No abstract

SCH527123 is a novel, selective CXC chemokine receptor 2 antagonist that inhibits neutrophil activation and modulates neutrophil trafficking in animal models, characteristics that may be beneficial in the treatment of conditions with unbalanced pulmonary neutrophilia, such as chronic obstructive pulmonary disease. The purpose of this proof-of-principle study was to determine whether SCH527123 inhibits ozone-induced neutrophil recruitment in healthy humans.In a randomised, double-blind, placebo-controlled, three-way crossover study, oral SCH527123 (50 mg once daily, 4 days), prednisolone (50 mg once), or placebo was alternated with 2-week washouts. 18 healthy ozone responders (.20% increase in sputum neutrophils) underwent ozone challenge tests (250 ppb, 3 h intermittent exercise) 1 h after the last treatment dose. Sputum was induced at 3 h post-challenge.After SCH527123 treatment, the ozone challenge resulted in significantly lower sputum neutrophil counts (0.13610 6 ?mL -1 ) compared with prednisolone (0.84610; p,0.001) or placebo (2.98610 6 ?mL -1 ; p,0.001). Comparable results were obtained for total cell count, percentage of sputum neutrophils, and for interleukin-8 and myeloperoxidase in sputum supernatant. Post-challenge, SCH527123 inhibited neutrophilia in peripheral blood but significantly less than in sputum. All treatments were safe and well tolerated. SCH527123 causes significant attenuation of ozone-induced airway neutrophilia in healthy subjects. Further evaluation in a large trial of patients with pulmonary disorders is warranted.

GSK961081 is a bifunctional molecule demonstrating both muscarinic antagonist and β-agonist activities.This was a 4-week, multicentre, randomised, double-blind, double-dummy, placebo and salmeterol controlled parallel group study. Doses ranging across three twice-daily doses and three once-daily doses were assessed in moderate and severe chronic obstructive pulmonary disease (COPD) patients. Trough forced expiratory volume in 1 s (FEV1) at day 29 was the primary end-point. At days 1 and 28, 12-h FEV1 spirometry was performed in all patients. A subset of patients underwent complete 24-h spirometry at day 28.The study recruited 436 patients. GSK961081 showed statistically and clinically significant differences from placebo in all doses and regimens for trough FEV1 on day 29 (155–277 mL). The optimal total daily dose was 400 μg, either as 400 μg once daily or as 200 μg twice daily, with an improvement in day 29 trough FEV1 of 215 mL and 249 mL, respectively. Other efficacy end-points also showed improvement. No effects were observed on glucose, potassium, heart rate, blood pressure and no dose–response effect was seen on corrected QT elongation.This study showed that GSK961081 is an effective bronchodilator in COPD and appeared to be safe and well tolerated.

BackgroundAsthma is a heterogeneous disease and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. The purpose of the ADEPT study was to correlate clinical features and biomarkers with molecular characteristics, by profiling asthma (NCT01274507). This report presents for the first time the study design, and characteristics of the recruited subjects.MethodsPatients with a range of asthma severity and healthy non-atopic controls were enrolled. The asthmatic subjects were followed for 12 months. Assessments included history, patient questionnaires, spirometry, airway hyper-responsiveness to methacholine, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum, blood, and bronchoscopy samples. All subjects underwent sputum induction and 30 subjects/cohort had bronchoscopy.ResultsMild (n = 52), moderate (n = 55), severe (n = 51) asthma cohorts and 30 healthy controls were enrolled from North America and Western Europe. Airflow obstruction, bronchodilator response and airways hyperresponsiveness increased with asthma severity, and severe asthma subjects had reduced forced vital capacity. Asthma control questionnaire-7 (ACQ7) scores worsened with asthma severity. In the asthmatics, mean values for all clinical and biomarker characteristics were stable over 12 months although individual variability was evident. FENO and blood eosinophils did not differ by asthma severity. Induced sputum eosinophils but not neutrophils were lower in mild compared to the moderate and severe asthma cohorts.ConclusionsThe ADEPT study successfully enrolled asthmatics across a spectrum of severity and non-atopic controls. Clinical characteristics were related to asthma severity and in general asthma characteristics e.g. lung function, were stable over 12 months. Use of the ADEPT data should prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0299-y) contains supplementary material, which is available to authorized users.

Suboptimal adherence to maintenance therapy contributes to poor asthma control and exacerbations. This study evaluated the effect of different elements of a connected inhaler system (CIS), comprising clip-on inhaler sensors, a patient-facing app, and a healthcare professional (HCP) dashboard, on adherence to asthma maintenance therapy.This was an open-label, parallel-group, 6-month, randomised controlled trial in adults with uncontrolled asthma (Asthma Control Test (ACT) score <20) on fixed-dose inhaled corticosteroid/long-acting beta-agonist maintenance therapy (n=437). All received fluticasone furoate/vilanterol ELLIPTA dry powder maintenance and salbutamol/albuterol metered dose rescue inhalers with a sensor attached to each inhaler. Participants were randomised to one of five CIS study arms (1:1:1:1:1) reflecting the recipient of the data feedback from the sensors: 1) Maintenance use to participants and HCPs (N=87); 2) Maintenance use to participants (N=88); 3) Maintenance and rescue use to participants and HCPs (N=88); 4) Maintenance and rescue use to participants (N=88); 5) No feedback (control) (N=86).For the primary endpoint, observed mean adherence (sd) to maintenance therapy over months 4–6, was 82.2% (16.58) (n=83) in the “maintenance to participants and HCPs” arm and 70.8% (27.30) (n=85) in the control arm and the adjusted LS mean (se) was 80.9% (3.19) and 69.0% (3.19), respectively (study arm difference: 12.0% (95% CI: 5.2%, 18.8%; p<0.001)). Adherence was also significantly greater in the other CIS arms versus control. Mean percentage of rescue medication-free days (months 4–6) was significantly greater in participants receiving data on their rescue use compared with control. ACT scores improved in all study arms with no significant differences between groups.A CIS can improve adherence to maintenance medication and reduce rescue medication use in patients with uncontrolled asthma.

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.

Phosphoinositide 3-kinase (PI3K) is a lipid kinase involved in leukocyte recruitment and activation. Activation of PI3K 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 PI3K inhibitor, nemiralisib (GSK2269557), in patients with persistent, uncontrolled asthma. Patients ( = 50) received once-daily inhaled nemiralisib (1000 g) 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 (FEV) 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 FEV (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 [ = 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 PI3K 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.

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