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Asthma; Asthma worsening; Eosinophilic asthma Asma; Empitjorament de l'asma; Asma eosinofílica Asma; Empeoramiento del asma; Asma eosinofílica Background Prostaglandin D2 receptor 2 (DP2) antagonists inhibit prostaglandin D2-induced effects, including recruitment and activation of cells driving asthma pathogenesis. However, challenges identifying target population and end points persist. Research Question What is the effect of the DP2 antagonist GB001 on asthma worsening in patients with moderate to severe eosinophilic asthma? Study Design and Methods In this phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter study, GB001 or placebo was added to standard-of-care treatment in patients with moderate to severe asthma with a blood eosinophil count ≥ 250 cells/μL. Patients aged ≥ 18 years to < 75 years received one of four once-daily treatments (GB001 20 mg, 40 mg, or 60 mg or placebo). The primary end point was the proportion of patients who experienced asthma worsening by 24 weeks. Efficacy analyses were performed for the intention-to-treat population and safety analyses for patients who received at least one dose of study treatment. Results A total of 480 patients were treated. The ORs for asthma worsening for GB001 20 mg, 40 mg, and 60 mg vs placebo were 0.674 (95% CI, 0.398-1.142), 0.677 (95% CI, 0.399-1.149), and 0.651 (95% CI, 0.385-1.100), respectively. Analysis according to baseline blood eosinophil levels and/or fractional exhaled nitric oxide did not show greater treatment effects with higher values. Elevated liver aminotransferase levels and adverse events leading to discontinuation were more frequent for GB001 60 mg than with placebo, GB001 20 mg, and GB001 40 mg. Interpretation Although GB001 did not significantly reduce the odds of asthma worsening, reductions favoring GB001 were observed. Treatment effects were consistent regardless of high/low type 2 phenotype. The overall safety profile was acceptable, although GB001 60 mg was associated with risk of liver injury. This work was supported by GB001, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.

BackgroundOral corticosteroid (OCS) dependence among patients with severe eosinophilic asthma can cause adverse outcomes, including adrenal insufficiency. PONENTE's OCS reduction phase showed that, following benralizumab initiation, 91.5% of patients eliminated corticosteroids or achieved a final dosage ≤5 mg·day−1(median (range) 0.0 (0.0–40.0) mg).MethodsThe maintenance phase assessed the durability of corticosteroid reduction and further adrenal function recovery. For ∼6 months, patients continued benralizumab 30 mg every 8 weeks without corticosteroids or with the final dosage achieved during the reduction phase. Investigators could prescribe corticosteroids for asthma exacerbations or increase daily dosages for asthma control deteriorations. Outcomes included changes in daily OCS dosage, Asthma Control Questionnaire (ACQ)-6 and St George's Respiratory Questionnaire (SGRQ), as well as adrenal status, asthma exacerbations and adverse events.Results598 patients entered PONENTE; 563 (94.1%) completed the reduction phase and entered the maintenance phase. From the end of reduction to the end of maintenance, the median (range) OCS dosage was unchanged (0.0 (0.0–40.0) mg), 3.2% (n=18/563) of patients experienced daily dosage increases, the mean ACQ-6 score decreased from 1.26 to 1.18 and 84.5% (n=476/563) of patients were exacerbation free. The mean SGRQ improvement (–19.65 points) from baseline to the end of maintenance indicated substantial quality-of-life improvements. Of patients entering the maintenance phase with adrenal insufficiency, 32.4% (n=104/321) demonstrated an improvement in adrenal function. Adverse events were consistent with previous reports.ConclusionsMost patients successfully maintained maximal OCS reduction while achieving improved asthma control with few exacerbations and maintaining or recovering adrenal function.

