Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial.

BACKGROUND: Umeclidinium (UMEC; long-acting muscarinic antagonist) plus vilanterol (VI; long-acting beta2 agonist [LABA]) and the LABA/inhaled corticosteroid fluticasone propionate/salmeterol (FP/SAL) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD). This 12-week, multicentre, double-blind, parallel-group, double-dummy study compared the efficacy and safety of these treatments in symptomatic patients with moderate-to-severe COPD with no exacerbations in the year prior to enrolment. METHODS: Patients (n = 717) were randomised 1:1 to once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 500/50 mcg. Endpoints included 0-24 h weighted mean (wm) forced expiratory volume in 1 s (FEV1) (Day 84; primary), trough FEV1 (Day 85; secondary), other lung function endpoints, symptoms, quality of life (QoL) and safety. RESULTS: Improvements with UMEC/VI versus FP/SAL were 0.080 L (95 % confidence interval: 0.046-0.113; wmFEV1) and 0.090 L (0.055-0.125; trough FEV1) (both p < 0.001). UMEC/VI statistically significantly improved all other lung function measures versus FP/SAL. Both treatments demonstrated a clinically meaningful improvement in symptoms (Transition Dyspnoea Index ≥1 unit) and QoL (St George's Respiratory Questionnaire Total score ≥4 unit decrease from baseline) over 12 weeks. The incidence of adverse events was 28 % (UMEC/VI) and 29 % (FP/SAL); nasopharyngitis and headache were most common. CONCLUSIONS: Once-daily UMEC/VI 62.5/25 mcg over 12 weeks resulted in significant and sustained improvements in lung function versus twice-daily FP/SAL 500/50 mcg in patients with moderate-to-severe COPD and with no exacerbations in the year prior to enrolment. TRIAL REGISTRATION: NCT01822899 Registration date: March 28, 2013.

The ion channel transient receptor potential melastatin-2 does not play a role in inflammatory mouse models of chronic obstructive pulmonary diseases.

BACKGROUND: There is strong evidence that oxidative stress is associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). The transient receptor potential melastatin-2 (TRPM2) is an oxidative stress sensing channel that is expressed in a number of inflammatory cells and therefore it has been suggested that inhibition of TRPM2 could lead to a beneficial effect in COPD patients. In this study, we have investigated the role of TRPM2 in a variety of mouse models of oxidative stress and COPD using TRPM2-deficent mice. METHODS: Mice were exposed to ozone (3 ppm for 4 h) or lipopolysaccharide (LPS, 0.3 mg/kg, intranasaly). In another model, mice were exposed to tobacco smoke (750 µg/l total wet particulate matter) for 30 min twice a day on three consecutive days. For the exacerbation model, the smoke exposure on the morning of day 3 animals was replaced with intranasal administration of LPS (0.3 mg/kg). Animals were killed 3 and 24 h after the challenge (ozone and LPS model) or 18 h after the last tobacco smoke exposure. In vitro neutrophil chemotaxis and monocyte activation were also studied using cells isolated from wild type and TRPM2-deficient animals. Statistical significance for the in vivo data (P < 0.05) was determined using analysis of variance with Kruskal-Wallis and Dunns multiple comparison test. RESULTS: In all models studied, no difference in the bronchoalveolar lavage inflammation could be evidenced when comparing wild type and TRPM2-deficient mice. In addition, no difference could be seen in the lung inflammation as assessed by the measurement of various cytokines/chemokines. Similarly in various in vitro cellular activation assays using isolated neutrophils and monocytes no significant differences could be observed when comparing wild type and TRPM2-deficient mice. DISCUSSION: We have shown, in all the models tested, no difference in the development of airway inflammation or cell activation between TRPM2-deficient mice and their wild type counterparts. These results would suggest that inhibiting TRPM2 activity in COPD would have no anti-inflammatory effect.

Feasibility and physiological relevance of designing highly potent aminopeptidase-sparing leukotriene A4 hydrolase inhibitors.

Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The epoxide hydrolase function of the enzyme catalyzes the biosynthesis of the pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests that the aminopeptidase function of LTA4H is responsible for degradation of the tripeptide Pro-Gly-Pro (PGP) for which neutrophil chemotactic activity has been postulated. It has been speculated that the design of epoxide hydrolase selective LTA4H inhibitors that spare the aminopeptidase pocket may therefore lead to more efficacious anti-inflammatory drugs. In this study, we conducted a high throughput screen (HTS) for LTA4H inhibitors and attempted to rationally design compounds that would spare the PGP degrading function. While we were able to identify compounds with preference for the epoxide hydrolase function, absolute selectivity was not achievable for highly potent compounds. In order to assess the relevance of designing such aminopeptidase-sparing LTA4H inhibitors, we studied the role of PGP in inducing inflammation in different settings in wild type and LTA4H deficient (LTA4H KO) animals but could not confirm its chemotactic potential.  Attempting to design highly potent epoxide hydrolase selective LTA4H inhibitors, therefore seems to be neither feasible nor relevant.

Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations.

BACKGROUND: Umeclidinium (UMEC; long-acting muscarinic antagonist [LAMA])/vilanterol (VI; long-acting beta2-agonist [LABA]) and fluticasone propionate/salmeterol (FP/SAL) (inhaled corticosteroid/LABA) are approved maintenance therapies for chronic obstructive pulmonary disease (COPD). Two studies compared efficacy and safety of UMEC/VI with FP/SAL in patients with moderate-to-severe COPD with no exacerbations in the previous year. METHODS: In these 12-week, multicenter, double-blind, parallel-group, double-dummy trials, randomized (1:1) patients received once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 250/50 mcg (DB2114930 n = 353 and 353; DB2114951 n = 349 and 348, respectively; intent-to-treat). Endpoints included 0-24 h weighted mean (wm) forced expiratory volume in 1 s (FEV1) (Day 84; primary), trough FEV1 (Day 85; secondary), other lung function endpoints, dyspnea, quality of life (QoL) and safety. RESULTS: UMEC/VI demonstrated statistically significant, clinically meaningful improvements in lung function measures versus FP/SAL. For 0-24 h wmFEV1 (Day 84), improvements with UMEC/VI versus FP/SAL were 74 mL (95% confidence interval [CI]: 38-110; DB2114930) and 101 mL (63-139; DB2114951) (both p < 0.001). Trough FEV1 improvements were 82 mL (45-119) and 98 mL (59-137) (both p < 0.001) for UMEC/VI versus FP/SAL, respectively. Both treatments demonstrated similar, clinically meaningful improvements from baseline in dyspnea (Transition Dyspnea Index focal score >1 unit) and QoL (St George's Respiratory Questionnaire Total score >4-unit decrease) in both studies with no statistical differences between treatments. Adverse event rates were similar: 26 and 30% UMEC/VI; 27 and 31% FP/SAL. CONCLUSIONS: Once-daily UMEC/VI 62.5/25 mcg over 12 weeks resulted in statistically significant, clinically meaningful improvements in lung function versus twice-daily FP/SAL 250/50 mcg in patients with moderate-to-severe COPD with infrequent exacerbations. Both treatments improved dyspnea and QoL. CLINICAL TRIAL REGISTRATION: DB2114930/NCT01817764; DB2114951/NCT01879410.