Fevipiprant in CRSwNP and comorbid asthma: Wrong target population or wrong PGD2 receptor?

Abstract

Before the approval of dupilumab in 2019, the treatment of chronic rhinosinusitis with nasal polyposis (CRSwNP) was limited to topical and/or systemic steroids or surgical intervention. Biologic therapy has offered meaningful medical management options for CRSwNP; however, given the high cost of such therapy and its requirement for parenteral administration, novel medical treatments are sought. For the significant subset of patients with CRSwNP and comorbid asthma, medical options that address upper and lower airway inflammation are of particular importance.Prostaglandin (PGD2) is a key inflammatory mediator produced by tissue-resident mast cells and recruited inflammatory cells implicated in both asthma and CRSwNP. PGD2 and PGD2 metabolites have effects at 3 receptors: the D prostanoid 1 (DP1) receptor, the D prostanoid 2 (DP2) receptor (also known as CRTH2), and the thromboxane (TP) receptor. Each receptor facilitates unique and different functions of PGD2 that are relevant in chronic airway inflammation. DP1 is responsible for vasodilation, inhibition of platelet aggregation, TH0 cell polarization to TH2 cells by inhibition of dendritic cell IL-12 release, and dendritic cell migration.1Jandl K. Heinemann A. The therapeutic potential of CRTH2/DP2 beyond allergy and asthma.Prostaglandins Other Lipid Mediat. 2017; 133: 42-48Crossref PubMed Scopus (21) Google Scholar DP2 contributes to the recruitment of inflammatory cells (group 2 innate lymphoid cells [ILC2s], eosinophils, basophils, TH2 cells, and macrophages) to sites of tissue inflammation and promotes ILC2 survival and type 2 cytokine production.1Jandl K. Heinemann A. The therapeutic potential of CRTH2/DP2 beyond allergy and asthma.Prostaglandins Other Lipid Mediat. 2017; 133: 42-48Crossref PubMed Scopus (21) Google Scholar,2Hardman C. Chen W. Luo J. Batty P. Chen Y.L. Nahler J. et al.Fevipiprant, a selective prostaglandin D2 receptor 2 antagonist, inhibits human group 2 innate lymphoid cell aggregation and function.J Allergy Clin Immunol. 2019; 143: 2329-2333Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Signaling at the TP receptor facilitates bronchospasm.1Jandl K. Heinemann A. The therapeutic potential of CRTH2/DP2 beyond allergy and asthma.Prostaglandins Other Lipid Mediat. 2017; 133: 42-48Crossref PubMed Scopus (21) Google Scholar Both DP1 and DP2 receptors are implicated in the antifibrotic effects of PGD2 in bleomycin-induced pulmonary fibrosis models, whereas DP2 demonstrates a profibrotic role in Hermansky-Pudlack syndrome–associated lung disease.1Jandl K. Heinemann A. The therapeutic potential of CRTH2/DP2 beyond allergy and asthma.Prostaglandins Other Lipid Mediat. 2017; 133: 42-48Crossref PubMed Scopus (21) Google Scholar These proinflammatory effects of PGD2 support a potential therapeutic benefit from PGD2 pathway inhibition in asthma and CRSwNP. In phase II clinical trials in asthma, the selective DP2 antagonist fevipiprant showed promise, with improvements in FEV1 and reductions in sputum eosinophil count. However, the development of fevipiprant in asthma was halted after phase III studies demonstrated its safety but failed to achieve the targeted reductions in asthma exacerbations or improvements in FEV1 among patients with moderate-to-severe and uncontrolled asthma.In this issue of the Journal of Allergy and Clinical Immunology, Gevaert et al report the results of THUNDER, a phase IIIb, multicenter, randomized controlled trial of fevipiprant versus placebo in 98 subjects with CRSwNP and concomitant asthma.3Gevaert P. Bachert C. Maspero J.F. Cuevas M. Steele D. Acharya S. Altman P. Phase 3b randomized controlled trial of fevipiprant in patients with nasal polyposis with asthma (THUNDER).J Allergy Clin Immunol. 2022; 149: 1675-1682Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Subjects with a total nasal polyp score of 4 or higher despite 4 weeks of mometasone furoate nasal spray (200 μg once daily) were randomized 1:1:1 to add-on oral fevipiprant at a dose of 150 mg or 450 mg or matched placebo once daily for 16 weeks. The primary end point was change from baseline to week 16 in nasal polyp score as assessed by the centralized, 2-reader, blinded review of rhinoscopy videos. Secondary end points included change in nasal congestion score, the 22-item Sinonasal Outcome Test (SNOT-22) score, and smell as assessed by the University of Pennsylvania Smell Identification Test. No asthma outcomes were reported. The sample size was determined on the basis of a mean reduction of 1.5 points in nasal polyp score in the fevipiprant groups versus the placebo group. This primary end point projection was optimistic. Currently approved biologic therapies have failed to achieve a mean reduction in change from baseline in nasal polyp score of 1.5 points relative to placebo in study populations with higher starting nasal polyp scores.4Lipworth B.J. Chan R. The choice of biologics in patients with severe chronic rhinosinusitis with nasal polyps.J Allergy Clin Immunol Pract. 