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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

Tezepelumab is a human monoclonal antibody that blocks activity of thymic stromal lymphopoietin (TSLP). In the phase IIb PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma. We evaluated the effects of tezepelumab in reducing type 2 (T2) inflammatory biomarker levels in the PATHWAY population, and the relationship between baseline T2 biomarker levels and AAER.Adults with severe, uncontrolled asthma (n = 550) were randomized to tezepelumab (70 mg or 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. Blood eosinophil count, fractional exhaled nitric oxide (FeNO), and serum total immunoglobulin (Ig)E, interleukin (IL)-5, IL-13, periostin, thymus and activation-regulated chemokine (TARC), and TSLP were measured at baseline and over 52 weeks. AAERs were analyzed by baseline threshold (high/low) biomarker levels.Positive correlations were observed between T2 inflammatory biomarkers (blood eosinophil count, FeNO, IL-5, IL-13 and periostin) at baseline. At Week 52, treatment with tezepelumab 210 mg reduced all biomarker levels measured from baseline versus placebo. Exacerbations were reduced by 55-83% in the pooled tezepelumab cohort versus placebo, irrespective of baseline blood eosinophil count, FeNO, or serum total IgE, IL-5, IL-13, periostin, TARC, or TSLP, when these biomarkers were assessed individually.At baseline, positive correlations between specific T2 inflammatory biomarkers were observed. Tezepelumab reduced multiple T2 inflammatory biomarkers, which indicates decreased airway inflammation, and reduced exacerbations irrespective of baseline T2 biomarker profiles in patients with severe asthma.

Summary Background No consensus exists on how to reduce oral corticosteroids after the initiation of biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency monitoring, after benralizumab initiation. Methods This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment centres across 17 countries. We enrolled adult patients (age ≥18 years) with severe, eosinophilic asthma (blood eosinophil count ≥150 cells per μL at enrolment or ≥300 cells per μL in the previous year) requiring maintenance oral corticosteroids for at least 3 months preceding enrolment. Patients received benralizumab 30 mg (subcutaneous injection) every 4 weeks for three doses, then every 8 weeks thereafter. The oral corticosteroid reduction phase began at week 4 with daily oral corticosteroid dosages reduced by 1–5 mg every 1–4 weeks depending on the starting dosage, asthma control, and adrenal function status. Adrenal function was assessed with an early morning serum cortisol measurement, followed by adrenocorticotropic hormone stimulation when required, once patients achieved a daily oral corticosteroid dosage of 5 mg/day for 4 weeks. Repeat cortisol measurements were taken for patients with evidence of adrenal insufficiency at first testing. Asthma control was assessed with the Asthma Control Questionnaire-6 (ACQ-6) weekly throughout the induction and oral corticosteroid reduction phases. The primary endpoints were the percentage of patients eliminating daily oral corticosteroids, sustained for at least 4 weeks, and the percentage achieving elimination or a daily prednisone or prednisolone dosage of 5 mg or less, for at least 4 weeks, if the reason for no further reduction was adrenal insufficiency. Safety and efficacy analyses included all patients who received at least one dose of benralizumab and were descriptive. We present results after the oral corticosteroid reduction phase; a maintenance phase is ongoing. The trial is registered with ClinicalTrials.gov , NCT03557307 . Findings Between April 1, 2018, and Sept 5, 2020, of 705 patients assessed for eligibility, 598 were recruited and all received at least one dose of benralizumab. Overall, 376 (62·88%, 95% CI 58·86–66·76) of 598 patients eliminated oral corticosteroids and 490 (81·94%, 78·62–84·94) of 598 eliminated use or achieved a dosage of 5 mg or less if the reason for stopping the reduction was adrenal insufficiency. Subgroup analysis showed that dosage reductions were achieved irrespective of baseline eosinophil count, baseline oral corticosteroid dosage, or oral corticosteroid treatment duration. Adrenal insufficiency was detected in 321 (60%) of 533 patients at first assessment and in 205 (38%) of 533 patients 2–3 months later. The safety profile was consistent with previous experience. Most patients (448 [75%] of 598) had no asthma exacerbations during the oral corticosteroid reduction phase with an annualised exacerbation rate of 0·63. Of 598 patients, 38 (6%) experienced a total of 46 exacerbations resulting in emergency department or urgent care visits or hospitalisations. Interpretation Despite a high prevalence of adrenal insufficiency, most patients with eosinophilic asthma treated with benralizumab achieved elimination of oral corticosteroids or maximal possible reduction using a personalised dosage-reduction algorithm. Funding AstraZeneca.

