Pollen allergy imposes a large and growing disease burden. The accuracy of pollen forecasts is not well known. We compared the predictive accuracy of 4 publicly available pollen forecasting websites with pollen counts reported by the National Allergy Bureau (NAB).

BackgroundThere is evidence that global anthropogenic climate change may be impacting floral phenology and the temporal and spatial characteristics of aero-allergenic pollen. Given the extent of current and future climate uncertainty, there is a need to strengthen predictive pollen forecasts.MethodsThe study aims to use CatBoost (CB) and deep learning (DL) models for predicting the daily total pollen concentration up to 14 days in advance for 23 cities, covering all five continents. The model includes the projected environmental parameters, recent concentrations (1, 2 and 4 weeks), and the past environmental explanatory variables, and their future values.ResultsThe best pollen forecasts include Mexico City (R2(DL_7) approximate to .7), and Santiago (R2(DL_7) approximate to .8) for the 7th forecast day, respectively; while the weakest pollen forecasts are made for Brisbane (R2(DL_7) approximate to .4) and Seoul (R2(DL_7) approximate to .1) for the 7th forecast day. The global order of the five most important environmental variables in determining the daily total pollen concentrations is, in decreasing order: the past daily total pollen concentration, future 2 m temperature, past 2 m temperature, past soil temperature in 28-100 cm depth, and past soil temperature in 0-7 cm depth. City-related clusters of the most similar distribution of feature importance values of the environmental variables only slightly change on consecutive forecast days for Caxias do Sul, Cape Town, Brisbane, and Mexico City, while they often change for Sydney, Santiago, and Busan.ConclusionsThis new knowledge of the ecological relationships of the most remarkable variables importance for pollen forecast models according to clusters, cities and forecast days is important for developing and improving the accuracy of airborne pollen forecasts. CatBoost is a preferable model for short-term forecasts, while Deep Learning is for longer ones, but there is no definite answer to what the better model is for every day or city. Past pollen trends are strong indicators of future pollen concentrations. CatBoost can be used to determine the importance of environmental variables in forecasting daily total pollen concentration. Abbreviations: 2mT, 2 m temperature; CB, CatBoost; DL, Deep Learning; DOY, day of the year; ERA5, the fifth generation ECMWF (European Centre for Medium-Range Weather Forecasts) atmospheric reanalysis dataset; pevap, potential evapotranspiration; st, soil temperature.image

Background: Exposure to air pollutants is known to exacerbate asthma, with prior studies focused on associations between single pollutant exposure and asthma exacerbations. As air pollutants often exist as a complex mixture, there is a gap in understanding the association between complex air pollutant mixtures and asthma exacerbations. We evaluated the association between the air pollutant mixture (52 pollutants) and pediatric asthma exacerbations. Method: This study focused on children (age ≤ 19 years) who lived in Douglas County, Nebraska, during 2016–2019. A seasonal-scale joint association between the outdoor air pollutant mixture adjusting for potential confounders (temperature, precipitation, wind speed, and wind direction) in relation to pediatric asthma exacerbation-related emergency department (ED) visits was evaluated using the generalized weighted quantile sum (qWQS) regression with repeated holdout validation. Results: We observed associations between air pollutant mixture and pediatric asthma exacerbations during spring (lagged by 5 days), summer (lag 0–5 days), and fall (lag 1–3 days) seasons. The estimate of the joint outdoor air pollutant mixture effect was higher during the summer season (adjusted-βWQS = 1.11, 95% confidence interval [CI]: 0.66, 1.55), followed by spring (adjusted-βWQS = 0.40, 95% CI: 0.16, 0.62) and fall (adjusted-βWQS = 0.20, 95% CI: 0.06, 0.33) seasons. Among the air pollutants, PM2.5, pollen, and mold contributed higher weight to the air pollutant mixture. Conclusion: There were associations between outdoor air pollutant mixture and pediatric asthma exacerbations during the spring, summer, and fall seasons. Among the 52 outdoor air pollutant metrics investigated, PM2.5, pollen (sycamore, grass, cedar), and mold (Helminthosporium, Peronospora, and Erysiphe) contributed the highest weight to the air pollutant mixture.

BackgroundDupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4/-13, key and central drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA VENTURE (VENTURE) study (NCT02528214), dupilumab versus placebo reduced oral corticosteroid (OCS) dose and improved clinical outcomes in patients with OCS-dependent severe asthma. Dupilumab efficacy in patients with varying disease burden (defined by baseline OCS dose) has not been assessed.ObjectiveThis post hoc analysis of VENTURE evaluated dupilumab efficacy across subgroups defined by baseline OCS dose.MethodsThe OCS dose, proportion no longer needing OCS at week 24, annualized severe exacerbation rate, and least squares mean change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 second at week 24 were evaluated in VENTURE patients with OCS-dependent severe asthma receiving dupilumab 300 mg every 2 weeks versus placebo, categorized by a baseline OCS dose of less than 10 mg/d or 10 or more mg/d.ResultsDupilumab reduced daily OCS dose from baseline at week 24 in both dose groups. In dupilumab-/placebo-treated patients with a baseline OCS dose of less than 10 mg/d and 10 or more mg/d, 72%/42% and 37%/23% stopped OCS by week 24 (P < .01/P < .05), respectively. Dupilumab significantly reduced the annualized severe exacerbation rate by 71% and 48% (P < .01/P < .05). At week 24, dupilumab improved pre- and post-bronchodilator forced expiratory volume in 1 second in patients in both dose groups.ConclusionsIn patients with OCS-dependent severe asthma receiving lower or higher baseline OCS doses, dupilumab significantly reduced the OCS dose and improved the likelihood of no longer requiring OCS while also reducing exacerbations and improving lung function.

Background Clinical trials have shown treatment benefits of dupilumab in patients with uncontrolled asthma for up to 1 year. This study aimed to evaluate the long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma, as data for extended treatment with dupilumab beyond 1 year are not available. Methods TRAVERSE was an open-label extension study in 362 hospitals and clinical centres across 27 countries that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in adults and adolescents (aged 12–84 years) with moderate-to-severe or oral-corticosteroid-dependent severe asthma who had completed a previous dupilumab asthma study (phase 2A EXPEDITION, phase 2B DRI [P2b], phase 3 QUEST, or VENTURE). The primary endpoint was the number and percentage of patients with any treatment-emergent adverse events. Secondary endpoints included annualised exacerbation rate (AER) over the treatment period and change from parent study baseline in pre-bronchodilator FEV1, the five-item asthma control questionnaire (ACQ-5), the asthma quality of life questionnaire (AQLQ), type 2 biomarkers (blood eosinophils and serum total IgE), and anti-drug antibodies (ADAs). Statistical analyses were descriptive. We report safety in all enrolled patients, and efficacy in patients with non-oral-corticosteroid-dependent asthma and in subgroups, including patients with a type 2 inflammatory phenotype who received 148 weeks of treatment. This study is registered with ClinicalTrials.gov, NCT02134028. Findings Between Aug 5, 2014, and Oct 11, 2019, of 2302 patients assessed for eligibility, 2282 adults and adolescents were enrolled (median age 50 years, 62·1% female and 37·9% male). Safety during TRAVERSE was consistent with the known dupilumab safety profile. The proportion of patients reporting treatment-emergent adverse events throughout the study duration was similar to that observed in the parent studies and ranged from 76·3% to 94·7%. The most frequently reported treatment-emergent adverse events were nasopharyngitis (17·5–25·9%), injection-site erythema (2·2–23·4%), and bronchitis (9·3–19·0%). Serious asthma exacerbations (0·5–3·6%) and pneumonia (0·7–2·7%) were the most frequently reported serious adverse events. There were four treatment-emergent adverse events leading to death. Efficacy during TRAVERSE was also consistent with the results of parent studies. In patients who were non-oral-corticosteroid-dependent, AER remained low (0·277–0·327) across parent study and treatment groups, pre-bronchodilator FEV1 improvements were sustained to the end of treatment at week 96 (mean changes from parent study baseline ranged from 0·22 L [SD 0·44] to 0·33 L [0·44] across parent study and treatment groups), and improvements in ACQ-5 and AQLQ scores were sustained to the last timepoint assessed at week 48. Rapid improvements were observed in pre-bronchodilator FEV1 and sustained improvements were seen in all outcome measures for patients given dupilumab who previously received placebo in parent studies; further improvements in AER, asthma control, and health-related quality of life were observed in patients who continued receiving dupilumab. Blood eosinophils and serum total IgE decreased progressively. ADA status had no effect on safety or efficacy. In the subgroup of patients with a type 2 inflammatory phenotype followed-up for 148 weeks, AER decreased progressively, and initial lung function improvements were sustained over 148 weeks. Interpretation Data show that safety and efficacy of dupilumab in adult and adolescent patients with moderate-to-severe asthma are sustained when treatment is extended up to 148 weeks. These findings therefore support the long-term use of dupilumab in this patient population. Funding Sanofi and Regeneron Pharmaceuticals.

