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Jonathan Corren,1 David J Jackson,2,3 Thomas B Casale,4 Larry Borish,5,6 Klaus F Rabe,7,8 William W Busse,9 Jorge F Maspero,10 Daniel J Jackson,11 Nadia Daizadeh,12 Arman Altincatal,12 Amr Radwan,13 Angela Khodzhayev,13 Michel Djandji,12 Juby A Jacob-Nara,12,14 Paul J Rowe,14 Yamo Deniz13 1David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 2King’s College London, London, UK; 3Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 4Division of Allergy and Immunology, University of South Florida, Tampa, FL, USA; 5Asthma and Allergic Disease Center, University of Virginia Health System, Charlottesville, VA, USA; 6Carter Immunology Center, University of Virginia Health System, Charlottesville, VA, USA; 7LungenClinic Grosshansdorf (Member of the German Center for Lung Research [DZL]), Airway Research Center North (ARCN), Grosshansdorf, Germany; 8Christian-Albrechts University (Member of the German Center for Lung Research [DZL]), Airway Research Center North (ARCN), Kiel, Germany; 9UW Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 10Fundación CIDEA, Buenos Aires, Argentina; 11University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 12Sanofi, Cambridge, MA, USA; 13Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 14Sanofi, Bridgewater, NJ, USACorrespondence: Jonathan Corren, David Geffen School of Medicine at UCLA, 10780 Santa Monica Blvd., Suite 280, Los Angeles, CA, 90025, USA, Email jcorren@ucla.eduPurpose: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4/-13, key and central drivers of type 2 (T2) inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), dupilumab vs placebo significantly reduced asthma exacerbation rates (AER) and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater effects in patients with elevated T2 biomarkers (≥ 150 eosinophils/μL or fractional exhaled nitric oxide [FeNO] ≥ 25 parts per billion). Overall safety was consistent with the known dupilumab safety profile. This post hoc analysis assessed dupilumab efficacy in QUEST patients with T2 asthma with evidence of an allergic phenotype (baseline serum IgE ≥ 30 IU/mL and aeroallergen-specific IgE ≥ 0.35 IU/mL) by number of aeroallergen sensitizations: 1, 2, 3, or ≥ 4. Non-sensitized patients (serum total IgE < 30 IU/mL without evidence of allergic phenotype) were also assessed.Patients and Methods: Endpoints were annualized AER, change from baseline in pre-bronchodilator FEV1 and asthma control (5-item Asthma Control Questionnaire [ACQ-5]), and FeNO and serum total IgE levels over the 52-week treatment period.Results: In all subgroups by number of allergens sensitized, dupilumab vs placebo reduced AER by 35– 67% and improved both pre-bronchodilator FEV1 at Week 12 (least squares mean differences: 0.10– 0.26 L across subgroups) and ACQ-5 score at Week 52 (– 0.26 to – 0.43). Dupilumab significantly reduced FeNO and total IgE levels at Week 52 compared with placebo. Similar results were observed in non-sensitized patients.Conclusion: Dupilumab improved clinical outcomes and reduced biomarker levels in patients with uncontrolled, moderate-to-severe T2 asthma irrespective of allergen sensitization status or number.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02414854.Keywords: dupilumab, allergic asthma, type 2 asthma, perennial aeroallergen

Transient increases in blood eosinophil counts have been observed in dupilumab clinical trials.To assess eosinophil counts and eosinophilia-related treatment-emergent adverse events (TEAEs) across 11 dupilumab clinical trials, comparing adult and adolescent patients with asthma and adult patients with chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis, and eosinophilic esophagitis.Eosinophil counts, rates of eosinophilia-related TEAEs or treatment-emergent eosinophilia (1,500 cells/μL), discontinuations, clinical symptoms, and efficacy in patients with asthma or CRSwNP with treatment-emergent eosinophilia are presented.Transient increases in mean eosinophil counts were observed in dupilumab-treated patients with asthma (mean range across studies at baseline: 349-370 cells/μL; week 4: 515-578 cells/μL), CRSwNP (baseline: 440-448 cells/μL; week 16: 595 cells/μL), and atopic dermatitis (baseline: 434-600 cells/μL; week 4: 410-710 cells/μL), followed by a decline starting by week 24 to baseline or lower. No increases were seen in patients with eosinophilic esophagitis (baseline: 310 cells/μL; week 4: 230 cells/μL). In dupilumab-treated patients across all studies, rates of eosinophilia TEAEs were 0% to 13.6%. Clinical symptoms associated with increased eosinophils were rare (seven of 4,666 dupilumab-treated patients, including six cases of eosinophilic granulomatosis with polyangiitis) and occurred only in patients with asthma or CRSwNP. Eosinophilia was not associated with reduced dupilumab efficacy.Transient increases in eosinophil counts with dupilumab treatment did not affect efficacy and were rarely of clinical consequence. It remains important for physicians to base judgment on individual patient history and baseline eosinophil counts and to be alert to hypereosinophilic symptoms.

Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease of increasing prevalence, characterized by symptoms of dysphagia and reduced quality of life. A dysregulated type 2 immune response to food and aeroallergen leads to barrier dysfunction, chronic esophageal inflammation, remodeling, and fibrosis. Patients with EoE have impaired quality of life because of dysphagia and other symptoms. They may also suffer social and psychological implications of food-related illness and expensive out-of-pocket costs associated with treatment. Disease burden in EoE is often compounded by the presence of comorbid type 2 inflammatory diseases. Current conventional treatments include elimination diet, proton pump inhibitors, and swallowed topical corticosteroids, as well as esophageal dilation in patients who have developed strictures. These treatments demonstrate variable response rates and may not always provide long-term disease control. There is an unmet need for long-term histologic, endoscopic, and symptomatic disease control; for targeted therapies that can normalize the immune response to triggers, reduce chronic inflammation, and limit or prevent remodeling and fibrosis; and for earlier diagnosis, defined treatment outcomes, and a greater understanding of patient perspectives on treatment. In addition, healthcare professionals need a better understanding of the patient perspective on disease burden, the disconnect between symptoms and disease activity, and the progressive nature of EoE and the need for continuous monitoring and maintenance treatment. In this review, we explore the progression of disease over the patient's lifespan, highlight the patient perspective on disease, and discuss the unmet need for effective long-term treatments.

William Walter Busse,1 Ian Douglas Pavord,2 Shahid Siddiqui,3 Asif Hameed Khan,4 Amy Praestgaard,5 Scott Nash,3 Juby Anne Jacob-Nara,6 Paul Jonathan Rowe,6 Yamo Deniz3 1Department of Medicine, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin, Madison, WI, USA; 2Oxford Respiratory NIHR BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 3Medical Affairs, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 4Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 5Department of Biostatistics, Sanofi, Cambridge, MA, USA; 6Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: William Walter Busse, Department of Medicine, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin, Madison, WI, USA, Tel +1 608 263-6183, Email wwb@medicine.wisc.eduPurpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease frequently coexisting with other type 2 conditions including asthma and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Coexisting asthma leads to increased CRSwNP symptom burden. Dupilumab, a monoclonal antibody that blocks the shared receptor component for interleukin-4 and -13, demonstrated efficacy in adults with severe CRSwNP in the Phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies, including in patients with coexisting asthma/NSAID-ERD. However, the impact of different asthma characteristics on dupilumab treatment in this population is unknown. We report CRSwNP and asthma outcomes with dupilumab in patients with CRSwNP and coexisting asthma according to baseline asthma characteristics.Methods: Change from baseline at Week 24 (pooled studies) and Week 52 (SINUS-52) in CRSwNP outcomes (nasal polyp score, nasal congestion, 22-item Sino-Nasal Outcome Test [SNOT-22], loss of smell score, University of Pennsylvania Smell Identification Test) and asthma outcomes (5-item Asthma Control Questionnaire [ACQ-5], pre-bronchodilator forced expiratory volume in 1 second [FEV1]) were analyzed post hoc for placebo and dupilumab 300 mg every 2 weeks according to baseline blood eosinophils ≥ 150/≥ 300 cells/μL, ACQ-5 scores < 1.5/≥ 1.5, and FEV1 < 80%.Results: In the pooled studies, 428/724 patients (59.1%) had coexisting asthma, of which 181/428 (42.3%) had coexisting NSAID-ERD. Dupilumab significantly improved all CRSwNP and asthma outcomes vs placebo at Week 24 (P < 0.001) regardless of baseline eosinophil or ACQ-5 category, or FEV1 < 80%. Similar magnitude of improvement was seen at Week 52 (SINUS-52) and in patients with NSAID-ERD (pooled studies, Week 24). By Week 24, improvements with dupilumab exceeded the minimum clinically important differences for ACQ-5 and SNOT-22 in 35.2% to 74.2% and 72.0% to 78.7% of patients, respectively.Conclusion: Dupilumab improved CRSwNP outcomes in patients with CRSwNP and coexisting asthma, and improved asthma outcomes, regardless of differences in baseline asthma characteristics.Keywords: chronic rhinosinusitis with nasal polyps, dupilumab, asthma

BACKGROUND: Patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP) experience recurrent respiratory tract infections. Dupilumab targets type 2 inflammation, a common underlying pathophysiology of both conditions, with proven efficacy. OBJECTIVE: To examine investigator-reported respiratory infection adverse events and anti-infective medication use with dupilumab versus placebo in patients with moderate-to-severe asthma or severe CRSwNP. METHODS: We performed a post hoc analysis of the pivotal phase 3 trials LIBERTY ASTHMA QUEST (NCT02414854) and LIBERTY NP SINUS-52 (NCT02898454) in moderate-to-severe asthma and severe CRSwNP, respectively. RESULTS: Investigator-reported respiratory infection events occurred at a significantly lower incidence in patients treated with dupilumab versus placebo, in both asthma (22% lower; P < .0001; 95% CI 0.71-0.85) and CRSwNP (38% lower; P

