ranging DREAM study. Safety endpoints were presented as drug exposure patient-years (MELTEMI, q4w 784.28, q8w 797.03; COLUMBA 1,201) for nonserious adverse events, serious adverse events, and infections; malignancies were counted numerically., Results: This analysis included 446 MELTEMI patients (benralizumab q4w 220; benralizumab q8w 226) and 347 COLUMBA patients (mepolizumab q4w). Viral upper respiratory tract infection was the most common nonserious adverse event in both studies (MELTEMI q8w 46.5%; q4w 47.3%; COLUMBA, 48.7%). Asthma-related events were the most common serious adverse events in both studies: MELTEMI 8.0% (q8w) and 8.6% (q4w) and COLUMBA 9.5%. Serious infections included pneumonia (MELTEMI q8w, 2 [0.9%]; COLUMBA, 6 [1.7%]); cellulitis (MELTEMI q8w, 1 [0.4%]; COLUMBA, 2 [0.6%]); and respiratory tract infections (COLUMBA, 2 [0.6%]). COLUMBA reported 6 malignancies and MELTEMI reported 4 malignancies in each group., Conclusions: This analysis demonstrated generally similar safety events between mepolizumab and benralizumab in patients with SEA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting β-agonists with or without maintenance oral corticosteroids. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16-52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-β-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified.

Background: Pivotal phase 3 trials and real-world studies have demonstrated benralizumab's overall efficacy and safety in severe eosinophilic asthma (SEA). Additional large-cohort data are needed to confirm its real-world effectiveness in SEA according to previous biologic use and key baseline characteristics important for treatment selection., Methods: XALOC-1 is a large, multinational, retrospective, observational, real-world study programme of benralizumab in adults with SEA. This 48-week integrated analysis assessed annualised exacerbation rate (AER), maintenance oral corticosteroid (mOCS) use, asthma symptom control and lung function during a 12-month baseline period and up to 48 weeks after benralizumab initiation. Subgroup analyses were based on previous biologic use and key baseline clinical characteristics (mOCS use, blood eosinophil count, exacerbation history, age at asthma diagnosis, fractional exhaled nitric oxide level and presence of atopy and chronic rhinosinusitis with nasal polyps)., Results: Out of 1002 patients analysed, 380 were biologic-experienced. At week 48, 71.3% were exacerbation-free ( versus 17.2% at baseline); relative reduction in AER was 82.7% overall and 72.9% in biologic-experienced patients; rates were maintained across all key clinical characteristic subgroups. Of patients using mOCS at baseline (n=274), 47.4% (130 out of 274) eliminated their use by week 48; the mean reduction from baseline in daily dose was 51.2% and, notably, 34.9% in biologic-experienced patients (n=115). Clinically significant improvements in asthma symptom control and lung function were observed., Conclusion: In this large, real-world programme, SEA patients treated with benralizumab had substantial improvements in clinical outcomes irrespective of previous biologic use and key clinical characteristics important to therapeutic decision-making in clinical practice., Competing Interests: Conflict of interest: D.J. Jackson has received consultancy fees and speakers’ fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Sanofi Regeneron, and research grants from AstraZeneca. G. Pelaia has received lecture fees and advisory board fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Guidotti, Insmed, Lusofarmaco, Menarini, Neopharmed Gentili, Novartis, Sanofi and Zambon. B. Emmanuel, T.N. Tran, D. Cohen, V.H. Shih, A. Shavit, M. Watt, S. Kayaniyil, M. Pardal, D. Arbetter and A.P.J. Rabe are employees of, and own stock in, AstraZeneca. S. Boarino and J. Nuevo are employees of AstraZeneca. R. Katial (currently of National Jewish Health and University of Colorado Denver, Denver, CO, USA) and E. Garcia-Gil (currently of Almirall, Barcelona, Spain) were employees of AstraZeneca at the time the study was conducted. C. Chaves Loureiro has received consultancy fees and speakers’ fees from AstraZeneca, Chiesi, GlaxoSmithKline, Sanofi Regeneron and Teva, and research grants from GlaxoSmithKline. A. Padilla-Galo reports grants, personal fees and non-financial support from AstraZeneca and Sanofi, personal fees, and non-financial support from Chiesi, GlaxoSmithKline, Novartis and Teva, and personal fees from ALK, Bial and FAES, outside the submitted work. P. Nair reports that in the past two years, his institution received grant support from AstraZeneca, Cyclomedica, Equillium, Foresee, Genentech, Sanofi and Teva; he has also received honoraria from Arrowhead, AstraZeneca, CSL Behring, GlaxoSmithKline and Sanofi., (Copyright ©The authors 2024.)

Background: Dupilumab is an anti-IL-4R monoclonal antibody (mAb) with proven efficacy in severe eosinophilic asthma (SEA). A suboptimal response to anti-IL-5/5R mAbs is seen in some patients with ongoing evidence of type 2 (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-IL-5/5R biologics. The ability to achieve clinical remission and the change in the remission domains of exacerbation rate (AER), maintenance oral corticosteroid dose (mOCS), lung function (forced expiratory volume in 1 second), and asthma control (Asthma Control Questionnaire 6) were recorded., Results: Thirty-seven patients (mean age 41 years, 70% female) were included in the analysis. The mean (standard deviation) AER fell by almost 90% from 3.16 (1.28) at dupilumab initiation to 0.35 (0.72) after 1 year. The median (interquartile range) mOCS dose (n = 20) fell from 10 (5-25) mg to 0 (0-5) mg at 1 year, with 14 of 20 (70%) able to stop prednisolone altogether. Clinical remission was achieved in 16 of 37 (43%). Patients who achieved remission had a higher pre-IL-5/5R fractional exhaled nitric oxide (FeNO) level (85 [39-198] parts per billion [ppb] vs 75 [42-96] ppb, P = .03)., Conclusions: Significant improvements in clinical outcomes are possible after a switch to dupilumab in patients experiencing a suboptimal response to anti-IL-5/5R therapies. A higher FeNO in poor responders to anti-IL-5/5R who achieve remission with dupilumab is suggestive of an IL-13-driven subphenotype of T2-high asthma in which the eosinophil appears unlikely to play a key role in the disease pathogenesis., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma., Objective: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma., Methods: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV 1 ]: <50% to ≥80%)., Results: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV 1 . The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV 1 domains, irrespective of pre-biologic impairment., Conclusion: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies., Trial Registration: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220)., Competing Interests: Disclosures Dr Perez-de-Llano reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from GlaxoSmithKline, grants, personal fees and non-financial support from Teva, personal fees and non-financial support from Chiesi, grants, personal fees and non-financial support from Sanofi, personal fees from MSD, personal fees from Techdow Pharma, grants, personal fees and non-financial support from Faes Farma, personal fees from Leo-Pharma, grants and personal fees from Gebro, personal fees from Gilead, outside the submitted work. Dr Scelo is a consultant for Observational and Pragmatic Research Institute (OPRI). OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. Dr Canonica has received research grants and lecture or advisory board fees from Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, Merck Sharp & Dohme, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. Dr Henley is affiliated with OPRI and reports receiving travel support from Eisai Limited. Dr Larenas-Linnemann reports receiving personal fees from ALK-Abelló, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GlaxoSmithKline national and global, Viatris, Menarini, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, Siegfried, UCB, Carnot, grants from AbbVie, Bayer, Lilly, Sanofi, AstraZeneca, Pfizer, Novartis, Circassia, UCB, and GlaxoSmithKline, outside the submitted work. Dr Peters declares receiving personal fees and nonfinancial support from AstraZeneca, GlaxoSmithKline, and Sanofi. Dr Pfeffer has attended advisory boards for AstraZeneca, GlaxoSmithKline, and Sanofi; has given lectures at meetings supported by AstraZeneca and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi, for which his institution received remuneration; and has a current research grant funded by GlaxoSmithKline. Dr Tran is an employee of AstraZeneca and may own stock or stock options in AstraZeneca. Dr Suppli Ulrik reports receiving personal fees for talks and having participation in advisory boards and others from AstraZeneca, GlaxoSmithKline, TEVA, Boehringer Ingelheim, Orion Pharma, Sanofi Genzyme, TFF Pharmaceuticals, Covis Pharma, Berlin-Chemie, Takeda, Chiesi, and Pfizer, outside the submitted work. Dr Popov declares relevant research support from Novartis and Chiesi Pharma. Dr Sadatsafavi has received honoraria from AstraZeneca, Boehringer Ingelheim, TEVA, and GlaxoSmithKline for purposes unrelated to the content of this manuscript and has received research funding from AstraZeneca and Boehringer Ingelheim directly into his research account from AstraZeneca for unrelated projects. Dr Hew declares receiving grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus, for unrelated projects. Dr Maspero reports receiving speaker fees and grants or serving on the advisory boards for AstraZeneca, Sanofi, GlaxoSmithKline, Novartis, Inmunotek, Menarini, and Noucor. Dr Gibson has received speaker fees and grants to his institution from AstraZeneca, GlaxoSmithKline, and Novartis. Dr FitzGerald previously declared receiving grants from AstraZeneca, GlaxoSmithKline, Sanofi Regeneron, and Novartis paid directly to UBC and receiving personal fees for lectures and attending advisory boards for AstraZeneca, GlaxoSmithKline, Sanofi Regeneron, and