BACKGROUND:Monoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear.METHODS:In a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety.RESULTS:A total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P = 0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P = 0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups.CONCLUSIONS:Interleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03387852.).

Background The phase 3 LIBERTY ASTHMA QUEST study ( ClinicalTrials.gov : NCT02414854 ) in patients with uncontrolled, moderate-to-severe asthma has demonstrated the efficacy and safety of dupilumab 200 and 300 mg every 2 weeks versus placebo. This post hoc analysis assessed the effect of dupilumab on efficacy outcomes and asthma control across a range of historical exacerbation rates in patients with type 2-high asthma. Methods Annualised severe exacerbation rates over the 52-week treatment period, pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) at weeks 12 and 52, and the five-item Asthma Control Questionnaire (ACQ-5) score at weeks 24 and 52 were assessed in patients with ≥1, ≥2 or ≥3 exacerbations in the previous year. Subgroups were stratified by baseline blood eosinophils ≥150 or ≥300 cells·μL −1 or baseline exhaled nitric oxide fraction ≥25 ppb and baseline inhaled corticosteroid (ICS) dose. Results Across all type 2-high subgroups, dupilumab versus placebo significantly reduced severe exacerbations by 54–90%, with greater improvements in patients with more exacerbations prior to study initiation. Similarly, improvements in FEV 1 (least squares (LS) mean difference versus placebo: ≥1 exacerbations, 0.15–0.25 L; ≥2 exacerbations, 0.12–0.32 L; ≥3 exacerbations, 0.09–0.38 L; majority p<0.05) and ACQ-5 score (LS mean difference range: ≥1 exacerbations, −0.30 to −0.57; ≥2 exacerbations, −0.29 to −0.56; ≥3 exacerbations, −0.43 to −0.61; all p<0.05) were observed, irrespective of prior exacerbation history, across all subgroups. Conclusions Dupilumab significantly reduced severe exacerbations and improved FEV 1 and asthma control in patients with elevated type 2 biomarkers irrespective of exacerbation history and baseline ICS dose.