Jorge F Maspero,1 Asif H Khan,2 Carl Philpott,3 Peter W Hellings,4 Claire Hopkins,5 Martin Wagenmann,6 Shahid Siddiqui,7 Jérôme Msihid,8 Scott Nash,7 Chien-Chia Chuang,9 Siddhesh Kamat,7 Paul J Rowe,10 Yamo Deniz,7 Juby A Jacob-Nara10 1Allergy & Respiratory Research Unit, Fundación CIDEA, Buenos Aires, Argentina; 2Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 3Rhinology and ENT Research Group, Norwich Medical School, University of East Anglia, Norwich, UK; 4Department of Otorhinolaryngology – Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; 5Department of Otorhinolaryngology, King’s College London, London, UK; 6Department of Otorhinolaryngology, Düsseldorf University Hospital (UKD), Düsseldorf, Germany; 7Medical Affairs, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 8Health Economics and Value Assessment, Sanofi, Chilly-Mazarin, France; 9Health Economics and Value Assessment, Sanofi, Cambridge, MA, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Jorge F Maspero, Allergy & Respiratory Research Unit, Fundación CIDEA, Paraguay 2035, 2SS, Buenos Aires, Argentina, Tel +54 9 11 4183-7294, Email jorge.maspero@fundacioncidea.org.arPurpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease with a high symptom burden. Data are lacking on the comparative health status of patients with CRSwNP. This analysis compared baseline physical and mental health-related quality of life (HRQoL) and overall health status of patients with severe CRSwNP enrolled in a Phase 3 clinical trial with general population norms and with other chronic diseases.Methods: In this post hoc cross-sectional analysis of baseline data from the SINUS-24 study (NCT02912468), HRQoL was measured using the 36-item Short Form (SF-36) questionnaire and general health status was measured using the EuroQol-5 Dimension visual analog scale (EQ-VAS). Analyses included the intention-to-treat (ITT) population and subgroups defined by prior sinonasal surgery, systemic corticosteroid use, and coexisting asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Scores were compared with published values for population norms (50 for SF-36 physical component summary (PCS) and mental component summary (MCS), 70.4− 83.3 for EQ-VAS) and for rheumatoid arthritis, type 2 diabetes, and asthma.Results: In the ITT population (n=276), mean SF-36 physical component summary (PCS), SF-36 mental component summary (MCS), and EQ-VAS scores were below general population norms (46.4, 48.6, and 66.0, respectively). Mean SF-36 PCS and EQ-VAS scores were below population norms across all subgroups; mean SF-36 MCS scores were below the population norm in all subgroups except no prior surgery. SF-36 PCS and MCS scores from SINUS-24 were generally similar to other chronic diseases, except SF-36 PCS which was lower in rheumatoid arthritis. EQ-VAS scores in SINUS-24 were lower than in other chronic diseases. HRQoL scores weakly correlated with objective measures of disease severity.Conclusion: In patients with severe CRSwNP, including those with coexisting asthma/NSAID-ERD, HRQoL was worse than population norms and as burdensome as diseases such as type 2 diabetes, asthma, and rheumatoid arthritis.Graphical Abstract: Keywords: chronic rhinosinusitis with nasal polyps, health-related quality of life, symptom burden

Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations.In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEVPatients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per μL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per μL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011).In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations.Sanofi and Regeneron Pharmaceuticals.

Background: Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins 4/13, key and central drivers of type 2 inflammation. The LIBERTY ASTHMA TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who had participated in a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Methods: This analysis includes patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose inhaled corticosteroids (ICS) at parent study baseline (PSBL) and enrolled in TRAVERSE. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (pre-BD) FEV (L), asthma control (5-item asthma control questionnaire), and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. Results: Of patients with type 2 asthma (n=1,666) in this analysis, 891 (53.5%) were receiving high‑dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab vs placebo were 0.517 vs. 1.883 (phase 2b) and 0.571 vs. 1.300 (QUEST) over 52 weeks of the parent study, and remained low throughout TRAVERSE (0.313–0.494). Improvements in pre-BD FEV from PSBL were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. Conclusions: Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.

Severe asthma impacts quality of life (QoL), including dyspnea, sleep, and activity limitation. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4/-13, key and central drivers of type 2 inflammation. Phase 3 VENTURE (NCT02528214) and TRAVERSE open-label extension (NCT02134028) evaluated dupilumab 300 mg vs placebo every 2 weeks for 24 weeks (VENTURE) and dupilumab only for an additional 48-96 weeks (TRAVERSE) in patients with oral corticosteroid (OCS)-dependent severe asthma.To assess dupilumab's impact on Asthma Quality of Life Questionnaire (AQLQ) items related to breathing symptoms, sleep, and activity limitation, and on OCS reduction.Proportion of patients with AQLQ scores of 6/7 for breathing symptoms-, sleeping-, and activity-related items in VENTURE and TRAVERSE, together with OCS dose reductions in VENTURE.In VENTURE, significantly greater proportions of dupilumab- vs placebo-treated patients achieved scores of 6/7 by week 24 in breathing symptoms- (42.7-60.2% vs 22.4-39.3%), sleeping- (45.6-65.0% vs 27.1-47.7%), and activity-related (44.7-51.5% vs 22.4-34.6%) AQLQ items. Improvements were maintained through TRAVERSE in the dupilumab/dupilumab group and increased to dupilumab treatment levels in the placebo/dupilumab group. Significant OCS dose reductions were observed in VENTURE; up to 90% and 60% of dupilumab- vs 65% and 41% of placebo-treated patients with AQLQ scores of 6/7 in breathing symptoms-, sleeping-, and activity-related items achieved ≥50% dose reduction and eliminated OCS at week 24, respectively.In patients with severe OCS-dependent asthma, dupilumab improved QoL related to breathing symptoms, sleep, and activity limitation, and reduced OCS use.

