ANORO ELLIPTA 55MCG/22MCG Metered dose powder for inhalation

Pharmacotherapeutic group: Drugs for obstructive airway diseases, sympathomimetics in combination with anticholinergics, including triple combinations with corticosteroids.​​​‍​​‍​​​​‍​​‍‍ ATC code: R03AL03 Mechanism of action The combination of umeclidinium and vilanterol is a combination of an inhaled long-acting muscarinic antagonist (LAMA) and a long-acting beta2-adrenergic agonist (LABA). Following oral inhalation, both components act locally on the airways and produce bronchodilation via distinct mechanisms. Umeclidinium Umeclidinium is a long-acting muscarinic antagonist (also referred to as an anticholinergic). It is a quinuclidine derivative with activity across multiple muscarinic cholinergic receptor subtypes. Umeclidinium exerts its bronchodilatory activity through competitive inhibition of acetylcholine binding to muscarinic receptors in airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and prolonged duration of action in vivo when administered directly to the lungs in preclinical models. Vilanterol Vilanterol is a selective long-acting beta2-adrenergic receptor agonist (LABA). The pharmacological effects of beta2-adrenergic receptor agonists, including vilanterol, are at least partly attributable to stimulation of intracellular adenylyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cAMP). Increased cAMP levels lead to relaxation of bronchiolar smooth muscle and inhibition of the release of immediate hypersensitivity mediators from cells, particularly from mast cells. Pharmacodynamic effects In six-month Phase III studies, the umeclidinium/vilanterol combination demonstrated clinically meaningful improvements over placebo in lung function (measured by forced expiratory volume in 1 second, FEV1) over 24 hours following once-daily administration, which were apparent within 15 minutes of the first dose [improvement versus placebo of 112 ml (p< 0.001)]. The mean peak improvement in FEV1 over the first 6 hours post-dose versus placebo at Week 24 was 224 ml (p< 0.001*). No tachyphylaxis to the effect of ANORO ELLIPTA was observed over the course of treatment. Cardiac electrophysiology The effects of the umeclidinium/vilanterol combination on the QT interval were evaluated in a placebo- and active-comparator (moxifloxacin)-controlled QT study with metered doses of umeclidinium/vilanterol 113/22 micrograms or 500/100 micrograms (a metered dose with umeclidinium at eight times the recommended dose and vilanterol at four times the recommended dose) once daily for 10 days in 103 healthy volunteers. The maximum mean difference in QT interval prolongation (corrected using Fridericia's method, QTcF) versus placebo after baseline correction was 4.3 milliseconds (90% CI = 2.2 to 6.4) recorded 10 minutes after administration of umeclidinium/vilanterol at the 113/22 microgram dose and 8.2 milliseconds (90% CI = 6.2 to 10.2) recorded 30 minutes after administration of umeclidinium/vilanterol at the 500/100 microgram dose. Therefore, no clinically relevant proarrhythmogenic effects with respect to QT interval prolongation were observed with umeclidinium/vilanterol at the 113/22 microgram dose. A dose-dependent increase in heart rate was also observed. The maximum mean difference in heart rate versus placebo after baseline correction was 8.4 beats/minute (90% CI = 7.0 to 9.8) recorded 10 minutes after administration of the metered dose of umeclidinium/vilanterol 113/22 micrograms and 20.3 beats/minute (90% CI = 18.9 to 21.7) observed 10 minutes after administration of the metered dose of umeclidinium/vilanterol 500/100 micrograms. During 24-hour Holter monitoring in 53 COPD patients treated for up to 6 months who received umeclidinium/vilanterol 55/22 micrograms once daily, or an additional 55 patients who received umeclidinium/vilanterol 113/22 micrograms once daily in another six-month study, and a further 226 patients treated with 113/22 micrograms once daily in a twelve-month study, no additional clinically significant effects on cardiac rhythm were observed. Clinical efficacy and safety The clinical efficacy of once-daily umeclidinium/vilanterol was evaluated in eight Phase III clinical studies in 6,835 adult patients with a clinical diagnosis of COPD; 5,618 patients were in five 6-month clinical efficacy studies [two placebo-controlled and three active-comparator (tiotropium)-controlled], 655 patients were in two 12-week exercise testing/lung function studies, and 562 patients were in a 12-month supportive study. Effects on lung function ANORO ELLIPTA demonstrated clinically meaningful improvements in lung function (defined as change in trough FEV1 from baseline) in several studies. In one