Vijay Alagappan

Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study

NVA237 (glycopyrronium bromide) is a once-daily long-acting muscarinic antagonist (LAMA) in development for chronic obstructive pulmonary disease (COPD). The GLycopyrronium bromide in COPD airWays clinical Study 2 (GLOW2) evaluated the efficacy and safety of NVA237 in moderate-to-severe COPD over 52 weeks. Patients were randomised 2:1:1 to NVA237 50 μg, placebo or open-label tiotropium 18 μg for 52 weeks. Primary end-point was trough forced expiratory volume in 1 s (FEV1) at 12 weeks. 1,066 patients were randomised, 810 completed the study. At week 12, trough FEV1 increased significantly by 97 mL with NVA237 (95% CI 64.6–130.2; p<0.001) and 83 mL with tiotropium (95% CI 45.6–121.4; p<0.001). Compared with placebo, NVA237 produced significant improvements in dyspnoea (Transition Dyspnoea Index at week 26; p=0.002) and health status (St Georges Respiratory Questionnaire at week 52; p<0.001). NVA237 significantly reduced the risk of moderate-to-severe COPD exacerbations by 34% (p=0.001) and the use of rescue medication (p=0.039), versus placebo. NVA237-placebo and tiotropium-placebo differences were comparable for all outcomes. Safety profiles were similar across groups. NVA237 50 μg provided significant improvements in lung function, dyspnoea, health status, exacerbations and rescue medication use, versus placebo, and was comparable to tiotropium. NVA237 can potentially be an alternative choice of LAMA for COPD patients.

Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease

Background: Ongoing inflammatory processes resulting in airway and vascular remodelling characterise chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) could play a role in tissue remodelling and angiogenesis in COPD. Methods: The cellular expression pattern of VEGF, Flt-1, and KDR/Flk-1 was examined by immunohistochemistry in central and peripheral lung tissues obtained from ex-smokers with COPD (forced expiratory volume in 1 second (FEV1) <75% predicted; n = 14) or without COPD (FEV1 >85% predicted; n = 14). The immunohistochemical staining of each molecule was quantified using a visual scoring method with grades ranging from 0 (no) to 3 (intense). Results: VEGF, Flt-1, and KDR/Flk-1 immunostaining was localised in vascular and airway smooth muscle (VSM and ASM) cells, bronchial, bronchiolar and alveolar epithelium, and macrophages. Pulmonary endothelial cells expressed Flt-1 and KDR/Flk-1 abundantly but not VEGF. Bronchial VEGF expression was higher in microvascular VSM cells and ASM cells of patients with COPD than in patients without COPD (1.7 and 1.6-fold, p<0.01, respectively). VEGF expression in intimal and medial VSM (1.7 and 1.3-fold, p<0.05) of peripheral pulmonary arteries associated with the bronchiolar airways was more intense in COPD, as was VEGF expression in the small pulmonary vessels in the alveolar region (1.5 and 1.7-fold, p<0.02). In patients with COPD, KDR/Flk-1 expression was enhanced in endothelial cells and in intimal and medial VSM (1.3, 1.9 and 1.5-fold, p<0.02) while endothelial Flt-1 expression was 1.7 times higher (p<0.03). VEGF expression was significantly increased in bronchiolar and alveolar epithelium as well as in bronchiolar macrophages (1.5-fold, p<0.001). The expression of VEGF in bronchial VSM and mucosal microvessels as well as bronchiolar epithelium was inversely correlated with FEV1 (r<−0.45; p<0.01). Conclusions: VEGF and its receptors Flt-1 and KDR/Flk-1 may be involved in peripheral vascular and airway remodelling processes in an autocrine and/or paracrine manner. This system may also be associated with epithelial cell viability during airway wall remodelling in COPD.

Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study

We evaluated the effect of QVA149, a dual bronchodilator combining indacaterol and glycopyrronium, on direct patient-reported dyspnoea in patients with moderate-to-severe chronic obstructive pulmonary disease. In this multicentre, blinded, double-dummy, three-period crossover study, 247 patients were randomised to once-daily QVA149 110/50 μg, placebo or tiotropium 18 μg. Superiority of QVA149 versus placebo (primary objective) and tiotropium (secondary objective) was assessed for improvement in dyspnoea via the self-administered computerised (SAC) version of the Baseline and Transition Dyspnoea Index after 6 weeks. Secondary end-points included lung function, rescue medication use and safety. After 6 weeks, the SAC Transition Dyspnoea Index total score was significantly higher with QVA149 versus placebo (least squares mean (LSM) treatment difference 1.37, p<0.001) and tiotropium (LSM treatment difference 0.49, p=0.021). QVA149 provided significant improvements in lung function, with higher forced expiratory volume in 1 s area under the curve from 0–4 h post-dose versus placebo and tiotropium at day 1 and week 6 (all p<0.001). Rescue medication use was significantly lower with QVA149 versus placebo (p<0.001) and tiotropium (p=0.002). All treatments were well tolerated. Once-daily QVA149 provided superior improvements in patient-reported dyspnoea and lung function versus placebo and tiotropium. These benefits were associated with improvements in other symptoms and reduced use of rescue medication. Two different bronchodilators in a single inhaler were effective in relieving patient-reported dyspnoea in COPD http://ow.ly/qjIpe

Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: The ENLIGHTEN study

BACKGROUND QVA149 is an inhaled, once-daily fixed-dose dual bronchodilator combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium (NVA237) for the treatment of chronic obstructive pulmonary disease (COPD). We investigated the safety and efficacy of QVA149 over 52 weeks. METHODS This 52-week, multicenter, double-blind, parallel-group, placebo-controlled study randomized (2:1) patients with moderate-to-severe COPD to once-daily QVA149 (110 μg indacaterol/50 μg glycopyrronium) or placebo delivered via the Breezhaler device. Primary endpoint was safety and tolerability for treatment-emergent adverse events (AEs). Secondary endpoints included safety based on vital signs, electrocardiograms (ECGs), laboratory evaluations, and pre-dose forced expiratory volume in 1 s (FEV1). RESULTS Of 339 patients randomized, QVA149 [n = 226], placebo [n = 113]; 76.9% male, mean age: 62.6 years, post-bronchodilator FEV1: 57.4% predicted, 83.5% completed study. A smaller percentage of patients discontinued in the QVA149 group (14.2%) compared with placebo (21.2%). Overall incidence of AEs was similar in the QVA149 (57.8%) and placebo (56.6%) groups, with most AEs being mild to moderate in severity. The numerical differences in some AEs observed could be at least in part explained by differences in baseline patient characteristics. No clinically relevant differences were observed between treatment groups for vital signs or ECG parameters. The five deaths reported were unrelated to study medication (QVA149, n = 4 [1.8%]; placebo, n = 1 [0.9%]). QVA149 demonstrated rapid and clinically meaningful bronchodilation sustained over 52 weeks versus placebo. CONCLUSION QVA149 demonstrated a good safety and tolerability profile, providing rapid and sustained bronchodilation over 52 weeks in patients with moderate-to-severe COPD. ClinicalTrials.gov identifier: NCT01120717.

Angiogenesis and Vascular Remodeling in Chronic Airway Diseases

AbstractAsthma and chronic obstructive pulmonary disease remain a global health problem, with increasing morbidity and mortality. Despite differences in the causal agents, both diseases exhibit various degrees of inflammatory changes, structural alterations of the airways leading to airflow limitation. The existence of transient disease phenotypes which overlap both diseases and which progressively decline the lung function has complicated the search for an effective therapy. Important characteristics of chronic airway diseases include airway and vascular remodeling, of which the molecular mechanisms are complex and poorly understood. Recently, we and others have shown that airway smooth muscle (ASM) cells are not only structural and contractile components of airways, rather they bear capabilities of producing large number of pro-inflammatory and mitogenic factors. Increase in size and number of blood vessels both inside and outside the smooth muscle layer as well as hyperemia of bronchial vasculature are contributing factors in airway wall remodeling in patients with chronic airway diseases, proposing for the ongoing mechanisms like angiogenesis and vascular dilatation. We believe that vascular changes directly add to the airway narrowing and hyper-responsiveness by exudation and transudation of proinflammatory mediators, cytokines and growth factors; facilitating trafficking of inflammatory cells; causing oedema of the airway wall and promoting ASM accumulation. One of the key regulators of angiogenesis, vascular endothelial growth factor in concerted action with other endothelial mitogens play pivotal role in regulating bronchial angiogenesis. In this review article we address recent advances in pulmonary angiogenesis and remodelling that contribute in the pathogenesis of chronic airway diseases.

