Targeting Downstream Type 2 Cytokines or Upstream Epithelial Alarmins for Severe Asthma

Biologics, including omalizumab, mepolizumab, benralizumab, and dupilumab, targeting downstream IgE, cytokines IL-5, and IL-4/13, respectively, have shown promising effects in terms of reduction in annualized asthma exacerbation rates (AER), oral corticosteroid-sparing effects, improvements in forced expiratory volume in 1 second, and improved Asthma Control Questionnaire scores. However, despite these welcome advances, approximately 30% of patients with severe asthma receiving biologics tailored to their specific downstream type 2 biomarkers, including total IgE, peripheral blood eosinophils, and fractional exhaled nitric oxide, do not experience meaningful improvements in their AER. Instead of blocking downstream cytokines, targeting upstream epithelial alarmins, including IL-33, thymic stromal lymphopoietin, and IL-25, has been proposed to tackle the immunologic heterogeneity of asthma. This review article aims to pragmatically summarize the latest key clinical data on antialarmin therapies in severe asthma and put these findings into context with regard to currently available downstream cytokine blockers. Biologics, including omalizumab, mepolizumab, benralizumab, and dupilumab, targeting downstream IgE, cytokines IL-5, and IL-4/13, respectively, have shown promising effects in terms of reduction in annualized asthma exacerbation rates (AER), oral corticosteroid-sparing effects, improvements in forced expiratory volume in 1 second, and improved Asthma Control Questionnaire scores. However, despite these welcome advances, approximately 30% of patients with severe asthma receiving biologics tailored to their specific downstream type 2 biomarkers, including total IgE, peripheral blood eosinophils, and fractional exhaled nitric oxide, do not experience meaningful improvements in their AER. Instead of blocking downstream cytokines, targeting upstream epithelial alarmins, including IL-33, thymic stromal lymphopoietin, and IL-25, has been proposed to tackle the immunologic heterogeneity of asthma. This review article aims to pragmatically summarize the latest key clinical data on antialarmin therapies in severe asthma and put these findings into context with regard to currently available downstream cytokine blockers. In recent years, new therapeutic options have become available for patients with refractory severe asthma driven by type 2 (T2) inflammation.1Global Initiative for AsthmaDifficult-to-treat & severe asthma in adolescent and adult patients. Diagnosis and management.https://ginasthma.org/wp-content/uploads/2019/04/GINA-Severe-asthma-Pocket-Guide-v2.0-wms-1.pdfGoogle Scholar Biologics including omalizumab, mepolizumab, benralizumab, and dupilumab targeting downstream IgE, cytokines IL-5, and IL-4/13, respectively, have shown promising effects in terms of reduction in annualized asthma exacerbation rates (AER), oral corticosteroid (OCS)-sparing effects, improvements in forced expiratory volume in 1 second (FEV1), and Asthma Control Questionnaire (ACQ).2Chan R. RuiWen Kuo C. Lipworth B. Pragmatic clinical perspective on biologics for severe refractory type 2 asthma.J Allergy Clin Immunol Pract. 2020; 8: 3363-3370Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar However, despite these welcome advances, it is increasingly recognized that approximately 30% of patients with severe asthma receiving biologics tailored to their specific downstream T2 biomarkers including total IgE, peripheral blood eosinophils (PBE), and fractional exhaled nitric oxide (FeNO) do not experience meaningful improvements in their AER.2Chan R. RuiWen Kuo C. Lipworth B. Pragmatic clinical perspective on biologics for severe refractory type 2 asthma.J Allergy Clin Immunol Pract. 2020; 8: 3363-3370Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Super-responders to biologics are characterized as having no exacerbations and cessation of maintenance OCS accompanied by a large improvement in asthma control, comprising 2 or more times the minimal clinically important difference (MCID),3Rupani H. Hew M. Super-responders to severe asthma treatments: defining a new paradigm.J Allergy Clin Immunol Pract. 