six-month Phase III clinical study, ANORO ELLIPTA demonstrated statistically significant improvements in trough FEV1 (primary endpoint) at Week 24 compared with placebo and each monocomponent treatment arm. In addition, ANORO ELLIPTA demonstrated clinically meaningful and statistically significant improvements in trough FEV1 compared with tiotropium as an active comparator in two of three six-month studies and showed numerically greater improvements over tiotropium in the third active-comparator study (see Table 1). No attenuation of the bronchodilatory effect was observed over the course of treatment. Symptomatic outcomes A step-down statistical testing procedure was used in this study and this comparison fell below a comparison that did not achieve statistical significance. Therefore, statistical significance cannot be inferred for this comparison. Dyspnoea: ANORO ELLIPTA demonstrated statistically and clinically significant reductions in dyspnoea, as assessed by increases in the Transition Dyspnoea Index (TDI) focal score at Week 24 (key secondary endpoint) compared with placebo (see Table 1). Improvements in TDI score compared with each monotherapy component and tiotropium were not statistically significant (see Table 1). The proportion of patients responding with at least the minimum clinically important difference (MCID) of 1 unit in TDI focal score at Week 24 was higher for ANORO ELLIPTA (58%) compared with placebo (41%) and the individual monotherapy components (53% for umeclidinium and 51% for vilanterol). Health-related quality of life: ANORO ELLIPTA also demonstrated improvements in health-related quality of life assessed using the St. George's Respiratory Questionnaire (SGRQ), as reflected by reductions in SGRQ total score at Week 24 compared with placebo and the individual monotherapy components (see Table 1). ANORO ELLIPTA demonstrated statistically significant reductions in SGRQ total score compared with tiotropium in one of three active-comparator studies (see Table 1). The proportion of patients responding with at least an MCID in SGRQ score (defined as a decrease of 4 units from baseline) at Week 24 was higher for ANORO ELLIPTA (49%) compared with placebo (34%) and the individual monotherapy components (44% for umeclidinium and 48% for vilanterol). In one active-comparator study, a higher percentage of patients receiving ANORO ELLIPTA demonstrated clinically meaningful improvement in SGRQ score at Week 24 (53%) compared with tiotropium (46%). In the other two active-comparator studies, the proportion of patients achieving at least an MCID with ANORO ELLIPTA and tiotropium was similar; 49% and 54% for ANORO ELLIPTA 55/22 micrograms and 52% and 55% for tiotropium. Rescue medication use ANORO ELLIPTA compared with placebo and umeclidinium reduced rescue salbutamol use over Weeks 1–24 (see Table 1) and demonstrated an increase in the number of rescue-free days from baseline (mean 11.1%) compared with placebo (mean 0.9%). In three 6-month active-comparator studies, ANORO ELLIPTA reduced rescue salbutamol use compared with tiotropium, with statistically significant reductions observed in two studies (see Table 1). In the three studies, ANORO ELLIPTA also demonstrated an increase in the number of rescue-free days from baseline (mean range 17.6% to 21.5%) compared with tiotropium (mean range 11.7% to 13.4%). Table 1: Lung function, symptom and health-related quality outcomes at Week 24 Treatment comparisons with ANORO ELLIPTA 55/22 µg Treatment differences1 (95% confidence interval, p-value) FEV1 (ml) TDI focal score SGRQ total score Rescue medication use3 ANORO ELLIPTA (N = 413) versus placebo (N = 280) 167 (128; 207) < 0.001 1.2 (0.7; 1.7) < 0.001 -5.51 (-7.88; -3.13) < 0.001 -0.8 (-1.3; -0.3) 0.001* ANORO ELLIPTA (N = 413) versus umeclidinium 55 µg (N = 418) 52 (17; 87) 0.004 0.3 (-0.2; 0.7) 0.244 -0.82 (-2.90; 1.27) 0.441 -0.6 (-1.0; -0.1) 0.014* ANORO ELLIPTA (N = 413) versus vilanterol 22 µg (N = 421) 95 (60; 130) < 0.001 0.4 (-0.1; 0.8) 0.117 -0.32 (-2.41; 1.78) 0.767 0.1 (-0.3; 0.5) 0.675 ANORO ELLIPTA (N = 454) versus tiotropium 18 µg (N = 451) (Study ZEP117115) 112 (81; 144) < 0.001 n/a -2.10 (-3.61; -0.59) 0.006 -0.5 (-0.7; -0.2) < 0.001 ANORO ELLIPTA (N = 207) versus tiotropium 18 µg (N = 203) (Study DB2113360) 90 (39; 141) < 0.001 0.12 (-0.4, 0.5) 0.817 0.75 (-2.12; 3.63) 0.607 -0.7 (-1.2; -0.1) 0.022 ANORO ELLIPTA (N = 217) versus tiotropium 18 µg (N = 215) (Study DB2113374) 60 (10, 109) 0.018* -0.17 (-2.85; 2.52) 0.904 -0.6 (-1.2; 0.0) 0.069 N = number of subjects included in each group µg = micrograms n/a = not assessed Least squares mean Pooled data from Study DB2113360 and Study DB2113374 Difference in mean number of puffs per day over Weeks 