Search

Jorge F Maspero,1 Claus Bachert,2,3 Fernando J Martinez,4 Nicola A Hanania,5 Benjamin Ortiz,6 Naimish Patel,7 Leda P Mannent,8 Amy Praestgaard,7 Nami Pandit-Abid,9 Shahid Siddiqui,6 Megan Hardin7 1Allergy and Respiratory Research Unit, Fundación CIDEA, Buenos Aires, Argentina; 2Upper Airway Research Laboratory, Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium; 3Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; 4Division of Pulmonary and Critical Care, Weill Cornell Medical College, New York, NY, USA; 5Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 6Immunology and Allergy Medical Affairs, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 7Immunology and Inflammation, Sanofi, Cambridge, MA, USA; 8Global Clinical Development, Sanofi, Chilly-Mazarin, France; 9Immunology and Inflammation, Sanofi, Bridgewater, NJ, USACorrespondence: Jorge F Maspero, Allergy and Respiratory Research Unit, Fundación CIDEA, Paraguay 2035, Buenos Aires, C1121ABE, Argentina, Tel +54 91141837294, Email jorge.maspero@fundacioncidea.org.arPurpose: To provide a descriptive summary of clinical efficacy and health-related quality of life (HRQoL) measures in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and clinical features of obstructive lung disease in the Phase III dupilumab studies SINUS-24 and SINUS-52 (NCT02912468, NCT02898454).Patients and Methods: Patients met a “broad” definition of having clinical features of obstructive lung disease with any of 3 criteria: (i) pre-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 0.70 and smoking history; (ii) patient-reported medical history of chronic obstructive pulmonary disease (COPD); or (iii) asthma with > 10 pack-years’ smoking history. A “narrow” definition including criteria (i) or (ii) was also analyzed. CRSwNP and HRQoL measures were evaluated in all patients and lung function (FEV1; FEV1/FVC ratio) was captured and analyzed only in those patients who had a self-reported history of asthma.Results: Across both studies, 131 patients met the “broad” definition, of whom 90 also had asthma, and 115 patients met the “narrow” definition, of whom 74 had asthma. CRSwNP outcomes and HRQoL were improved with dupilumab vs placebo in both the broad and narrow subgroups. Among the 90 patients who met the broad definition and had asthma, dupilumab improved pre-bronchodilator FEV1 and FEV1/FVC ratio at Week 16 (least squares mean differences vs placebo: 0.38 L [95% confidence interval: 0.17, 0.59; p = 0.0004] and 4.8% [1.7%, 7.9%; p = 0.0024], respectively) sustained through Week 24. Similar results were seen in the “narrow” subgroup with asthma.Conclusion: In a population of patients with CRSwNP and clinical features of obstructive lung disease, dupilumab improved CRSwNP and HRQoL outcomes, and, among those with a history of asthma, also improved lung function. These results support further analyses of dupilumab in patients with evidence of type 2 inflammation and obstructive lung disease such as COPD.Keywords: obstructive lung disease, chronic obstructive pulmonary disease, dupilumab, type 2 inflammation, interleukin-4, interleukin-13

Asif H Khan,1 Adeline Abbe,1 Bruno Falissard,2 Paulo Carita,1 Claus Bachert,3,4 Joaquim Mullol,5 Matthew Reaney,6 Jingdong Chao,7 Leda P Mannent,1 Nikhil Amin,7 Puneet Mahajan,8 Gianluca Pirozzi,8 Laurent Eckert1 1Sanofi, Chilly-Mazarin, France; 2Centre de recherche en epidémiologie et santé des populations (CESP), INSERM U1018, Paris, France; 3Upper Airways Research Laboratory, Ghent University, Ghent, Belgium; 4CLINTEC, Karolinska Institutet, Stockholm, Sweden; 5Rhinology Unit & Smell Clinic, ENT Department, Hospital Clínic, Universitat de Barcelona; Clinical and Experimental Respiratory Immunoallergy, IDIBAPS; and CIBERES, Barcelona, Catalonia, Spain; 6IQVIA, Reading, UK; 7Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 8Sanofi, Bridgewater, NJ, USACorrespondence: Asif H KhanSanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin, 91380, FranceTel +33 1 60 49 77 77Email asif.khan@sanofi.comPurpose: Patient perspective is an important and increasingly sought-after complement to clinical assessment. The aim of this study was to