2021; 9: 4005-4006Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar,4Upham J.W. Le Lievre C. Jackson D.J. Masoli M. Wechsler M.E. Price D.B. Defining a severe asthma super-responder: findings from a Delphi process.J Allergy Clin Immunol Pract. 2021; 9: 3997-4004Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar although in real life such cases are the exception. In contrast, a study of 250 patients with moderate-to-severe asthma receiving mepolizumab or reslizumab therapy revealed that 43% experienced a suboptimal treatment response with the latter being associated with daily OCS requirement, sinus disease, and late onset asthma.5Mukherjee M. Forero D.F. Tran S. Boulay M.E. Bertrand M. Bhalla A. et al.Sub-optimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena.Eur Respir J. 2020; 56: 2000117Crossref PubMed Scopus (36) Google Scholar Hence, there clearly remains an unmet need for many patients taking current biologics as monotherapy. Furthermore, although improvements in FEV1 and ACQ are statistically significant in multicentre randomized controlled trials (RCTs), we should interpret these findings in the context that they do not exceed the MCID of 230 mL and 0.5 units, respectively.6Santanello N.C. Zhang J. Seidenberg B. Reiss T.F. Barber B.L. What are minimal important changes for asthma measures in a clinical trial?.Eur Respir J. 1999; 14: 23-27Crossref PubMed Scopus (206) Google Scholar,7Juniper E.F. O'Byrne P.M. Roberts J.N. Measuring asthma control in group studies: do we need airway calibre and rescue beta2-agonist use?.Respir Med. 2001; 95: 319-323Abstract Full Text PDF PubMed Scopus (102) Google Scholar Instead of blocking downstream cytokines, targeting upstream epithelial alarmins including IL-33, thymic stromal lymphopoietin (TSLP), and IL-25 has been proposed to tackle the immunologic heterogeneity of asthma.8Tamari M. Trier A.M. Kim B.S. Emerging targeted therapeutics underscore immunologic heterogeneity of asthma.J Allergy Clin Immunol. 2021; 148: 719-721Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar This review article aims to pragmatically summarize the latest key clinical data on antialarmin therapies in severe asthma and put these findings into context with regard to currently available downstream cytokine blockers (Table I). It is not meant to be an exhaustive systematic review nor will the aim be to discuss currently available downstream anticytokine therapies in detail as it has previously been published.2Chan R. RuiWen Kuo C. Lipworth B. Pragmatic clinical perspective on biologics for severe refractory type 2 asthma.J Allergy Clin Immunol Pract. 2020; 8: 3363-3370Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Furthermore, the scope of this review will not include a detailed discussion on omalizumab.Table IRCT data on effects of antialarmin therapy and downstream cytokine blockade on pulmonary function, asthma control, annualized exacerbation rate, type 2 biomarkers, and airway hyperresponsiveness for severe asthma patients compared with placeboBiologicAnti-IL-33Anti-TSLPAnti-IL-4rαAnti-IL-5(rα)FEV1 (L)↑↑↑↑FEF25-75 (L/s)↑N/A↑N/A ACQ↓↓↓↓ AERN/A↓↓↓PBE (cells/μL)↓↓↑/↔↓↓ FeNO (ppb)↓↓↓↔ Total IgE (IU/mL)↓↓↓↔OCS sparingN/A↔↓↓ AHRN/A↓N/AN/AACQ, Asthma Control Questionnaire; AER, annualized exacerbation rate; AHR, airway hyperresponsiveness; FeNO, fractional exhaled nitric oxide; FEF25-75, forced expiratory flow rate between 25% and 75% of full vital capacity; FEV1, forced expiratory volume in 1 second; N/A, not applicable; OCS, oral corticosteroid; PBE, peripheral blood eosinophils; RCT, randomized controlled trial; TSLP, thymic stromal lympoietin. Open table in a new tab ACQ, Asthma Control Questionnaire; AER, annualized exacerbation rate; AHR, airway hyperresponsiveness; FeNO, fractional exhaled nitric oxide; FEF25-75, forced expiratory flow rate between 25% and 75% of full vital capacity; FEV1, forced expiratory volume in 1 second; N/A, not applicable; OCS, oral corticosteroid; PBE, peripheral blood eosinophils; RCT, randomized