TEVA. Dr Torres-Duque has received fees as advisory board participant and/or speaker from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has taken part in clinical trials from AstraZeneca, Novartis, and Sanofi-Aventis; and has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, and Novartis. Dr Porsbjerg has attended advisory boards for AstraZeneca, Novartis, TEVA, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, TEVA, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, Merck Sharp & Dohme, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Novartis, TEVA, GlaxoSmithKline, ALK, and Sanofi-Genzyme. Dr Papadopoulos has been a speaker and/or advisory board member for Abbott, AbbVie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GlaxoSmithKline, HAL, Faes Farma, Medscape, Menarini, Merck Sharp & Dohme, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris. Dr Papaioannou has received fees and honoraria from Menarini, GlaxoSmithKline, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, and Chiesi. Dr Heffler declares receiving personal fees from Sanofi, Regeneron, GlaxoSmithKline, Novartis, AstraZeneca, Stallergenes, and Circassia. Dr Iwanaga received lecture fees from Kyorin, GlaxoSmithKline, Novartis, Boehringer Ingelheim, and AstraZeneca. Dr Al-Ahmad has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline and received a grant from Kuwait Foundation for the Advancement of Sciences. Dr Kuna reports receiving personal fees from Adamed, AstraZeneca, Berlin Chemie Menarini, FAES, Glenmark, Novartis, Polpharma, Boehringer Ingelheim, Teva, and Zentiva, outside the submitted work. Dr Fonseca reports receiving grants from research agreements with AstraZeneca, Mundipharma, Sanofi Regeneron, and Novartis and personal fees for lectures and attending advisory boards for AstraZeneca, GlaxoSmithKline, Mundipharma, Novartis, Sanofi Regeneron, and TEVA. Dr Al-Lehebi has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Novartis, and Abbott. Dr Rhee received consulting/lecture fees from Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline, Novartis, Takeda, Mundipharma, Boehringer Ingelheim, Teva, Sanofi, and Bayer. Dr Koh reports receiving grant support from AstraZeneca and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi, and Boehringer Ingelheim, outside the submitted work. Dr Cosio declares receiving grants from Chiesi and GlaxoSmithKline; personal fees for advisory board activities from Chiesi, GlaxoSmithKline, Novartis, Sanofi, Teva, and AstraZeneca; and payment for lectures/speaking engagements from Chiesi, Novartis, GlaxoSmithKline, Menarini, and AstraZeneca, outside the submitted work. Dr Perng (Steve) has received sponsorship to attend or speak at international meetings, honoraria for lecturing or attending advisory boards, and research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Daiichi Sankyo, Shionogi, and Orient Pharma. Dr Menzies-Gow is an employee of AstraZeneca and may own stock or stock options in AstraZeneca. Dr Jackson has received speaker fees and consultancy fees from AstraZeneca, GlaxoSmithKline, Sanofi Regeneron, and Boehringer Ingelheim and research funding from AstraZeneca. Dr Busby has received research grants from AstraZeneca and personnel fees from NuvoAir, outside the submitted work. Dr Heaney has received grant funding, participated in advisory boards, and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann-La Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva; has received grants from MedImmune, Novartis United Kingdom, Roche/Genentech Inc, GlaxoSmithKline, Amgen, Genentech/Hoffman-La Roche, AstraZeneca, MedImmune, Aerocrine, and Vitalograph; has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals; has taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann-La Roche, and GlaxoSmithKline for which his institution received remuneration; and is the Academic Lead for the Medical Research Council Stratified Medicine United Kingdom Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche, and Janssen. Dr Patel has received advisory board and speaker fees from AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi/Regeneron. Dr Wang has received honoraria from AstraZeneca, GlaxoSmithKline, and Genentech; has been an investigator on studies sponsored by AstraZeneca, GlaxoSmithKline, Genentech, Sanofi, Novartis, and Teva, for which her institution has received funding. Dr Wechsler reports receiving grants and/or personal fees from Novartis, Sanofi, Regeneron, Genentech, Sentien, Restorbio, Equillium, Genzyme, Cohero Health, Teva, Boehringer Ingelheim, AstraZeneca, Amgen, GlaxoSmithKline, Cytoreason, Cerecor, Sound Biologics, Incyte, and Kinaset. Dr Altraja has received lecture fees from AstraZeneca, Boehringer Ingelheim, Berlin-Chemie Menarini, GlaxoSmithKline, Merck Sharp & Dohme, Norameda, Novartis, Orion, Sanofi, and Zentiva; has sponsorships from AstraZeneca, Boehringer Ingelheim, Berlin-Chemie Menarini, GlaxoSmithKline, Merck Sharp & Dohme, Norameda, Novartis, and Sanofi; and has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva. Dr Lehtimäki has received personal fees from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Novartis, Orion Pharma, and Sanofi. Dr Bourdin has received industry-sponsored grants from AstraZeneca/MedImmune, Boehringer Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, and Sanofi-Regeneron and conducted consultancies with AstraZeneca/MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron-Sanofi, Med-in-Cell, Actelion, Merck, Roche, and Chiesi. Dr Bjermer has (in the last 3 years) received lecture or advisory board fees from Alk-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Novartis, Sanofi, Genzyme/Regeneron, and Teva. Ms Bulathsinhala is an employee of the OPRI. OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. Ms Carter is an employee of Optimum Patient Care, which is a co-funder of the International Severe Asthma Registry. Dr Murray is a consultant for OPRI. OPRI conducted this study in collaboration with Optimum Patient Care and AstraZeneca. Mr Beastall is an employee of the Optimum Patient Care Global, a co-funder of the International Severe Asthma Registry. Dr Denton declares receiving grants to her institution from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva, and Seqirus, for unrelated projects and speaker fees from Sanofi. Dr Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, and Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, and Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies (conducted through OPRI Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and United Kingdom National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Commune Digital, GlaxoSmithKline, Medscape, Viatris, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme, and Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Medscape, and Teva Pharmaceuticals; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and United Kingdom) and 92.61% of OPRI Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the United Kingdom Efficacy and Mechanism Evaluation Programme and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. The remaining authors have no conflicts of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: ML reports grants for research or clinical trials, paid to his institution, from AstraZeneca, Deutsche Forschungsgemeinschaft (DFG), and GSK; and consulting fees, travel expenses, or honoraria for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, HAL Allergy, Leti, Novartis, MSD, Sanofi, Stallergenes, and Teva. RB reports grants, paid to his institution, from Boehringer Ingelheim, GSK, Novartis, and Roche; speaker fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Sanofi, Roche, and Teva; and payment for advisory board participation from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Sanofi, Roche, and Teva. GWC reports research or clinical trial grants, paid to his institution, from Menarini, AstraZeneca, GSK, Sandi, and Genzyme; and personal fees for lectures and advisory board participation from Menarini, AstraZeneca, Chiesi, Faes Farma, Genentech, Guidotti-Malesci, GSK, HAL Allergy, Innovacaremed, Novartis, OM Pharma, Red Maple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes, and Uriach Pharma. CDR reports funding for travel and speaker fees from Novartis, Sanofi, GSK, TEVA, MSD, Almirall, AstraZeneca, Chiesi, Menarini, Stallergens, ALK-Abello, Allergy Therapeutics, HAL Allergy, Immunotek, and Royal. HN reports grants from GSK and personal fees from AstraZeneca, GSK, Kyorin Pharmaceutical, Novartis, and Sanofi; he is a scientific advisor for GSK. GGB reports personal fees for advisory board participation and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi, outside of the submitted work. DJJ has received an investigator-initiated research grant from AstraZeneca and reports fees for advisory board participation and lectures from AstraZeneca, Sanofi, and GSK. In the past 5 years, IDP has received honoraria for speaking at sponsored meetings from AstraZeneca, Aerocrine, Chiesi, Sanofi/Regeneron, Menarini, and GSK; payments for organising educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Teva; honoraria for advisory panel participation from Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi, and Knopp; and sponsorship to attend international scientific meetings from GSK, AstraZeneca, Teva, and Chiesi. SK reports consulting fees and speaker fees from AstraZeneca, GSK, Chiesi, Sanofi, and Novartis. KM reports consulting fees and speaker frees from AstraZeneca, GSK, and Sanofi; and speaker fees from Chiesi and Novartis. JCV reports research grants from DFG, Land Mecklenburg-Vorpommern, GSK, and MSD; he has given independent lectures for and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Lupin, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Regeneron, Revotar, Sandoz-Hexal, Sanofi-Aventis, Stallergens, TEVA, UCB/Schwarz-Pharma, and Zydus/Cadila; and participated on advisory boards and provided independent advice for AstraZeneca, Avontec, Bayer, Bencard, Boehringer Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, TEVA, and UCB/Schwarz-Pharma. CT declares no competing interests.