1–24 The higher umeclidinium/vilanterol dose (113/22 micrograms) was also investigated in a 24-week placebo-controlled clinical study and in two of three 24-week active-controlled studies. These results were comparable to those obtained with the ANORO ELLIPTA dose and provided additional supportive evidence of the efficacy of ANORO ELLIPTA. A step-down statistical testing procedure was used in this study and this comparison fell below a comparison that did not achieve statistical significance. Therefore, statistical significance cannot be inferred for this comparison. COPD exacerbations ANORO ELLIPTA reduced the risk of moderate/severe COPD exacerbations by 50% compared with placebo in a 24-week placebo-controlled study in patients with symptomatic COPD [based on time-to-first exacerbation analysis: hazard ratio (HR) 0.5; 95% CI: 0.3, 0.8; p = 0.004*]; by 20% compared with umeclidinium (HR 0.8; 95% CI: 0.5, 1.3; p = 0.391); and by 30% compared with vilanterol (HR 0.7; 95% CI: 0.4, 1.1; p = 0.121). In three active-comparator studies in patients with symptomatic COPD, the risk of moderate/severe COPD exacerbations was reduced by 50% compared with tiotropium in one study (HR 0.5; 95% CI: 0.3, 1.0; p = 0.044). In the other two studies, the risk of moderate/severe COPD exacerbations was increased by 20% and by 90% (HR 1.2; 95% CI: 0.5, 2.6; p = 0.709 and HR 1.9; 95% CI: 1.0, 3.6; p = 0.062). These studies were not specifically designed to evaluate the effect of treatment on COPD exacerbations, and patients were withdrawn from the study if an exacerbation occurred. Supportive efficacy studies In a randomised, double-blind, 52-week study (CTT116855, IMPACT), 10,355 adult patients with symptomatic COPD and a history of 1 or more moderate/severe exacerbations in the preceding 12 months were randomised (1:2:2) to receive umeclidinium/vilanterol (UMEC/VI 55/22 micrograms), fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI 92/55/22 micrograms), or fluticasone furoate/vilanterol (FF/VI 92/22 micrograms) once daily in a single inhaler. The primary endpoint was the annual rate of moderate and severe exacerbations in subjects treated with FF/UMEC/VI compared with those treated with FF/VI and UMEC/VI. The mean annual exacerbation rate was 0.91 for FF/UMEC/VI, 1.07 for FF/VI, and 1.21 for UMEC/VI. Comparison of FF/UMEC/VI with FF/VI and UMEC/VI showed a statistically significant 14.8% reduction in the risk of moderate/severe exacerbations (based on time-to-first exacerbation analysis) (hazard ratio 0.85; 95% CI: 0.80, 0.91; p < 0.001) and a 16.0% reduction in the risk of moderate/severe exacerbations (based on time-to-first exacerbation analysis) (hazard ratio 0.84; 95% CI: 0.78, 0.91; p < 0.001), respectively. Exercise tests and lung volumes ANORO ELLIPTA 55/22 micrograms improved exercise endurance time compared with placebo, as assessed by the Endurance Shuttle Walk Test (ESWT) in one study but not in the other, and improved lung volumes measured compared with placebo in both studies in adult COPD patients with hyperinflation [functional residual capacity (FRC) > 120%]. In the first study, treatment with ANORO ELLIPTA 55/22 micrograms once daily demonstrated a statistically significant improvement [based on the minimum clinically important difference (MCID) of 45 to 85 seconds] over placebo in Exercise Endurance Time (EET) recorded 3 hours post-dose at Week 12 (69.4 seconds [p = 0.003]). Improvement in EET compared with placebo was observed on Day 2 and persisted through Weeks 6 and 12. In the second study, the treatment difference in EET for ANORO ELLIPTA 55/22 micrograms compared with placebo was 21.9 seconds (p = 0.234) at Week 12. ANORO ELLIPTA 55/22 micrograms also demonstrated statistically significant improvements compared with placebo in change from baseline in lung volumes measured pre-dose and 3 hours post-dose at Week 12 in the first study (inspiratory capacity: 237 ml to 316 ml, residual volume: -466 ml to -643 ml, and functional residual capacity: -351 ml to -522 ml, all p < 0.001). In the second study, ANORO ELLIPTA 55/22 micrograms showed improvements in lung volumes compared with placebo in the change from baseline pre-dose and 3 hours post-dose at Week 12 [inspiratory capacity: 198 ml to 238 ml, residual volume: -295 ml to -351 ml, and functional residual capacity: -238 ml to -302 ml; all p < 0.001]. A step-down statistical testing procedure was used in this study and this comparison fell below a comparison that did not achieve statistical significance. Therefore, statistical significance cannot be inferred for this comparison. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with ANORO ELLIPTA in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use).