controlled trial; TSLP, thymic stromal lympoietin. In the United Kingdom, Europe, and USA, commonly used current licensed subcutaneously administered biologics that block downstream cytokines for the treatment of severe asthma include mepolizumab, benralizumab, and dupilumab, with intravenous reslizumab being reserved for patients with higher body mass.9National Institute for Health and Care Excellence GuidelinesOmalizumab for treating severe persistent allergic asthma.https://www.nice.org.uk/guidance/ta278Google Scholar, 10National Institute for Health and Care Excellence GuidelinesMepolizumab for treating severe eosinophilic asthma.https://www.nice.org.uk/guidance/ta671Google Scholar, 11National Institute for Health and Care Excellence GuidelinesBenralizumab for treating severe eosinophilic asthma.https://www.nice.org.uk/guidance/ta565Google Scholar, 12National Institute for Health and Care Excellence GuidelinesReslizumab for treating severe eosinophilic asthma.https://www.nice.org.uk/guidance/ta479Google Scholar The National Institute for Health and Care Excellence and the Scottish Medicines Consortium have recently approved dupilumab only as second line for those who have previously failed on anti-IgE or anti-IL-5 therapies.13National Institute for Health and Care ExcellenceDupilumab for treating severe asthma [ID1213].https://www.nice.org.uk/guidance/indevelopment/gid-ta10276Google Scholar,14Scottish Medicines Consortium Guidelines. Dupilumab (Dupixent). Accessed November 6, 2021..https://www.scottishmedicines.org.uk/medicines-advice/dupilumab-dupixent-full-smc2317/Google Scholar We have previously published a pragmatic review article examining factors that determine optimal choice of biologic therapy for patients including disease endotype, patient preference, and presence of concomitant T2 comorbidities.2Chan R. RuiWen Kuo C. Lipworth B. Pragmatic clinical perspective on biologics for severe refractory type 2 asthma.J Allergy Clin Immunol Pract. 2020; 8: 3363-3370Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar All classes of biologics targeting IL-5 and IL-4/13 pathways have been shown in systematic and Cochrane reviews to improve exacerbation rates by approximately 60% to 70% as well as OCS-sparing effects amounting to an approximately 50% dose reduction.15Rodrigo G.J. Neffen H. Castro-Rodriguez J.A. Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review.Chest. 2011; 139: 28-35Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 16Farne H.A. Wilson A. Powell C. Bax L. Milan S.J. Anti-IL5 therapies for asthma.Cochrane Database Syst Rev. 2017; : CD010834PubMed Google Scholar, 17Zayed Y. Kheiri B. Banifadel M. Hicks M. Aburahma A. Hamid K. et al.Dupilumab safety and efficacy in uncontrolled asthma: a systematic review and meta-analysis of randomized clinical trials.J Asthma. 2019; 56: 1110-1119Crossref PubMed Scopus (28) Google Scholar Figure 1 depicts their effects on commonly measured T2 biomarkers in clinical practice. These main classes of cytokine blockers have also been shown to significantly improve FEV1 and ACQ although these do not usually exceed MCID aside from super-responders.16Farne H.A. Wilson A. Powell C. Bax L. Milan S.J. Anti-IL5 therapies for asthma.Cochrane Database Syst Rev. 2017; : CD010834PubMed Google Scholar,18Normansell R. Walker S. Milan S.J. Walters E.H. Nair P. Omalizumab for asthma in adults and children.Cochrane Database Syst Rev. 2014; : CD003559PubMed Google Scholar In the phase 3 RCT involving benralizumab, the median difference reduction in OCS dose amounted to 50% compared with placebo, whereas for mepolizumab after 24 weeks there was a 50% median reduction in OCS dose.19Nair P. Wenzel S. Rabe K.F. Bourdin A. Lugogo N.L. Kuna P. et al.Oral glucocorticoid–sparing effect of benralizumab in severe asthma.N Engl J Med. 2017; 376: 2448-2458Crossref PubMed Scopus (538) Google Scholar,20Bel E.H. Wenzel S.E. Thompson P.J. Prazma C.M. Keene O.N. Yancey S.W. et al.Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.N Engl J Med. 2014; 371: 1189-1197Crossref PubMed Scopus (1044) Google Scholar Comparatively, the phase 3 trial studying dupilumab showed a slightly lesser OCS-sparing effect after 24 weeks with a 28% difference.21Rabe K.F. Nair P. Brusselle G. Maspero J.F. Castro M. Sher L. et al.Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.N Engl J Med. 2018; 378: 2475-2485Crossref PubMed Scopus (534) Google Scholar Another open-labeled real-life study (PONENTE) with benralizumab showed that 63% of patients were able to wean off OCS completely.22Menzies-Gow A. Gurnell M. Heaney L.G. Corren J. Bel E.H. Maspero J. et al.Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study.Lancet Respir Med. 2022; 10: 47-58Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar TSLP is a key epithelial alarmin involved in binding of antigen-presenting cells in turn resulting in activation of downstream T2 inflammatory cytokines including IL-4, IL-5, and IL-13 (Figure 1).23Liu S. Verma M. Michalec L. Liu W. Sripada A. Rollins D. et al.Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: the role of thymic stromal lymphopoietin.J Allergy Clin Immunol. 2018; 141 (257-68.e6)Abstract Full Text Full Text PDF Scopus (157) Google Scholar, 24Gauvreau G.M. Sehmi R. Ambrose C.S. Griffiths J.M. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma.Expert Opin Ther Targets. 2020; 24: 777-792Crossref PubMed Scopus (42) Google Scholar, 25Kitajima M. Lee H.C. Nakayama T. Ziegler S.F. TSLP enhances the function of helper type 2 cells.Eur J Immunol. 2011; 41: 1862-1871Crossref PubMed Scopus (129) Google Scholar In addition, TSLP is involved in interactions between airway epithelium and other immune cells that are not part of the T2 inflammatory process per se.24Gauvreau G.M. Sehmi R. Ambrose C.S. Griffiths J.M. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma.Expert Opin Ther Targets. 2020; 24: 777-792Crossref PubMed Scopus (42) Google Scholar In allergic eosinophilic asthma, TSLP initiates pathways involving TH2 lymphocytes, basophils, and mast cells to generate airway eosinophilia. TSLP can also directly stimulate mast cells to produce T2 cytokines, whereas mast cells can produce significant amounts of TSLP from IgE cross-linking.24Gauvreau G.M. Sehmi R. Ambrose C.S. Griffiths J.M. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma.Expert Opin Ther Targets. 2020; 24: 777-792Crossref PubMed Scopus (42) Google Scholar Tezepelumab is a monoclonal antibody (IgG2λ) that specifically binds to the TSLP ligand in turn blocking receptor activation. In the phase 2b PATHWAY trial over 52 weeks, tezepelumab 210 mg every 4 weeks reduced the primary end point of overall AER by 71% (90% confidence interval [CI]: 54, 82).26Corren J. Parnes J.R. Wang L. Mo M. Roseti S.L. Griffiths J.M. et al.Tezepelumab in adults with uncontrolled asthma.N Engl J Med. 2017; 377: 936-946Crossref PubMed Scopus (492) Google Scholar Here significant reductions in AER were evident in patients with both T2 low and high disease using a threshold of PBE ≥250 or <250 cells/μL or FeNO <24 or ≥24 ppb. Furthermore, tezepelumab conferred reductions in PBE, FeNO, and total IgE compared with placebo inferring a broad-spectrum effect by attenuating downstream cytokine signaling including IL-4 (IgE), IL-13 (FeNO), and IL-5 (PBE) (Figure 1). However, reductions in PBE amounting to a mean fall of approximately 150 cells/μL from a mean baseline of 365 cells/μL are not as profound as those seen with anti-IL-5 agents. In the subsequent phase 3 NAVIGATOR trial over 52 weeks, tezepelumab 210 mg significantly improved the primary end point resulting in an overall 56% (95% CI: 47, 63) reduction in AER. Tezepelumab also conferred significant mean improvements in key secondary end points including FEV1 (130 mL), ACQ (−0.33), and Asthma Quality of Life Questionnaire (−0.34), although these were all less than their respective MCIDs.27Menzies-Gow A. Corren J. Bourdin A. Chupp G. Israel E. Wechsler M.E. et al.Tezepelumab in adults and adolescents with severe, uncontrolled asthma.N Engl J Med. 2021; 384: 1800-1809Crossref PubMed Scopus (102) Google Scholar As in the PATHWAY trial, there were decreased T2 biomarkers with mean falls amounting to 14 ppb in