The 52-week, phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) in patients aged above or equal to 12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks vs matched placebo.To assess whether dupilumab improves clinical outcomes in QUEST patients with persistent airflow obstruction (PAO) defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity ratio less than 0.7 at baseline.End points were annualized rate of severe exacerbations, pre and post-bronchodilator forced expiratory volume in 1 second over time, proportion achieving reversal of PAO, and quality of life. Efficacy was evaluated in patients with or without PAO at baseline in subpopulations with eosinophils ≥ 150 cells/µL or fractional exhaled nitric oxide (FeNO) ≥ 25 ppb or eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb.Of 1902 patients enrolled in QUEST, 1039 (55%) had PAO at baseline. Dupilumab vs placebo rapidly and significantly improved lung function in patients with PAO and elevated type 2 inflammatory biomarkers at baseline. Dupilumab improved probability of reversing airflow obstruction (hazard ratio vs placebo 1.616 [95% confidence interval, 1.272-2.052] and 1.813 [1.291-2.546]; both P.001) and significantly reduced severe exacerbations by 69% (relative risk, 0.411; 95% confidence interval [0.327-0.516]; P.0001) and by 75% (0.252 [0.178-0.356]; P.0001) in patients with PAO with eosinophils ≥ 150 cells/µL or FeNO ≥ 25 ppb and eosinophils ≥ 300 cells/µL and FeNO ≥ 25 ppb, respectively. Similar results were observed in patient subgroups without PAO.In patients with uncontrolled moderate-to-severe asthma, treatment with dupilumab facilitates reversal of PAO status and improves clinical outcomes.ClinicalTrials.gov identifier: NCT02414854.

Although eosinophils are the hallmark of eosinophilic esophagitis (EoE) with threshold levels required for diagnosis, their exact role in EoE is unclear. The EoE-Endoscopic Reference Score (EREFS) assesses endoscopic inflammatory (edema/exudate/furrows) and remodeling (rings/strictures) features. We assessed the correlations between peak esophageal intraepithelial eosinophil count (eos/high-power field [hpf]) and EREFS in placebo-treated EoE patients from two clinical trials: phase 2 proof-of-concept (POC; NCT02379052; n = 24) and part A of phase 3 TREET (Phase3-PartA; NCT03633617; n = 39). POC was a 12-week trial in adults and Phase3-PartA was a 24-week trial in adults and adolescents. Endoscopic examination of the esophagus was performed at baseline (BL) and end of treatment (EOT) and scored for inflammatory and remodeling subscores and total score using EREFS (higher scores indicate greater severity). Peak eos/hpf was measured from pinch biopsies of proximal, mid, and distal esophagus at BL and EOT. Pearson correlations were performed between total/proximal/mid/distal eos/hpf and EREFS total, subscores, and components at BL, EOT, and for change from BL at EOT. Some strong correlations (r > 0.5) were observed between total peak eos/hpf and EREFS at BL in both studies and at EOT in Phase3-Part A (Table). Moderate-to-strong correlations (r > 0.3) were observed between total peak eos/hpf and EREFS inflammation subscore and edema/exudates/furrows individual components (some P > 0.5) in both studies. Correlations of total peak eos/hpf with EREFS remodeling subscore and rings/stricture components were not significant (P = 0.07–0.94). Peak eos/hpf in the proximal, mid, or distal esophagus were more strongly associated with EREFS inflammation subscore (majority moderate-to-strong correlations; P = 0.001–0.66) than EREFS remodeling subscore (weak correlations, P = 0.22–0.99) at BL/EOT for both studies. In these EoE patients, moderate-to-strong correlations were observed between eos/hpf and endoscopic markers of inflammation. No strong correlations were observed between total, proximal, mid, or distal peak eos/hpf and endoscopic parameters of remodeling. These data support a role for intact eosinophils in inflammatory changes in the esophagus in EoE and demonstrate the need for both histology and endoscopic evaluation. Further study, with larger sample sizes, is required to verify these findings in other contexts.