transcribe individual patients’ experience of treatment in a dupilumab clinical trial through free-text responses with analysis using natural language processing (NLP) to obtain the unique perspective of patients on disease impact and unmet needs with existing treatment to inform future trial design.Patients and Methods: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) who were enrolled in a Phase IIa randomized controlled trial comparing dupilumab with placebo (NCT01920893) were invited to complete a self-assessment of treatment (SAT) tool at the end of treatment, asking, “What is your opinion on the treatment you had during the trial? What did you like or dislike about the treatment?” Free-text responses were analyzed for the overall cohort and according to treatment assignment using natural language processing including sentiment scoring. In a mixed-methods approach, quantitative patient-reported outcome (PRO) results were utilized to complement the qualitative analysis of free-text responses.Results: Of 60 patients enrolled in the study, 43 (71.6%) completed the SAT and responses from 37 patients were analyzed (placebo, n = 16; dupilumab, n = 21). Word analyses showed that the most common words were “smell,” “improve,” “staff,” “great,” “time,” and “good.” Across the whole cohort, “smell” was the most common symptom-related word. The words “smell” and “experience” were more likely to occur in patients treated with dupilumab. Patients treated with dupilumab also had more positive sentiment in their SAT responses than those who received placebo. The results from this qualitative analysis were reflected in quantitative PRO results.Conclusion: “Smell” was important to patients with CRSwNP, highlighting its importance as a patient-centric efficacy outcome measure in the context of clinical trials in CRSwNP.Trial Registration: ClinicalTrials.gov, NCT01920893. Registered 12 August 2013, https://www.clinicaltrials.gov/ct2/show/NCT01920893.Keywords: CRSwNP, free-text data mining, patient perspective, self-assessment, sense of smell

BACKGROUND: In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. METHODS: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEVp and in the scores on the St. George's Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS-COPD; range, 0 to 40, with lower scores indicating less severe symptoms). RESULTS: A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEVj increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of -9.7 (95% CI, -11.3 to -8.1) with dupilumab and -6.4 (95% CI, -8.0 to -4.8) with placebo (LS mean difference, -3.4; 95% CI, -5.5 to -1.3; P=0.002). The E-RS-COPD score at week 52 had improved by an LS mean of-2.7 (95% CI, -3.2 to -2.2) with dupilumab and -1.6 (95% CI, -2.1 to -1.1) with placebo (LS mean difference, -1.1; 95% CI, -1.8 to -0.4; P=0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups. Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo. [ABSTRACT FROM AUTHOR]

BACKGROUND Dupilumab, a fully human monoclonal antibody, blocks interleukin-4 and interleu-kin-13 signaling, which have key roles in eosinophilic esophagitis. METHODS. We conducted a three-part, phase 3 trial in which patients 12 years of age or older underwent randomization in a 1:1 ratio to receive subcutaneous dupilumab at a weekly dose of 300 mg or placebo (Part A) or in a 1:1:1 ratio to receive 300 mg of dupilumab either weekly or every 2 weeks or weekly placebo (Part B) up to week 24. Eligible patients who completed Part A or Part B continued the trial in Part C, in which those who completed Part A received dupilumab at a weekly dose of 300 mg up to week 52 (the Part A-C group); Part C that included the eligible patients from Part B is ongoing. The two primary end points at week 24 were histologic remission (<6 eosinophils per high-power field) and the change from baseline in the Dysphagia Symptom Questionnaire (DSQ) score (range, 0 to 84, with higher values indicating more frequent or more severe dysphagia). RESULTS In Part A, histologic remission occurred in 25 of 42 patients (60%) who received weekly dupilumab and in 2 of 39 patients (5%) who received placebo (difference, 55 percentage points; 