Background: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists., Methods: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519., Findings: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study., Interpretation: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control., Funding: AstraZeneca., Competing Interests: Declaration of interests DJJ has received advisory board and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi. LGH has received grant funding, participated in advisory boards, and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Evelo Biosciences, GSK, Hoffmann-La Roche, Novartis, Sanofi, Teva, and Theravance; he has received grants from Aerocrine, Amgen, AstraZeneca, Genentech/Hoffman-La Roche, GSK, MedImmune, Novartis UK, Roche/Genentech, and Vitalograph; he has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, and Napp Pharmaceuticals; he has also taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, GSK, and Hoffmann-La Roche, for which his institution received remuneration; he is the academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies, including Amgen, AstraZeneca, Boehringer Ingelheim, GSK, Hoffmann-La Roche, and Janssen. MH has received consulting fees from AstraZeneca, Chiesi, GSK, Novartis, and Sanofi. BDK has participated in advisory boards or received speaker fees from AstraZeneca, Chiesi, GSK, Novartis, and Teva; has received educational travel bursaries from Boehringer Ingelheim, Chiesi, and Napp Pharmaceuticals; and has received research funding from Itamar Medical. AS was an employee of AstraZeneca at the time of this study and may own stock. LH was an employee of AstraZeneca at the time of this study and may own stock. LO is an employee of Cytel and was on contract to AstraZeneca at the time of this study. DC was an employee of AstraZeneca at the time of this study and may own stock. AM-G was an employee of AstraZeneca at the time of this study and may own stock; has attended advisory boards for AstraZeneca, GSK, Novartis, Regeneron, Sanofi, and Teva; has received speaker fees from AstraZeneca, Novartis, Sanofi, and Teva; has participated in research with AstraZeneca, for which his institution was remunerated; and has had consultancy agreements with AstraZeneca and Sanofi. SK has received grants and personal fees for lectures and advisory boards from AstraZeneca, GSK, Novartis, Sanofi-Genzyme, and Teva., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Novel biologic therapies have revolutionised the management of severe asthma with more ambitious treatment aims. Here we analyse the definition of clinical remission as a suggested treatment goal and consider the characteristics associated with clinical remission in a large, real-world severe asthma cohort., Methods: This was a retrospective analysis of severe asthma patients registered in the UK Severe Asthma Registry (UKSAR) who met strict national access criteria for biologics. Patients had a pre-biologics baseline assessment and annual review. The primary definition of clinical remission applied included Asthma Control Questionnaire (ACQ)-5 <1.5 and no oral corticosteroids for disease control and forced expiratory volume in 1 s above lower limit of normal or no more than 100 mL less than baseline., Results: 18.3% of patients achieved the primary definition of remission. The adjusted odds of remission on biologic therapy were 7.44 (95% CI 1.73-31.95)-fold higher in patients with type 2 (T2)-high biomarkers. The adjusted odds of remission were lower in patients who were female (OR 0.61, 95% CI 0.45-0.93), obese (OR 0.49, 95% CI 0.24-0.65) or had ACQ-5 ≥1.5 (OR 0.19, 95% CI 0.12-0.31) pre-biologic therapy. The likelihood of remission reduced by 14% (95% CI 0.76-0.97) for every 10-year increase in disease duration. 12-21% of the cohort attained clinical remission depending on the definition applied; most of those who did not achieve remission failed to meet multiple criteria., Conclusions: 18.3% of patients achieved the primary definition of clinical remission. Remission was more likely in T2-high biomarker patients with shorter duration of disease and less comorbidity. Further research on the optimum time to commence biologics in severe asthma is required., Competing Interests: Conflict of interest: The UK Severe Asthma Registry (UKSAR) does not receive any monetary benefits or benefits-in-kind from any pharmaceutical entity; UKSAR does make limited data contributions to the International Severe Asthma Registry (ISAR) and the European Respiratory Society Clinical Research Collaborative (SHARP), which do receive pharmaceutical funding. P.J. McDowell reports speaker fees from GlaxoSmithKline and scientific meeting support from Chiesi. R. McDowell and M. Patel have no conflicts of interest to declare. M.C. Eastwood reports support to attend meetings from GlaxoSmithKline. J. Busby reports grants from AstraZeneca and personal fees from Nuvoair. P.H. Patel received advisory board fees and lecture fees from AstraZeneca, GlaxoSmithKline, Novartis and Sanofi. D.J. Jackson has received speaker fees and consultancy fees from AstraZeneca, GlaxoSmithKline and Sanofi Regeneron. A. Mansur declares personal and to institution payment for talks, advisory board meetings and sponsorship to attend conferences from AstraZeneca, GlaxoSmithKline, Teva, Sanofi, Novartis and Boehringer Ingelheim; he also declares research grants from GlaxoSmithKline. H. Burhan reports fees for advisory board meetings from AstraZeneca and Novartis, honoraria for lectures from AstraZeneca, Chiesi, GSK and Sanofi, and support for attending conferences from AstraZeneca, Chiesi and GSK. S. Doe has participated on advisory boards for Vertex, Gilead and Novartis, and has received support for travel to meetings from GlaxoSmithKline, AstraZeneca, Gilead, Teva; Sanofi, Chiesi and Forest, and fees for lectures from GlaxoSmithKline, AstraZeneca and Sanofi. R. Chaudhuri has received lecture fees from GlaxoSmithKline, AstraZeneca, Teva, Chiesi, Sanofi and Novartis, honoraria for advisory board meetings from GlaxoSmithKline and AstraZeneca, sponsorship to attend international scientific meetings from Chiesi, Sanofi and GlaxoSmithKline, and a research grant (paid to institute) from AstraZeneca for a UK multicentre study. R. Gore has received fees for lecturing from AstraZeneca, Novartis, Sanofi and GlaxoSmithKline. J.W. Dodd declares he has received honoraria for participating in advisory boards and given lectures at meetings supported by GlaxoSmithKline, Boehringer Ingelheim, Chiesi, AstraZeneca, Fisher & Paykel and Aerogen; he has received sponsorship for attending international scientific meetings from Chiesi; he has also taken part in asthma clinical trials sponsored by Sanofi, AstraZeneca and Chiesi, for which his institution received remuneration; his institution has received funding for research from the MRC, NIHR, SBRI, NHSx, Templeton Foundation and Southmead Hospital research charity. T. Brown has received fees as an external expert from AstraZeneca, speaker fees from AstraZeneca, GlaxoSmithKline, Sanofi, Teva, Novartis and Chiesi, honoraria for advisory board attendance from AstraZeneca, Sanofi and Teva, and sponsorship to attend international scientific meetings from Sanofi, GlaxoSmithKline, Teva, Chiesi and Napp Pharmaceuticals. D. Subramanian is part of the AstraZeneca Precision National Working group and has received speaker fees from Chiesi. L.G. Heaney is academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies., (Copyright ©The authors 2023.)