Introduction and Objectives For asthma patients, achieving asthma control and improving health-related quality of life (HRQoL) are important long-term management goals. Dupilumab is a monoclonal antibody targeting interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases. Here, we report effects of long-term dupilumab treatment on asthma control and HRQoL outcomes from the TRAVERSE open-label extension (OLE) study (NCT02134028) in patients with moderate-to-severe asthma who had previously completed a dupilumab asthma study (phase 2b (P2b) or phase 3 QUEST). Methods During TRAVERSE, patients received add on dupilumab 300 mg every 2 weeks. Asthma control (5-item Asthma Control Questionnaire, ACQ-5; range 0–6, lower scores indicate better control) and HRQoL (Asthma Quality of Life Questionnaire - standardized, AQLQ(S); range 1–7, higher scores indicate improved asthma-specific quality of life) were assessed at TRAVERSE Week 0, 24, and 48. The overall intention-to-treat population and the type 2 asthma population, defined as patients with blood eosinophils ≥150 cells/µL or FeNO ≥25 ppb at parent study baseline (PSBL), were evaluated. Results 2,062 patients from QUEST (n=1,530; 517 PBO/DPL and 1,013 DPL/DPL patients) and P2b (n=532; 111 PBO/DPL and 421 DPL/DPL patients) rolled over into TRAVERSE. Mean (SD) ACQ-5 scores improved from PSBL at OLE Week 0, Week 24, and Week 48 in dupilumab/dupilumab and placebo/dupilumab groups from both QUEST and P2b studies. ACQ-5 scores exceeded the clinically meaningful response threshold (≥ 0.5 reduction) in 79–87% of patients (table 1). Mean (SD) AQLQ(S) scores improved from PSBL at OLE Week 0, Week 24, and Week 48; 65–78% of all patients showed clinically meaningful improvements (≥ 0.5 increase) (Table). In general, the largest mean improvements and percentage of patients with a clinically meaningful response was seen in the patient group who had received dupilumab in the parent study. Improvements were comparable in patients with a type 2 phenotype. The dupilumab safety profile during TRAVERSE was similar to that observed in the parent study populations. Conclusions In line with patient-reported outcomes observed in P2b and QUEST, dupilumab-treated patients with moderate-to-severe asthma demonstrated clinically meaningful and sustained improvements in asthma control and HRQoL during the TRAVERSE OLE study. Please refer to page A191 for declarations of interest related to this abstract.

Achieving asthma control and improving HRQoL are important long-term asthma management goals. Dupilumab, a monoclonal antibody targeting IL-4/IL-13, is approved for management of moderate-to-severe asthma. We report effects of long-term use of dupilumab on asthma control and HRQoL outcomes from the TRAVERSE open-label extension (OLE) study (NCT02134028) in patients who completed a previous dupilumab asthma study. 5-item Asthma Control Questionnaire (ACQ-5) and overall Asthma Quality of Life Questionnaire (AQLQ) scores up to 48 weeks of OLE in patients with moderate-to-severe asthma who had participated in the DRI (24-week) or QUEST (52-week) studies and received add-on dupilumab 300 mg q2w during the OLE were evaluated in the overall ITT population and type 2 asthma population (defined as blood eosinophils ≥150 cells/mL or FeNO ≥25 ppb at parent study baseline [PSBL]). A within-patient change of ≥0.5 in ACQ-5 or AQLQ score was considered clinically meaningful. 2,062 patients from DRI and QUEST were enrolled. ACQ-5 and AQLQ scores improved throughout the OLE. Mean (SD) ACQ-5 scores at PSBL for placebo-dupilumab/dupilumab-dupilumab patients in DRI and QUEST were 2.63(0.77)/2.74(0.80) and 2.73(0.74)/2.76(0.79), respectively; at Week 48 of OLE, mean (SD) change from baseline was −1.33(1.07)/−1.57(1.11) and −1.64(1.08)/−1.69(1.08). Mean (SD) AQLQ scores at PSBL for placebo-dupilumab/dupilumab-dupilumab patients in DRI and QUEST were 4.27(1.12)/3.98(1.10) and 4.25(1.01)/4.29(1.08), respectively; at Week 48 of OLE, mean (SD) change from baseline was 1.07(1.13)/1.40(1.19) and 1.39(1.17)/1.40(1.18). Similar efficacy was observed in DRI/QUEST patients with type 2 asthma. The safety profile during the OLE was similar to that observed in the overall populations of the parent studies. Asthma control and HRQoL in patients with moderate-to-severe asthma continued to improve with dupilumab and were sustained over the long-term treatment duration of the OLE study.

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 <.05 for both) and improved FEV1 at week 12 by 0.14 L and 0.18 L (P <.01 for both); greater efficacy was observed in patients with elevated baseline blood eosinophil counts (>= 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.

