Bretaris Genuair

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combination with anticholinergics, ATC code: R03AL05 Mechanism of action Duaklir Genuair contains two bronchodilators: aclidinium is a long-acting muscarinic antagonist (also known as an anticholinergic) and formoterol is a long-acting β 2 -adrenergic agonist.​‍​​​​​‍​‍‍‍‍​‍‍ The combination of these substances with different mechanisms of action results in additive efficacy compared to that achieved with either component alone. As a consequence of the differential density of muscarinic receptors and β 2 -adrenoceptors in the central and peripheral airways of the lung, muscarinic antagonists should be more effective in relaxing central airways and β 2 -adrenergic agonists should be more effective in relaxing peripheral airways; relaxation of both central and peripheral airways with combination treatment may contribute to its beneficial effects on lung function. Further information regarding these two substances is provided below. Aclidinium is a competitive, selective muscarinic receptor antagonist, with a longer residence time at the M 3 receptors than the M 2 receptors. M 3 receptors mediate contraction of airway smooth muscle. Inhaled aclidinium bromide acts locally in the lungs to antagonise M 3 receptors of airway smooth muscle and induce bronchodilation. Aclidinium has also been shown to provide benefits to patients with COPD in terms of symptoms reduction, improvement in disease-specific health status, reduction in exacerbation rates and improvements in exercise tolerance. Since aclidinium bromide is quickly broken down in plasma, the level of systemic anticholinergic undesirable effects is low. Formoterol is a potent selective β 2 -adrenoceptor agonist. Bronchodilation is induced by causing direct relaxation of airway smooth muscle as a consequence of the increase in cyclic AMP through activation of adenylate cyclase. In addition to improving pulmonary function, formoterol has been shown to improve symptoms and quality of life in patients with COPD. Pharmacodynamic effects Clinical efficacy studies showed that Duaklir Genuair provides clinically meaningful improvements in lung function (as measured by the forced expiratory volume in 1 second [FEV 1 ]) over 12 hours following administration. Duaklir Genuair demonstrated a rapid onset of action within 5 minutes of the first inhalation relative to placebo (p<0.0001). The onset of action of Duaklir Genuair was comparable to the effect of the fast-acting β 2 -agonist formoterol 12 micrograms. Maximal bronchodilator effects (peak FEV 1 ) relative to baseline were evident from day one (304 ml) and were maintained over the 6-month treatment period (326 ml). Cardiac electrophysiology No clinically relevant effects of Duaklir Genuair on ECG parameters (including QT-interval) compared with aclidinium, formoterol and placebo were seen in Phase III studies of 6 to 12 months duration conducted in approximately 4,000 patients with COPD. No clinically significant effects of Duaklir Genuair on cardiac rhythm were observed on 24-hour Holter monitoring in a subset of 551 patients, of whom 114 received Duaklir Genuair twice daily. Clinical Efficacy and Safety The Phase III clinical development programme included approximately 4,000 patients with a clinical diagnosis of COPD and comprised two 6-month randomised, placebo- and active-controlled studies (ACLIFORM-COPD and AUGMENT), a 6-month extension of the AUGMENT study and a further 12-month randomised controlled study. During these studies, patients were permitted to continue their stable treatment with inhaled corticosteroids, low doses of oral corticosteroids, oxygen therapy (if less than 15h/day) or methylxanthines and to use salbutamol as rescue medication. Efficacy was assessed by measures of lung function, symptomatic outcomes, disease-specific health status, rescue medication use, and exacerbations. In long-term safety studies, Duaklir Genuair was associated with sustained efficacy when administered over a one-year treatment period with no evidence of tachyphylaxis. Effects on lung function Duaklir Genuair 340/12 micrograms twice daily consistently provided clinically meaningful improvements in lung function (as assessed by FEV 1 , forced vital capacity and inspiratory capacity) compared with placebo. In Phase III studies, clinically meaningful bronchodilator effects were seen within 5 minutes of the first dose and were maintained over the dosing interval. There was a sustained effect over time in the six-months and one-year Phase III studies. FEV 1 at 1 hour post-dose and trough FEV 1 (compared to aclidinium 400 micrograms and formoterol 12 micrograms, respectively) were defined as co-primary endpoints in both 6-month pivotal Phase III studies to demonstrate the bronchodilator contributions of formoterol and aclidinium in Duaklir Genuair, respectively. In study ACLIFORM-COPD, Duaklir Genuair showed improvements in FEV 1 at 1 hour post-dose relative to placebo and aclidinium of 299 ml and 125 ml, respectively (both p<0.0001) and improvements in trough FEV 1 relative to placebo and formoterol of 143 ml and 85 ml, respectively (both p<0.0001). In study AUGMENT, Duaklir Genuair showed improvements in FEV 1 at 1 hour post-dose relative to placebo and aclidinium of 284 ml and 108 ml (both p<0.0001), respectively, and improvements in trough FEV 1 relative to placebo and formoterol of 130 ml (p<0.0001) and 45 ml (p=0.01), respectively. Symptom relief and disease-specific health status benefits Breathlessness and other symptomatic outcomes : Duaklir Genuair provided a clinically meaningful improvement in breathlessness (assessed by the Transition Dyspnoea Index [TDI]) with an improvement in the TDI