The Histologic Scoring System (HSS) assesses severity/extent of histologic features (eosinophil density [ED]/basal zone hyperplasia [BZH]/eosinophil abscesses [EA]/eosinophil surface layering [SL]/surface epithelial alteration [SEA]/dyskeratotic epithelial cells [DEC]/dilated intercellular spaces [DIS]/lamina propria fibrosis [LPF]) in eosinophilic esophagitis (EoE). The Endoscopic Reference Score (EREFS) assesses endoscopic feature severity (edema/exudates/furrows/rings/strictures). We correlated HSS components with inflammatory/remodeling EREFS components in placebo-treated EoE patients from 2 trials—phase 2 proof-of-concept (POC; NCT02379052), phase 3 TREET part A (Phase3-PartA; NCT03633617). POC was a 12-week trial in adults, and Phase3-PartA was a 24-week trial in adults and adolescents. Proximal/mid/distal esophagus biopsies were collected at baseline/end of treatment (EOT) and scored by HSS for grade (severity)/stage (extent)/components (higher scores = greater severity). Endoscopies were scored by EREFS (higher scores = greater severity) and inflammatory (edema+exudates+furrows) and remodeling (rings+stricture) subscores calculated. Pearson correlation and single co-variate regression model analyses were performed between baseline HSS grade/stage, total/individual components scores and EREFS total/components scores and subscores, and for the change in scores from baseline at EOT (ΔEOT). Moderate-to-strong correlations (r > 0.3) were observed between total EREFS and HSS grade/stage for baseline/ΔEOT in POC and baseline in Phase3-PartA (Table). Moderate correlations were observed between BZH and EREFS remodeling subscore and rings for ΔEOT in Phase3-PartA; DIS grade and EREFS remodeling subscore and strictures for baseline and ΔEOT in POC but not Phase3-PartA; and EREFS inflammation and remodeling subscores and components for SEA and SL at baseline and ΔEOT in POC. Moderate-to-strong correlations were observed between EREFS inflammation subscore and DIS stage and between edema and DIS grade/stage at baseline in both studies. Similar results were observed using regression analyses. Specific components of HSS and EREFS, reflecting inflammatory and remodeling processes, are closely correlated, when examined by Pearson correlations or regression analyses, and can aid identification of fibrostenotic or inflammatory phenotypes in EoE. Correlations of DIS with endoscopic inflammatory and remodeling features reflect the role of barrier dysfunction in maintaining chronic inflammation that ultimately leads to remodeling.

Coexisting chronic rhinosinusitis and nasal polyps (CRS-NPs) substantially increases the disease burden of asthma. Dupilumab, a fully human monoclonal antibody, has established efficacy and an acceptable safety profile in asthma and CRS with NP.To evaluate long-term dupilumab efficacy in TRAVERSE (NCT02134028) patients with uncontrolled, moderate-to-severe (QUEST) or oral corticosteroid (OCS)-dependent (VENTURE) asthma with or without coexisting CRS-NP.In TRAVERSE, 317 of 1530 (21%) QUEST and 61 of 187 (48%) VENTURE patients had self-reported CRS-NP; they received subcutaneous 300 mg dupilumab every 2 weeks up to 96 weeks. Patients were categorized by parent study treatment group (placebo/dupilumab, dupilumab/dupilumab). End points included annualized asthma exacerbation rates and mean change from parent study baseline in prebronchodilator forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, Asthma Quality of Life Questionnaire score, and OCS dose.Patients with coexisting CRS-NP had higher OCS dose and a history of more exacerbations. Concluding TRAVERSE, exacerbation rates decreased from 2.39 to 0.32 and 2.32 to 0.35 in dupilumab/dupilumab and 2.36 to 0.41 and 2.36 to 0.45 in placebo/dupilumab by week 96 from QUEST and VENTURE baselines, respectively. Non-CRS-NP results were similar. Improvements in forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, and Asthma Quality of Life Questionnaire score during parent studies were maintained in TRAVERSE; placebo/dupilumab patients achieved similar improvements to dupilumab/dupilumab by week 48. By week 96, 71% and 39% of OCS-dependent patients with CRS-NP and 83% and 47% without CRS-NP treated with dupilumab/dupilumab and placebo/dupilumab, respectively, stopped OCS.Long-term dupilumab efficacy was maintained in patients with asthma with or without self-reported coexisting CRS-NP, including OCS-sparing effects observed in OCS-dependent severe asthma.ClinicalTrials.gov Identifiers: NCT02528214, NCT02414854, and NCT02134028.

Fractional exhaled nitric oxide (FeNO) may have a role both as a prognostic and predictive biomarker, in combination with eosinophils, for assessing responsiveness to some biological therapies.We evaluated the value of baseline FeNO, adjusted for baseline blood eosinophil levels and other clinical characteristics, as an independent predictor of treatment response to dupilumab in patients with uncontrolled, moderate-to-severe asthma.We performed a post-hoc analysis of LIBERTY ASTHMA QUEST (NCT02414854), a phase 3, double-blind study in patients aged ≥ 12 years with uncontrolled moderate-to-severe asthma who received dupilumab 200/300 mg, or placebo every 2 weeks up to 52 weeks. Annualized event rate (AER) of severe exacerbations and least squares mean change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEVAER increased with increasing baseline FeNO in placebo, and decreased in dupilumab groups. The relative risk of severe exacerbations was 22·7%, 58·3%, and 69·3% lower for dupilumab vs placebo for the FeNO25, 25 to50, and ≥ 50 ppb subgroups. The magnitude of FEVIncreased baseline FeNO was associated with greater clinical effects in dupilumab vs placebo, independent of eosinophil levels and other clinical characteristics.