A novel model-based approach for dose determination of glycopyrronium bromide in COPD

BackgroundGlycopyrronium bromide (NVA237) is an inhaled long-acting muscarinic antagonist in development for treatment of COPD. This study compared the efficacy and safety of once-daily (OD) and twice-daily (BID) glycopyrronium bromide regimens, using a novel model-based approach, in patients with moderate-to-severe COPD.MethodsDouble-blind, randomized, dose-finding trial with an eight-treatment, two-period, balanced incomplete block design. Patients (smoking history ≥10 pack-years, post-bronchodilator FEV1 ≥30% and <80% predicted, FEV1/FVC <0.7) were randomized to one of 16 independent sequences for 28 days. Primary endpoint: mean trough FEV1 at Day 28.Results385 patients (mean age 61.2 years; mean post-bronchodilator FEV1 53% predicted) were randomized; 88.6% completed. All OD and BID dosing regimens produced dose-dependent bronchodilation; at Day 28, increases in mean trough FEV1 versus placebo were statistically significant for all regimens, ranging from 51 mL (glycopyrronium bromide 12.5 μg OD) to 160 mL (glycopyrronium bromide 50 μg BID). Pharmacodynamic steady-state was reached by Day 7. There was a small separation (≤37 mL) between BID and OD dose–response curves for mean trough FEV1 at steady-state in favour of BID dosing. Over 24 hours, separation between OD and BID regimens was even smaller (FEV1 AUC0-24h maximum difference for equivalent daily dose regimens: 8 mL). Dose–response results for FEV1 at 12 hours, FEV1 AUC0-12h and FEV1 AUC0-4h at steady-state showed OD regimens provided greater improvement over placebo than BID regimens for total daily doses of 25 μg, 50 μg and 100 μg, while the reverse was true for OD versus BID regimens from 12–24 hours. The 12.5 μg BID dose produced a marginally higher improvement in trough FEV1 versus placebo than 50 μg OD, however, the response at 12 hours over placebo was suboptimal (74 mL). Glycopyrronium bromide was safe and well tolerated at all doses.ConclusionsGlycopyrronium bromide 50 μg OD provides significant bronchodilation over a 24 hour period, and in terms of FEV1 AUC0-24h is not significantly different than the same total daily dose administered BID. Importantly, OD dosing may confer better patient adherence. The results are consistent with previous glycopyrronium bromide studies and support once-daily dosing of glycopyrronium bromide 50 μg in patients with moderate-to-severe COPD.Trial registrationClinicalTrials.gov: NCT01119950

Safety of formoterol in adults and children with asthma: a meta-analysis

BACKGROUND The safety of long-acting β2 agonists (LABA) for the treatment of persistent asthma remains a topic of ongoing debate. OBJECTIVE To evaluate the risk of serious asthma-related events among patients treated with formoterol, a meta-analysis of all Novartis-sponsored controlled clinical trials was conducted. METHODS Forty-five randomized, placebo- and active-controlled, parallel-group or crossover studies with formoterol were included. Background inhaled corticosteroid (ICS) use was permitted in all studies; however, in only 2 studies was ICS randomized as study medication. Sub-analyses of the pooled data were performed according to age (5-12; 13-18; >18 years), baseline ICS use, and lung function. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated between formoterol (twice-daily), albuterol (salbutamol) 4 times per day (active control), and placebo. RESULTS Patients were randomized to formoterol (n = 5,367), placebo (n = 2,026), and albuterol (n = 976). Two deaths were reported, 1 each in the formoterol (asthma exacerbation) and the placebo (hemorrhagic pancreatitis) groups. No statistically significant differences in serious asthma exacerbations were observed compared with placebo in adolescents and adults. In children, a higher frequency of hospitalizations was observed among patients treated with formoterol compared with placebo (OR 8.4; 95% CI: 1.1-65.3). A trend toward fewer exacerbations was observed among subjects reporting concomitant ICS use at baseline. CONCLUSIONS This analysis supports current guideline recommendations for the use of LABAs only as add-on therapy to ICS.

P253 NVA237 once daily offers rapid and clinically meaningful bronchodilation in COPD patients that is maintained for 24 h: the GLOW1 trial