Reynold A Panettieri Jr,1 Carlos A Camargo Jr,2 Tariq Cheema,3 Sherif G El Bayadi,4 Stanley Fiel,5 Tania M Vila,6 Renu G Jain,6 Dawn Midwinter,7 Byron Thomashow,8 Andrea Ludwig-Sengpiel,9 David A Lipson10,11 1Child Health Institute of New Jersey, Rutgers University School of Medicine, New Brunswick, NJ, USA; 2Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 3Breathing Disorder Center, Allegheny Health Network, Pittsburgh, PA, USA; 4Department of Medicine, St. Joseph’s Health/SUNY Upstate, Syracuse, NY, USA; 5Atlantic Health Systems/Morristown Medical Center, Morristown, NJ, 07960, USA; 6GSK, Research Triangle Park, NC, USA; 7GSK, Brentford, UK; 8Department of Medicine, Columbia University Medical Center, New York, NY, USA; 9KLB Gesundheitsforschung Lübeck GmbH, Lübeck, Germany; 10Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 11GSK, Collegeville, PA, USACorrespondence: Reynold A Panettieri Jr, Rutgers University School of Medicine, 89 French Street, Suite 4210, New Brunswick, NJ, 08901, USA, Tel +1 732-235-6404, Email rp856@rbhs.rutgers.eduBackground: In the FULFIL trial, once-daily single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) resulted in reduced moderate/severe exacerbation rates and conferred significant improvements in lung function and health status in patients with chronic obstructive pulmonary disease (COPD) versus twice-daily budesonide/formoterol (BUD/FOR) dual therapy.Methods: FULFIL was a Phase III, randomized, double-blind, double-dummy, parallel-group study. Patients ≥ 40 years of age with symptomatic COPD were randomized 1:1 to FF/UMEC/VI 100/62.5/25 mcg or BUD/FOR 400/12 mcg. In this post hoc analysis, patients were categorized by exacerbation history in the year prior to study entry (≥ 1 moderate/severe exacerbation [recent exacerbation] versus no recent exacerbation). Endpoints included annual rate of on-treatment moderate/severe exacerbations up to Week 24, annual rate of on-treatment severe exacerbations up to Week 24, change from baseline in trough forced expiratory volume in 1 second at Week 24, and change from baseline in health status as measured by St George’s respiratory questionnaire total score at Week 24.Results: Of the 1810 patients in the intent-to-treat population, 1180 (65%) had one or more moderate/severe exacerbation in the year prior to entry, while 630 (35%) patients did not. FF/UMEC/VI versus BUD/FOR significantly reduced moderate/severe exacerbation rates in the recent exacerbation subgroup (mean annualized rate: 0.19 vs 0.29; rate ratio [95% confidence interval [CI]]: 0.64: [0.45, 0.91]; p=0.014) and numerically reduced moderate/severe exacerbation rates in the no recent exacerbation subgroup (mean annualized rate: 0.29 vs 0.43; rate ratio [95% CI]: 0.67 [0.43, 1.04]; p=0.073). Severe exacerbation rates were numerically reduced with FF/UMEC/VI versus BUD/FOR treatment across both subgroups. FF/UMEC/VI conferred significant improvements in lung function and health status versus BUD/FOR, regardless of recent exacerbation history.Conclusion: FF/UMEC/VI reduced moderate/severe and severe exacerbation rates and improved lung function and health status versus BUD/FOR in patients with symptomatic COPD, regardless of recent exacerbation history.Keywords: COPD, exacerbations, severe exacerbations, triple therapy, ICS/LABA

Supplemental material, sj-pdf-1-bmi-10.1177_1177271917730306 for Inhaled Steroids and Active Smoking Drive Chronic Obstructive Pulmonary Disease Symptoms and Biomarkers to a Greater Degree Than Airflow Limitation by Philip E Silkoff, Dave Singh, J Mark FitzGerald, Andreas Eich, Andrea Ludwig-Sengpiel, Geoffrey C Chupp, Vibeke Backer, Celeste Porsbjerg, Pierre-Olivier Girodet, Mark T Dransfield, Frederic Baribaud, Vedrana S Susulic and Matthew J Loza in Biomarker Insights

