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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

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.

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.