95% confidence interval [CI], 40 to 71; P<0.001). In Part B, histologic remission occurred in 47 of 80 patients (59%) with weekly dupilumab, in 49 of 81 patients (60%) with dupilumab every 2 weeks, and in 5 of 79 patients (6%) with placebo (difference between weekly dupilumab and placebo, 54 percentage points; 95% CI, 41 to 66 [PcO.001]; difference between dupilumab every 2 weeks and placebo, 56 percentage points; 95% CI, 43 to 69 [not significant per hierarchical testing]). The mean (±SD) DSQ scores at baseline were 33.6±12.41 in Part A and 36.7±11.22 in Part B; the scores improved with weekly dupilumab as compared with placebo, with differences of -12.32 (95% CI, -19.11 to -5.54) in Part A and -9.92 (95% CI, -14.81 to -5.02) in Part B (both P<0.001) but not with dupilumab every 2 weeks (difference in Part B, -0.51; 95% CI, -5.42 to 4.41). Serious adverse events occurred in 9 patients during the Part A or B treatment period (in 7 who received weekly dupilumab, 1 who received dupilumab every 2 weeks, and 1 who received placebo) and in 1 patient in the Part A-C group during the Part C treatment period who received placebo in Part A and weekly dupilumab in Part C). CONCLUSIONS Among patients with eosinophilic esophagitis, subcutaneous dupilumab administered weekly improved histologic outcomes and alleviated symptoms of the disease. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03633617.). [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of long-term dupilumab on histological, symptomatic and endoscopic aspects of eosinophilic oesophagitis (EoE) in adolescent and adult patients with and without prior use of swallowed topical corticosteroids (STC) or prior inadequate response, intolerance or contraindication to STC., Design: Pre-specified analysis of data from the phase 3 LIBERTY EoE TREET study on patients who received dupilumab 300 mg once a week or placebo for 24 weeks (W24) in parts A and B, and an additional 28 weeks (W52) in part C. Patients were categorised as with/without prior STC use and with/without inadequate/intolerance/contraindication to STC. The proportion of patients achieving ≤6 eosinophils per high-power field (eos/hpf), absolute change in Dysphagia Symptom Questionnaire (DSQ) score, mean change in Endoscopic Reference Score and Histologic Scoring System grade/stage scores were assessed for each subgroup., Results: Regardless of prior STC use, dupilumab increased the proportion of patients achieving ≤6 eos/hpf and improved DSQ score versus placebo at W24, with improvements maintained or improved at W52. The DSQ score and the proportion of patients achieving ≤6 eos/hpf after switching from placebo to dupilumab at W24 were similar to those observed in the dupilumab group at W24, regardless of prior STC use or inadequate/intolerance/contraindication to STC. Improvements in other outcomes with dupilumab were similar in patients with/without prior STC use or inadequate/intolerance/contraindication to STC., Conclusion: Dupilumab 300 mg once a week demonstrated efficacy and was well tolerated in patients with EoE regardless of prior STC use or inadequate response, intolerance and/or contraindication to STC., Trial Registration Number: NCT03633617., Competing Interests: Competing interests: AJB: Dr Falk Pharma, Norgine, Nutricia, Sanofi, SST and Thelial—research funding; Alimentiv, Aqilion, AstraZeneca, Dr Falk Pharma, Laborie, Medtronic, Regeneron Pharmaceuticals and Sanofi—consulting fees. ED: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Celgene/Receptos/BMS, GSK, Meritage, Miraca, Nutricia, Regeneron Pharmaceuticals, Revolo and Shire/Takeda—research funding; Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, Gossamer Bio, GSK, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron Pharmaceuticals, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE and Upstream Bio—consulting fees; Allakos, Holoclara and Invea—educational funding. IH: Allakos, AstraZeneca, Calyx/Parexel, Eli Lilly, Ellodi/Adare, EsoCap, Gossamer Bio, Nexstone, Pfizer/Arena, Phathom, Receptos/BMS, Sanofi/Regeneron Pharmaceuticals and Shire/Takeda—consulting fees; Allakos, AstraZeneca, Ellodi/Adare, Pfizer/Arena, Receptos/BMS, Regeneron