Jonathan Corren,1 Sarbjit S Saini,2 Remi Gagnon,3 Mark H Moss,4 Gordon Sussman,5 Joshua Jacobs,6 Elizabeth Laws,7 Elinore S Chung,8 Tatiana Constant,8 Yiping Sun,8 Jennifer Maloney,8 Jennifer D Hamilton,8 Marcella Ruddy,8 Claire Q Wang,8 Meagan P O’Brien8 1Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Department of Internal Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA; 3Clinique Spécialisée en Allergie de la Capitale, Québec, QC, Canada; 4Departments of Medicine and Pediatrics, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 5Department of Medicine, University of Toronto, Toronto, ON, Canada; 6Allergy and Asthma Clinical Research, Inc, Walnut Creek, CA, USA; 7Sanofi, Bridgewater, NJ, USA; 8Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USACorrespondence: Meagan P O’BrienRegeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USATel +1 914 826-5271Email meagan.obrien@regeneron.comJonathan CorrenDepartments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, Los Angeles, CA, 90095, USATel +1 310 312-5050, ext 250Email jcorren@ucla.eduBackground: Subcutaneous immunotherapy (SCIT) has been proven as an effective therapy against some allergens for seasonal allergic rhinitis (SAR) patients unresponsive to intranasal corticosteroids and/or antihistamines but carries risk of systemic allergic reactions. Dupilumab blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases.Objective: To evaluate the efficacy and safety of SCIT+dupilumab vs SCIT alone.Methods: This phase 2a, multicenter, double-blind, placebo-controlled parallel-group study conducted in 103 adults with grass pollen-induced SAR (NCT03558997) randomized patients 1:1:1:1 to SCIT, dupilumab (300 mg every 2 weeks), SCIT+dupilumab, or placebo. SCIT was administered using an 8-week cluster protocol followed by 8 weeks of maintenance injections. Primary endpoint was change from pre-treatment baseline in area under the curve (AUC) in total nasal symptom score (TNSS) 0– 1 h following nasal allergen challenge (NAC) with timothy grass extract at Week 17.Results: Although 16 weeks of treatment with SCIT+dupilumab did not significantly improve TNSS AUC (0– 1 h) following NAC at Week 17 vs SCIT (least squares mean − 56.76% vs − 52.03%), a higher proportion of SCIT+dupilumab-treated patients (61.5%) achieved SCIT maintenance dose vs SCIT (46.2%). A lower proportion of SCIT+dupilumab-treated patients (7.7%) required epinephrine rescue treatment vs SCIT (19.2%). There were significantly fewer withdrawals in the SCIT+dupilumab group than in the SCIT group (n = 2 [7.7%] vs n = 8 [30.8%]; P = 0.0216); the majority of SCIT group withdrawals were due to SCIT-related intolerability, compared with no discontinuations from the SCIT+dupilumab group.Conclusion: In SAR patients, 16 weeks of SCIT+dupilumab may improve SCIT tolerability but did not incrementally reduce post-allergen challenge nasal symptoms compared with SCIT alone.Clinical Study Number: NCT03558997.Keywords: dupilumab, seasonal allergic rhinitis, subcutaneous immunotherapy, nasal allergen responses

International audience; BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell–derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment.METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire–6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]).RESULTS: Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P