International audience; BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with changes in the sputum microbiome, including an increased prevalence of pathogenic bacteria. Vaccination against the most frequent bacteria identified in AECOPD might reduce exacerbation frequency. We assessed the efficacy, safety, and immunogenicity of a candidate vaccine containing surface proteins from non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) in patients with COPD.MethodsThis multicentre, randomised, observer-blinded, placebo-controlled, proof-of-concept, phase 2b trial recruited patients with stable COPD, moderate-to-very severe airflow limitation (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2, 3, or 4), at 67 clinical sites in Belgium, Canada, France, Germany, Italy, Spain, UK, and USA. Eligible patients were aged 40–80 years and had a history of at least one moderate or severe exacerbation in the previous year. Patients were allocated (1:1) using a minimisation algorithm to receive two intramuscular injections of NTHi–Mcat vaccine or placebo 60 days apart, in addition to standard care. The allocation algorithm considered age category, number of previous exacerbations, COPD severity at study entry, and country as minimisation factors, to guarantee treatment balance within each factor. Vaccine recipients and those responsible for evaluating study endpoints were masked to group allocation. In the analysis of efficacy, the primary outcome was the rate of any moderate or severe AECOPD occurring within a 1-year period, starting 1 month after the second dose in patients who received two vaccine doses (modified total vaccinated cohort). Safety was assessed in the total vaccinated cohort. The trial is registered with ClinicalTrials.gov, number NCT03281876, and is complete.FindingsBetween Nov 27, 2017, and Nov 30, 2018, 606 adults were enrolled and included in the total vaccinated cohort (304 in the NTHi–Mcat vaccine group, 302 in the placebo group); 571 received two doses and were included in the primary efficacy analysis (279 in the NTHi–Mcat vaccine group, 292 in the placebo group). 23 participants dropped-out in the NTHi–Mcat vaccine group and 39 in the placebo group; this included 4 patients in the NTHi–Mcat vaccine group and 15 in the placebo group who withdrew from the study because of an adverse event. The primary analysis included 340 exacerbations (in follow-up time 102 123 days) in the NTHi–Mcat vaccine group and 333 (in 104 443 days) in the placebo group, with a yearly rate of moderate or severe AECOPD of 1·22 in the NTHi–Mcat vaccine group and 1·17 in the placebo group, with vaccine efficacy in reducing the yearly rate of moderate or severe AECOPD estimated to be zero (vaccine efficacy point estimate 2·26% [87% CI –18·27 to 11·58]; p=0·82). Solicited local adverse events were more frequent in the NTHi–Mcat vaccine group (216 [72%] of 301 patients) than with placebo (34 [11%] of 299 patients), and the frequency of solicited general adverse events was similar between groups (239 [79%] of 301 vs 235 [79%] of 299 patients). There was one death in the NTHi–Mcat vaccine group (acute respiratory failure, not related to vaccination) and ten in the placebo group (seven due in part to COPD or respiratory failure). There were 158 serious adverse events (89 [29%] of 304 patients) in the NTHi–Mcat vaccine group, not related to vaccination, and 214 (99 [33%] of 302 patients) in the placebo group.InterpretationNTHi–Mcat vaccine administered to patients with COPD did not show efficacy in reducing the yearly rate of moderate or severe exacerbations. No safety concerns were identified.

Prostaglandin DWhat is the effect of the DPIn this phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter study, GB001 or placebo was added to standard-of-care treatment in patients with moderate to severe asthma with a blood eosinophil count ≥ 250 cells/μL. Patients aged ≥ 18 years to 75 years received one of four once-daily treatments (GB001 20 mg, 40 mg, or 60 mg or placebo). The primary end point was the proportion of patients who experienced asthma worsening by 24 weeks. Efficacy analyses were performed for the intention-to-treat population and safety analyses for patients who received at least one dose of study treatment.A total of 480 patients were treated. The ORs for asthma worsening for GB001 20 mg, 40 mg, and 60 mg vs placebo were 0.674 (95% CI, 0.398-1.142), 0.677 (95% CI, 0.399-1.149), and 0.651 (95% CI, 0.385-1.100), respectively. Analysis according to baseline blood eosinophil levels and/or fractional exhaled nitric oxide did not show greater treatment effects with higher values. Elevated liver aminotransferase levels and adverse events leading to discontinuation were more frequent for GB001 60 mg than with placebo, GB001 20 mg, and GB001 40 mg.Although GB001 did not significantly reduce the odds of asthma worsening, reductions favoring GB001 were observed. Treatment effects were consistent regardless of high/low type 2 phenotype. The overall safety profile was acceptable, although GB001 60 mg was associated with risk of liver injury.ClinicalTrials.gov; No.: NCT03683576; URL: www.gov.

