Rationale Admission to hospital with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with a high risk of readmission and death. A proportion of patients with COPD have type 2 inflammation, as indicated by raised blood eosinophil count, for which targeted biologic treatment has been shown to reduce moderate, community-treated exacerbations. Mepolizumab is a monoclonal antibody to interleukin-5 which effectively reduces eosinophilic inflammation, but effects on future hospitalisations and mortality in COPD are uncertain. Methods COPD-HELP was a single-centre, phase IIb, double-blind, placebo-controlled study that randomised patients who were admitted to hospital with an acute exacerbation of COPD to either mepolizumab 100mg or placebo every 4 weeks for 48 weeks. All participants (≥40 years) had a blood eosinophil count of at least 300 cells per microlitre in the 12 months prior to admission, were established on inhaled corticosteroids at time of admission and alternative diagnoses or causes of eosinophilia were excluded. The primary end point was the time to readmission or death due to any cause. Key secondary endpoints included number of hospital readmissions, number of moderate or severe exacerbations, and health related quality of life. Results A total of 238 patients were randomised (119 in each group). The median time to rehospitalisation or death (all cause) was 25.4 weeks in the mepolizumab arm and 26.1 weeks in the placebo arm, with Kaplan-Meier estimates of 33.9% and 31.0% respectively (HR 0.96 (95%CI 0.7 to 1.32, p=0.811). The adjusted mean (95% CI) number of hospital readmissions over 48 weeks was 1.65 (1.25 to 2.05) with mepolizumab and 1.85 (1.42 to 2.29) with placebo (rate ratio [95% CI] 0.89 [0.64 to 1.25]). The adjusted mean (95% CI) number of moderate or severe exacerbations over 48 weeks was 2.80 (2.36 to 3.23) with mepolizumab and 3.45 (2.94 to 3.95) with placebo (rate ratio [95% CI] 0.81 [95% CI 0.66 to 1.00]). Conclusion Patients hospitalised with an acute exacerbation of COPD and evidence of eosinophilic inflammation had no benefit in risk of severe exacerbations or death when given mepolizumab for 48 weeks. A numerical reduction in the number of exacerbations was observed, consistent with previous trials.

BACKGROUND:Component-resolved diagnosis allows detection of IgE sensitization having the advantage of reproducibility and standardization compared to crude extracts. The main disadvantage of the traditional allergen identification methods, 1- or 2-dimensional western blotting and screening of expression cDNA libraries with patients' IgEs, is that the native structure of the protein is not necessarily maintained. METHODS:We used a novel immunoprecipitation technique in combination with mass spectrometry to identify new allergens of Aspergillus fumigatus. Magnetic Dynabeads coupled with anti-human IgE antibodies were used to purify human serum IgE and subsequently allergens from A. fumigatus protein extract. RESULTS:Of the 184 proteins detected by subsequent mass peptide fingerprinting, a subset of 13 were recombinantly expressed and purified. In a panel of 52 A. fumigatus-sensitized people with asthma, 23 non-fungal-sensitized asthmatics and 18 healthy individuals, only the former showed an IgE reaction by immunoblotting and/or ELISA. We discovered 11 proteins not yet described as A. fumigatus allergens, with fructose-bisphosphate aldolase class II (FBA2) (33%), NAD-dependent malate dehydrogenase (31%) and Cu/Zn superoxide dismutase (27%) being the most prevalent. With respect to these three allergens, native versus denatured protein assays indicated a better recognition of the native proteins. Seven of 11 allergens fulfilled the WHO/IUIS criteria and were accepted as new A. fumigatus allergens. CONCLUSION:In conclusion, we introduce a straightforward method of allergen identification from complex allergenic sources such as A. fumigatus by immunoprecipitation combined with mass spectrometry, which has the advantage over traditional methods of identifying allergens by maintaining the structure of the proteins.