Background Patients with severe, uncontrolled asthma experience frequent exacerbations and hospitalization, leading to poor health-related quality of life. In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced exacerbations by up to 71% and improved lung function, asthma control, and health-related quality of life vs placebo. Objective This analysis further assessed the impact of tezepelumab on patient-reported outcomes (PROs) in PATHWAY. Methods Adults with severe, uncontrolled asthma were randomized to subcutaneous tezepelumab (70 mg every 4 weeks, 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. PROs were assessed using the asthma control questionnaire–6 (ACQ-6) and the asthma quality of life questionnaire (standardized) for patients aged 12 years or older (AQLQ[S]+12). The proportions of responders (defined by improvements of ≥0.5 in ACQ-6 or AQLQ(S)+12 scores) and patients whose asthma was well-controlled, partially-controlled, or uncontrolled in the tezepelumab and placebo groups were identified. The Asthma Daily Diary questionnaire was used to assess changes in overall symptom severity. Results Overall, 550 patients were randomized. Up to 82% and 77% of tezepelumab-treated patients were ACQ-6 and AQLQ(S)+12 responders, respectively, compared with 70% and 64% of placebo-treated patients, respectively. The proportions of patients with well-controlled or partially-controlled asthma were higher in the tezepelumab-treated group than in the placebo group. In addition, tezepelumab improved the overall symptom severity. Conclusion Tezepelumab treatment improved PROs vs placebo, as indicated by the higher proportion of ACQ-6 and AQLQ(S)+12 responders and improvements in symptom severity in the tezepelumab dose groups. These data further support the benefits of tezepelumab in patients with severe, uncontrolled asthma.

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.

Jonathan Corren,1 Martin Karpefors,2 Åsa Hellqvist,3 Jane R Parnes,4 Gene Colice5 1Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Data Science and AI, AstraZeneca, Gothenburg, Sweden; 3Biometrics, Late-Stage Development, Respiratory and Immunology, AstraZeneca, Gothenburg, Sweden; 4Amgen, Thousand Oaks, CA, USA; 5Late-Stage Development, Respiratory and Immunology, AstraZeneca, Gaithersburg, MD, USACorrespondence: Jonathan CorrenDepartments of Medicine and Pediatrics, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USATel +1-310-312-5050Email jcorren@ucla.eduIntroduction: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine implicated in airway inflammation in asthma, from binding to its heterodimeric receptor. In the PATHWAY phase 2b study, tezepelumab significantly reduced exacerbation rates compared with placebo in adults with severe, uncontrolled asthma, irrespective of baseline disease characteristics.Objective: To evaluate the effect of tezepelumab on asthma exacerbations on a seasonal basis.Methods: This was a post hoc analysis of the PATHWAY study (NCT02054130). Adults (N=550) with severe, uncontrolled asthma were randomized 1:1:1:1 to receive subcutaneous tezepelumab 70 mg every 4 weeks (Q4W), 210 mg Q4W or 280 mg every 2 weeks (Q2W), or placebo Q2W, for 52 weeks. The annualized asthma exacerbation rate (AAER), total number of days with an exacerbation, proportion of patients with at least one exacerbation or 0, 1 or ≥ 2 exacerbations, and proportion of patients experiencing an exacerbation per day were evaluated by season and over the year, by treatment in the overall study population and in subgroups according to baseline blood eosinophil count (≥ 300 cells/μL or < 300 cells/μL) or atopic asthma status (fluoro-enzyme immunoassay [FEIA]+ or FEIA−).Results: Seasonal variations in exacerbation rates were found, with peaks observed in fall and winter, and greater variations in patients with high blood eosinophil counts (≥ 300 cells/μL). Tezepelumab treatment consistently reduced exacerbation rates across all seasons compared with placebo. Furthermore, there was a trend, which was not significant, toward a reduction in the total number of days with exacerbations and in the proportion of patients with exacerbations during each season in patients treated with tezepelumab compared with those who received placebo, irrespective of blood eosinophil count or atopic asthma status.Conclusion: Tezepelumab reduced exacerbations across all seasons, irrespective of evaluated baseline disease characteristics. These data support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma.Keywords: allergens, asthma, eosinophil, seasonal variation, tezepelumab, thymic stromal lymphopoietin

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: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously. Objective: Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2). Methods: Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events. Results: Patients in POLYP 1 (n = 138) and POLYP 2 (n = 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, -1.08 versus 0.06 (P < .0001) and - 0.90 versus -0.31 (P = .0140); Nasal Congestion Score, -0.89 versus -0.35 (P = .0004) and -0.70 versus -0.20 (P = .0017); and SNOT-22 score, -24.7 versus -8.6 (P < .0001) and -21.6 versus - 6.6 (P < .0001). Adverse events were similar between groups. Conclusion: Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.