Pharmaceuticals and Shire/Takeda—research funding; Sanofi/Regeneron Pharmaceuticals—speaker fees. AJL: Dr Falk Pharma and EsoCap—consulting fees; Dr Falk Pharma, Ellodi and Regeneron Pharmaceuticals—research funding. CS: Adare Pharmaceuticals, AstraZeneca, Calypso, EsoCap, Dr Falk Pharma, GmbH and Regeneron Pharmaceuticals—consulting fees. AS, EM, JM and XS: employees of Regeneron Pharmaceuticals and may hold stock and/or stock options in the company. EL, LG and LM: employees of Sanofi and may hold stock and/or stock options in the company., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives/hypothesis: The 22-item Sinonasal Outcome Test (SNOT-22) is a validated chronic rhinosinusitis health-related quality-of-life outcome (HRQoL) measure; however, SNOT-22 domains have not been validated specifically for chronic rhinosinusitis with nasal polyps (CRSwNP)., Study Design: Validation of SNOT-22 domain structure, using data from 3 randomized, placebo-controlled, double-blinded, multicenter clinical trials of dupilumab in adults with moderate-to-severe CRSwNP., Methods: Preliminary dimensional structure was derived by exploratory factor analyses of SNOT-22 data from a phase 2 trial (NCT01920893) of dupilumab for the treatment of CRSwNP. Data from 2 phase 3 clinical trials (NCT02912468 and NCT02898454) were then used for confirmatory factor analysis, and evaluated for reliability, construct validity, and responsiveness. In all three trials, the SNOT-22 was administered electronically on a tablet and trial participants were required to answer all items., Results: Factor analysis supported five domains: Nasal, Ear/Facial, Sleep, Function, and Emotion. Correlations between domains were moderate to high, ranging from 0.53 (Nasal-Emotion) to 0.88 (Function-Sleep). Construct validity was mostly supported; relationships with other measures were almost always in the intended direction and magnitude. Internal consistency reliability also confirmed questionnaire structure with strong Cronbach's alpha values (all >0.80). Moderate-to-high correlations were observed between change in SNOT-22 domain scores and other study patient-reported outcome measures, along with large effect-size estimates (≥0.7), demonstrating responsiveness of the Nasal, Sleep, and Function domains. Emotion and Ear/Facial domains had small-to-moderate effect sizes., Conclusions: Psychometric analyses support the validity, reliability, and responsiveness of five domains of SNOT-22 (Nasal, Ear/Facial, Sleep, Function, and Emotion) for assessing symptoms and impact on HRQoL in patients with CRSwNP. Laryngoscope, 132:933-941, 2022., (© 2021 RTI Health Solutions, Sanofi and Regeneron Pharmaceuticals, Inc. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Dupilumab is an antibody against interleukin-4 receptor α, used in the treatment of atopic dermatitis (AD)., Objectives: To evaluate the efficacy and safety of dupilumab in adult Chinese patients with moderate-to-severe AD., Methods: In this randomized, double-blind, placebo-controlled, parallel-group, phase III study, conducted between December 2018 and February 2020, patients with AD received dupilumab (300 mg) or placebo once every 2 weeks for 16 weeks, and were followed up for 12 weeks. The primary efficacy endpoint was the proportion of patients with both an Investigator's Global Assessment score of 0-1 and a reduction from baseline of ≥ 2 points at week 16., Results: Overall, 165 patients (mean age 30·6 years; 71·5% male patients) were randomized; 82 patients were randomized to dupilumab and 83 patients were randomized to placebo. At week 16, 26·8% of patients in the dupilumab group and 4·8% of patients in the placebo group achieved the primary endpoint [difference 22·0%, 95% confidence interval (CI) 11·37-32·65; P < 0·001]. Compared with placebo, higher proportions of patients in the dupilumab group achieved ≥ 75% reduction in the Eczema Area and Severity Index score (57·3% vs. 14·5%; difference 42·9%, 95% CI 29·75-55·97; P < 0·001) and had ≥ 3-point (52·4% vs. 9·6%; difference 42·8%, 95% CI 30·26-55·34; P < 0·001) and ≥ 4-point (39·0% vs. 4·8%; difference 34·2%, 95% CI 22·69-45·72; P < 0·001) reductions in weekly average daily peak daily pruritus numerical rating scale scores. The incidence of treatment-emergent adverse events during the treatment period was similar in the two groups. The incidence of conjunctivitis, allergic conjunctivitis and injection site reaction was higher in the dupilumab group than in the placebo group., Conclusions: In adult Chinese patients, dupilumab was effective in improving the signs and symptoms of AD and demonstrated a favourable safety profile., (© 2021 Sanofi. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation., Objective: Assessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE)., Methods: Data were extracted from three randomized placebo-controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count., Results: Dupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin-3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from -24.8% to -88.6% (placebo +2.6% to -53.6%); -38.2% to -51.5% (placebo +8.3% to -0.16%) in eotaxin-3; -24.8% to -76.7% (placebo +8.3% to -4.4%) in total IgE; and -13.6% to -41.1% (placebo +10.1% to -6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% [95% CI: -15.8, 0]); transient increases followed by decreases to below-baseline levels in asthma (-14.6% [-20.0, -7.7]) and CRSwNP (-29.4% [-40.0, -16.3]); and significant decreases in EoE (-50.0% [-50.0, -33.3])., Conclusion and Clinical Relevance: Dupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE., (© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Objectives/hypothesis: Dupilumab, which blocks the shared receptor component for interleukin-4 and interleukin-13, reduced polyp size, sinus opacification, and symptom severity, and was well tolerated in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) in the SINUS-52 study (NCT02898454). We assessed dupilumab in patients enrolled at Japanese centers., Methods: Patients on a background of mometasone furoate nasal spray, received dupilumab 300 mg every 2 weeks (q2w) for 52 weeks (Arm A); dupilumab 300 mg q2w for 24 weeks, followed by every 4 weeks (q4w) for 28 weeks (Arm B); or placebo (Arm C). Co-primary endpoints were week 24 nasal polyp score (NPS), nasal congestion (NC) score, and sinus Lund-Mackay CT (LMK-CT) scores. Symptoms, sense of smell, health-related quality of life, and safety were assessed during the 52-week treatment period., Results: Of 49 patients enrolled in Japan, 45 completed the study. Week 24 least squares (LS) mean improvement versus placebo were as follows: NPS (Arm A: -3.1, P < .0001; Arm B: -2.1, P = .0011); NC score (Arm A: -1.2, P < .0001; Arm B: -0.9, P < .0001); and LMK-CT (Arm A: -5.1, P = .0005; Arm B: -2.8, P = .0425). The most common treatment-emergent adverse event in dupilumab and placebo-treated patients was nasopharyngitis., Conclusion: Dupilumab provided rapid, significant, and clinically meaningful improvements for patients with CRSwNP in Japan. Dupilumab was well tolerated, and safety and efficacy were consistent with the overall study population., Level of Evidence: 2 Laryngoscope, 131:E1770-E1777, 2021., (© 2020 Sanofi. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease with a high symptom burden and poor quality of life. Treatment options include recurrent surgeries and/or frequent systemic corticosteroids (SCS). Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2-mediated inflammation. We report results of pooled analyses from 2 randomised, double-blind, placebo-controlled phase 3 studies (SINUS 24 [NCT02912468]; SINUS-52 [NCT02898454]) to evaluate dupilumab effect versus placebo in adults with CRSwNP with/without SCS use and sinonasal surgery., Methodology: SINUS-24 patients were randomised 1:1 to subcutaneous dupilumab 300 mg (n=143) or placebo (n=133) every 2 weeks (q2w) for 24 weeks. SINUS-52 patients were randomised 1:1:1 to 52 weeks of subcutaneous dupilumab 300 mg q2w (n=150), 24 weeks q2w followed by 28 weeks of dupilumab 300 mg every 4 weeks (n=145) or 52 weeks of placebo q2w (n=153)., Results: Dupilumab reduced the number of patients undergoing sinonasal surgery (82.6%), the need for in-study SCS use (73.9%), and SCS courses (75.3%). Significant improvements were observed with dupilumab vs placebo regardless of prior sinonasal surgery or SCS use in nasal polyp, nasal congestion, Lund-MacKay, and Sinonasal Outcome Test (22-items) scores, and the University of Pennsylvania Smell Identification Test., Conclusions: Dupilumab demonstrated significant improvements in disease signs and symptoms and reduced the need for sino-nasal surgery and SCS use versus placebo in patients with severe CRSwNP, regardless of SCS use in the previous 2 years, or prior sinonasal surgery.