BACKGROUND:Fungal involvement in asthma is associated with severe disease. The full spectrum of fungal species in asthma is not well described and is derived largely from insensitive culture techniques.OBJECTIVES:To use high-throughput sequencing to describe the airway mycobiota in asthmatics with and without fungal sensitization and healthy controls; to compare samples representing different airway compartments; to determine whether the mycobiota was influenced by the fungal composition of outdoor air; and to compare findings with clinically relevant outcomes.METHODS:We amplified the internal transcribed spacer region 2 of the nuclear ribosomal operon to identify the fungal species present. Ninety-seven subjects were recruited and provided sputum (83 asthmatics; 14 healthy subjects), with 29 also undergoing a bronchoscopy. A subset of airway samples were compared with matched outdoor air and mouthwash samples.RESULTS:Two hundred and six taxa at the species level were identified in sputum, most at low relative abundance. Aspergillus fumigatus, Candida albicans and Mycosphaerella tassiana had the highest relative abundances and were the most prevalent species across all subjects. The airway mycobiota consisted of a complex community with high diversity between individuals. Notable shifts in the balance of fungi detected in the lung were associated with asthma status, asthma duration and biomarkers of inflammation. Aspergillus tubingensis, a member of the Aspergillus niger species complex, was most prevalent from bronchoscopic protected brush samples and significantly associated with a low sputum neutrophilia. Cryptococcus pseudolongus, from the Cryptococcus humicola species complex, was more abundant from bronchoscopy samples than sputum, and differentially more abundant in asthma than health.CONCLUSIONS AND CLINICAL RELEVANCE:The airway mycobiota was dominated by a relatively small number of species, but was distinct from the oropharyngeal mycobiota and air samples. Members of the A. niger and C. humicola species complexes may play unexpected roles in the pathogenesis of asthma.

To the Editor: Mepolizumab (anti-IL-5) depletes blood and airway eosinophils, and, clinically, allows down-titration of oral corticosteroid and a reduction in the frequency of eosinophil-dependent exacerbations.1 Basophils also express IL-5Rα, participate in T2-mediated inflammatory pathways2 and have been associated with exacerbation frequency.3 Whilst basophil progenitors are unlikely to depend on IL-5 for development,4 blood basophil counts measured in routine clinical laboratories suggest they decrease following mepolizumab treatment.5-8 Our primary objective was to determine whether anti-IL-5 monoclonal antibody treatment reduces blood basophil levels as an additional potential efficacy mechanism. To achieve this, we measured blood basophils, eosinophils and other type 2 inflammatory cells, before and after 16 weeks of mepolizumab ("Nucala," GlaxoSmithKline) by flow cytometry. Patient eligibility criteria are in the online supplement and the study schedule in Figure S1. Blood samples were obtained from 26 severe asthma subjects, attending a difficult asthma clinic at a single UK centre, at baseline and following a median (IQR) of 16 (16-17) weeks of mepolizumab, administered as a 100 mg subcutaneous injection every 4 weeks. In 2 cases, it was not possible to obtain post-treatment samples (n = 1, withdrew consent; n = 1, discontinued), totalling 24 (Figure S1 and Table S1). We also recruited 15 nonasthmatic healthy controls (Table S1) to obtain samples at parallel time points but without an intervention (Figure S1). Flow cytometric measurements were compared with data derived through the routine pathology service, which utilizes an ADVIA 2120/2120i analyser (Siemens, UK). A detailed description of the methodology for both approaches is described in the online supplement, and for flow cytometry, the gating strategy is shown in Figure S2. Our criteria for identifying cell subsets were as follows: eosinophils (CD45+CD3-CD193+CD294+SSChiCD123−/+), basophils (CD45+CD3-CD193+CD294+SSCloCD123+), cTH2 and peTH2 (both CD4+CD294+ but CD161− or +, respectively), cTC2 (CD8+CD294+) and ILC2s (Lineage−CD294+CD161+). For