Five biologicals have been approved for severe eosinophilic asthma, a well-recognized phenotype. Systematic reviews (SR) evaluated the efficacy and safety of benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab (alphabetical order) compared to standard of care for severe eosinophilic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated for each of the biologicals. The risk of bias and the certainty of the evidence were assessed using GRADE. 19 RCTs (three RCTs for benralizumab, three RCTs for dupilumab, three RCTs for mepolizumab, five RCTs for omalizumab and five RCTs for reslizumab), including subjects 12 to 75 years old (except for omalizumab including also subjects 6-11 years old), ranging from 12 to 56 weeks were evaluated. All biologicals reduce exacerbation rates with high certainty of evidence: benralizumab incidence rate ratio (IRR) 0.53 (95% CI 0.39 to 0.72), dupilumab (IRR) 0.43 (95% CI 0.32 to 0.59), mepolizumab IRR 0.49 (95% CI 0.38 to 0.66), omalizumab (IRR) 0.56 (95% CI 0.40 to 0.77) and reslizumab (IRR) 0.46 (95% CI 0.37 to 0.58). Benralizumab, dupilumab and mepolizumab reduce the daily dose of oral corticosteroids (OCS) with high certainty of evidence. All evaluated biologicals probably improve asthma control, QoL and FEV1 , without reaching the minimal important difference (moderate certainty). Benralizumab, mepolizumab and reslizumab slightly increase drug-related adverse events (AE) and drug-related serious AE (low to very low certainty of evidence). The incremental cost-effectiveness ratio per quality-adjusted life year value is above the willingness to pay threshold for all biologicals (moderate certainty). Potential savings are driven by decrease in hospitalizations, emergency and primary care visits. There is high certainty that all approved biologicals reduce the rate of severe asthma exacerbations and for benralizumab, dupilumab and mepolizumab for reducing OCS. There is moderate certainty for improving asthma control, QoL, FEV1 . More data on long-term safety are needed together with more efficacy data in the paediatric population.

BACKGROUND: Dupilumab blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation, including IgE-mediated allergic inflammation in asthma. In the LIBERTY ASTHMA QUEST (NCT02414854) study, dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers (blood eosinophils and fractional exhaled nitric oxide) at baseline. OBJECTIVE: We assessed dupilumab's effect on key asthma outcomes in QUEST patients with/without evidence of allergic patients with uncontrolled, moderate-to-severe asthma with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers (blood eosinophils and fractional exhaled nitric oxide) at baseline. OBJECTIVE: We assessed dupilumab's effect on key asthma outcomes in QUEST patients with/without evidence of allergic asthma (total serum IgE >= 30 IU/mL and >= 1 perennial aeroallergen-specific IgE >= 0.35 kU/L at baseline). METHODS: Severe exacerbation rates and change from baseline in FEV1, asthma control, and markers of type 2 inflammation during the 52-week treatment period were assessed. RESULTS: In the allergic asthma subgroup (n = 1083), dupilumab 200/300 mg every 2 weeks versus placebo reduced severe asthma exacerbation rates (-36.9%/-45.5%; both P < .01), improved FEV1 at week 12 (0.13 L/0.16 L; both P < .001; improvements were evident by the first evaluation at week 2) with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline, and improved asthma control. Dupilumab treatment also resulted in rapid and sustained reductions in type 2 inflammatory biomarkers. Comparable results were observed in patients without evidence of allergic asthma (n = 819). CONCLUSION: Dupilumab reduced severe exacerbation rates, improved FEV1 and asthma control, and suppressed type 2 inflammatory biomarkers in patients with uncontrolled, moderate-to-severe asthma with or without evidence of allergic asthma, highlighting the key role of IL-4 and IL-13 in airway inflammation. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology

Background Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) in patients with uncontrolled, moderate-to-severe asthma, add-on dupilumab 200 mg or 300 mg every 2 weeks reduced exacerbations and improved forced expiratory volume in 1 s (FEV1) and quality of life over 52 weeks. This analysis evaluates dupilimab's effect on lung function in the overall population, and subgroups with baseline elevated type 2 inflammatory biomarkers. Methods Patients were randomised to 52 weeks of subcutaneous dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched-volume placebos. Lung function outcomes were analysed in the overall population, in patients with ≥150 eosinophils·µL−1, ≥300 eosinophils·µL−1, ≥25 ppb fractional exhaled nitric oxide (FeNO), and both ≥150 eosinophils·µL−1 and ≥25 ppb FeNO, at baseline. Results Dupilumab treatment (200 mg and 300 mg every 2 weeks) resulted in significant improvements versus placebo after 52 weeks in pre-bronchodilator FEV1 (0.20 and 0.13 L, respectively, versus placebo) and post-bronchodilator FEV1 (0.19 and 0.13 L, respectively), forced vital capacity (FVC) (0.20 and 0.14 L, respectively), forced expiratory flow (0.19 and 0.13 L·s−1, respectively) and pre-bronchodilator FEV1/FVC ratio (1.75% and 1.61%, respectively) in the overall population (p, Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation, improving lung function outcomes in patients with uncontrolled, moderate-to-severe asthma http://bit.ly/2OhKMpi

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine implicated in the initiation and persistence of inflammatory pathways in asthma. Released in response to a range of epithelial insults (eg, allergens, viruses, bacteria, pollutants, and smoke), TSLP initiates multiple downstream innate and adaptive immune responses involved in asthma inflammation. Inhibition of TSLP is postulated to represent a novel approach to treating the diverse phenotypes and endotypes of asthma. Tezepelumab, the TSLP inhibitor farthest along in clinical development, is a human monoclonal antibody (IgG2λ) that binds specifically to TSLP, preventing interactions with its heterodimeric receptor. Results of recently published phase 2 and 3 studies, reviewed in this article, provide evidence of the safety and efficacy of tezepelumab that builds on initial findings. Tezepelumab is safe, well tolerated, and provides clinically meaningful improvements in asthma control, including reduced incidence of exacerbations and hospitalizations in patients with severe asthma. Clinical benefits were associated with reductions in levels of a broad spectrum of cytokines (eg, interleukin [IL]-5, IL-13) and baseline biomarkers (eg, blood eosinophils, immunoglobulin [Ig]E, fractional exhaled nitric oxide [FeNO]) and were observed across a range of severe asthma phenotypes (ie, eosinophilic and non-eosinophilic). These data strengthen the notion that anti-TSLP elicits broad inhibitory effects on pathways that are key to asthma inflammation rather than on narrower inhibition of individual downstream factors. This review presents the rationale for targeting TSLP to treat asthma, as well as the clinical effects of TSLP blockade on asthma outcomes, biomarkers of disease activity, airway inflammation, lung physiology, and patient symptoms.

Background Mepolizumab is a humanized anti–interleukin-5 monoclonal antibody approved for the treatment of patients with severe eosinophilic asthma (SEA). There is limited evidence that patients treated with mepolizumab can reduce inhaled corticosteroid (ICS) use. Objective To investigate changes in ICS use and clinical outcomes in patients with SEA who initiated mepolizumab treatment. Methods This retrospective cohort study (GSK ID: 212695/HO-20-19951) used administrative claims data from the IBM Watson Health MarketScan Database (identification period: November 2015–March 2018). Eligible patients had SEA and were receiving high-dose ICS and mepolizumab. ICS, oral corticosteroid (OCS), short acting β2-agonist (SABA) use, and exacerbation frequency were analyzed quarterly during the 12-month follow-up period following mepolizumab initiation. Results In total, 351 patients were included. The proportion of patients using highdose ICS decreased in quarters 1–4 following mepolizumab initiation (79.8%, 74.6%, 68.9%, 65.5%, respectively); 49.0% of patients reduced or discontinued ICS for ≥1 quarter. Comparing patients who discontinued ICS versus those who remained on high-dose ICS, a lower proportion had chronic OCS use (3.4–9.2% vs 13.9–16.8%) and OCS burst use (15.4–20.8% vs 19.7–26.1%) in quarters 1–4; similarly in quarters 3 and 4, a lower proportion of patients had exacerbations (16.9% and 20.3% vs 27.2% and 27.7%) and SABA claims (35.4% and 39.2% vs 43.3% and 49.0%, respectively). Conclusion: In patients with SEA on high-dose ICS, a reduction in both ICS and OCS use was observed after initiating mepolizumab. These findings have important implications for clinical outcomes and follow-up care in this patient population.