Background: Effectiveness of biologics has neither been established in patients with high oral corticosteroid exposure (HOCS) nor been compared with effectiveness of continuing with HOCS alone., Objective: To examine the effectiveness of initiating biologics in a large, real-world cohort of adult patients with severe asthma and HOCS., Methods: This was a propensity score-matched, prospective cohort study using data from the International Severe Asthma Registry. Between January 2015 and February 2021, patients with severe asthma and HOCS (long-term OCSs for ≥1 year or ≥4 courses of rescue OCSs within a 12-month period) were identified. Biologic initiators were identified and, using propensity scores, matched 1:1 with noninitiators. The impact of biologic initiation on asthma outcomes was assessed using generalized linear models., Results: We identified 996 matched pairs of patients. Both groups improved over the 12-month follow-up period, but improvement was greater for biologic initiators. Biologic initiation was associated with a 72.9% reduction in the average number of exacerbations per year versus noninitiators (0.64 vs 2.06; rate ratio, 0.27 [95% CI, 0.10-0.71]). Biologic initiators were 2.2 times more likely than noninitiators to take a daily long-term OCS dose of less than 5 mg (risk probability, 49.6% vs 22.5%; P = .002) and had a lower risk of asthma-related emergency department visits (relative risk, 0.35 [95% CI, 0.21-0.58]; rate ratio, 0.26 [0.14-0.48]) and hospitalizations (relative risk, 0.31 [95% CI, 0.18-0.52]; rate ratio, 0.25 [0.13-0.48])., Conclusions: In a real-world setting, including patients with severe asthma and HOCS from 19 countries, and within an environment of clinical improvement, initiation of biologics was associated with further improvements across multiple asthma outcomes, including exacerbation rate, OCS exposure, and health care resource utilization., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Oral corticosteroids (OCS) for asthma are associated with increased risks of developing adverse outcomes (adverse outcomes); no previous study has focused exclusively on intermittent OCS use., Methods: This historical (2008-2019) UK cohort study using primary care medical records from two anonymised, real-life databases (OPCRD and CPRD) included patients aged≥4 years with asthma receiving only intermittent OCS. Patients were indexed on their first recorded intermittent OCS prescription for asthma and categorised by OCS prescribing patterns: one-off (single), less frequent (≥90 day gap) and frequent (<90 day gap). Non-OCS patients matched 1:1 on gender, age and index date served as controls. The association of OCS prescribing patterns with OCS-related AO risk was studied, stratified by age, Global Initiative for Asthma (GINA) 2020 treatment step, and pre index inhaled corticosteroid (ICS) and short-acting β 2 -agonist (SABA) prescriptions using a multivariable Cox-proportional hazard model., Findings: Of 476 167 eligible patients, 41.7%, 26.8% and 31.6% had one-off, less frequent and frequent intermittent OCS prescribing patterns, respectively. Risk of any AO increased with increasingly frequent patterns of intermittent OCS versus non-OCS (HR; 95% CI: one-off 1.19 (1.18 to 1.20), less frequent 1.35 (1.34 to 1.36), frequent 1.42 (1.42 to 1.43)), and was consistent across age, GINA treatment step and ICS and SABA subgroups. The highest risks of individual OCS-related adverse outcomes with increasingly frequent OCS were for pneumonia and sleep apnoea., Conclusion: A considerable proportion of patients with asthma receiving intermittent OCS experienced a frequent prescribing pattern. Increasingly frequent OCS prescribing patterns were associated with higher risk of OCS-related adverse outcomes. Mitigation strategies are needed to minimise intermittent OCS prescription in primary care., Competing Interests: Competing interests: HH, DS, JSKC, CA and VC are employees of Observational and Pragmatic Research Institute Singapore who conducted this study, funded by AstraZeneca. JC, EM and TNT are employees of, and own stock in, AstraZeneca. AB has received consultancy fees and speakers’ fees from of AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, GlaxoSmithKline, Sanofi Regeneron and Chiesi, and research grants from GlaxoSmithKline, Boehringer Ingelheim and AstraZeneca. AM-G has received grants, advisory board fees, lecture fees and consulting fees from AstraZeneca; advisory board fees from GlaxoSmithKline; advisory board fees and lecture fees from Novartis; advisory board fees, lecture fees and travel expenses from Teva; advisory board fees from Regeneron; advisory board fees, lecture fees and consulting fees from Sanofi. DJJ has received consultancy fees and speakers’ fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Sanofi Regeneron and Chiesi, and research grants from AstraZeneca. JH reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Circassia and Teva unrelated to the conduct of the study. DP has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Thermofisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, Theravance and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life., Methods: This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions., Results: In the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p < 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs. 20.55% reduction; p = 0.023). There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43)., Conclusions: In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods., Methods: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete., Findings: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 μg daily to 1000 μg daily (500 μg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 μg once daily to 500 μg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA., Interpretation: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden., Funding: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline., Competing Interests: Declaration of interests DJJ reports grants from AstraZeneca and personal fees from Sanofi Regeneron, AstraZeneca, and GlaxoSmithKline. BDK report personal fees from AstraZeneca and GlaxoSmithKline. GG reports patents to quantify adherence and to predict exacerbations. CH reports fees from Alphabet, granted as part of employment by Google. DMM reports personal fees from AstraZeneca, Teva, GlaxoSmithKline, Sanofi, and Novartis. RBR reports a patent for the use of acoustics to assess inhaler adherence. JFMvB reports institutional grants from Aardex, AstraZeneca, Chiesi, European Commission COST Action 19132 ENABLE, Lung Alliance Netherlands, Novartis, Trudell Medical and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Teva, Trudell Medical, and Vertex. LGH was academic lead for the UK MRC Consortium for Stratified Medicine in Severe Asthma—Industrial Pharma partners Amgen, AstraZeneca, Medimmune, Janssen, Novartis, Roche–Genentech, GlaxoSmithKline, and Boehringer Ingelheim; grants or contracts from GlaxoSmithKline, Schering Plough, Synairgen, Novartis and Roche–Genentech MedImmune, Novartis UK, Roche–Genentech and GlaxoSmithKline; and lectures supported by AstraZeneca, Novartis, Roche–Genentech, Sanofi, Circassia, GlaxoSmithKline, Chiesi, and Teva. RWC reports institutional grants from GlaxoSmithKline, Aerogen, and Enterprise Ireland; personal fees from AstraZeneca, Teva, GlaxoSmithKline, PMD solutions, and Novartis; and a patent for the use of acoustics to assess inhaler adherence, to quantify adherence and to predict exacerbations. EM, CM, MCM, BC, IS, VB, PJK, MB, IC, JF, JH, MK, RC, LL, JW, SP, TAM, and AMNK declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Approximately 5% to 10% of patients with asthma have severe disease, with a consistent preponderance in females. Current asthma guidelines recommend stepwise treatment to achieve symptom control with no differential treatment considerations for either sex., Objective: To examine whether patient sex affects outcomes when using a composite T2-biomarker score to adjust corticosteroid (CS) treatment in patients with severe asthma compared with standard care., Methods: This is a post hoc analysis, stratifying patient outcomes by sex, of a 48-week, multicenter, randomized controlled clinical trial comparing a biomarker-defined treatment algorithm with standard care. The primary outcome was the proportion of patients with a reduction in CS treatment (inhaled and oral corticosteroids). Secondary outcomes included exacerbation rates, hospital admissions, and lung function., Results: Of the 301 patients randomized, 194 (64.5%) were females and 107 (35.5%) were males. The biomarker algorithm led to a greater proportion of females being on a lower CS dose versus standard care, which was not seen in males (effect estimate: females, 3.57; 95% CI, 1.14-11.18 vs males, 0.54; 95% CI, 0.16-1.80). In T2-biomarker-low females, reducing CS dose was not associated with increased exacerbations. Females scored higher in all domains of the 7-item Asthma Control Questionnaire, apart from FEV1, but with no difference when adjusted for body mass index/anxiety and/or depression. Dissociation between symptoms and T2 biomarkers were noted in both sexes, with a higher proportion of females being symptom high/T2-biomarker low (22.8% vs 15.6%; P = .0002), whereas males were symptom low/T2-biomarker high (22.3% vs 11.4%; P < .0001)., Conclusions: This exploratory post hoc analysis identified that females achieved a greater benefit from biomarker-directed CS optimization