Background: Conjunctivitis is a known comorbidity of atopic dermatitis. Dupilumab clinical trials for moderate-to-severe atopic dermatitis in adults showed a higher conjunctivitis incidence for dupilumab-treated patients than placebo-treated patients, whereas trials for uncontrolled asthma reported lower rates for both dupilumab and placebo., Objective: The objective of this study was to evaluate the incidence and severity of conjunctivitis in dupilumab clinical trials in adolescents with moderate-to-severe atopic dermatitis or uncontrolled asthma., Methods: We evaluated the incidence of conjunctivitis in adolescents (aged 12 to < 18 years) in three phase III trials. Ocular events were diagnosed and treated based on patient-reported symptoms and an external eye examination by study investigators, in most cases without an ophthalmologic referral. In LIBERTY AD ADOL (16-week, randomized, placebo-controlled, double-blinded trial), adolescents with moderate-to-severe atopic dermatitis were randomized to subcutaneous placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks (200 mg, patients < 60 kg at baseline; 300 mg, ≥ 60 kg at baseline). In LIBERTY AD PED-OLE (open-label extension), pediatric patients from previous dupilumab atopic dermatitis trials received dupilumab 2 mg/kg or 4 mg/kg weekly (up to 300 mg) or 300 mg every 4 weeks. In LIBERTY ASTHMA QUEST (randomized, double-blinded, placebo-controlled trial), patients with uncontrolled moderate-to-severe asthma were randomized to 52 weeks of add-on therapy with dupilumab 200 or 300 mg every 2 weeks or matched-volume placebo., Results: In ADOL, more dupilumab-treated (17/165; 10.3%) than placebo-treated patients (4/85; 4.7%) reported one or more conjunctivitis event. All events were mild to moderate in severity; 12 (7.3%) dupilumab-treated and 4 (4.7%) placebo-treated patients received treatment. Most patients with conjunctivitis (dupilumab, 12/17; placebo, 4/4) recovered/resolved during the treatment period. The risk of conjunctivitis showed no relationship with dupilumab serum concentration. In PED-OLE, 12/275 adolescents (4.4%) reported one or more conjunctivitis event. Most conjunctivitis events were mild to moderate. Ten patients received treatment for conjunctivitis. Ten patients recovered/resolved during the study. In QUEST, similar low proportions of dupilumab-treated (2/68, 2.9%) and placebo-treated (1/39, 2.6%) adolescents reported one or more conjunctivitis event. All events were mild to moderate. One dupilumab-treated patient received treatment for conjunctivitis. All cases recovered/resolved during the study. No patients in these trials discontinued study treatment temporarily or permanently because of conjunctivitis. In ADOL, one case of unspecified viral keratitis (specific viral etiology not known) in the dupilumab 300-mg every 4 weeks group and one case of allergic blepharitis in the placebo group were reported; both events resolved during the treatment period, and neither led to treatment discontinuation., Conclusions: Dupilumab-treated adolescents in atopic dermatitis trials had a higher incidence of conjunctivitis than placebo-treated patients, whereas overall rates of conjunctivitis among adolescents in the asthma trial were lower than in atopic dermatitis trials and were similar for dupilumab- and placebo-treated patients. Most events were mild to moderate, most recovered/resolved, and none prompted study withdrawal. These results are similar to those reported in adult trials and support a drug-disease interaction. CLINICALTRIALS., Gov Identifiers: NCT03054428, NCT02612454, NCT02414854. Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma (MP4 18453 kb).