Immune modulation is a key therapeutic tool for allergic diseases and asthma. It can be achieved in an antigen-specific way via allergen immunotherapy (AIT) or in endotype-driven approach using biologicals that target the major pathways of the type 2 (T2) immune response: IgE, IL-5 and IL-4/IL-13. COVID-19 vaccine provides an excellent opportunity to tackle the global pandemics and is currently being applied in an accelerated rhythm worldwide. It works as well through immune modulation. Thus, as there is an obvious interference between these treatment modalities recommendations on how they should be applied in sequence are expected. The European Academy of Allergy and Clinical Immunology (EAACI) gathered an outstanding expert panel under its Research and Outreach Committee (ROC). This expert panel was called to evaluate the evidence and formulate recommendation on the administration of COVID-19 vaccine in patients with allergic diseases and asthma receiving AIT or biologicals. The panel also formulated recommendations for COVID-19 vaccine in association with biologicals targeting the type 1 or type 3 immune response. In formulating recommendations, the panel evaluated the mechanisms of COVID-19 infection, of COVID-19 vaccine, of AIT and of biologicals and considered the data published for other anti-infectious vaccines administered concurrently with AIT or biologicals.

Summary Background Dupilumab blocks the shared receptor component for interleukin (IL)‐4 and IL‐13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate‐to‐severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate‐to‐severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate‐to‐severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. Objectives To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. Methods We evaluated randomized placebo‐controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). Results In most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. Conclusions Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD).In most dupilumab AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than those receiving placebo.Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare.Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials.Baseline disease‐related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation‐regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis.Patients who responded well to dupilumab had reduced incidence of conjunctivitis.Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab‐treated patients with AD., Linked Editorial: https://doi.org/10.1111/bjd.18255. https://doi.org/10.1111/bjd.18276 available online https://www.bjdonline.com/article/

Rationale: Blood eosinophil counts are used to inform diagnosis/management of eosinophilic asthma. Objectives: Examine blood eosinophil variability and identify factors affecting eosinophil levels to inform clinical interpretation. Methods: Post hoc analysis to understand eosinophil variability using data from four randomized controlled asthma trials. We examined 1) influence of intrinsic/extrinsic factors (comorbidities, medication, and patient history) using baseline data (n = 2,612); 2) monthly variation using placebo-treated patient data (n = 713); 3) stability of eosinophil classification (

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

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently remains uncontrolled despite maximal medical therapy and sinonasal surgery, presenting several unmet needs and challenges. Omalizumab previously demonstrated efficacy in CRSwNP in duplicate phase 3, randomized, placebo-controlled trials (POLYP 1, POLYP 2). Objective: This open-label extension evaluated the continued efficacy, safety, and durability of response of omalizumab in adults with CRSwNP who completed POLYP 1 or 2. Methods: After 24 weeks of omalizumab or placebo in POLYP 1 and 2, patients (n = 249) received open-label omalizumab plus background nasal mometasone therapy for 28 weeks and were subsequently followed for 24 weeks after omalizumab discontinuation. Efficacy end points assessed change from baseline for the coprimary end points, Nasal Polyp Score and Nasal Congestion Score, and the secondary end points of Sino-Nasal Outcome Test 22, Total Nasal Symptom Score and its components, and University of Pennsylvania Smell Identification Test scores. Safety objectives included incidence of adverse events and adverse events leading to omalizumab discontinuation. Results: Patients who continued omalizumab experienced further improvements across coprimary end points and secondary end points through 52 weeks. Patients who switched from placebo to omalizumab experienced favorable responses across end points through week 52 that were similar to POLYP 1 and 2 at week 24. After omalizumab discontinuation, scores gradually worsened over the 24-week follow-up, but remained improved from pretreatment levels for both groups. The safety profile was similar to previous reports. Conclusions: The efficacy and safety profile from this study supports extended omalizumab treatment up to 1 year for CRSwNP with inadequate response to nasal corticosteroids.