FeNO, 130 cells/μL in PBE, and 208 IU/mL in total IgE compared with placebo. Of note, post hoc analysis of the primary end point in NAVIGATOR showed that AER were significantly reduced in the tezepelumab group to a greater degree in patients who had higher eosinophil counts.27Menzies-Gow A. Corren J. Bourdin A. Chupp G. Israel E. Wechsler M.E. et al.Tezepelumab in adults and adolescents with severe, uncontrolled asthma.N Engl J Med. 2021; 384: 1800-1809Crossref PubMed Scopus (102) Google Scholar For example, there was a 70% relative reduction in AER (95% CI: 60, 78) associated with baseline PBE ≥300 cells/μL compared with a 41% reduction (95% CI: 25, 54) with <300 cells/μL, which is a significant difference as indicated by CIs that do not overlap. Even in patients with PBE <150 cells/μL, there was a 39% (95% CI: 12, 68) reduction in AER. The same was observed in regard to non-overlapping CIs for AER with a 68% (95% CI: 58, 75) reduction for FeNO ≥25 ppb versus 32% (95% CI: 8, 49) for FeNO <25 ppb. For patients with T2 low asthma who had both PBE <300 cells/μL and FeNO <25 ppb, there were borderline significant reductions in AER compared with placebo amounting to 29% (CI: 0, 50). Intriguingly, for patients with PBE ≥300 cells/μL and FeNO <25 ppb, a 39% reduction in AER was observed (95% CI: −7, 65) although this was nonsignificant, which could be related to lower patient numbers in this particular subgroup analysis. The greatest reduction in AER was seen in those patients who had T2 high asthma with PBE ≥300/μL and FeNO ≥25 ppb where there was a 77% (95% CI: 67, 84) reduction. The wide CIs for T2 low patients indicate that in such cases there is considerable heterogeneity in response to tezepelumab, as compared with the much narrower CIs in T2 patients with a more homogeneous response. In other words, clinicians can expect a more predictable response to tezepelumab in those individuals with T2 high asthma. When inspecting data for AER in NAVIGATOR where T2 biomarkers were plotted as a continuous variable, it is evident that the slope is much steeper for increased AER with placebo compared with reduced AER with tezepelumab, this being the case for both PBE and FeNO. In contrast, the separation between regression lines remains constant across the range for total IgE, indicating that this is not a key determinant of response. For FEV1 the response was greater among those with PBE ≥300 cells/μL: 230 mL (95% CI: 150, 310) compared with PBE <150 cells/μL: 30 mL (95% CI: −70, 130), with non-overlapping CIs indicating a significant difference. Similar results occurred for ACQ: −0.50 (95% CI: −0.69, −0.31) versus −0.09 (−0.33, 0.16). Taken together these results from phase 2/3 trials suggest that blocking the upstream alarmin TSLP with tezepelumab results in clinically meaningful improvements in asthma control in patients with T2 high asthma with regard to exacerbations, ACQ, and FEV1. Tezepelumab also appears to confer lesser degrees of improvements in T2 low asthma in relation to exacerbation reductions but not for FEV1 or ACQ, along with a more variable response. Nonetheless, it is notable that tezepelumab is the first biologic with at least some degree of activity in T2 low refractory severe asthma that is at present an unmet need. It would be helpful to have T2 low biomarkers that might be able to predict a better response with tezepelumab in preventing exacerbations. Preliminary abstracted data from the phase 3 SOURCE trial28Wechsler M. Gow A.M. Brightling C.E. Kuna P. Korn S. Welte T. et al.Oral corticosteroid-sparing effect of tezepelumab in adults with severe asthma.Am J Respir Crit Care Med. 2021; 203: A1197Google Scholar (NCT03406078) with subcutaneous tezepelumab 210 mg over 48 weeks in severe OCS-dependent asthma patients were disappointing in terms of showing an overall nonsignificant 22% (CI: −47, 31) reduction in the primary end point of OCS dose along with no signification reduction in AER: 31% (95% CI: −9, 56). Post hoc analysis in patients with baseline PBE ≥300 cells/μL revealed a 71% (CI: 14, 90) OCS dose reduction, with the wide CI indicating a variable response perhaps due to the inherent PBE suppressive effect of OCS. Post hoc analysis of OCS-dependent patients in NAVIGATOR observed a 28% (95% CI: −26, 59) reduction in AER indicating futility for tezepelumab, although in such patients there were improvements in FEV1 of 270 mL (95% CI: 100, 440) and ACQ of −0.65 (95% CI: −1.08, −0.22), both of which exceeded MCIDs of 230 mL and 0.5 units.29Menzies-Gow A. Brightling C.E. Ambrose C.S. Cook B. Hellqvist Llanos Ackert J.