methodological comparisons, data from asthma and healthy subjects (n = 39) were pooled. A good correlation was observed between flow cytometry and the ADVIA 2120i for total cells (r2 = 0.24, P = 0.0014) and eosinophils (r2 = 0.75, P < 0.0001), but not basophils (r2 = 0.06, P = 0.13 Figure S3). In addition, the change in cell concentration between baseline and follow-up showed a good correlation between the two analytical methods for eosinophils (r2 = 0.72, P < 0.0001, n = 38) but not basophils (r2 = 0.02, P = 0.39, n = 38). As expected, following 16 weeks of mepolizumab, we observed a significant reduction in blood eosinophil concentration (flow cytometry [mean ± SD] −6442 ± 6852, ADVIA −20 688 ± 19 355 cells/100 µL, Figure 1A) and frequency (flow cytometry [mean ± SD] −1.2 ± 1.2% of total leukocytes, Figure S4A) compared with baseline levels for both methods. This decrease was not observed in our control group (mean ± SD 2475 ± 4148, 285 ± 6977 cells/100 µL and 0.70 ± 1.38%, respectively) (Figure 1A). Notably, the reduction in blood eosinophil levels following mepolizumab was related to baseline eosinophil levels (r2 = 0.69, P < 0.0001, Figure S5). In contrast to eosinophils, basophil concentration and frequency at baseline were similar to that following 16 weeks of mepolizumab, when measured by flow cytometry (pre vs post [mean ± SD] 2232 ± 1309 vs 1873 ± 1647 cells/100 µL, P = 0.23, Figure 1B and 0.40 ± 0.19 vs 0.37 ± 0.27% of total leukocytes, P = 0.076, Figure S4B). Surprisingly, measurements obtained on the ADVIA 2120i suggested a statistically significant reduction in the basophil concentration following 16 weeks of mepolizumab (pre vs post [mean ± SD] 5521 ± 2003 vs 3792 ± 3623 cells/100 µL, P = 0.0009, Figure 1B). The mean ± SD reduction in basophil concentration of −1667 ± 3988 cells/100 µL in asthma was significantly greater compared with the change observed in the control group (vs −571 ± 1222, P = 0.011, Mann-Whitney). In the healthy group, the concentration and frequency of basophils were similar when comparing baseline and follow-up samples, regardless of analytical method (Figures 1B and S4). These data suggest that basophil concentration and frequency, alongside other T2 inflammatory cells (Figure S6), are likely to be IL-5/mepolizumab-independent in severe asthma. However, our real-world study was not sufficiently powered to detect small differences in relation to basophil concentration or frequency. A strength of our flow cytometric approach is that we have measured cell concentration as well as frequency, and also reported recently identified T2 cell subsets (eg peTH2 cells). Our data suggest there were also no indirect effects of mepolizumab on type-2 polarised T cell or group 2 ILC concentration over this 16-week time frame as indicated by others.5 Clinically, we observed a significant change in ACQ6 symptom score from a baseline of 2.9 ± 1.6 to 1.9 ± 1.3 at 16 weeks post-treatment, which is a reduction of −0.92 (97.73% CI of −2 to −0.16, Wilcoxon matched pairs, P = 0.0085), corresponding to an improvement in symptoms above the minimal clinically important difference (MCID) threshold of −0.5. Since baseline eosinophil concentration was associated with basophils (r = 0.53, P = 0.0073), cTH2 (r = 0.59, P = 0.0023), peTH2 (r = 0.45, P = 0.026) and TC2 (r = 0.45, P = 0.026) cells but not total cells (r = 0.2, P = 0.35) or ILC2s (r = 0.2, P = 0.35), we examined their relationship to ACQ6 improvement (ΔACQ6). The baseline cellular parameters described above were not associated with ΔACQ6 (Figure 2, shown for eosinophils, cTH2 and peTH2 cells only). ΔACQ6 was also not associated with the Δ change in eosinophil (r2 = 0.04, P = 0.36) or basophil (r2 = 0.09, P = 0.15) levels post-treatment, limiting the utility of these measurements as symptom response biomarkers. Of further interest was the effect of mepolizumab on eosinophil and basophil cell surface expression of the IL-3 receptor α (CD123), and their relationship to ΔACQ6. IL-3 is upregulated in the serum of poorly controlled asthmatic patients,9 and it can potentiate eosinophil chemotactic and degranulation responses. Recently, mepolizumab treatment, in the context of allergen challenge,8 was associated with reduced levels of IL-3Rα