BACKGROUND: Gefapixant is a P2X3 receptor antagonist that has shown promise for the treatment of refractory and unexplained chronic cough. The aim of this study was to evaluate the efficacy of gefapixant compared with placebo after 12 weeks of treatment for refractory chronic cough or unexplained chronic cough.METHODS: We did a 12-week, phase 2b, randomised, double-blind, placebo-controlled study in patients with refractory chronic cough or unexplained chronic cough aged 18-80 years who were recruited from 44 primarily outpatient pulmonologist or allergist sites in the UK and the USA. Eligible patients had refractory or unexplained chronic cough lasting 1 year or longer, no radiographic chest abnormality, and 40 mm or more on a 100-mm cough severity visual analogue scale at enrolment. Patients were randomly assigned to receive placebo or one of three doses (7·5 mg, 20 mg, or 50 mg) of oral gefapixant twice daily, every day, for 84 days; visits to investigative sites were on days 1, 28, 42, 56, 70, 84, and 85. The randomisation schedule was computer generated using a permuted block algorithm by Advance Research Associates (Santa Clara, CA, USA). Patients and all personnel involved in the conduct and interpretation of the study were masked to treatment assignment. The primary endpoint was placebo-adjusted change from baseline in awake cough frequency after 12 weeks, assessed in the full analysis set, which is a subset of the intention-to-treat population. Adverse events were monitored and safety was evaluated in all patients receiving one or more doses of study drug. This trial is registered with ClinicalTrials.gov, NCT02612610.FINDINGS: Between Dec 21, 2015, and July 26, 2016, 253 patients were randomly assigned to placebo (n=63), gefapixant 7·5 mg (n=64), gefapixant 20 mg (n=63), or gefapixant 50 mg (n=63) twice daily. The mean age of patients was 60·2 (SD 9·9) years and 193 (76%) were women. At 12 weeks, patients' geometric mean awake cough frequency was 18·2 coughs per h (geometric SD 3·1) with placebo, and 14·5 coughs per h (3·7) with 7·5 mg, 12·0 coughs per h (4·2) with 20 mg, and 11·3 coughs per h (2·8) with 50 mg gefapixant. Estimated percentage change relative to placebo was -22·0% (-41·8 to 4·6; p=0·097) with 7·5 mg, -22·2% (-42·0 to 4·3; p=0·093) with 20 mg, and -37·0% (95% CI -53·3 to -14·9; p=0·0027) with 50 mg gefapixant. Dysgeusia was the most common adverse event, occurring in three (5%) patients given placebo, six (10%) given 7·5 mg gefapixant, 21 (33%) given 20 mg gefapixant, and 30 (48%) given 50 mg gefapixant.INTERPRETATION: Targeting purinergic receptor P2X3 with gefapixant at a dose of 50 mg twice daily significantly reduced cough frequency in patients with refractory chronic cough or unexplained chronic cough after 12 weeks of treatment compared with placebo. Further development of gefapixant is warranted for the treatment of chronic cough.FUNDING: Afferent Pharmaceuticals (acquired by Merck & Co., Inc., Kenilworth, NJ, USA).