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. SOURCE evaluated the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma.We conducted this phase 3, multicentre, randomised, double-blind, placebo-controlled study across 60 sites in seven countries. Participants aged 18-80 years with physician-diagnosed asthma, who had been receiving medium-dose or high-dose inhaled corticosteroids and had at least one asthma exacerbation in the 12 months before screening were eligible. Patients who were receiving medium-dose inhaled corticosteroids must have had their dose increased to a high dose for at least 3 months before screening. After an oral corticosteroid optimisation phase of up to 8 weeks, participants were randomly assigned according to a computer-generated fixed block randomisation sequence to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks during a 48 week treatment period (4 week induction phase, 36 week oral corticosteroid reduction phase, and 8 week maintenance phase). Randomisation was stratified by region. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoint was the categorised percentage reduction from baseline in daily oral corticosteroid dose at week 48 without the loss of asthma control. Efficacy and safety endpoints were assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03406078.Between March 5, 2018, and Sept 27, 2019, 150 participants were randomly assigned to receive tezepelumab 210 mg (n=74) or placebo (n=76). The cumulative odds of achieving a category of greater percentage reduction in an oral corticosteroid dose for daily maintenance at week 48 were similar with tezepelumab or placebo in the overall population (odds ratio [OR] 1·28 [95% CI 0·69-2·35], p=0·43; the primary endpoint was not met). The cumulative odds were higher with tezepelumab than with placebo in participants with baseline blood eosinophil counts of at least 150 cells per μL (2·58 [1·16-5·75]), but not in participants with counts below 150 cells per μL (0·40 [0·14-1·13]). Tezepelumab was well tolerated, with no safety concerns identified. 53 (72%) of 74 tezepelumab-assigned participants and 65 (86%) of 76 placebo-assigned participants reported an adverse event. Serious adverse events were reported in 12 (16%) participants in the tezepelumab group and 16 (21%) participants in the placebo group.We did not observe a significant improvement in oral corticosteroid dose reduction with tezepelumab versus placebo in the overall population of this oral corticosteroid-sparing study, although an improvement was observed in participants with baseline blood eosinophil counts of at least 150 cells per μL.AstraZeneca and Amgen.

Background Inhaled bronchodilator therapy is currently the mainstay of treatment for patients with chronic obstructive pulmonary disease (COPD). Some inhalers require patients to achieve certain inhalation efforts either to activate the device or to deliver medication to the site of action. For dry powder inhalers, low peak inspiratory flow (PIF) can result in poor medication delivery but the clinical significance of this is not well understood. Methods TRONARTO was a 4-week, randomized, double-blind, placebo-controlled, multicenter, parallel-group study which stratified patients with moderate-to-severe COPD according to their PIF against medium-low resistance at screening. Patients were randomized to receive tiotropium/olodaterol (5 μg/5 μg) or matched placebo delivered via the Respimat® Soft Mist™ inhaler (SMI). After 4 weeks of treatment, we assessed change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0–3 hours (FEV1 AUC0–3h) and trough FEV1. Results Overall, 213 patients were randomized, of whom 106 received tiotropium/olodaterol (PIF, Graphical Abstract

Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm 3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

Rationale: Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited.Objectives: We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD.Methods: The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 μg/62.5 μg/25 μg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co–primary endpoints were change from baseline in trough FEV1 and in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 24.Measurements and Main Results...