versus symptom-directed treatment., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Oral corticosteroid (OCS) dependence among patients with severe eosinophilic asthma can cause adverse outcomes, including adrenal insufficiency. PONENTE's OCS reduction phase showed that, following benralizumab initiation, 91.5% of patients eliminated corticosteroids or achieved a final dosage ≤5 mg·day -1 (median (range) 0.0 (0.0-40.0) mg)., Methods: The maintenance phase assessed the durability of corticosteroid reduction and further adrenal function recovery. For ∼6 months, patients continued benralizumab 30 mg every 8 weeks without corticosteroids or with the final dosage achieved during the reduction phase. Investigators could prescribe corticosteroids for asthma exacerbations or increase daily dosages for asthma control deteriorations. Outcomes included changes in daily OCS dosage, Asthma Control Questionnaire (ACQ)-6 and St George's Respiratory Questionnaire (SGRQ), as well as adrenal status, asthma exacerbations and adverse events., Results: 598 patients entered PONENTE; 563 (94.1%) completed the reduction phase and entered the maintenance phase. From the end of reduction to the end of maintenance, the median (range) OCS dosage was unchanged (0.0 (0.0-40.0) mg), 3.2% (n=18/563) of patients experienced daily dosage increases, the mean ACQ-6 score decreased from 1.26 to 1.18 and 84.5% (n=476/563) of patients were exacerbation free. The mean SGRQ improvement (-19.65 points) from baseline to the end of maintenance indicated substantial quality-of-life improvements. Of patients entering the maintenance phase with adrenal insufficiency, 32.4% (n=104/321) demonstrated an improvement in adrenal function. Adverse events were consistent with previous reports., Conclusions: Most patients successfully maintained maximal OCS reduction while achieving improved asthma control with few exacerbations and maintaining or recovering adrenal function., Competing Interests: Conflict of interest: A. Menzies-Gow has attended advisory boards for AstraZeneca, GlaxoSmithKline, Novartis, Sanofi and Teva, and is a steering committee member for the AstraZeneca PONENTE study; received speakers’ fees from AstraZeneca, Novartis, Sanofi and Teva; participated in research with AstraZeneca, for which his institution has been remunerated; attended international conferences with Teva; and made consultancy agreements with AstraZeneca and Sanofi. M. Gurnell is a steering committee member for the AstraZeneca PONENTE study; received travel support from AstraZeneca; and has received speakers’ fees from AstraZeneca, Novartis and Teva. L.G. Heaney is academic lead for the UK MRC Consortium for Stratified Medicine in Severe Asthma; he is industrial partner with Amgen, AstraZeneca, MedImmune, Janssen, Novartis, Roche/Genentech, GlaxoSmithKline and Boehringer Ingelheim; has prior project grant funding from MedImmune, Novartis UK, Roche/Genentech and GlaxoSmithKline; has taken part in advisory boards/lectures supported by AstraZeneca, Chiesi, Novartis, Roche/Genentech, GlaxoSmithKline, Teva, Theravance and Vectura; received travel funding support to attend international respiratory meetings from AstraZeneca, Chiesi, Novartis, Boehringer Ingelheim, Teva and GlaxoSmithKline; and has taken part in asthma clinical trials for GlaxoSmithKline, Schering-Plough, Synairgen, Novartis and Roche/Genentech, for which his institution was remunerated. J. Corren has received grants from AstraZeneca, in addition to grants and personal fees from Genentech, Novartis, Regeneron Pharmaceuticals and Sanofi. E.H. Bel reports grants from GlaxoSmithKline and Teva, which were paid to her institution; serves on the AstraZeneca data safety monitoring board for benralizumab; is a steering committee member for the AstraZeneca PONENTE and NOVELTY studies; serves on the GlaxoSmithKline Nucala Global Steering Committee; and received personal fees from GlaxoSmithKline, AstraZeneca, Chiesi, Sanofi/Regeneron and Teva. J. Maspero has consulted for AstraZeneca, Sanofi and Teva; was a speaker for GlaxoSmithKline, Menarini, Novartis and Uriach; and received research grants from Novartis. T. Harrison reports grants from AstraZeneca and the National Institute for Health Research, UK; personal fees and non-financial support from AstraZeneca; and is a steering committee member for the AstraZeneca PONENTE study, GlaxoSmithKline, Vectura, Boehringer Ingelheim, Chiesi and Synairgen; during the study's completion, he also became an employee of AstraZeneca. D.J. Jackson has received speakers’ honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis and Teva, and honoraria for attending advisory panels with AstraZeneca, GlaxoSmithKline, Novartis, Chiesi, Sanofi/Regeneron and Teva. D. Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme and Thermo Fisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc., Strategic North Limited, Synapse Research Management Partners SL, Talos Health Solutions, Theravance and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; received payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; received payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis and Thermo Fisher; has stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); has 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. N. Lugogo received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GlaxoSmithKline, Novartis, Regeneron, Sanofi and Teva; honoraria for non-speakers’ bureau presentations from GlaxoSmithKline and AstraZeneca; and travel support from AstraZeneca; her institution received research support from Amgen, AstraZeneca, Avillion, Evidera, Gossamer Bio, Genentech, GlaxoSmithKline, Regeneron, Sanofi, Novartis and Teva. J. Kreindler, A. de Giorgio-Miller, S. Faison and K. Padilla are full-time employees of and stockholders in AstraZeneca. K. Padilla is also a member of the board of advisors for TruLab, Inc., Durham, NC. U.J. Martin was an employee of and stockholder in AstraZeneca at the time of the study. A. Burden was a contract employee of AstraZeneca at the time of the study; her current affiliation is Ardnamhor Consulting Limited, Kilcreggan, UK. E. Garcia Gil was an employee and stockholder of AstraZeneca at the time of the study; her current affiliation is Almirall, Barcelona, Spain., (Copyright ©The authors 2022.)

Background: The benefits of specialist assessment and management have yet to be evaluated within the biologic era of UK severe asthma treatment, and potential disparities have not been considered., Methods: In an uncontrolled before-and-after study, we compared asthma symptoms (Asthma Control Questionnaire-6 (ACQ-6)), exacerbations, unscheduled secondary care use, lung function (forced expiratory volume in 1 s (FEV 1 )) and oral corticosteroid (OCS) dose after 1 year. We compared outcomes by sex, age (18-34, 35-49, 50-64 and ≥65 years), ethnicity (Caucasian versus non-Caucasian) and hospital site after adjusting for demographics and variation in biologic therapy use., Results: 1140 patients were followed-up for 1370 person-years from 12 specialist centres. At annual review, ACQ-6 score was reduced by a median (interquartile range (IQR)) of 0.7 (0.0-1.5), exacerbations by 75% (33-100%) and unscheduled secondary care by 100% (67-100%). FEV 1 increased by a median (IQR) of 20 (-200-340) mL, while OCS dose decreased for 67% of patients. Clinically meaningful improvements occurred across almost all patients, including those not receiving biologic therapy. There was little evidence of differences across demographic groups, although those aged ≥65 years demonstrated larger reductions in exacerbations (69% versus 52%; p<0.001) and unscheduled care use (77% versus 50%; p<0.001) compared with patients aged 18-34 years. There were >2-fold differences between the best and worst performing centres across all study outcomes., Conclusions: Specialist assessment and management is associated with substantially improved patient outcomes, which are broadly consistent across demographic groups and are not restricted to those receiving biologic therapy. Significant variation exists between hospitals, which requires further investigation., Competing Interests: Conflict of interest: C. Redmond and J. Busby declare no competing interests. L.G. Heaney is academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies. A. Menzies-Gow has consultancy agreements with AstraZeneca and Sanofi; is participating in research funded by AstraZeneca; has received lecture fees from Teva, AstraZeneca, Novartis and Sanofi; has attended advisory boards for Novartis, Sanofi, GlaxoSmithKline, AstraZeneca and Teva; and has attended international conferences with Teva. D.J. Jackson has received advisory board and speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Napp and Novartis. P. Pfeffer has attended advisory boards for AstraZeneca, GlaxoSmithKline and Sanofi; has given lectures at meetings with/without lecture honoraria supported by AstraZeneca and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline and Novartis; and is conducting research funded by GlaxoSmithKline for which his institution receives remuneration. R. Chaudhuri has received lecture fees from GlaxoSmithKline, AstraZeneca, Teva, Chiesi, Sanofi and Novartis; honoraria for advisory board meetings from GlaxoSmithKline, AstraZeneca, Teva, Chiesi and Novartis; sponsorship to attend international scientific meetings from Chiesi, Napp, Sanofi and GlaxoSmithKline; and a research grant to her institute from AstraZeneca for a UK multicentre study., (Copyright ©The authors 2022.)