BACKGROUND: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13 signaling, key drivers of type 2 inflammation. In the phase 3 study (NCT02414854), add-on dupilumab 200mg/300mg every 2 weeks, versus placebo, significantly reduced severe asthma exacerbations and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) and quality-of-life measures in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in those with a high baseline type 2 phenotype. OBJECTIVE: To assess the efficacy and safety of dupilumab in patients with uncontrolled, moderate-to-severe asthma with or without self-reported comorbid chronic rhinosinusitis (CRS or non-CRS). METHODS: Comorbid CRS was self-reported by patients using an e-diary. Annualized severe exacerbation rates, changes from baseline in pre- and post-bronchodilator FEV1, patient-reported outcomes, type 2 biomarkers, and safety were assessed. RESULTS: CRS was self-reported by 382 of 1902 (20.1%) patients. Dupilumab 200 mg/300 mg reduced annualized severe exacerbation rates by 63%/61%, respectively, in patients with CRS, and by 42%/40% in patients without CRS (all P < .001 vs placebo). Dupilumab also improved lung function and patient-reported asthma control and quality of life, and suppressed type 2 biomarkers versus placebo in both subgroups. Clinical responses were rapid, with near-maximal responses observed at the earliest measured time points and sustained at week 52. Improvements observed in the CRS subgroup were similar to or numerically greater than those in the non-CRS subgroup. CONCLUSION: Dupilumab showed efficacy and was generally well tolerated in patients with uncontrolled, moderate-to-severe asthma with or without CRS. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Introduction: Dupilumab (DPL), a fully human mAb, blocks the shared receptor component for IL‑4/IL‑13. The efficacy and safety of DPL in asthma have been demonstrated up to 52 wks in phase (P) 2/3 studies. Aim: This open-label extension (OLE) study (NCT02134028) assessed long-term safety and efficacy of DPL in adult and adolescent patients (pts) who had completed a DPL asthma study (P2b DRI, P2 EXPEDITION, P3 QUEST or VENTURE). Methods: 2282 moderate-to-severe asthma or OCS-dependent severe asthma pts received add‑on SC DPL 300mg every 2 wks up to 96 wks. Treatment-emergent adverse events (TEAE), annualized rate of severe asthma exacerbations (AER) during the treatment period, and change from parent study baseline (BL) in FEV1 and biomarkers up to Wk 96 were assessed. Results: 2039 pts completed the OLE treatment period with a safety profile that was consistent with the shorter-duration parent studies (Table). The low unadjusted AER and improvement in FEV1 observed in the parent studies were sustained during the OLE. Similar efficacy was seen in pts with elevated type 2 biomarkers from DRI/QUEST. By Wk 96, blood eosinophils decreased to below-parent study BL levels in pts from DRI/QUEST and were near-parent study BL levels in pts from VENTURE; total IgE levels decreased by 82% (median % change from parent BL). Conclusion: Long-term use of dupilumab was well tolerated and showed sustained efficacy in asthma pts up to 96 wks.

Background Dupilumab, a fully human monocolonal antibody, blocks the shared receptor component for interleukin (IL) 4 and IL 13, key and central drivers of type 2 inflammation in multiple diseases. The efficacy and safety of dupilumab in asthma have been demonstrated up to 52 weeks in phase 2 and phase 3 studies. This open-label extension (OLE) study (NCT02134028) assessed long-term safety and efficacy of dupilumab in adult and adolescent patients who had completed a dupilumab asthma study (phase 2b DRI, phase 2 EXPEDITION, phase 3 QUEST, or phase 3 VENTURE). Methods Patients with moderate-to-severe or oral corticosteroid (OCS)-dependent severe asthma received add on subcutaneous dupilumab 300 mg every 2 weeks (q2w) up to 96 weeks. Treatment-emergent adverse events (TEAEs), annualized rate of severe asthma exacerbations (AER) during the treatment period, change from parent study baseline (PSBL) in forced expiratory volume in 1 second (FEV1), and biomarkers up to Week 96 were assessed. Results 2,282 patients were enrolled overall. Patient safety profile was consistent with the parent studies (Table). The low unadjusted AER and improvement in FEV1 observed in the parent studies were sustained during the OLE. Similar efficacy was seen in patients with elevated type 2 biomarkers from DRI/QUEST. By Week 96, blood eosinophils decreased to below-PSBL levels in patients from DRI/QUEST and were near-PSBL levels in patients from VENTURE; total IgE levels decreased by 82% (median percent change from PSBL). Conclusion Long-term use of dupilumab was well tolerated and showed sustained efficacy in asthma patients up to 96 weeks.