2021; 9: 4235-4238Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The fevpiprant dose, study duration, requirement for background mometasone furoate, and selection of primary and secondary end points align with those of other recent studies of medical therapeutics in CRSwNP and other phase III studies of fevipiprant in asthma. Even with the aggressive primary end point target, the primary end point data are decisively negative across both fevipiprant doses studied. Although the fevipiprant dose of 450 mg demonstrated a significant improvement in smell over placebo (by 4.5 points on the University of Pennsylvania Smell Identification Test), patients' scores on the SNOT-22 failed to improve and their nasal congestion scores showed a trend toward worsening. The results of post hoc analyses of the primary end point and the secondary end point nasal congestion score stratified by baseline peripheral blood eosinophil count (cutoff 450 μL) were also negative. Despite the mechanistic data to suggest benefit from DP2 antagonism in CRSwNP, these results from the first randomized controlled trial of fevipiprant in CRSwNP are negative.Could selection of the wrong study population or disease state explain a study with negative results? PGD2 is particularly relevant in the aspirin-exacerbated respiratory disease (AERD) subgroup of subjects with CRSwNP and comorbid asthma. At baseline, subjects with AERD have elevated levels of urinary PGD2 metabolites compared with those of aspirin-tolerant subjects with asthma—levels that are inversely correlated with the aspirin-induced decline in FEV1.5Cahill K.N. Bensko J.C. Boyce J.A. Laidlaw T.M. Prostaglandin D(2): a dominant mediator of aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2015; 135: 245-252Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar PGD2 levels increase acutely in aspirin-induced reactions during which peak PGD2 levels are correlated with increases in nasal congestion scores and reductions in FEV1 and blood eosinophil counts.5Cahill K.N. Bensko J.C. Boyce J.A. Laidlaw T.M. Prostaglandin D(2): a dominant mediator of aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2015; 135: 245-252Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar,6Buchheit K.M. Cahill K.N. Katz H.R. Murphy K.C. Feng C. Lee-Sarwar K. et al.Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2016; 137: 1566-1576.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar The acute rise in PGD2 levels following aspirin ingestion is associated with the acute influx of DP2/CRTH2+ cells from the blood into the nasal mucosa, which is then reversed by high-dose aspirin therapy, at which time PGD2 levels fall and blood DP2/CRTH2+ cell counts increase.7Cahill K.N. Immunologic effects of aspirin desensitization and high-dose aspirin therapy in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2021; 148: 344-347Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Moreover, suppression of PGD2 in subjects with AERD by high-dose aspirin therapy is understood to be one mechanism of the benefit of high-dose aspirin therapy in AERD.7Cahill K.N. Immunologic effects of aspirin desensitization and high-dose aspirin therapy in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2021; 148: 344-347Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Such data support the idea that targeting the PGD2 pathway could benefit the acute COX1 inhibitor–induced respiratory reactions and the chronic baseline inflammation associated with AERD.Regrettably, the THUNDER study population was not enriched for subjects with AERD. The randomization of only 1 subject with AERD is unfortunate and a bit unexpected, given that 10% to 16% of subjects with CRSwNP and comorbid asthma have AERD.8Stevens W.W. Jerschow E. Baptist A.P. Borish L. Bosso J.V. Buchheit K.M. et al.The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: a work group report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.J Allergy Clin Immunol. 