Introduction NVA237 (glycopyrronium bromide) is an inhaled long-acting muscarinic antagonist (LAMA) in development for the once-daily (qd) treatment of COPD. The GLOW1 study evaluated the efficacy and safety of NVA237 in patients with moderate-to-severe COPD. Methods Patients were randomised (2:1) to 26 weeks double-blind treatment with NVA237 50 μg qd or placebo (PBO). Study drugs were administered via a single-dose dry powder inhaler (Breezhaler® device). Primary efficacy endpoint: trough FEV1 (mean of 23 h 15 min and 23 h 45 min post-dose values) vs PBO after 12 weeks. Results 822 patients were randomised; mean age was 63.9 years, mean post-bronchodilator FEV1 was 55% predicted. 80.5% completed the study. At Week 12 there was a statistically significant and clinically relevant difference between NVA237 vs PBO in mean trough FEV1 (108 ml; p<0.001). Trough FEV1 was also significantly higher at Day 1 and Week 26 (treatment difference: 105 ml and 113 ml, respectively; p<0.001). Serial spirometry in a subpopulation of patients showed statistically superior (p<0.001) and clinically meaningful improvements in FEV1 with NVA237 vs PBO at all timepoints on Day 1, Week 12 and Week 26. NVA237 had a rapid onset of action with an increased FEV1 of 93 ml at 5 min and 144 ml at 15 min vs PBO after the first dose on Day 1 (p<0.001). Overall, the incidence of adverse events (AEs) was similar between treatment groups (NVA237: 57.5%; PBO: 65.2%). Serious AEs were reported by 7.5% of NVA237- vs 9.0% of PBO-treated patients. Conclusion NVA237 50 μg once daily was generally safe and well tolerated. Improvements in bronchodilation were rapid, clinically meaningful and maintained for 24 h throughout the study.

P190 QVA149 Once Daily Provides Significant Improvements in Lung Function Over 1 Year in Patients with COPD: The Enlighten Study

Introduction QVA149 is a novel inhaled once-daily dual bronchodilator, containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist NVA237 (glycopyrronium) in development for the treatment of COPD. This study evaluated the long-term effect of QVA149 on lung function in patients with COPD. Methods This was a multicentre, double-blind, parallel group, placebo-controlled study in which patients with moderate-to-severe COPD were randomised (2:1) to receive QVA149 (110/50µg) or placebo once daily via the Breezhaler® device for 52 weeks. Treatment was taken in the morning at the same time of day. Lung function was measured as forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) at 30 and 60 minutes post-dose at clinic visits over 52 weeks. Results 339 patients (77% male, mean age 63 years; mean post-salbutamol FEV1 57% predicted, FEV1/FVC 54%) were randomised to receive QVA149 (n=226) or placebo (n=113); 86% and 79% of patients respectively completed treatment, respectively. QVA149 significantly increased FEV1 and FVC versus placebo at all assessment points (table). Abstract P190 Table 1 QVA149 versus placebo least squares mean (LSM) differences in FEV1 and FVC QVA149-placebo LSM treatment difference (SE) in mL Visit FEV1 FVC 30 min post-dose 60 min post-dose 30 min post-dose 60 min post-dose Day 1 156 (14.2) 200 (16.9) 221 (29.7) 255 (35.8) Week 3 255 (24.8) 275 (25.1) 342 (43.3) 335 (44.7) Week 6 266 (26.2) 275 (27.2) 341 (47.3) 342 (46.5) Week 12 236 (25.4) 260 (26.7) 277 (43.2) 294 (44.1) Week 26 265 (31.5) 270 (29.6) 345 (49.7) 331 (48.1) Week 39 240 (32.4) 286 (32.7) 296 (51.0) 340 (51.7) Week 52 247 (33.3) 255 (33.6) 289 (52.9) 317 (56.9) all p<0.001 Conclusion QVA149 once daily provided rapid and clinically meaningful bronchodilation compared with placebo. No tachyphylaxis was observed and the bronchodilator effect was sustained over the 52 week treatment period. Ronal Dahl: he participated in advisory boards for Novartis, AstraZeneca, Boehringer-Ingelheim, Pfizer, ALK-Abello, UCB, Nycomed, Dainippon and ONO. Kenneth R Chapman: he holds the GSK-CIHR Research Chair in Respiratory Healthcare Delivery at the University Health Network, has served as a consultant to CSL Behring, GlaxoSmithKline, Novartis, Nycomed (Takeda), and Talecris (Grifols), and has received payment for lectures or service on speakers bureaus from Boehringer-Ingelheim, GlaxoSmithKline, Grifols, Nycomed (Takeda), Family Physicians Airways Group of Canada, Canadian Network for Respiratory Care, and Talecris. Michael Rudolf: he has been reimbursed by the following companies for speaking at educational meetings, for consultancy work, or for attending scientific conferences: Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck Sharp and Dohme, Napp, Novartis, Pfizer, Schering-Plough, and Teva. Rajendra Mehta: he has no conflicts of interest.