Dupilumab, a fully human mAb, blocks the shared receptor component for IL-4/IL-13. The efficacy and safety of dupilumab in asthma have been demonstrated up to 52 weeks in phase 2/3 studies. This open-label extension (OLE) study (NCT02134028) assessed long-term safety and efficacy of dupilumab in adult/adolescent patients who had completed a dupilumab asthma study (phase 2b DRI, phase 2 EXPEDITION, phase 3 QUEST, or phase 3 VENTURE).

Allergic rhinitis (AR), a common type 2 comorbidity in asthma patients, contributes to increased overall disease burden. Dupilumab, a fully human, VelocImmune®-derived anti-interleukin-(IL)-4Rα mAb that inhibits signaling of IL-4/IL-13, key drivers of type 2 inflammation, is approved for treatment of adults with inadequately controlled, moderate-to-severe atopic dermatitis. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), dupilumab every 2 weeks versus matched placebo suppressed biomarkers of type 2 inflammation in patients with uncontrolled, moderate-to-severe asthma and improved health-related quality of life for those with AR.

Dupilumab, a fully human VelocImmune®-derived anti-interleukin-(IL)-4Rα mAb that inhibits signaling of IL-4/IL-13, key drivers of type 2 inflammation, is approved for treatment of adults with inadequately controlled, moderate-to-severe atopic dermatitis. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), dupilumab 200/300mg every 2 weeks versus matched placebo suppressed type 2 biomarkers in patients with uncontrolled, moderate-to-severe asthma and improved health-related quality of life, assessed by SNOT-22, in the difficult-to-treat subgroup with comorbid chronic rhinosinusitis with/without nasal polyposis (CRS/NP). This post hoc analysis assessed dupilumab's effect on type 2 biomarkers in this subgroup. Baseline/change from baseline over time were assessed for fractional exhaled nitric oxide (FeNO), total IgE, and eotaxin-3. CRS/NP was self-reported by 20.1% (n/N=382/1,897) patients. Baseline FeNO and eotaxin-3 values were numerically higher in patients with CRS/NP than in those without. Biomarker suppression was evident in all dupilumab-treated groups by Week 12. At Week 52, significant biomarker suppression was observed in patients with and without CRS/NP, as shown by median percentage changes from baseline (dupilumab 200/300mg vs matched placebo), with CRS/NP: FeNO –46.2/–37.7 vs –5.5/–6.4, IgE –74.8/–76.8 vs 0.0/–2.0, eotaxin-3 –47.7/–50.9 vs 1.5/–5.4 (all P≤0.0001); without CRS/NP: FeNO –31.0/–35.9 vs –5.9/–10.1, IgE –67.3/–67.7 vs –3.3/–6.6, eotaxin-3 –31.8/–37.2 vs 0.0/–0.8 (all P<0.0001). The most common adverse event, with higher frequency in dupilumab vs placebo, was injection-site reactions (15%/18% vs 5%/10%). Dupilumab suppressed local and systemic type 2 biomarkers in patients with and without CRS/NP.