mRNA and protein on circulating blood but not lung eosinophils. Consistent with Kelly et al, we observed a decrease in eosinophil IL-3Rα cell surface expression in response to mepolizumab in asthma (pre [mean ± SD] 415 ± 306 vs post 204 ± 192 GMFI, P < 0.0001, n = 21) and not in our healthy control group (baseline [mean ± SD] 587 ± 626 vs post 558 ± 535 GMFI, P = 0.32, n = 15) (example in Figure S2 and cumulative in S7). This represents a % decrease of −54 ± 25% in asthma compared with +9 ± 55% in the healthy group (mean ± SD, P < 0.0001, Mann-Whitney test). We also noted that eosinophil expression of CRTH2 (CD294) was increased following mepolizumab (Figure S7); however, there was no relationship between the reduction in eosinophil IL-3Rα expression and CRTH2 expression. Importantly, there was no relationship between changes in eosinophil IL-3Ra or CRTH2 expression with ΔACQ6 in these patients. Furthermore, there were no mepolizumab-dependent effects on eosinophil/basophil Siglec-8, CD69 or IL-5Rα expression (not shown), consistent with others8 or basophil IL-3Rα (Figure S7),.and thus, these parameters were not examined for a relationship with ΔACQ6. In summary, our flow cytometric data do not support a direct inhibitory effect of mepolizumab on basophil levels, and therefore, clinical benefit is likely to be independent of basophils. Our data suggest that the specificity and sensitivity of basophil detection on routine clinical analysers should be validated prior to reporting/interpreting basophil data in the context of an intervention. Our data do support others8 that mepolizumab reduces eosinophil, but not basophil, IL-3Rα expression and, importantly, extends the applicability of this phenomenon to the "real-world" scenario. However, neither changes in eosinophil levels nor changes in IL-3Rα expression were associated with clinical efficacy determined by change in asthma control in this study, and thus, biological correlates of response to treatment require further study. This research was funded by Leicester Drug Discovery and Diagnostics (LD3) with financial contributions from MRC grant MC_PC_15045 and supported by the NIHR Leicester Biomedical Research Centre. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation, and contributes significantly to asthma-associated morbidity and mortality. No current drug therapy for asthma affects airway smooth muscle mass. We report that the prostaglandin D2 type 2 receptor antagonist, fevipiprant, is the first drug in a randomized placebo-controlled trial to reduce airway smooth muscle mass in asthma. By integrating in vitro experiments with a novel agent-based computational modeling strategy we found this reduction in airway smooth muscle mass was a consequence of inhibiting eosinophilic inflammation in concert with reduced recruitment of myofibroblasts to the airway smooth muscle bundle. Thus, fevipiprant represents a novel therapy to ameliorate airway remodeling in asthma.

Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D-2 type 2 receptor (DP2) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP2 in airway smooth muscle cells. We report that the DP2 antagonist fevipiprant reduced airway smooth muscle mass in bronchial biopsies from patients with asthma who had participated in a previous randomized placebo-controlled trial. We developed a computational model to capture airway remodeling. Our model predicted that a reduction in airway eosinophilia alone was insufficient to explain the clinically observed decrease in airway smooth muscle mass without a concomitant reduction in the recruitment of airway smooth muscle cells or their precursors to airway smooth muscle bundles that comprise the airway smooth muscle layer. We experimentally confirmed that airway smooth muscle migration could be inhibited in vitro using DP2-specific antagonists in an airway smooth muscle cell culture model. Our analyses suggest that fevipiprant, through antagonism of DP2, reduced airway smooth muscle mass in patients with asthma by decreasing airway eosinophilia in concert with reduced recruitment of myofibroblasts and fibrocytes to the airway smooth muscle bundle. Fevipiprant may thus represent a potential therapy to ameliorate airway remodeling in asthma.