Background & Aims: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE., Methods: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety., Results: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group)., Conclusions: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) significantly affects health-related quality of life (HRQoL). Few multinational observational studies have evaluated the impact of CRS with nasal polyps (CRSwNP) on patients’ HRQoL. This study aimed to assess HRQoL outcomes (including analyses by disease severity and impact of comorbidities and refractory disease) in CRSwNP patients from a large European database., Methodology: Data were analysed from the Global Allergy and Asthma European Network (GALEN) Rhinosinusitis Cohort, including sociodemographic data, patient-reported disease severity (visual analogue scale), and scores on the 36-Item ShortForm Health Survey (SF-36) questionnaire. Differences in mean SF-36 scores were evaluated between patients with CRSwNP and population norms and between subgroups of interest (disease severity, comorbidity, and refractory disease, defined by a history of sinonasal surgery)., Results: Patients with CRSwNP (N = 445) had significantly lower mean SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores vs population norms, demonstrating that CRSwNP negatively affects HRQoL. The presence of comorbidities affected HRQoL, as shown by significant differences in PCS scores in patients with asthma or non-steroidal antiinflammatory drug-exacerbated respiratory disease, compared with patients without asthma. Patients with moderate-to-severe disease had significantly lower PCS scores than patients with mild disease. Severe disease had a significant impact on MCS score. History of surgery had a clinically meaningful negative effect on HRQoL compared with no history of surgery., Conclusions: CRSwNP patients have significantly lower HRQoL compared with population norms. The impact is greater in patients with greater disease severity, comorbidities, or refractory disease.

Objectives/hypothesis: Establish treatment patterns and economic burden in US patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) versus without chronic rhinosinusitis (CRS). Determine comparative costs of subgroups with high clinical burden., Study Design: Observational, retrospective, case-control study., Methods: This study matched patients with CRSwNP to patients without CRS (1:1) using the Truven Health MarketScan US claims database. Categorical and continuous variables were compared using McNemar test and paired t test (normal distribution) or Wilcoxon signed rank tests (non-normal distribution). Within subgroups, χ 2 and Wilcoxon or t tests were used (normal distribution)., Results: There were 10,841 patients with CRSwNP and 10,841 patients without CRS included. Mean age in the CRSwNP cohort was 45.8 years; 56.2% were male. During follow-up, patients with CRSwNP had an increased diagnosis of asthma versus patients without CRS (20.8% vs. 8.1%, respectively; P < .001). Annual incremental costs were $11,507 higher for patients with CRSwNP versus those without CRS. Costs were higher in subgroups of patients with CRSwNP undergoing functional endoscopy sinus surgery (FESS), with a comorbid diagnosis of asthma, receiving oral corticosteroids, or macrolides versus the overall CRSwNP group. Patients with CRSwNP undergoing FESS had the highest costs of the four subgroups ($26,724, $22,456, $20,695, and $20,990, respectively)., Conclusions: Annual incremental costs were higher among patients with CRSwNP versus without CRS. Patients with CRSwNP with high clinical burden had higher overall costs than CRSwNP patients without., Level of Evidence: NA Laryngoscope, 129:1969-1975, 2019., (© 2019 The Authors. The Laryngoscope published by Wiley Periodicals, Inc. on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Traumatic brain injury (TBI) results in long-term neurological deficits, which may be mediated in part by pro-inflammatory responses in both the injured brain