Lack of control of moderate-to-severe asthma results in a substantial disease burden and poor quality of life for affected patients and represents a significant unmet clinical need.1Chen H. Gould M.K. Blanc P.D. et al.Asthma control, severity, and quality of life: quantifying the effect of uncontrolled disease.J Allergy Clin Immunol. 2007; 120: 396-402Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar Dupilumab is a fully human monoclonal antibody inhibiting the signaling of interleukin (IL)-4 and IL-13, key drivers of inflammation in type 2 inflammatory diseases such as asthma, allergic rhinitis, atopic dermatitis, and food allergies—conditions that frequently manifest as comorbidities2Gandhi N.A. Pirozzi G. Graham N.M.H. Commonality of the IL-4/IL-13 pathway in atopic diseases.Exp Rev Clin Immunol. 2017; 13: 425-437Crossref PubMed Scopus (240) Google Scholar—and is approved in the United States for patients aged 12 years or older with moderate-to-severe eosinophilic or oral corticosteroid–dependent asthma3Wenzel S. Castro M. Corren J. et al.Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-controlled pivotal phase 2b dose-ranging trial.Lancet. 2016; 388: 31-44Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar, 4Castro M. Corren J. Pavord I.D. et al.Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma.N Engl J Med. 2018; 378: 2486-2496Crossref PubMed Scopus (948) Google Scholar, 5Rabe K.F. Nair P. 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Corren J. et al.Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-controlled pivotal phase 2b dose-ranging trial.Lancet. 2016; 388: 31-44Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar Asthma exacerbation history, particularly number of recent exacerbations, is considered a significant independent predictor of future exacerbation risk,9Miller M.K. Lee J.H. Miller D.P. Wenzel S.E. TENOR Study GroupRecent asthma exacerbations: a key predictor of future exacerbations.Respir Med. 2007; 101: 481-489Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar and frequent exacerbations (defined as a deterioration of asthma requiring use of systemic corticosteroids for ≥3 days, or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids and confirmed by chart review) tend to be associated with poorer lung function, worse asthma control, and greater use of high-dose ICS+LABA.3Wenzel S. Castro M. Corren J. et al.Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-controlled pivotal phase 2b dose-ranging trial.Lancet. 2016; 388: 31-44Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar Other factors associated with frequent exacerbations include blood eosinophil count, bronchodilator responsiveness, body mass index, and comorbid chronic rhinosinusitis and gastroesophageal reflux disease.10Denlinger L.C. Phillips B.R. Ramratnam S. et al.Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations.Am J Respir Crit Care Med. 2017; 195: 302-313Crossref PubMed Scopus (268) Google Scholar This post hoc analysis of the phase 2b asthma study (NCT01854047) assessed the effects of dupilumab (200 mg or 300 mg every 2 weeks), compared with placebo, on annualized rates of severe asthma exacerbations, changes in lung function, asthma control, and quality of life in patients categorized by the number of exacerbations they had experienced in the year before study entry. In the study, 465 patients had had 1 or more exacerbations; 227, 2 or more; 122, 3 or more; and 62, 4 or more. The highest number of exacerbations in the year prior to the study was 20 in the overall study population, 20 in the placebo group, 15 in the dupilumab 300 mg group, and 12 in the dupilumab 200 mg group. The annualized rate of severe exacerbations during the 24-week treatment period was derived from a negative binomial model. Change from baseline in lung function, measured by FEV1 at weeks 12 and 24, was analyzed using a mixed-effects model with a repeated-measures approach to determine least squares (LS) mean and standard error (SE), as previously described.7Simpson E.L. Bieber T. Guttman-Yassky E. et al.Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.N Engl J Med. 2016; 375: 2335-2348Crossref PubMed Scopus (1123) Google Scholar Asthma control was assessed using the 5-item Asthma Control Questionnaire (ACQ-5), and patient-reported quality of life was assessed with the Asthma Quality of Life Questionnaire (AQLQ); again, a mixed-effects repeated-measures model was used to determine the LS mean (±SE).4Castro M. Corren J. Pavord I.D. et al.Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma.N Engl J Med. 2018; 378: 2486-2496Crossref PubMed Scopus (948) Google Scholar Because this was an exploratory analysis, no attempt was made to control for type I errors. Safety was also evaluated across subgroups by using adverse event reports and laboratory assessments. Treatment with either dose of dupilumab significantly reduced the annualized rate of severe exacerbations to a similar extent (P < .05 vs placebo), with greatest treatment effect observed in patients with the highest number of exacerbations in the previous year (Fig 1A ). In patients receiving placebo, the number of exacerbations during the study increased with the number of historical exacerbations during the previous year (Fig 1A). Treatment with dupilumab 200 mg and 300 mg every 2 weeks dose regimens significantly improved FEV1 at weeks 12 and 24 (P < .05 vs placebo) in all patients, except at week 12 in patients who received dupilumab 200 mg every 2 weeks and had experienced 4 or more exacerbations in the previous year (P = .1227; Fig 1B). In patients receiving dupilumab, the higher the number of prior exacerbations, the greater the improvement observed. In the placebo group, however, the higher the number of exacerbations in the previous year, the lesser were the improvements in FEV1. At week 24, all patients receiving dupilumab experienced significantly improved asthma control (P < .05 vs placebo). The largest improvements in asthma control occurred in patients who had experienced the highest numbers of exacerbations in the previous year (eFig 1). Findings were similar for asthma-related quality of life; LS mean changes in AQLQ scores from baseline to week 24 showed improvement with both dupilumab regimens in all patients. Again, improvements increased with the number of prior exacerbations, particularly in patients receiving the higher dose of dupilumab (eFig 1). In the overall study population, dupilumab was well tolerated at either dose during the study; the incidence of treatment-emergent adverse events was similar across treatment groups and independent of exacerbation history. To conclude, our results show that dupilumab significantly reduced the rate of severe asthma exacerbations and improved lung function, asthma control, and quality of life in patients with uncontrolled, persistent, moderate-to-severe asthma, regardless of their exacerbation frequency in the previous year. Treatment effects tended to be better with higher number of exacerbations in the year before the study. This analysis was limited in that it is a retrospective analysis using data from only a small number of patients. Analysis of a larger data set should confirm the present findings that systemic immunomodulatory therapy with dupilumab every 2 weeks may be beneficial for patients with poorly controlled asthma, irrespective of severity.