Claire Hopkins,1 Kathleen M Buchheit,2 Enrico Heffler,3,4 Noam A Cohen,5 Heidi Olze,6 Asif H Khan,7 Jérôme Msihid,8 Shahid Siddiqui,9 Scott Nash,9 Juby A Jacob-Nara,10 Paul J Rowe,10 Yamo Deniz9 1Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, Boston, MA, USA; 3Personalized Medicine, Asthma & Allergy – Humanitas Clinical and Research Center IRCCS, Milan, Italy; 4Department of Biomedical Sciences, Humanitas University, Milan, Italy; 5Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 6Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany; 7Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 8Health Economics and Value Assessment, Sanofi, Chilly-Mazarin, France; 9Medical Affairs, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Claire Hopkins, Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK, Tel +44 2071882215, Email clairehopkins@yahoo.comAbstract: Patients with asthma frequently have comorbid chronic rhinosinusitis (CRS) with or without nasal polyps, increasing disease burden and complicating treatment. These post hoc analyses investigated disease-specific health-related quality of life (HRQoL) and general health status in the randomized, placebo-controlled QUEST study (NCT02414854) in patients treated with dupilumab for moderate-to-severe asthma with comorbid CRS. Patients received 300 mg of dupilumab or placebo every 2 weeks for 52 weeks. CRS HRQoL was assessed by the 22-item Sino-Nasal Outcome Test (SNOT-22; items scored 0– 5). The 22 items are categorized into 5 domains (nasal, ear/facial, sleep, function, and emotion), and patients report the top 5 most important items affecting their health. General health status was assessed by Euro-QoL visual analog scale (EQ-VAS). Of 1902 patients, 382 (20.1%) self-reported comorbid CRS; 193 patients receiving dupilumab 300 mg q2w or matched placebo were included in this analysis. At baseline, the most impacted SNOT-22 domain was nasal, and general health status was below population norms. Patients rated “decreased sense of taste/smell,” “nasal blockage,” “cough,” “reduced productivity,” and “wake up tired” as the 5 most important SNOT-22 items affecting their health. Percentage change from baseline in SNOT-22 total score was significantly greater for dupilumab vs placebo at Weeks 24, 36, and 52 (all p < 0.05). Improvements from baseline were significantly greater for dupilumab vs placebo at Week 52 for all SNOT-22 domains (p < 0.05), except emotion. At Week 52, significant changes from baseline with dupilumab vs placebo were observed for all 5 most important SNOT-22 items affecting their health (all p < 0.05). EQ-VAS was significantly improved with dupilumab vs placebo by Week 12, with improvements sustained to Week 52 (all p < 0.01). In patients with moderate-to-severe asthma who self-reported comorbid CRS, dupilumab treatment vs placebo improved CRS-specific HRQoL and general health status.Keywords: asthma, chronic rhinosinusitis, nasal polyps, dupilumab, health-related quality of life, SNOT-22

Purpose The Phase 3 LIBERTY ASTHMA QUEST study in patients aged ≥12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks (q2w) vs matched placebo in the overall population. This post hoc analysis assessed dupilumab efficacy by disease severity as evidenced by baseline % predicted forced expiratory volume in 1 second (FEV1) and dose of inhaled corticosteroids (ICS). Patients and Methods Severe asthma exacerbation rates, change from baseline in FEV1, asthma control, quality of life, and fractional exhaled nitric oxide (FeNO) levels over the 52-week treatment period were assessed in patients with elevated type 2 inflammation biomarkers stratified by ICS dose and FEV1% predicted at baseline. Results In patients with elevated baseline eosinophils, dupilumab 200 mg and 300 mg q2w vs placebo reduced severe exacerbation rates by 50% (P=0.06) and 67% (P=0.001), respectively, in those with medium-dose ICS/FEV1% predicted 60-90%, and by 59% (P