Dupilumab, a fully human monoclonal antibody against interleukin-4 receptor α, is approved as add-on maintenance treatment for inadequately controlled type 2 severe asthma. This systematic review evaluated the efficacy, safety and economic impact of dupilumab compared to standard of care for uncontrolled severe asthma. PubMed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. Three RCTs including 2735 subjects >12 years old and 24-52 weeks of follow-up were included. Dupilumab reduced with high certainty severe asthma exacerbations (Incidence rate ratio 0.51; 95% CI 0.45-0.59) and the percentage use of oral corticosteroid use (mean difference (MD) -28.2 mg/d; 95% CI -40.7 to -15.7). Asthma control (ACQ-5), quality of life (AQLQ) and rescue medication use [puffs/d] improved, without reaching the minimal important clinical difference: ACQ-5 MD -0.28 (95% CI -0.39 to -0.17); AQLQ MD +0.28 (95% CI 0.20-0.37); and rescue medication MD -0.35 (95% CI -0.73 to +0.02). FEV1 increased (MD +0.15; 95% CI +0.11 to +0.18) (moderate certainty). There was an increased rate of dupilumab-related adverse events (AEs) (moderate certainty) and of drug-related serious AEs (low certainty). The incremental cost-effectiveness ratio of dupilumab versus standard therapy was 464 000$/QALY (moderate certainty). More data on long-term safety are needed both for children and for adults, together with more efficacy data in the paediatric population.

Allergic asthma is a frequent asthma phenotype. Both IgE and type 2 cytokines are increased, with some degree of overlap with other phenotypes. Systematic reviews assessed the efficacy and safety of benralizumab, dupilumab and omalizumab (alphabetical order) vs standard of care for patients with uncontrolled severe allergic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. All three biologicals reduced with high certainty the annualized asthma exacerbation rate: benralizumab incidence rate ratios (IRR) 0.63 (95% CI 0.50 - 0.81); dupilumab IRR 0.58 (95%CI 0.47 - 0.73); and omalizumab IRR 0.56 (95%CI 0.42 - 0.73). Benralizumab and dupilumab improved asthma control with high certainty and omalizumab with moderate certainty; however, none reached the minimal important difference (MID). Both benralizumab and omalizumab improved QoL with high certainty, but only omalizumab reached the MID. Omalizumab enabled ICS dose reduction with high certainty. Benralizumab and omalizumab showed an increase in drug-related adverse events (AEs) with low to moderate certainty. All three biologicals had moderate certainty for an ICER/QALY value above the willingness to pay threshold. There was high certainty that in children 6-12 years old omalizumab decreased the annualized exacerbation rate [IRR 0.57 (95%CI 0.45-0.72)], improved QoL [relative risk 1.43 (95%CI 1.12 -1.83)], reduced ICS [mean difference (MD) -0.45 (95% CI -0.58 to -0.32)] and rescue medication use [ MD -0.41 (95%CI -0.66 to -0.15)].

Background: Comorbid perennial allergic rhinitis (PAR) or year-round aeroallergen sensitivity substantially contributes to disease burden in patients with asthma. Dupilumab blocks the shared receptor for interleukin (IL) 4 and IL-13, key drivers of type 2 inflammation that play important roles in asthma and PAR. In the LIBERTY ASTHMA QUEST trial (NCT02414854), dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline (blood eosinophils and fractional exhaled nitric oxide). Objective: To assess dupilumab efficacy in LIBERTY ASTHMA QUEST patients with comorbid PAR. Methods: Severe asthma exacerbation rates, FEV1, asthma control (5-item Asthma Control Questionnaire), rhinoconjunctivitis-specific health-related quality of life (Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores), and type 2 inflammatory biomarkers during the 52-week treatment period were assessed. Results: A total of 814 of the 1902 patients (42.8%) had comorbid PAR (defined as an allergic rhinitis history and >= 1 perennial aeroallergen specific immunoglobulin E (IgE) level >= 0.35 kU/L at baseline). Dupilumab, 200 and 300 mg every 2 weeks, vs placebo reduced severe exacerbations rates by 32.2% and 34.6% (P = 300 cells/mL) and fractional exhaled nitric oxide. Dupilumab treatment also numerically improved the 5-item Asthma Control Questionnaire and Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores and suppressed type 2 inflammatory biomarkers. Conclusion: Dupilumab improved key asthma-related outcomes, asthma control, and rhinoconjunctivitisspecific health-related quality of life while suppressing type 2 inflammatory biomarkers and perennial allergen-specific IgE in patients with moderate-to-severe asthma and comorbid PAR, highlighting its dual inhibitory effects on IL-4 and IL-13 and its role in managing asthma and PAR. (C) 2020 American College of Allergy, Asthma & Immunology.