Allergic rhinitis (AR), a common type 2 comorbidity in asthma patients, contributes to increased overall disease burden. Dupilumab, a fully human VelocImmune®-derived anti-interleukin (IL)-4Rα mAb that inhibits IL-4 and IL-13, key drivers of type 2 inflammation, is approved for treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Post hoc analysis of the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) in asthma patients (≥12 years, uncontrolled with medium-to-high-dose ICS plus ≤2 additional controllers) with a self-reported medical history of comorbid AR (63.5%; n/N=1,207/1,902) or without comorbid AR assessed the effect of add-on dupilumab 200mg or 300mg or matched placebo every 2 weeks (q2w) on the annualized rate of severe exacerbations and forced expiratory volume in 1 second (FEV1). A clinical diagnosis of AR was not recorded. Baseline characteristics of patients with and without AR were generally similar. The annualized rate of severe exacerbations was reduced vs placebo with dupilumab 200mg q2w (relative risk with AR:0.606 [95%CI,0.451–0.814];P=0.0009; without AR:0.406 [95%CI,0.273–0.605];P<0.0001) with similar results for 300mg q2w. FEV1 was improved at Week 12 with dupilumab 200mg q2w (LS mean difference vs placebo with AR:0.14L [95%CI,0.07–0.21];P<0.0001; without AR:0.13L [95%CI,0.05–0.22];P=0.0023) and sustained to Week 52 (both with/without AR: P<0.0001), with similar results at Week 52 for 300mg q2w. The most common adverse event in dupilumab-treated (vs placebo) groups was injection-site reactions (200mg/300mg vs matched-placebos: 15%/18%vs5%/10%). Dupilumab significantly improved FEV1 and reduced annual severe exacerbation rates in this difficult-to-control asthma population with comorbid AR and also in patients without concomitant AR.