Introduction and Background: Historically, respiratory research recruitment in Leicester has been inefficient; driven manually through clinics, word-of-mouth, advertisements and participant lists. To improve this, we implemented a new recruitment strategy, in line with local and national guidelines. Aims and Objectives: To determine how a new recruitment strategy affected patient recruitment in a respiratory research group. Methods: A recruitment strategy was created requiring patient consent, followed by entry of basic clinical details onto an ethically approved recruitment database. Staff training was provided and weekly recruitment meetings held. Data analysis was undertaken using qualitative staff and nurse surveys, and data/access logs recorded in the recruitment database. Results: Our analysis indicated that the new strategy and database streamlined the recruitment process. Not only by creating a steadily increasing pool of patients available for contact (Figure 1), but saving nurse time and allowing nurses to record/access clinical research data to confirm eligibility for studies. Additionally, it prevented patient re-contact and enabled more targeted recruitment. Conclusion: The implementation of a new strategy underpinned by an ethically approved recruitment database has become central to recruitment and identification of potentially eligible research participants.

Introduction: Asthma is associated with increased airway smooth muscle (ASM) mass with increased disease severity and impaired lung function. The prostaglandin D2 (PGD2) receptor 2 (DP2) antagonist, fevipiprant, reduces airway eosinophilia and improves epithelial integrity, lung function, ACQ and AQLQ. Aim: We investigated whether fevipiprant reduces ASM mass in asthma and potential mechanistic role of DP2 in airway remodelling using in vitro and computational modelling approaches. Methods: ASM mass was assessed in bronchial biopsies from moderate-to-severe asthmatics in 12 weeks randomised placebo-controlled study of fevipiprant 225 mg b.i.d. orally. Results: ASM mass was significantly reduced following 12 weeks treatment with fevipiprant (n = 14) vs placebo (n = 13) (mean±SE change in % ASM area: -13±5% vs 4±5%; P = 0.034). Computational modelling predicted that reduction in eosinophilic inflammation and direct effect on ASM cell recruitment was required to explain reduction in ASM mass. ASM cells secreted more PGD2 following wounding (129±19 vs 181±25 pg/mL/105 cells; P = 0.020, n = 10). Inhibition of DP2 activation by endogenous PGD2 resulted in reduced ASM migration (median [IQR] difference after 24h in presence of CAY10471 100 nM vs control, -11.0 [17.5] %; P = 0.008), but did not affect ASM proliferation over 72 h. Conclusion: Fevipiprant reduced ASM mass in moderate-to-severe asthma patients. This might reflect both reduced eosinophilic airway inflammation and a direct effect on ASM cells.

Although rarely used in clinical practice today, diurnal variability in peak expiratory flow (PEF) could offer insights into asthma control and airway hyperresponsiveness. To investigate diurnal variability in PEF following treatment with tiotropium Respimat across asthma severities. Methods: A post hoc analysis of PEF diurnal variability from five Phase III trials was conducted: PrimoTinA-asthma (pooled 2x 48-week trials, tiotropium 5μg or placebo once daily [morning], added onto maintenance ICS ≥800μg budesonide/equivalent + long-acting β2-agonists additional controller medications); MezzoTinA-asthma (pooled 2x 24-week trials, tiotropium 2.5μg, 5μg or placebo once daily [evening], added onto maintenance ICS 400–800μg budesonide/equivalent); and GraziaTinA-asthma (12week trial, tiotropium 2.5μg, 5μg or placebo once daily [evening], added onto maintenance ICS 200–400μg budesonide/equivalent). Pre-dose PEF was self-monitored at home using the asthma monitor AM2+/3. Results: Tiotropium improved morning and evening PEF in all studies. Mean baseline PEF variability was 14.14%, 13.51% and 12.08% (all patients) in PrimoTinA-asthma, MezzoTinA-asthma and GraziaTinAasthma, respectively. Adjusted mean change from baseline in PEF variability at Week 24 for tiotropium 5μg and placebo was –0.33% and – 0.87%, respectively, in PrimoTinA-asthma, and for tiotropium 5μg or 2.5μg and placebo was –0.32%, –1.78% and –1.01%, respectively, in MezzoTinA-asthma. A similar pattern was observed at Week 12 in GraziaTinA-asthma (Table 1). Conclusion: The differences between tiotropium Respimat and placebowere generally small and variable (even though the trials showed significant improvements in peak [0–3 hours post-dose] forced expiratory volume in 1 second [FEV1], trough FEV1 and PEF am/pm versus placebo). In these trials where tiotropium was added onto other maintenance asthma therapy, PEF diurnal variability was not a sensitivemeasure of bronchodilation. AO014