Background In the LIBERTY ASTHMA QUEST (ClinicalTrials.gov: NCT02414854 ) study, dupilumab 200 mg and 300 mg every 2 weeks vs matched-volume placebo reduced severe asthma exacerbations and improved lung function (FEV1), asthma control, and quality of life in patients with uncontrolled, moderate-to-severe asthma (N = 1902). Here, we examine the safety and efficacy of dupilumab in the subpopulation of Japanese patients who participated in QUEST (n = 114; 6%). Methods Endpoints assessed were annualized severe exacerbation rates and the effect of treatment over the 52-week treatment period on FEV1, asthma control, asthma-related quality of life, and markers of type 2 inflammation. Results In Japanese patients, dupilumab 200 and 300 mg every 2 weeks vs matched placebo reduced severe asthma exacerbation rates by 44% (P = 0.33) and 75% (P = 0.03), respectively, and improved FEV1 at Week 12 by 0.20 L (P = 0.05) and 0.17 L (P = 0.12). FEV1 improvements were rapid (by Week 2) and sustained throughout treatment. Significant and/or numerical improvements vs placebo in asthma control and quality of life were also observed throughout treatment. For each endpoint, greater efficacy was observed in patients with elevated baseline levels of type 2 inflammatory biomarkers (blood eosinophils or FeNO). Dupilumab treatment significantly reduced levels of FeNO and total IgE, but not blood eosinophils. Conclusions In this subanalysis of QUEST, the efficacy and safety of dupilumab in Japanese patients was comparable to that observed in the overall intention-to-treat population, suggesting no variability in efficacy on the basis of Japanese ethnicity. (Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov number: NCT02414854 )

Safety and efficacy data for dupilumab beyond 1 year are lacking for patients from Japan with moderate-to-severe asthma.The TRAVERSE open-label extension (OLE) study (NCT02134028) assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in 2282 patients who completed a previous dupilumab asthma study. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included annualized severe exacerbation rate and change from parent study baseline in pre-bronchodilator forced expiratory volume in 1 second (FEVTEAEs were consistent with the parent studies and the known safety profile of dupilumab. One patient permanently discontinued treatment due to TEAEs. Exacerbation rates remained low and were sustained to Week 96, as were improvements in pre-bronchodilator FEVLong-term dupilumab treatment was well tolerated and efficacious in patients with non-OCS-dependent, moderate-to-severe asthma recruited from Japan. (Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov identifier, NCT02134028).

BACKGROUND: Type 2 inflammatory diseases often coexist in patients. Dupilumab targets type 2 inflammation and has demonstrated treatment benefits in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP) with an acceptable safety profile. OBJECTIVE: This post hoc analysis across five phase 3 studies in patients with moderate to severe AD or asthma, or severe CRSwNP, evaluated time of onset and duration of the treatment response. METHODS: Patients received subcutaneous dupilumab 200/300 mg or placebo. Assessments included the Eczema Area and Severity Index, Peak Pruritus Numerical Rating Scale, and Dermatology Life Quality Index in AD; pre-bronchodilator FEV1, daily morning peak expiratory flow, and symptom scores in asthma; and University of Pennsylvania Smell Identification Test, daily nasal congestion, and loss of smell scores in CRSwNP. RESULTS:At week 2 after the initiation of dupilumab versus placebo, 67.8% versus 36.5% of AD patients achieved a clinically meaningful benefit (Eczema Area and Severity Index: 50% or greater improvement; Peak Pruritus Numerical Rating Scale: 3 point or greater improvement; or Dermatology Life Quality Index: 4 point or greater improvement) (P < .001). Moreover, 61.6% versus 39.9% of asthma patients achieved improvements in pre-bronchodilator FEV1 of 100 mL or greater and 48.8% versus 26.3% achieved 200 mL or greater improvement (both P < .001); 33.2% versus 5.6% of CRSwNP patients regained a sense of smell (P < .001). Treatment effects further improved or were sustained to the end of treatment. CONCLUSIONS: Clinically meaningful responses were achieved rapidly after the first dupilumab dose in AD, asthma, or CRSwNP and were sustained throughout treatment (see Video in this article's Online Repository at www.jaci-inpractice.org). (C) 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.

While advances in asthma care have been made in Latin America, there is still a large unmet need in patients with uncontrolled asthma. This post hoc analysis of the QUEST study assessed safety and efficacy of dupilumab in the subgroup of patients enrolled in Latin American countries with a type 2 inflammatory asthma phenotype (blood eosinophils ≥ 150cells/µL or FeNO ≥25ppb). LIBERTY ASTHMA QUEST (NCT02414854) was a phase 3, multinational, randomized, double-blind, placebo-controlled study in patients with uncontrolled, moderate-to-severe asthma. Eligible patients ≥ 12 years of age were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on subcutaneous dupilumab 200 or 300 mg every 2 weeks or matched-volume placebos. Pre-specified co-primary efficacy endpoints were the annualized rate of severe exacerbations during the treatment period and the change from baseline in pre-bronchodilator FEV1 at treatment week 12. Asthma control, changes in asthma biomarker levels, and dupilumab safety were also evaluated. 530 (27.9% of the overall QUEST population; dupilumab: 353, placebo: 177) Latin-American patients were recruited; 420 (79.2%) had a type 2 inflammatory asthma phenotype. Dupilumab vs placebo reduced the annualized rate of severe exacerbations by 52.7% (P < 0.001) and increased pre-bronchodilator FEV1 at week 12 by 0.15 L (P < 0.001), in the type 2 population. Safety was consistent with the known dupilumab safety profile. Consistent with the results in the overall population, dupilumab reduced the risk of severe asthma exacerbations and improved lung function in Latin American patients with uncontrolled, moderate-to-severe asthma and a type 2 phenotype.