2021; 147: 827-844Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In phase III studies of dupilumab in CRSwNP, 28% of the included study population had AERD.9Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar This raises the question of a study population with limited PGD2-driven pathology or undiagnosed AERD. Additionally, no assessment of baseline systemic or respiratory tract PGD2 levels was performed, despite the clinical availability of a laboratory test for the measurement of a urinary PGD2 metabolite. The opportunity to assess the clinical utility of fevipiprant in a study population with high levels of PGD2 and/or AERD was missed. Lacking a baseline assessment of the PGD2 pathway, we are left to question whether the wrong study population was targeted. Alternatively, the importance of DP2/CRTH2+ cell recruitment to the nasal polyp tissue and its contribution to the signs and symptoms of CRSwNP may be overestimated. Another investigational product depleted nasal polyp tissue eosinophils yet failed to reduce nasal polyp size, providing strong support that nasal polyp size is independent of tissue eosinophilia.10Laidlaw T.M. Prussin C. Panettieri R.A. Lee S. Ferguson B.J. Adappa N.D. et al.Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size.Laryngoscope. 2019; 129: E61-E66Crossref PubMed Scopus (47) Google Scholar The lack of post–fevipiprant treatment biopsy samples was a missed opportunity to evaluate the impact of DP2 antagonism on tissue-resident and recruited inflammatory cells (ie, mast cells and ILC2s) in nasal polyp tissue and the role of DP2/CRTH2+ inflammatory cells in nasal polyp size.Phase II and III studies of fevipiprant in asthma showed modest positive clinical effects but have fallen short of the clinically and statistically significant mark. The most promising data have come from study cohorts enriched for atopy and eosinophilia. As yet, no studies have been enriched for patients with elevations in PGD2 level. One conclusion from phase II and III studies of fevipiprant is that the ideal target population for DP2 antagonism has not yet been identified. Alternatively, the results from clinical trials of fevipiprant may indicate that broader inhibition of the PGD2 pathway is required to see therapeutic benefit in type 2 airway inflammation diseases (Fig 1). On the basis of our current understanding of receptor mechanisms, the inclusion of DP1 and TP receptor antagonism would be more likely to yield measurable clinical change in nasal congestion scores and lung function, respectively. Have studies targeted the wrong population or wrong receptor? Future studies enriched for subjects with AERD and paired with mechanistic assessments of the PGD2 pathway are required before fevipiprant is excluded as a viable therapeutic in CRSwNP. Before the approval of dupilumab in 2019, the treatment of chronic rhinosinusitis with nasal polyposis (CRSwNP) was limited to topical and/or systemic steroids or surgical intervention. Biologic therapy has offered meaningful medical management options for CRSwNP; however, given the high cost of such therapy and its requirement for parenteral administration, novel medical treatments are sought. For the significant subset of patients with CRSwNP and comorbid asthma, medical options that address upper and lower airway inflammation are of particular importance. Prostaglandin (PGD2) is a key inflammatory mediator produced by tissue-resident mast cells and recruited inflammatory cells implicated in both asthma and CRSwNP. PGD2 and PGD2 metabolites have effects at 3 receptors: the D prostanoid 1 (DP1) receptor, the D prostanoid 2 (DP2) receptor (also known as CRTH2), and the thromboxane (TP) receptor. Each receptor facilitates unique and different functions of PGD2 that are relevant in chronic airway inflammation. DP1 is responsible for vasodilation, inhibition of platelet aggregation, TH0 cell polarization to TH2 cells by inhibition of dendritic cell IL-12 release, and dendritic cell migration.1Jandl K. Heinemann A. The therapeutic potential of CRTH2/DP2 beyond allergy and asthma.Prostaglandins Other Lipid Mediat. 2017; 133: 42-48Crossref PubMed Scopus (21) Google Scholar DP2 contributes to the recruitment of inflammatory cells (group 2 innate lymphoid cells [ILC2s], eosinophils, basophils, TH2 cells, and macrophages) to sites of tissue inflammation and promotes ILC2 survival and type 2 cytokine production.1Jandl K. Heinemann A. The therapeutic potential of CRTH2/DP2 beyond allergy and asthma.Prostaglandins Other Lipid Mediat. 2017; 133: 42-48Crossref PubMed Scopus (21) Google Scholar,2Hardman C. Chen W. Luo J. Batty P. Chen Y.L. Nahler J. et al.Fevipiprant, a selective prostaglandin D2 receptor 2 antagonist, inhibits human group 2 innate lymphoid cell aggregation and function.J Allergy Clin Immunol. 2019; 143: 2329-2333Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Signaling at the TP receptor facilitates bronchospasm.1Jandl K. Heinemann A. The therapeutic potential of CRTH2/DP2 beyond allergy and asthma.Prostaglandins Other Lipid Mediat. 2017; 133: 42-48Crossref PubMed Scopus (21) Google Scholar Both DP1 and DP2 receptors are implicated in the antifibrotic effects of PGD2 in bleomycin-induced pulmonary fibrosis models, whereas DP2 demonstrates a profibrotic role in Hermansky-Pudlack syndrome–associated lung disease.1Jandl K. Heinemann A. The therapeutic potential of CRTH2/DP2 beyond allergy and asthma.Prostaglandins Other Lipid Mediat. 