Glycopyrronium bromide is a novel, once-daily long-acting inhaled anticholinergic bronchodilator (a long-acting muscarinic antagonist) licensed for maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). This new bronchodilator has been compared against placebo and in a clinical trial against tiotropium, one of its reference comparators together with formoterol and salmeterol.
COPD is a respiratory disease characterised by airflow limitation that is not fully reversible, tends to be progressive and is associated with an abnormal inflammatory response in the lungs to noxious particles or gases, primarily caused by cigarette smoking. COPD is characterised by the presence of exacerbations and is associated with various comorbidities that may aggravate the process. It appears mainly with dyspnoea, cough and sputum production. The use of inhaled bronchodilators (long-acting beta-adrenoceptor agonists or long-acting muscarinic antagonists), such as formoterol, salmeterol or tiotropium, is the first step towards the treatment of this disease and constitutes the mainstream for symptomatic treatment of patients with COPD and permanent symptoms.
The main objective of this report is to evaluate the efficacy and safety of glycopyrronium bromide in the treatment of COPD as compared to formoterol, salmeterol and tiotropium. Secondary objectives include the rating of the added therapeutic value of glycopyrronium bromide in the treatment of COPD, and to determine its place in the therapy of this disease.
Evaluation methodology has been carried out according to the Standard Operating Procedure of the Joint Committee of Evaluation of New Drugs (Comité Mixto de Evaluación de Nuevos Medicamentos).
Glycopyrronium bromide has been evaluated in four clinical trials for the treatment of COPD: GLOW1 and GLOW2 (pivotal studies), GLOW3 and GLOW5, of 26, 52, 3 and 12 weeks treatment, respectively. The first three studies were comparative trials against placebo, and GLOW5 (a blinded and non-inferiority trial) is the only direct comparative clinical trial available against one of its reference comparators, tiotropium. In GLOW2 trial, Glycopyrronium is also compared against tiotropium, but indirectly, through the inclusion of an open-label tiotropium arm. The primary efficacy variable was, both for pivotal studies and GLOW5, trough FEV1, an adequate lung function measurement. Secondary variables measured, amongst others, dyspnoea index, health status and time to exacerbations of COPD.
In GLOW5 trial comparing efficacy and safety of glycopyrronium (50mcg once daily) against tiotropium (18 mcg once daily), glycopyrronium was shown to be non-inferior to tiotropium, achieving mean changes from baseline in trough FEV1 of 103 mL for glycopyrronium and 99mL for tiotropium, although it did not achieve clinical relevance (established in 100 mL for NICE and 120 mL for most other authors). Superiority of glycopyrronium over tiotropium was, however, not demonstrated since no statistical significance was achieved. Although glycopyrronium was shown to be significantly more efficient than placebo in trough FEV1 over 12 weeks treatment in GLOW1 and GLOW2 comparative studies against placebo, it did not manage to achieve clinical relevance (108mL in GLOW1, and 97 mL with glycopyrronium and 83 mL with tiotropium in GLOW2).
Current data available comparing the safety of glycopyrronium against tiotropium are not conclusive since the duration of the only direct comparator clinical trial available is short (12 weeks), thus, hampering long-term safety evaluation. The overall incidence of adverse reactions and the safety profile are similar for both drugs and the incidence of anticholinergic adverse reactions associated to glycopyrronium is low. The most frequently reported adverse events associated to the use of glycopyrronium were rhinopharyngitis, insomnia, headache, dry mouth, gastroenteritis and bacterial upper respiratory tract infections. Safety cardiovascular profile of glycopyrronium is unknown since patients with cardiovascular risk factors were excluded from the studies. In this regard, the European Medicines Agency, in view of the potential risk of adverse cardiovascular outcomes, recommended a post-authorisation safety study to monitor cardiovascular adverse events post-marketing. Outcomes from this study are yet unknown.
Unlike formoterol and salmeterol, glycopyrronium bromide is administered once daily, at the same time each day. The cost of glycopyrronium is higher to that of salmeterol and formoterol, and slightly lower to that of tiotropium. Glycopyrronium bromide was shown to be non-inferior to one of its active comparators, tiotropium, in the only direct comparator clinical trial available, but not superior. The safety of glycopyrronium may be considered inconclusive due to the limited length of this trial (12 weeks), its condition of chronic disease and the unknown cardiovascular safety profile. In view of the above, glycopyrronium bromide “means no therapeutic innovation” in the treatment of COPD.