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4/-13, key and central drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA VENTURE (VENTURE) study (NCT02528214), dupilumab versus placebo reduced oral corticosteroid (OCS) dose and improved clinical outcomes in patients with OCS-dependent severe asthma. Dupilumab efficacy in patients with varying disease burden (defined by baseline OCS dose) has not been assessed., Objective: This post hoc analysis of VENTURE evaluated dupilumab efficacy across subgroups defined by baseline OCS dose., Methods: The OCS dose, proportion no longer needing OCS at week 24, annualized severe exacerbation rate, and least squares mean change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 second at week 24 were evaluated in VENTURE patients with OCS-dependent severe asthma receiving dupilumab 300 mg every 2 weeks versus placebo, categorized by a baseline OCS dose of less than 10 mg/d or 10 or more mg/d., Results: Dupilumab reduced daily OCS dose from baseline at week 24 in both dose groups. In dupilumab-/placebo-treated patients with a baseline OCS dose of less than 10 mg/d and 10 or more mg/d, 72%/42% and 37%/23% stopped OCS by week 24 (P < .01/P < .05), respectively. Dupilumab significantly reduced the annualized severe exacerbation rate by 71% and 48% (P < .01/P < .05). At week 24, dupilumab improved pre- and post-bronchodilator forced expiratory volume in 1 second in patients in both dose groups., Conclusions: In patients with OCS-dependent severe asthma receiving lower or higher baseline OCS doses, dupilumab significantly reduced the OCS dose and improved the likelihood of no longer requiring OCS while also reducing exacerbations and improving lung function., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Benralizumab is an IL-5 receptor alpha-directed cytolytic mAb that depletes eosinophils, reducing exacerbations and oral corticosteroid (OCS) use, and improves asthma control for patients with severe eosinophilic asthma (SEA). Data on response in patients previously treated with other biologic therapies are limited., Objective: To describe real-world clinical outcomes with benralizumab for patients with and without prior biologic use for uncontrolled SEA., Methods: This retrospective study compared clinical outcomes before and after benralizumab initiation in adults with uncontrolled SEA with 3 or more asthma exacerbations in the previous 12 months or on maintenance OCS treatment. Outcomes included exacerbations, OCS use, patient-reported outcomes, and health care resource utilization, including emergency department visits and hospitalizations., Results: In all, 208 patients were enrolled, including 90 (43.3%) with previous experience with an alternate biologic for SEA. Benralizumab led to an 81% reduction in exacerbation rate, with 48% of patients with previous exacerbations experiencing none after 48 weeks. Overall, 67% of patients requiring baseline maintenance OCS achieved greater than or equal to 50% reduction in daily OCS dosage, and 53% eliminated maintenance OCS. Clinically meaningful improvements in patient-reported outcomes were seen, with response at 4 weeks predicting longer-term benefits. Health care resource utilization also decreased. Improvements were observed irrespective of previous biologic experience, fractional exhaled nitric oxide concentrations, atopic status, or other baseline characteristics., Conclusions: In a multicenter real-world setting, patients with uncontrolled SEA achieved substantial improvements in all clinical outcome measures with benralizumab irrespective of previous biologic use, atopic status, or baseline fractional exhaled nitric oxide concentration., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Infrequent use of inhaled corticosteroids (ICS) and/or over-reliance of short-acting β-agonists (SABA) are recognised as key contributors to increased morbidity and mortality in asthma. The most frequent measures of ICS adherence and SABA use rely on patient-reported questionnaires or prescription refill records, neither of which are considered sufficiently reliable. Technological advancements in the development of electronic monitoring of inhaler devices allow for monitoring of use, as well as recording of and feedback on inhaler technique for some devices. Most electronic monitoring devices (EMDs) are paired with a smartphone application, allowing patients to set reminders and display both preventer and reliever use over time. This allows identification of intentional and unintentional ICS non-adherence as well as frequency of SABA use. This information assists clinicians in distinguishing difficult-to-control from severe asthma. Although additional evidence is required to assess the impact of EMDs on clinical outcome measures such as exacerbation rate, the introduction of EMDs into the asthma armoury is a significant step forward in asthma care with the potential to improve asthma-related outcomes., Competing Interests: Conflict of interest: H. Dhruve reports receiving honoraria from Asthma UK Centre for Applied Research, University College London, Pharmacy Management, and Primary Care Respiratory Society, outside the submitted work. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Pharmacy Management, Primary Care Respiratory Society, London Respiratory Network, Academic Health Science Network – Severe asthma sub-committee. Conflict of interest: D.J. Jackson reports receiving grants or contracts from AstraZeneca outside the submitted work. Consulting fees from AstraZeneca, GSK, and Sanofi Regeneron, outside the submitted work. Speaker fees received from AstraZeneca, GSK, and Sanofi Regeneron, outside the submitted work., (Copyright ©The authors 2022.)

Competing Interests: Declaration of interests ML has received consulting fees or honoraria, or both for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, HAL Allergy, Leti, Novartis, MSD, Sanofi, and TEVA; and grants for research or clinical trials, or both from Deutsche Forschungsgemeinschaft, AstraZeneca, and GSK. GGB has received honoraria for lectures from AstraZeneca, GSK, Boehringer Ingelheim, Novartis, Chiesi, and Sanofi. GWC has received consulting fees or honoraria, or both for lectures from AstraZeneca, Chiesi, Novartis, Sanofi, Menarini, Stallergenes Greer, GSK, and HAL Allergy. DJJ has received consulting fees or honoraria or both for lectures from AstraZeneca, GSK, and Sanofi; and grants for research from AstraZeneca. PN has received personal fees or grants, or both from AstraZeneca, TEVA, Sanofi, Equillium, Foresee, Arrowhead Pharma, Cyclomedica, and GSK. RB has received consulting fees or honoraria, or both for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, HAL Allergy, Leti, Novartis, Roche, Sanofi, and TEVA; and grants for research or clinical trials, or both from Boehringer Ingelheim, GSK, Novartis, and Roche. JCV has received consulting fees or honoraria, or both for lectures from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Genzyme, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed (Altana), Pfizer, Regeneron, Revotar, Sanofi, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, and Cadila; and received grants for research or clinical trials, or both from Deutsche Forschungsgemeinschaft, GSK, and MSD.