focal score at 6 months compared to placebo of 1.29 units in study ACLIFORM-COPD (p<0.0001) and 1.44 units in study AUGMENT (p<0.0001). The percentages of patients with clinically meaningful improvements in TDI focal score (defined as an increase of at least 1 unit) were higher with Duaklir Genuair than with placebo in ACLIFORM-COPD (64.8% compared to 45.5%; p<0.001) and AUGMENT (58.1% compared to 36.6%; p<0.0001). The pooled analysis of these two studies showed Duaklir Genuair to be associated with statistically significantly greater improvements in TDI focal score compared to aclidinium (0.4 units, p=0.016) or formoterol (0.5 units, p=0.009). In addition, a higher percentage of patients receiving Duaklir Genuair responded with a clinically meaningful improvement in TDI focal score compared to either aclidinium or formoterol (61.9% compared to 55.7% and 57.0%, respectively; p=0.056 and p=0.100, respectively). Duaklir Genuair improved daily symptoms of COPD such as 'breathlessness', 'chest symptoms', 'cough and sputum' (assessed by E-RS total score) as well as overall night-time symptoms, overall early morning symptoms and symptoms limiting early morning activities compared to placebo, aclidinium and formoterol but the improvements were not always statistically significant. Aclidinium/formoterol did not statistically significantly reduce the average number of night-time awakenings due to COPD compared with placebo or formoterol. Health-related quality of life : Duaklir Genuair provided a clinically meaningful improvement in disease-specific health status (as assessed by the St. George's Respiratory Questionnaire [SGRQ]) in study AUGMENT, with an improvement in the SGRQ total score compared to placebo of -4.35 units (p<0.0001). The percentage of patients in AUGMENT who achieved a clinically meaningful improvement from baseline in SGRQ total score (defined as a decrease of at least 4 units) was higher with Duaklir Genuair than with placebo (58.2% compared to 38.7%, respectively; p<0.001). In study ACLIFORM-COPD, only a small decrease in SGRQ total score compared to placebo was observed due to an unexpectedly large placebo response (p=0.598) and the percentages of patients who achieved clinically meaningful improvements from baseline were 55.3% with Duaklir Genuair and 53.2% with placebo (p=0.669). In the pooled analysis of these two studies, Duaklir Genuair showed greater improvements in SGRQ total score compared to formoterol (-1.7 units; p=0.018) or aclidinium (-0.79 units, p=0.273). In addition, a higher percentage of patients receiving Duaklir Genuair responded with a clinically meaningful improvement in SGRQ total score compared to aclidinium and formoterol (56.6% compared to 53.9% and 52.2%, respectively; p=0.603 and p=0.270, respectively). COPD exacerbation reductions Pooled efficacy analysis of the two 6-month Phase III studies demonstrated a statistically significant reduction of 29% in the rate of moderate or severe exacerbations (requiring treatment with antibiotics or corticosteroids or resulting in hospitalisations) with Duaklir Genuair compared to placebo (rates per patient per year: 0.29 vs. 0.42, respectively; p=0.036). In addition, Duaklir Genuair statistically significantly delayed the time to first moderate or severe exacerbation compared to placebo (hazard ratio=0.70; p=0.027). Use of rescue medication Duaklir Genuair reduced the use of rescue medication over 6 months compared to placebo (by 0.9 puffs per day [p<0.0001]), aclidinium (by 0.4 puffs/day [p<0.001]) and formoterol (by 0.2 puffs/day [p=0.062]). Lung volumes, exercise endurance and physical activity The effect of Duaklir Genuair on lung volumes, exercise endurance and physical activity was investigated in an 8-week parallel, randomised, placebo-controlled clinical study in COPD patients with hyperinflation (functional residual capacity [FRC] >120%). After 4 weeks of treatment Duaklir Genuair implied improvement versus placebo in change from baseline in morning pre-dose (trough) FRC, the primary endpoint, but the difference was not statistically significant (-0.125 L; 95% CI=(-0.259, 0.010); p=0.069*). Duaklir Genuair showed improvements compared to placebo in lung volumes at 2-3h post dose (FRC=-0.366 L [95% CI=-0.515, -0.216; p<0.0001]; residual volume [RV]=-0.465 L [95% CI=-0.648, -0.281; p<0.0001] and inspiratory capacity [IC]= 0.293 L [95% CI=0.208, 0.378; p<0.0001]). Duaklir Genuair also showed improvements in exercise endurance time compared to placebo after 8 weeks of treatment (55 seconds [95% CI=5.6, 104.8; p=0.0292]; baseline value: 456 seconds). After 4 weeks of treatment, Duaklir Genuair improved the number of steps per day compared to placebo (731 steps/day; 95% CI=279, 1181; p=0.0016) and reduced the percentage of inactive patients (<6000 steps per day) [40.8% compared to 54.5%; p<0.0001]. Improvements in the PROactive total score were observed in patients treated with Duaklir Genuair compared with placebo (p=0.0002). A behavioural intervention program was added to both treatment groups for an additional 4 weeks. The number of steps/day in the Duaklir Genuair treatment group was maintained resulting in a treatment effect compared to placebo of 510 steps/day (p=0.1588) and a reduction versus placebo in the percentage of inactive patients (<6000 steps per day) (41.5% compared to 50.4%; p=0.1134). *As the primary endpoint did not achieve statistical significance, all p-values for secondary endpoints are tested at a nominal significance level of 0.05, and no formal statistical inference can be drawn. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Duaklir Genuair in all subsets of the paediatric population in COPD (see section 4.2 for information on paediatric use).