and the circulation. Inflammation may be involved in the subsequent development of neurodegenerative diseases and post-injury seizures. The p75 neurotrophin receptor (p75NTR) has multiple biological functions, affecting cell survival, apoptotic cell death, axonal growth, and degeneration in pathological conditions. We recently found that EVT901, a novel piperazine derivative that inhibits p75NTR oligomerization, is neuroprotective, reduces microglial activation, and improves outcomes in two models of TBI in rats. Since TBI elicits both CNS and peripheral inflammation, we used a mouse model of TBI to examine whether EVT901 would affect peripheral immune responses and trafficking to the injured brain., Methods: Cortical contusion injury (CCI)-TBI of the sensory/motor cortex was induced in C57Bl/6 wild-type mice and CCR2(+/RFP) heterozygote transgenic mice, followed by treatment with EVT901, a selective antagonist of p75NTR, or vehicle by i.p. injection at 4 h after injury and then daily for 7 days. Brain and blood were collected at 1 and 6 weeks after injury. Flow cytometry and histological analysis were used to determine peripheral immune responses and trafficking of peripheral immune cells into the lesion site at 1 and 6 weeks after TBI. A battery of behavioral tests administered over 6 weeks was used to evaluate neurological outcome, and stereological estimation of brain tissue volume at 6 weeks was used to assess tissue damage. Finally, multivariate principal components analysis (PCA) was used to evaluate the relationships between inflammatory events, EVT901 treatment, and neurological outcomes., Results: EVT901 is neuroprotective in mouse CCI-TBI and dramatically reduced the early trafficking of CCR2+ and pro-inflammatory monocytes into the lesion site. EVT901 reduced the number of CD45(high)CD11b+ and CD45(high)F4/80+ cells in the injured brain at 6 weeks. TBI produced a significant increase in peripheral pro-inflammatory monocytes (Ly6C(int-high) pro-inflammatory monocytes), and this peripheral effect was also blocked by EVT901 treatment. Further, we found that blocking p75NTR with EVT901 reduces the expansion of pro-inflammatory monocytes, and their response to LPS in vitro, supporting the idea that there is a peripheral EVT901 effect that blunts inflammation. Further, 1 week of EVT901 blocks the expansion of pro-inflammatory monocytes in the circulation after TBI, reduces the number of multiple subsets of pro-inflammatory monocytes that enter the injury site at 1 and 6 weeks post-injury, and is neuroprotective, as it was in the rat., Conclusions: Together, these findings suggest that p75NTR signaling participates in the production of the peripheral pro-inflammatory response to CNS injury and implicates p75NTR as a part of the pro-inflammatory cascade. Thus, the neuroprotective effects of p75NTR antagonists might be due to a combination of central and peripheral effects, and p75NTR may play a role in the production of peripheral inflammation in addition to its many other biological roles. Thus, p75NTR may be a therapeutic target in human TBI.

Importance: Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases., Objective: To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis., Design, Setting, and Participants: A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up., Interventions: Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks., Main Outcomes and Measures: Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety., Results: Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was -0.3 (95% CI, -1.0 to 0.4) with placebo and -1.9 (95% CI, -2.5 to -1.2) with dupilumab (LS mean difference, -1.6 [95% CI, -2.4 to -0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 (95% CI, -11.1 to -6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, -18.1 [95% CI, -25.6 to -10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%)., Conclusions and Relevance: Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications., Trial Registration: clinicaltrials.gov Identifier: NCT01920893.