Background The human monoclonal antibody dupilumab blocks interleukin (IL)-4 andIL-13, key and central drivers of type 2 inflammation. Dupilumab, on background mometasone furoate nasal spray (MFNS), improved outcomes in the phase III SINUS-52 study (NCT02898454) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). This posthoc analysis of SINUS-52 examined whether eosinophilic status of CRSwNP was a predictor of dupilumab efficacy. Methods Patients were randomized 1:1:1 to dupilumab 300 mg every 2 weeks (q2w) until week 52; dupilumab 300 mg q2w until Week 24, then 300 mg every 4 weeks until week 52; or placebo (MFNS) until week 52. Coprimary endpoints were change from baseline in nasal polyps score (NPS), nasal congestion (NC), and Lund-Mackay score assessed by CT (LMK-CT) at week 24. Patients (n = 438) were stratified by eosinophilic chronic rhinosinusitis (ECRS) status according to the Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis algorithm. Results Dupilumab significantly improved NPS, NC, and LMK-CT scores versus placebo at week 24 in all ECRS subgroups (p < 0.001), with improvements maintained or increased at week 52 (p < 0.001). There was no significant interaction between ECRS subgroup (non-/mild or moderate/severe) and dupilumab treatment effect for all endpoints at weeks 24 and 52 (p > 0.05), except LMK-CT at week 24 (p = 0.0275). Similar results were seen for the secondary endpoints. Dupilumab was well tolerated across all ECRS subgroups. Conclusion Dupilumab produced consistent improvement in symptoms of severe CRSwNP irrespective of ECRS status. Therefore, blood eosinophil level may not be a suitable biomarker for dupilumab efficacy in CRSwNP.

Claus Bachert,1– 3 Asif H Khan,4 Claire Hopkins,5 Michael S Blaiss,6 Zachary M Soler,7 Scott Nash,8 Shahid Siddiqui,8 Amy Praestgaard,9 Yamo Deniz,8 Paul J Rowe,10 Juby A Jacob-Nara10 1Upper Airways Research Laboratory and Department of Otorhinolaryngology, Ghent University, Ghent, Belgium; 2Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; 3International Airway Research Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 5Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ Hospitals, London, UK; 6Department of Pediatrics, Medical College of Georgia at Augusta University, Augusta, GA, USA; 7Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA; 8Medical Affairs, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 9Department of Biostatistics, Sanofi, Cambridge, MA, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Claus Bachert, Upper Airways Research Laboratory and Department of Otorhinolaryngology, Ghent University, Ghent, B-9000, Belgium, Tel +32 9332 5513, Email claus.bachert@ugent.bePurpose: In the phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies in adults with severe chronic rhinosinusitis with nasal polyps (CRSwNP), dupilumab significantly improved the co-primary endpoints of change from baseline to Week 24 in nasal polyp score (NPS) and nasal congestion/obstruction (NC) vs placebo on background intranasal corticosteroids (standard of care [SOC]). This post hoc analysis of SINUS-24/-52 investigated the direction and magnitude of within-patient change in these endpoints over time.Methods: NPS (scale 0– 8) was assessed at Weeks 4, 8, 16, 24, 40, and 52 in SINUS-52 and Weeks 8, 16, and 24 in SINUS-24. Daily patient-reported NC scores (0 [no symptoms]– 3 [severe symptoms]) were averaged over 28 days. Within-patient changes from baseline were assessed through Week 24 in pooled SINUS-24/-52 (n = 438/286 dupilumab/SOC) and through Week 52 in SINUS-52 (n = 150/153).Results: In SINUS-52, NPS improved in 70.0% of dupilumab-treated patients at Week 4 vs 31.8% with SOC (odds ratio [OR] 5.2 [95% confidence interval 3.1– 8.8]) and 78.7% vs 28.2% at Week 52 (OR 10.6 [6.0– 18.7]) (all p < 0.0001). NC improved in 73.3% of dupilumab-treated patients at Week 4 vs 46.7% with SOC (OR 3.2 [2.0– 5.3]) and 86.9% vs 50.7% at Week 52 (OR 6.4 [3.5– 11.5]) (all p < 0.0001). Clinically meaningful (≥ 1 point) improvements in NPS occurred in 55.7% and 72.3% of dupilumab-treated patients at Weeks 4 and 52, respectively, vs 16.9% and 16.2% with SOC. Clinically meaningful (≥ 1 point) improvements in NC occurred in 16.7% and 67.6% of dupilumab-treated patients at Weeks 4 and 52, respectively, vs 3.9% and 20.8% with SOC. At Week 52, NPS worsening from baseline was observed in 5.7% of dupilumab-treated patients vs 40.1% with SOC and NC worsening in 2.1% vs 20.8%, respectively.Conclusion: Dupilumab provided rapid, continuing, and clinically relevant improvements over time in NPS and NC in most patients with severe CRSwNP in the SINUS studies.Graphical Abstract: Keywords: chronic rhinosinusitis with nasal polyps, dupilumab, nasal polyp score, nasal congestion