Background: Poor adherence is a key factor in poor asthma control. A connected inhaler system (CIS) comprising sensors on inhalers, a patient-facing app, and a Healthcare Professional (HCP) dashboard could improve asthma management by improving adherence. Methods: Study 207040 (NCT033800429) is one of the first to investigate the different elements of a CIS in improving adherence. The study had a 24-week, open-label, randomised, multi-centre, parallel group design with 5 treatment arms, in uncontrolled asthmatic patients [Asthma Control Test (ACT) Results: The primary endpoint was the effect of 6 months’ use of a CIS on adherence to maintenance therapy assessed over months 4-6, with the absolute adjusted mean adherence difference in arm 1 (data on maintenance to participant and HCP; 82.0%) being 13.2% (95% CI [6.3%, 20.0%]; p Conclusion: The study demonstrates that a CIS can improve adherence to maintenance medication for patients with uncontrolled asthma. Funding: GlaxoSmithKline plc. (207040)

ObjectivesAs tobacco companies can circumvent tax increases, a minimum retail price per-cigarette/per-gram of roll-your-own tobacco presents an additional mechanism for governments to reduce smoking. We examined (1) anticipated responses to a hypothetical minimum price-per-cigarette/per-gram among smokers in the UK; (2) what demographic and smoker characteristics are associated with anticipated responses; and (3) whether minimum pricing may help ex-smokers stay quit.DesignCross-sectional survey (May–July 2019).SettingUK.ParticipantsAdult cigarette smokers (n=2412) and ex-smokers (n=700).Main outcome measurementsAnticipated responses to a hypothetical minimum price of £10.00 for 20 cigarettes (£0.50 per-cigarette) and £13.50 for 30 grams of roll-your-own tobacco (£0.45 per-gram); approximately £0.10 per-cigarette/per-gram increases on the cheapest prices in leading UK supermarkets (January 2019). Smokers were presented with ten options (eg, ‘Try to quit’) and asked which they would do (Yes/No) and then which they would most likely do. Ex-smokers were asked to what extent the minimum prices would help them stay quit (A lot vs Lesser agreement).ResultsAmong smokers, 55.6% said they would most likely smoke the same amount, 10.7% they would smoke less, 9.5% they would try to quit and 5.8% they would use e-cigarettes more often. Anticipated reactions were associated with demography and smoker characteristics, for example, C2DE (lower social grade) smokers were less likely than ABC1 (higher social grade) smokers to say they would smoke the same as they do now (ORAdj=0.74, 95% CI 0.62 to 0.88). Among ex-smokers, 38.5% said the minimum prices would help them stay quit ‘A lot’, more so among C2DE than ABC1 participants (ORAdj=1.80, 95% CI 1.30 to 2.49).ConclusionsIn response to a hypothetical minimum price for cigarettes and roll-your-own tobacco, approximately a fifth of smokers in the UK indicated they would smoke less or quit and almost two-fifths of ex-smokers indicated the prices would help them stay quit.

Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase involved in leukocyte recruitment and activation. Activation of PI3Kδ has been linked to airway inflammation and asthma pathogenesis. This randomized, double-blind, placebo-controlled, crossover study investigated the efficacy, safety, tolerability, and pharmacokinetics of a PI3Kδ inhibitor, nemiralisib (GSK2269557), in patients with persistent, uncontrolled asthma. Patients (n = 50) received once-daily inhaled nemiralisib (1000 µg) or placebo for 28 days, with a crossover to the alternative treatment following a 4-week washout period. Spirometry demonstrated no discernible difference in trough forced expiratory volume in 1 second (FEV1) from baseline (adjusted posterior median 7 ml; 95% credible interval -83, 102 ml) between nemiralisib and placebo treatment at day 28 (primary endpoint). These results were supported by most secondary endpoints, including weighted mean FEV1 (0-4 hours) and change in trough forced vital capacity at day 28. Nemiralisib was generally well-tolerated, with few side effects except for post-inhalation cough (nemiralisib: 35%; placebo: 9%). At day 14, sputum interleukin (IL)-5, IL-13, IL-6, and IL-8 levels were reduced by a median of 17%, 7%, 15%, and 8%, respectively, when comparing nemiralisib with placebo [n = 15 (IL-5, IL-8) or 16 (IL-6, IL-13); posterior probability of a true ratio >0%: 78%, 64%, 76%, and 63%, respectively]. These results suggest that nemiralisib inhibited PI3Kδ locally; however, this did not translate into meaningful clinical improvement. Further studies will investigate the potential efficacy of nemiralisib in patients with asthma with other specific more severe phenotypes, including those who are colonized with bacteria and frequently exacerbate.