SummaryBackgroundImmunological biomarkers are the key to the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) and fungal sensitisation, but how these relate to clinically relevant outcomes is unclear.ObjectivesTo assess how fungal immunological biomarkers are related to fixed airflow obstruction and radiological abnormalities in moderate to severe asthma.MethodsCross‐sectional study of 431 asthmatics. Inflammatory biomarkers, lung function and an IgE fungal panel to colonising filamentous fungi, yeasts and fungal aeroallergens were measured. CT scans were scored for the presence of radiological abnormalities. Factor analysis informed the variables used in a k‐means cluster analysis. Fixed airflow obstruction and radiological abnormalities were then mapped to these immunological variables in the cluster analysis.Results329 (76.3%) subjects were sensitised to ≥ 1 fungi. Sensitisation to Aspergillus fumigatus and/or Penicillium chrysogenum was associated with a lower post‐bronchodilator FEV1 compared with those not sensitised to fungi ((73.0 (95% CI 70.2–76) vs. 82.8 (95% CI 78.5–87.2)% predicted, P < 0.001), independent of atopic status (P = 0.005)), and an increased frequency of bronchiectasis (54.5%, P < 0.001), tree‐in‐bud (18.7%, P < 0.001) and collapse/consolidation (37.5%, P = 0.002). Cluster analysis identified three clusters: (i) hypereosinophilic (n = 71, 16.5%), (ii) high immunological biomarker load and high frequency of radiological abnormalities (n = 34, 7.9%) and (iii) low levels of fungal immunological biomarkers (n = 326, 75.6%).Conclusions and Clinical RelevanceIgE sensitisation to thermotolerant filamentous fungi, in particular A. fumigatus but not total IgE, is associated with fixed airflow obstruction and a number of radiological abnormalities in moderate to severe asthma. All patients with IgE sensitisation to A. fumigatus are at risk of lung damage irrespective of whether they meet the criteria for ABPA.

Background IgE sensitisation to Aspergillus fumigatus is seen in a significant proportion of patients with refractory asthma. The EVITA3 study recently showed that three months’ treatment with voriconazole did not improve asthma-related outcomes in this patient group. It is not known whether daily variations in outdoor fungal spore levels are associated with concomitant fluctuations in symptoms and lung function in patients with Aspergillus-associated asthma. Methods Participants in the EVITA3 study kept daily diaries of peak expiratory flow (PEF) and asthma symptoms during their follow-up period. These diary records were retrospectively analysed together with contemporaneous fungal spore levels measured locally, in those patients (n = 36) who consented to the secondary use of their clinical and research data. Participants also underwent skin-prick tests for Aspergillus, Alternaria, Cladosporium, Penicillium and Botrytis. For each participant, cross-correlation was used to investigate the relationship between PEF and local spore counts of Aspergillus/Penicillium, Alternaria, Cladosporium, Botrytis, Sporobolomyces, Tilletiopsis, and Didymella. Group-level relationships were investigated using linear mixed models for PEF and generalised estimating equations for daily symptom scores, with participants stratified by skin prick test status. The analyses were performed with the exposure and outcome measured on the same day (lag 0), and with the exposure lagged by 1 day with respect to the outcome (lag 1). Results The analysis cohort comprised 20 men and 16 women with a mean (standard deviation) age of 60 (8) years. No significant or consistent relationships were observed between fungal spore counts and either PEF or self-reported symptom scores, regardless of skin prick test status and lag time between exposure and outcome. In a linear mixed model, the effect size of total fungal spore count on morning PEF was negligible (−0.000011, p = 0.343 for lag 0; −0.000002, p = 0.847 for lag 1). Conclusion In this retrospective analysis we found no evidence of a significant link between fungal spore counts and either PEF or symptoms in patients with Aspergillus-associated asthma. Further research is required to confirm this result in a prospective study and to identify whether aeroallergen levels relate to other important asthma outcomes such as exacerbations.

