Search

Background: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition. Given patients with COPD continue to experience exacerbations despite the availability of effective therapies, anti-inflammatory treatments targeting novel pathways are needed. Kinases, notably the phosphoinositide 3-kinases (PI3K), are thought to be involved in chronic airway inflammation, with this pathway proposed as a critical regulator of inflammation and oxidative stress response in COPD. CHF6523 is an inhaled PI3Kδ inhibitor that has shown positive preclinical results. This manuscript reports the results of a study of CHF6523 in patients with stable COPD (chronic bronchitis phenotype), and who had evidence of type-2 inflammation. Methods: This randomised, double-blind, placebo-controlled, two-way crossover study comprised two 28-day treatment periods separated by a 28-day washout. Patients (N = 44) inhaled CHF6523 in one period, and placebo in the other, both twice daily. The primary objective was to assess the safety and tolerability of CHF6523; the secondary objective was to assess CHF6523 pharmacokinetics. Exploratory endpoints included target engagement (the relative reduction in phosphatidylinositol (3,4,5)-trisphosphate [PIP3]), pharmacodynamic evaluations such as airflow obstruction, and hyperinflation, and to identify biomarker(s) of drug response using proteomics and transcriptomics. Results: CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (Cmax), reached 15 and 10 min after dosing on Days 1 and 28, respectively, followed by a rapid decline. Systemic exposure on Day 28 showed limited accumulation, with ratios < 1.6 for Cmax and area under the curve from 0 to 12 h post-dose, and with steady state achieved on Day 20. Target engagement was confirmed by a significant 29.7% reduction from baseline in induced sputum PIP3 (29.5% reduction vs. placebo; adjusted ratio 0.705 [0.580, 0.856]; p = 0.001), but this did not translate into an anti-inflammatory pharmacodynamic effect, as assessed through measures including biomarkers and multi-omics. Additionally, although CHF6523 was generally well-tolerated, 95.2% of patients reported cough as an adverse event, most mild to moderate and resolving within one-hour post-dose. Conclusions: These data, together with those from other PI3K inhibitors, suggest that PI3Kδ is not a suitable pathway for the management of COPD, as the achieved target engagement did not translate into any pharmacodynamic anti-inflammatory effect. Trial registration: ClinicalTrials.gov (NCT04032535); posted 23rd July 2019. [ABSTRACT FROM AUTHOR]

Background: The single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD. Methods: This double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7–10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3. Results: Of 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p < 0.001 for both). Adjusted mean differences vs. placebo for the key secondary endpoints were: 245 mL for dynamic IC (p < 0.001) and 69.2 s for exercise endurance time (nominal p < 0.001) with BDP/FF/G, and 96 mL (p = 0.053) and 70.1 s (nominal p < 0.001) with BDP/FF. Differences between BDP/FF/G and BDP/FF for resting and dynamic IC were 92 and 149 mL (p < 0.01 for both). All three treatments were generally well tolerated, with 27.3%, 25.3% and 19.0% of patients reporting adverse events with BDP/FF/G, BDP/FF and placebo, respectively, all mild or moderate. Conclusions: In patients with COPD, BDP/FF/G provided significant and clinically relevant improvements vs. placebo and BDP/FF in static and dynamic hyperinflation, with an improvement vs. placebo in exercise endurance. Trial registration: ClinicalTrials.gov (NCT05097014), registered 27th October 2021. [ABSTRACT FROM AUTHOR]

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.Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03683576; URL: www.Clinicaltrials: gov. [ABSTRACT FROM AUTHOR]

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: In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) and -29 ml (95% CI, -46 to -13), respectively, and mean changes from baseline in SGRQ scores were -6.6 units (95% CI, -7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14-51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components.Conclusions: These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161). [ABSTRACT FROM AUTHOR]

Ratio nal e: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. Objecti ves: The purpose of the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study was to correlate clinical features and biomarkers with molecular characteristics in a well-profiled COPD cohort. Methods : A total of 67 COPD subjects (forced expiratory volume in the first second of expiration [FEV1]: 45%-80% predicted) and 63 healthy smoking and nonsmoking controls underwent multiple assessments including patient questionnaires, lung function, and clinical biomarkers including fractional exhaled nitric oxide (FENO), induced sputum, and blood. Meas urements and mai n results : The impact of inhaled corticosteroids (ICSs), and to a lesser extent current smoking, was more associated with symptom control, exacerbation rates, and clinical biomarkers, than severity by FEV1. The ICS-treated smoking subjects were most symptomatic, with significantly elevated scores on patient-reported outcomes and more annual exacerbations (P < .05). Inhaled corticosteroid users had greater airflow obstruction and air trapping compared with non-ICS users, regardless of smoking status. Smoking, regardless of ICS use, was associated with significantly lower FENO (P < .05). Smoking, in non-ICS users, was associated with an elevated proportion of sputum neutrophils and reduced sputum macrophages. Increased serum C-reactive protein was observed in smokers but not in ICS and nonsmoking ICS users (P < .05). In contrast, only air trapping and neutrophilic inflammation increased with severity, defined by postbronchodilator FEV1. Concl usio ns: Compared with COPD severity by FEV1, ICS use and current smoking were better determinants of clinical characteristics and biomarkers. Use of the ADEPT COPD data promises to prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Asthma 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.Methods: Patients 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.Results: Mild (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.Conclusions: The 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. [ABSTRACT FROM AUTHOR]

GSK961081 (batefenterol) is a novel bifunctional molecule composed of a muscarinic antagonist and a β2-agonist. The aims of this substudy were (1) to characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of GSK961081 in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD); and (2) to investigate the relationship between systemic exposure to GSK961081 and key cardiac-related safety parameters. Three once-daily doses (100, 400, and 800 μg) and three twice-daily doses (100, 200, and 400 μg) of GSK961081 DISKUS were investigated. A two-compartment disposition PK model with first-order absorption adequately described the plasma GSK961081 concentration- time data. An empirical maximum-effects PD model adequately described the forced expiratory volume in 1 s (FEV1) response relationship with the covariate baseline FEV1 on day 1. No clear relationships between GSK961081 plasma drug levels and cardiac-related safety parameters were apparent. The PK and PD models will be used to guide the dose selection and development of GSK961081 in patients with COPD. [ABSTRACT FROM AUTHOR]