Background: No consensus exists on how to reduce oral corticosteroids after the initiation of biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency monitoring, after benralizumab initiation., Methods: This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment centres across 17 countries. We enrolled adult patients (age ≥18 years) with severe, eosinophilic asthma (blood eosinophil count ≥150 cells per μL at enrolment or ≥300 cells per μL in the previous year) requiring maintenance oral corticosteroids for at least 3 months preceding enrolment. Patients received benralizumab 30 mg (subcutaneous injection) every 4 weeks for three doses, then every 8 weeks thereafter. The oral corticosteroid reduction phase began at week 4 with daily oral corticosteroid dosages reduced by 1-5 mg every 1-4 weeks depending on the starting dosage, asthma control, and adrenal function status. Adrenal function was assessed with an early morning serum cortisol measurement, followed by adrenocorticotropic hormone stimulation when required, once patients achieved a daily oral corticosteroid dosage of 5 mg/day for 4 weeks. Repeat cortisol measurements were taken for patients with evidence of adrenal insufficiency at first testing. Asthma control was assessed with the Asthma Control Questionnaire-6 (ACQ-6) weekly throughout the induction and oral corticosteroid reduction phases. The primary endpoints were the percentage of patients eliminating daily oral corticosteroids, sustained for at least 4 weeks, and the percentage achieving elimination or a daily prednisone or prednisolone dosage of 5 mg or less, for at least 4 weeks, if the reason for no further reduction was adrenal insufficiency. Safety and efficacy analyses included all patients who received at least one dose of benralizumab and were descriptive. We present results after the oral corticosteroid reduction phase; a maintenance phase is ongoing. The trial is registered with ClinicalTrials.gov, NCT03557307., Findings: Between April 1, 2018, and Sept 5, 2020, of 705 patients assessed for eligibility, 598 were recruited and all received at least one dose of benralizumab. Overall, 376 (62·88%, 95% CI 58·86-66·76) of 598 patients eliminated oral corticosteroids and 490 (81·94%, 78·62-84·94) of 598 eliminated use or achieved a dosage of 5 mg or less if the reason for stopping the reduction was adrenal insufficiency. Subgroup analysis showed that dosage reductions were achieved irrespective of baseline eosinophil count, baseline oral corticosteroid dosage, or oral corticosteroid treatment duration. Adrenal insufficiency was detected in 321 (60%) of 533 patients at first assessment and in 205 (38%) of 533 patients 2-3 months later. The safety profile was consistent with previous experience. Most patients (448 [75%] of 598) had no asthma exacerbations during the oral corticosteroid reduction phase with an annualised exacerbation rate of 0·63. Of 598 patients, 38 (6%) experienced a total of 46 exacerbations resulting in emergency department or urgent care visits or hospitalisations., Interpretation: Despite a high prevalence of adrenal insufficiency, most patients with eosinophilic asthma treated with benralizumab achieved elimination of oral corticosteroids or maximal possible reduction using a personalised dosage-reduction algorithm., Funding: AstraZeneca., Competing Interests: Declaration of interests AM-G has attended advisory boards for AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, and Teva, and is a steering committee member for the AstraZeneca PONENTE study; has received speakers’ fees from AstraZeneca, Novartis, Roche, and Teva; has participated in research with AstraZeneca, for which his institution has been remunerated; has attended international conferences with Teva; and has made consultancy agreements with AstraZeneca, Sanofi, and Vectura. MG is a steering committee member for the AstraZeneca PONENTE study and has received speakers’ fees from AstraZeneca, Novartis, and Teva. LGH is a steering committee member for the AstraZeneca PONENTE study and has received research funding, consulting fees, and speakers’ fees from AstraZeneca. LGH has also received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals; lecture fees from Novartis, Hoffmann-La Roche and Genentech, Sanofi, Evelo Biosciences, GlaxoSmithKline, AstraZeneca, Teva, Theravance, and Circassia; and institutional grant funding from Medimmune, Novartis, Hoffman-La Roche and Genentech, and GlaxoSmithKline. He is academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with Amgen, Hoffman-La Roche and Genentech, AstraZeneca, Medimmune, GlaxoSmithKline, Aerocrine, and Vitalograph. JC has received grants from AstraZeneca in addition to grants and personal fees from Genentech, Novartis, Regeneron Pharmaceuticals, and Sanofi. EHB reports non-financial support, grants, and personal fees from GlaxoSmithKline; grants and personal fees from AstraZeneca; grants from Roche, personal fees from Chiesi and Sanofi and Regeneron; and grants and personal fees from Teva. EHB is also a steering committee member for the AstraZeneca PONENTE study, Novartis, Sterna, and Teva. JM has consulted for AstraZeneca, Sanofi, and Teva; was a speaker for GlaxoSmithKline, Menarini, Novartis, and Uriach; and has received research grants from Novartis. TH reports grants from AstraZeneca and the National Institute for Health Research, UK; and personal fees and non-financial support from AstraZeneca. TH is also a steering committee member for the AstraZeneca PONENTE study, GlaxoSmithKline, Vectura, Boehringer Ingelheim, Chiesi, and Synairgen. During the study's completion, he also became an employee of AstraZeneca. DJJ has received speakers’ honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva, and honoraria for attending advisory panels with AstraZeneca, GlaxoSmithKline, Novartis, Chiesi, Sanofi and Regeneron, and Teva. DP has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, and Thermo Fisher Scientific; consultancy agreements with Amgen and AstraZeneca; and is a steering committee member for the AstraZeneca PONENTE study, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, and Theravance. DP has also received grants and unrestricted funding for investigator-initiated studies (done through the Observational and Pragmatic Research Institute) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, and the UK National Health Service; payment for lectures or speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma and Novartis; payment for travel, accommodation, or meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, and Thermo Fisher Scientific; and funding for patient enrolment or completion of research from Novartis; stock or stock options from AKL Research and Development. He owns 74% of the social enterprise Optimum Patient Care (Australia and UK) and 74% of Observational and Pragmatic Research Institute (Singapore); and 5% shareholding in Timestamp. He is a peer reviewer for grant committees of the Efficacy and Mechanism Evaluation Programme and Health Technology Assessment (both National Institute of Health Research programmes); and was an expert witness for GlaxoSmithKline. NL has received consulting fees from AstraZeneca and is a steering committee member for the AstraZeneca PONENTE study and Teva; has participated in advisory boards for AstraZeneca, Genentech, GlaxoSmithKline, Novartis, and Sanofi; and has received grants for clinical trials from AstraZeneca, Genentech, GlaxoSmithKline, and Sanofi. JK, AdG-M, KP, UJM, and EGG are full time employees of and stockholders in AstraZeneca. AB is a contract employee of AstraZeneca., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The COVID-19 pandemic has witnessed a reduction in asthma exacerbations across the United Kingdom. Several factors may underpin this, including reduced transmission of seasonal viruses and improved adherence to inhaled corticosteroids (ICS). However, little is known about how ICS use has changed during the pandemic., Objective: To identify prescribing patterns for asthmatics during the pandemic., Methods: Using the OpenPrescribing database, we retrospectively analyzed prescribing patterns of ICS, salbutamol and peak flow meters from January 2019 to January 2021 across England. In addition, using a sample asthma cohort at 3 primary care practices in London, we assessed individual prescription patterns., Results: A sharp increase in national ICS prescriptions occurred in March 2020 representing a 49.9% increase compared with February 2020. The sample cohort included 1132 patients (762 ICS treated across both years). Overall ICS adherence improved in 2020 (P < .001), with the proportion of patients meeting "good adherence" (≥75%) increasing from 33.9% to 42.0% (P < .001). The March 2020 spike predominantly reflected improved adherence rather than a hoarding effect of multiple inhalers. Female gender and increasing age were associated with the most significant improvements in adherence. A similar spike in salbutamol occurred in March 2020; however, an overall reduction in salbutamol prescriptions occurred in 2020 (P = .039). National figures highlighted a progressive increase in prescription of peak flow meters over 2020., Conclusion: ICS adherence rates remain low; however, a modest improvement in adherence was observed during the first year of the COVID-19 pandemic. Salbutamol prescription rates reduced over the same time period, whereas prescriptions for peak flow meters have steadily increased., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

A 56-year-old man has difficult-to-control asthma and a history of four exacerbations in the prior 12 months despite high-dose inhaled corticosteroids (ICS) and additional controller therapies. Is he suitable for more advanced therapeutic options? To address this query, we herein review the clinical assessment of a patient with suspected severe asthma and discuss factors contributing to poor asthma control and how biomarkers assist in disease investigation and stratification. The key components of our multidisciplinary approach are to confirm an asthma diagnosis and adherence to treatment, to assess any contributing comorbidities or confounding factors, and to stratify what type of asthma the patient has. The combination of spirometry and repeated measures of key biomarkers of type 2 airway inflammation-the blood eosinophil count and fractional exhaled nitric oxide-identifies whether poor disease control is driven by uncontrolled, ICS-resistant type 2 airway inflammation or ongoing airflow obstruction. A failure to elicit evidence of either suggests an alternative driver for the patient's symptoms, including chronic airway infection and non-asthma causes. Each phenotype represents a treatable trait that requires a specific targeted approach. Critically, steroids can cause harm, and their use should be guided by objective evidence of inflammation rather than symptoms alone. To conclude, after assessment of treatment adherence and exclusion of relevant comorbidities, the patient was found to have severe asthma with ICS-resistant type 2 airway inflammation. We will consider additional treatment options at our next appointment in part 2/2 of this How I Do It series., (Copyright © 2021. Published by Elsevier Inc.)