2017; 133: 42-48Crossref PubMed Scopus (21) Google Scholar These proinflammatory effects of PGD2 support a potential therapeutic benefit from PGD2 pathway inhibition in asthma and CRSwNP. In phase II clinical trials in asthma, the selective DP2 antagonist fevipiprant showed promise, with improvements in FEV1 and reductions in sputum eosinophil count. However, the development of fevipiprant in asthma was halted after phase III studies demonstrated its safety but failed to achieve the targeted reductions in asthma exacerbations or improvements in FEV1 among patients with moderate-to-severe and uncontrolled asthma. In this issue of the Journal of Allergy and Clinical Immunology, Gevaert et al report the results of THUNDER, a phase IIIb, multicenter, randomized controlled trial of fevipiprant versus placebo in 98 subjects with CRSwNP and concomitant asthma.3Gevaert P. Bachert C. Maspero J.F. Cuevas M. Steele D. Acharya S. Altman P. Phase 3b randomized controlled trial of fevipiprant in patients with nasal polyposis with asthma (THUNDER).J Allergy Clin Immunol. 2022; 149: 1675-1682Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Subjects with a total nasal polyp score of 4 or higher despite 4 weeks of mometasone furoate nasal spray (200 μg once daily) were randomized 1:1:1 to add-on oral fevipiprant at a dose of 150 mg or 450 mg or matched placebo once daily for 16 weeks. The primary end point was change from baseline to week 16 in nasal polyp score as assessed by the centralized, 2-reader, blinded review of rhinoscopy videos. Secondary end points included change in nasal congestion score, the 22-item Sinonasal Outcome Test (SNOT-22) score, and smell as assessed by the University of Pennsylvania Smell Identification Test. No asthma outcomes were reported. The sample size was determined on the basis of a mean reduction of 1.5 points in nasal polyp score in the fevipiprant groups versus the placebo group. This primary end point projection was optimistic. Currently approved biologic therapies have failed to achieve a mean reduction in change from baseline in nasal polyp score of 1.5 points relative to placebo in study populations with higher starting nasal polyp scores.4Lipworth B.J. Chan R. The choice of biologics in patients with severe chronic rhinosinusitis with nasal polyps.J Allergy Clin Immunol Pract. 2021; 9: 4235-4238Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The fevpiprant dose, study duration, requirement for background mometasone furoate, and selection of primary and secondary end points align with those of other recent studies of medical therapeutics in CRSwNP and other phase III studies of fevipiprant in asthma. Even with the aggressive primary end point target, the primary end point data are decisively negative across both fevipiprant doses studied. Although the fevipiprant dose of 450 mg demonstrated a significant improvement in smell over placebo (by 4.5 points on the University of Pennsylvania Smell Identification Test), patients' scores on the SNOT-22 failed to improve and their nasal congestion scores showed a trend toward worsening. The results of post hoc analyses of the primary end point and the secondary end point nasal congestion score stratified by baseline peripheral blood eosinophil count (cutoff 450 μL) were also negative. Despite the mechanistic data to suggest benefit from DP2 antagonism in CRSwNP, these results from the first randomized controlled trial of fevipiprant in CRSwNP are negative. Could selection of the wrong study population or disease state explain a study with negative results? PGD2 is particularly relevant in the aspirin-exacerbated respiratory disease (AERD) subgroup of subjects with CRSwNP and comorbid asthma. At baseline, subjects with AERD have elevated levels of urinary PGD2 metabolites compared with those of aspirin-tolerant subjects with asthma—levels that are inversely correlated with the aspirin-induced decline in FEV1.5Cahill K.N. Bensko J.C. Boyce J.A. Laidlaw T.M. Prostaglandin D(2): a dominant mediator of aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2015; 135: 245-252Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar PGD2 levels increase acutely in aspirin-induced reactions during which peak PGD2 levels are correlated with increases in nasal congestion scores and reductions in FEV1 and blood eosinophil counts.5Cahill K.N. Bensko J.C. Boyce J.A. Laidlaw T.M. Prostaglandin D(2): a dominant mediator of aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2015; 135: 245-252Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar,6Buchheit K.M. Cahill K.N. Katz H.R. Murphy K.C. Feng C. Lee-Sarwar K. et al.Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2016; 137: 1566-1576.e5Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar The acute rise in PGD2 levels following aspirin ingestion is associated with the acute influx of DP2/CRTH2+ cells from the blood into the nasal mucosa, which is then reversed by high-dose aspirin therapy, at which time PGD2 levels fall and blood DP2/CRTH2+ cell counts increase.7Cahill K.N. Immunologic effects of aspirin desensitization and high-dose aspirin therapy in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2021; 148: 344-347Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Moreover, suppression of PGD2 in subjects with AERD by high-dose aspirin therapy is understood to be one mechanism of the benefit of high-dose aspirin therapy in AERD.7Cahill K.N. Immunologic effects of aspirin desensitization and high-dose aspirin therapy in aspirin-exacerbated respiratory disease.J Allergy Clin Immunol. 2021; 148: 344-347Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Such data support the idea that targeting the PGD2 pathway could benefit the acute COX1 inhibitor–induced respiratory reactions and the chronic baseline inflammation associated with AERD. Regrettably, the THUNDER study population was not enriched for subjects with AERD. The randomization of only 1 subject with AERD is unfortunate and a bit unexpected, given that 10% to 16% of subjects with CRSwNP and comorbid asthma have AERD.8Stevens W.W. Jerschow E. Baptist A.P. Borish L. Bosso J.V. Buchheit K.M. et al.The role of aspirin desensitization followed by oral aspirin therapy in managing patients with aspirin-exacerbated respiratory disease: a work group report from the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the American Academy of Allergy, Asthma & Immunology.J Allergy Clin Immunol. 2021; 147: 827-844Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In phase III studies of dupilumab in CRSwNP, 28% of the included study population had AERD.9Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar This raises the question of a study population with limited PGD2-driven pathology or undiagnosed AERD. Additionally, no assessment of baseline systemic or respiratory tract PGD2 levels was performed, despite the clinical availability of a laboratory test for the measurement of a urinary PGD2 metabolite. The opportunity to assess the clinical utility of fevipiprant in a study population with high levels of PGD2 and/or AERD was missed. Lacking a baseline assessment of the PGD2 pathway, we are left to question whether the wrong study population was targeted. Alternatively, the importance of DP2/CRTH2+ cell recruitment to the nasal polyp tissue and its contribution to the signs and symptoms of CRSwNP may be overestimated. Another investigational product depleted nasal polyp tissue eosinophils yet failed to reduce nasal polyp size, providing strong support that nasal polyp size is independent of tissue eosinophilia.10Laidlaw T.M. Prussin C. Panettieri R.A. Lee S. Ferguson B.J. Adappa N.D. et al.Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size.Laryngoscope. 2019; 129: E61-E66Crossref PubMed Scopus (47) Google Scholar The lack of post–fevipiprant treatment biopsy samples was a missed opportunity to evaluate the impact of DP2 antagonism on tissue-resident and recruited inflammatory cells (ie, mast cells and ILC2s) in nasal polyp tissue and the role of DP2/CRTH2+ inflammatory cells in nasal polyp size. Phase II and III studies of fevipiprant in asthma showed modest positive clinical effects but have fallen short of the clinically and statistically significant mark. The most promising data have come from study cohorts enriched for atopy and eosinophilia. As yet, no studies have been enriched for patients with elevations in PGD2 level. One conclusion from phase II and III studies of fevipiprant is that the ideal target population for DP2 antagonism has not yet been identified. Alternatively, the results from clinical trials of fevipiprant may indicate that broader inhibition of the PGD2 pathway is required to see therapeutic benefit in type 2 airway inflammation diseases (Fig 1). On the basis of our current understanding of receptor mechanisms, the inclusion of DP1 and TP receptor antagonism would be more likely to yield measurable clinical change in nasal congestion scores and lung function, respectively. Have studies targeted the wrong population or wrong receptor? Future studies enriched for subjects with AERD and paired with mechanistic assessments of the PGD2 pathway are required before fevipiprant is excluded as a viable therapeutic in CRSwNP. Phase 3b randomized controlled trial of fevipiprant in patients with nasal polyposis with asthma (THUNDER)Journal of Allergy and Clinical ImmunologyVol. 149Issue 5PreviewChronic rhinosinusitis with nasal polyps (CRSwNP) is associated with asthma, particularly of late onset. Current treatment options for CRSwNP have limitations, and there is an unmet need for other safe and effective therapies. Full-Text PDF