Background Eosinophilic airway inflammation is often present in asthma, and reduction of such inflammation results in improved clinical outcomes. We hypothesised that fevipiprant (QAW039), an antagonist of prostaglandin D-2 receptor 2, might reduce eosinophilic airway inflammation in patients with moderate-to-severe eosinophilic asthma.Methods We performed a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial at Glenfield Hospital (Leicester, UK). We recruited patients with persistent, moderate-to-severe asthma and an elevated sputum eosinophil count (>= 2%). After a 2-week single-blind placebo run-in period, patients were randomly assigned (1:1) by the trial pharmacist, using previously generated treatment allocation cards, to receive fevipiprant (225 mg twice per day orally) or placebo, stratified by the use of oral corticosteroid treatment and bronchoscopy. The 12-week treatment period was followed by a 6-week single-blind placebo washout period. The primary outcome was the change in sputum eosinophil percentage from baseline to 12 weeks after treatment, analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01545726, and with EudraCT, number 2011-004966-13.Findings Between Feb 10,2012, and Jan 30,2013,61 patients were randomly assigned to receive fevipiprant (n=30) or placebo (n=31). Three patients in the fevipiprant group and four patients in the placebo group withdrew because of asthma exacerbations. Two patients in the fevipiprant group were incorrectly given placebo (one at the mid-treatment visit and one throughout the course of the study). They were both included in the fevipiprant group for the primary analysis, but the patient who was incorrectly given placebo throughout was induded in the placebo group for the safety analyses. Between baseline and 12 weeks after treatment, sputum eosinophil percentage decreased from a geometric mean of 5.4% (95% CI 3.1-9.6) to 1.1% (0.7-1.9) in the fevipiprant group and from 4.6% (2.5-8.7) to 3.9% (CI 2.3-6.7) in the placebo group. Compared with baseline, mean sputum eosinophil percentage was reduced by 4.5 times in the fevipiprant group and by 1.3 times in the placebo group (difference between groups 3.5 times, 95% CI 1.7-7.0; p=0.0014). Fevipiprant had a favourable safety profile, with no deaths or serious adverse events reported. No patient withdrawals were judged by the investigator to be related to the study drug.Interpretation Fevipiprant reduces eosinophilic airway inflammation and is well tolerated in patients with persistent moderate-to-severe asthma and raised sputum eosinophil counts despite inhaled corticosteroid treatment.

The bronchial epithelium contributes to airway remodeling in asthma. DP2/CRTh2 is expressed by intact bronchial epithelium, and its stimulation in vitro increases bronchial epithelial cell migration and metaplasia which are inhibited by CRTh2 antagonism. This study investigated the effects of QAW039, an oral CRTh2 antagonist on bronchial epithelial cell integrity in asthmatics with treatment-resistant sputum eosinophilia. Asthmatic subjects (GINA II-V) with a ≥2% baseline sputum eosinophil count were randomized to QAW039 225mg BID or placebo in addition to their standard-of-care treatment for 12 weeks following a 2-week placebo run-in. Bronchial biopsies were obtained at the end of run-in and after the treatment period. Subjects were stratified at randomization so that background oral corticosteroid (OCS) usage was balanced between QAW039 and placebo patients undergoing biopsy. The analysis presented is unadjusted for baseline variability and OCS treatment. Subjects treated with QAW039 demonstrated both an increase in the percentage of their epithelium that was intact (27.8±12.1%, p=0.030) and a significant decrease in the percentage of denuded epithelium (-26.6±8.9%,p=0.006) compared with their placebo-treated counterparts. Epithelial thickness increased by 15.4μm following QAW039 compared to placebo, but this did not reach statistical significance. While further studies are required to confirm these findings, these data suggest that QAW039 acts directly or indirectly on bronchial epithelial cells to promote epithelial cellular integrity and may reduce remodeling of the airway epithelium in asthma.