Background: Frequent exacerbations are an important cause of morbidity in patients with severe asthma., Objective: Our aim was to identify factors associated with frequent exacerbations in a large well-characterized severe asthma population and determine whether factors differed in patients treated with and without maintenance oral corticosteroids (OCS)., Methods: Adults with severe asthma from specialized asthma centers across the United Kingdom were recruited to the UK Severe Asthma Registry. Demography, comorbidities and physiological measurements were collected. We conducted univariable and multivariable logistic regression analyses to identify factors associated with frequent exacerbations, defined as 3 or more exacerbations treated with high-dose systemic corticosteroids in the past year., Results: Of 1,592 patients with severe asthma from the UK Severe Asthma Registry, 1,137 (71%) were frequent exacerbators and 833 (52%) were on maintenance OCS. The frequent exacerbators were more likely to be ex-smokers, have gastroesophageal reflux disease, higher Asthma Control Questionnaire-6 (ACQ-6) score, and higher blood eosinophilia. Multivariable regression analyses showed ACQ-6 score greater than 1.5 (odds ratio [OR] 4.25; P < .001), past smoking history (OR 1.55; P = .024), and fractional exhaled nitric oxide greater than 50ppb (OR 1.54; P = .044) were independently associated with frequent exacerbations. Past smoking history correlated with frequent exacerbations only in patients on maintenance OCS (OR 2.25; P = .004), whereas ACQ-6 score greater than 1.5 was independently associated with frequent exacerbations in those treated with and without maintenance OCS (OR 2.74; P = .017 and OR 6.42; P < .001, respectively)., Conclusions: Several factors were associated with frequent exacerbations in a large UK severe asthma registry population. High ACQ-6 score had the strongest association with frequent exacerbations irrespective of maintenance OCS status., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe asthma may be underrecognized in primary care., Objective: Identify and quantify patients with potential severe asthma (PSA) in UK primary care, the proportion not referred, and compare primary care patients with PSA with patients with confirmed severe asthma from UK tertiary care., Methods: This was a historical cohort study including patients from the Optimum Patient Care Research Database (aged ≥16 years, active asthma diagnosis pre-2014) and UK patients in the International Severe Asthma Registry (UK-ISAR aged ≥18 years, confirmed severe asthma in tertiary care). In the OPCRD, PSA was defined as Global INitiative for Asthma 2018 step 4 treatment and 2 or more exacerbations/y or at Global INitiative for Asthma step 5. The proportion of these patients and their referral status in the last year were quantified. Demographic and clinical characteristics of groups were compared., Results: Of 207,557 Optimum Patient Care Research Database patients with asthma, 16,409 (8%) had PSA. Of these, 72% had no referral/specialist review in the past year. Referred patients with PSA tended to have greater prevalence of inhaled corticosteroid/long-acting β 2 -agonist add-ons (54.1 vs 39.8%), and experienced significantly (P < .001) more exacerbations per year (median, 3 vs 2/y), worse asthma control, and worse lung function (% predicted postbronchodilator FEV 1 /forced vital capacity, 0.69 vs 0.72) versus nonreferred patients. Confirmed patients with severe asthma (ie, UK patients in the International Severe Asthma Registry) were younger (51 vs 65 years; P < .001), and significantly (P < .001) more likely to have uncontrolled asthma (91.4% vs 62.5%), a higher exacerbation rate (4/y [initial assessment] vs 3/y), use inhaled corticosteroid/long-acting β 2 -agonist add-ons (67.7% vs 54.1%), and have nasal polyposis (24.2% vs 6.8) than referred patients with PSA., Conclusions: Large numbers of patients with PSA in the United Kingdom are underrecognized in primary care. These patients would benefit from a more systematic assessment in primary care and possible specialist referral., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Benralizumab is an IL5-receptor monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA). It has demonstrated efficacy in clinical trials in reducing asthma exacerbation rates and maintenance oral corticosteroids (mOCSs)., Research Question: What is the real-world effectiveness of benralizumab and what baseline characteristics are associated with response to therapy?, Study Design and Methods: We assessed outcomes in all SEA patients who began benralizumab treatment at our specialist center. At each dosing visit, exacerbation history, mOCS dose, spirometry, and Asthma Control Questionnaire (ACQ6) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) scores were recorded. Response to treatment was defined as a reduction of ≥ 50% in annualized exacerbation rate (AER) or in mOCS dose after 48 weeks of treatment. Super response was defined as zero exacerbations and no mOCSs for asthma., Results: One hundred thirty patients were included in the analysis. At 48 weeks, a 72.8% reduction in AER was noted, from 4.92 ± 3.35 per year in the year preceding biologic treatment to 1.34 ± 1.71 per year (P < .001), including 57 patients (43.8%) who were exacerbation-free with benralizumab. In those receiving mOCSs (n = 74 [56.9%]), the median daily prednisolone dose fell from 10 mg (interquartile range, 5-20 mg) to 0 mg (interquartile range, 0-5 mg; P < .001), and 38 of 74 patients (51.4%) were able to discontinue mOCS therapy. Clinically and statistically significant improvements were found in ACQ6 scores, mAQLQ scores, and FEV 1 . Overall, 51 patients (39%) met the super responder definition and 112 patients (86%) met the responder definition. The optimal regression model of super responders vs other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease. Eighteen patients (13.8%) were nonresponders to benralizumab. Evidence of chronic airway infection was observed in 6 of 18 patients, and an increase in the blood eosinophil count consistent with the development of anti-drug antibodies was observed in 5 of 18 patients., Interpretation: In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures. A lack of response was seen in a minority of patients and should be a focus for future investigation., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Eosinophils play a pivotal role in the inflammatory pathology of asthma and have been the target of new biologic treatments for patients with eosinophilic asthma. Given the central role of interleukin (IL)-5 in the eosinophil lifecycle, several therapies directed against the IL-5 pathway have been developed, including the anti-IL-5 antibodies mepolizumab and reslizumab and the IL-5 receptor α (IL-5Rα)-directed cytolytic antibody benralizumab. Eosinophil-depleting therapies represent a relatively new class of asthma treatment, and it is important to understand their long-term efficacy and safety. Eosinophils have been associated with host protection and tumor growth, raising potential concerns about the consequences of long-term therapies that deplete eosinophils. However, evidence for these associations in humans is conflicting and largely indirect or based on mouse models. Substantial prospective clinical trial and postmarketing data have accrued, providing insight into the potential risks associated with eosinophil depletion. In this review, we explore the current safety profile of eosinophil-reducing therapies, with particular attention to the potential risks of malignancies and severe infections and a focus on benralizumab. Benralizumab is an IL-5Rα-directed cytolytic monoclonal antibody that targets and efficiently depletes blood and tissue eosinophils through antibody-dependent cell-mediated cytotoxicity. Benralizumab is intended to treat patients with severe, uncontrolled asthma with eosinophilic inflammation. The integrated analyses of benralizumab safety data from the phase III SIROCCO and CALIMA trials and subsequent BORA extension trial for patients with asthma, and the phase III GALATHEA and TERRANOVA trials for patients with chronic obstructive pulmonary disease, form the principal basis for this review.

Introduction: For patients with eosinophilic asthma with allergic characteristics, understanding the key drivers of exacerbations is important to identify optimal treatment strategies. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody that significantly reduces exacerbation frequency for patients with severe, uncontrolled eosinophilic asthma. We evaluated the predictive value of baseline blood eosinophil counts vs. serum immunoglobulin E (IgE) concentrations on exacerbation risk and the association of these variables with benralizumab treatment effect., Methods: Analyses were performed with data pooled from the phase III SIROCCO and CALIMA benralizumab trials. Crude annual asthma exacerbation rates (AERs) were determined for placebo as a function of baseline blood eosinophil counts and serum IgE concentrations with prespecified blood eosinophil count categories (< 150, ≥ 150 to < 300, ≥ 300 to < 450, ≥ 450 cells/µL) and IgE concentration quartiles (< 62.0, ≥ 62.0 to < 176.2, ≥ 176.2 to < 453.4, and ≥ 453.4 kU/L). We compared AERs for patients receiving benralizumab 30 mg every 8 weeks (first three doses every 4 weeks) vs. placebo for overlapping baseline blood eosinophil count categories and serum IgE concentration quartiles via a regression approach and by continuously using locally weighted regression smoothing analysis., Results: Exacerbation risk for patients with severe asthma receiving placebo increased with increasing baseline blood eosinophil counts but not with increasing serum IgE concentrations. Addition of baseline atopy status did not influence the relationship between IgE concentrations and exacerbation risk for patients receiving placebo. Patients with blood eosinophil counts ≥ 300 cells/µL had consistent decreases in exacerbation risk with benralizumab relative to placebo across all serum IgE concentration quartiles., Conclusion: Baseline blood eosinophil counts, but not serum IgE concentrations, are an important predictor of exacerbation risk. Patients with severe eosinophilic asthma treated with benralizumab had consistent reductions in exacerbation risk, regardless of IgE concentrations., Clinical Trial Registration: ClinicalTrials.gov: SIROCCO, NCT01928771; CALIMA, NCT01914757.