-P. et al.Effect of tezepelumab in oral corticosteroid-dependent patients with severe asthma: results from the phase 3 NAVIGATOR study.Am J Respir Crit Care Med. 2021; 203: A1442PubMed Google Scholar Given the impressive overall results of NAVIGATOR and the known OCS-sparing effect of blocking downstream IL-4/13 signaling with dupilumab,21Rabe K.F. Nair P. Brusselle G. Maspero J.F. Castro M. Sher L. et al.Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.N Engl J Med. 2018; 378: 2475-2485Crossref PubMed Scopus (534) Google Scholar it is difficult to explain this anomaly with tezepelumab. A potential explanation for this phenomenon has been proposed as a 2-compartment model for T2 inflammation recently.30Couillard S. Shrimanker R. Chaudhuri R. Mansur A.H. McGarvey L.P. Heaney L.G. et al.Fractional exhaled nitric oxide nonsuppression identifies corticosteroid-resistant type 2 signaling in severe asthma.Am J Respir Crit Care Med. 2021; 204: 731-734Crossref PubMed Scopus (15) Google Scholar It is hypothesized that for a biologic to be OCS sparing, it must effectively regulate the systemic compartment of circulating eosinophils (anti-IL-5rα) or prevent eosinophils from escaping the vascular compartment (anti-IL-4rα). Tezepelumab reduces airway chemotactic pull mediated by IL-13 and measured using FeNO by a similar magnitude to dupilumab (Table II) albeit with suboptimal eosinophil suppression compared with anti-IL-5rα. Nonetheless both tezepelumab and dupilumab appear to confer similar clinical impacts on asthma control as AER, ACQ, and improved lung function as FEV1 (Table II).Table IIMean improvements in AER, FEV1, FeNO, and asthma control with tezepelumab or dupilumab versus placebo from phase 3 trialsPhase III trialDupilumab liberty quest31Castro M. Corren J. Pavord I.D. Maspero J. Wenzel S. Rabe K.F. et al.Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma.N Engl J Med. 2018; 378: 2486-2496Crossref PubMed Scopus (812) Google ScholarTezepelumab navigator27Menzies-Gow A. Corren J. Bourdin A. Chupp G. Israel E. Wechsler M.E. et al.Tezepelumab in adults and adolescents with severe, uncontrolled asthma.N Engl J Med. 2021; 384: 1800-1809Crossref PubMed Scopus (102) Google ScholarAER Baseline2.092.11 Absolute Δ0.981.18 % Δ−47%−56%FEV1 (L) Baseline1.781.85 Absolute Δ0.170.13 % Δ9.6%7.0%FeNO (ppb) Baseline3544 Absolute Δ−12.3−13.8 % Δ−35.1%−31.4%ACQ Baseline2.82.8 Absolute Δ−0.31−0.33 % Δ−11.1%−11.8%ACQ, Asthma Control Questionnaire; AER, annual exacerbation rate; FEV1, forced expiratory volume in 1 second; FeNO, fractional exhaled nitric oxide. Open table in a new tab ACQ, Asthma Control Questionnaire; AER, annual exacerbation rate; FEV1, forced expiratory volume in 1 second; FeNO, fractional exhaled nitric oxide. Another key part of the asthma disease phenotype is the presence of airway hyperresponsiveness (AHR), which can be measured by an indirect bronchial challenge using the osmotic agent mannitol. Ex vivo it has been shown that IL-13 is a key cytokine in mediating AHR that can be blocked by dupilumab.32Manson M.L. Säfholm J. James A. Johnsson A.K. Bergman P. Al-Ameri M. et al.IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways.J Allergy Clin Immunol. 2020; 145 (808-17.e2)Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The CASCADE phase 2 RCT in uncontrolled asthma investigating tezepelumab 210 mg every 4 weeks demonstrated a significant (P = .03) 1.15 doubling dose improvement in the secondary end point of mannitol AHR compared with placebo as well as significantly reducing the primary end point of airway biopsy eosinophils.33Diver S. Khalfaoui L. Emson C. Wenzel S.E. Menzies-Gow A. Wechsler M.E. et al.Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial.Lancet Respir Med. 2021; 9: 1299-1312Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Meanwhile the UPSTREAM phase 2 RCT in patients with uncontrolled asthma using intravenous tezepelumab 700 mg found a mean 0.9 doubling dose difference in the primary outcome of mannitol AHR, which was not significant (P = .06), whereas airway biopsy and lavage eosinophils were both significantly suppressed.34Sverrild A. Hansen S. Hvidtfeldt M. Clausson C.-M. Cozzolino O. Cerps S. et al.The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM).Eur Respir J. 2021; 59: 2101296Crossref PubMed Scopus (19) Google Scholar Tezepelumab is therefore unique among the currently available biologics in the sense that it significantly suppresses all 3 T2 biomarkers (PBE, total IgE, and FeNO) as well as attenuating AHR (Figure 1). The lack of apparent efficacy in OCS-dependent patients requires further investigation given the known OCS-sparing efficacy of anti-IL-5 and anti-IL-4rα agents.19Nair P. Wenzel S. Rabe K.F. Bourdin A. Lugogo N.L. Kuna P. et al.Oral glucocorticoid–sparing effect of benralizumab in severe asthma.N Engl J Med. 2017; 376: 2448-2458Crossref PubMed Scopus (538) Google Scholar, 20Bel E.H. Wenzel S.E. Thompson P.J. Prazma C.M. Keene O.N. Yancey S.W. et al.Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.N Engl J Med. 2014; 371: 1189-1197Crossref PubMed Scopus (1044) Google Scholar, 21Rabe K.F. Nair P. Brusselle G. Maspero J.F. Castro M. Sher L. et al.Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.N Engl J Med. 2018; 378: 2475-2485Crossref PubMed Scopus (534) Google Scholar In a sense tezepelumab could be considered to have similar efficacy to dupilumab in terms of IL-4/13 blockade through FeNO and IgE suppression but with the additional action of IL-5 blockade partially suppressing blood eosinophils. Thus, tezepelumab confers a theoretical advantage over dupilumab in terms of obviating escape of blood eosinophils. We are intrigued to know if locally acting inhaled anti-TSLP will prove to be as effective as systemic tezepelumab given that the former may not adequately address the systemic component of T2 inflammation or indeed be able to target the small airways. In a recent RCT, 12 weeks of therapy with the potent inhaled anti-TSLP CSJ117 was shown to reduce allergen-induced bronchoconstriction, sputum eosinophilia, and FeNO levels in mild allergic asthma patients compared with placebo.35Gauvreau G. Hohlfeld J. Boulet L.-P. Cockcroft D. Davis B. Fitzgerald J.M. et al.Late Breaking Abstract—Efficacy of CSJ117 on allergen-induced asthmatic responses in mild atopic asthma patients.Eur Respir J. 2020; 56: 3690Google Scholar The putative difference between inhaled and injected anti-TSLP is analogous to patients with refractory severe asthma despite using high-dose inhaled corticosteroid (ICS) who can then be adequately controlled by a small maintenance dose of OCS inferring a systemic component to refractory T2 inflammation. IL-33 is an inducer of TH2 adaptive immunity and signals via the IL-1 receptor–related protein ST2 triggering the release of chemokines and cytokines that promote T2 inflammation.36Préfontaine D. Nadigel J. Chouiali F. Audusseau S. Semlali A. Chakir J. et al.Increased IL-33 expression by epithelial cells in bronchial asthma.J Allergy Clin Immunol. 2010; 125: 752-754Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar Elevated levels of IL-33 messenger RNA produced by airway smooth muscle cells are detected from biopsies of patients with asthma compared with control subjects, especially those with severe asthma.37Préfontaine D. Lajoie-Kadoch S. Foley S. Audusseau S. Olivenstein R. Halayko A.J. et al.Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells.J Immunol. 2009; 183: 5094-5103Crossref PubMed Scopus (422) Google Scholar Along with IL-5, IL-33 is involved in the production, activation, and survival of eosinophils and hence plays a key role in T2 high asthma.38Cherry W.B. Yoon J. Bartemes K.R. Iijima K. Kita H. A novel IL-1 family cytokine, IL-33, potently activates