Expert Opinion on Pharmacotherapy
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Once-daily glycopyrronium bromide (Seebri ® Breezhaler ) for the treatment of chronic obstructive pulmonary disease (COPD) Charlotte Suppli Ulrik To cite this article: Charlotte Suppli Ulrik (2015): Once-daily glycopyrronium bromide (Seebri ®
Breezhaler ) for the treatment of chronic obstructive pulmonary disease (COPD), Expert Opinion on Pharmacotherapy, DOI: 10.1517/14656566.2015.1100171 To link to this article: http://dx.doi.org/10.1517/14656566.2015.1100171
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Date: 09 December 2015, At: 18:34
Drug Evaluation
1.
Introduction
2.
Activity profile and safety of
3.
Clinical studies of glycopyrro-
glycopyrronium bromide
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nium bromide 4.
Conclusions
5.
Regulatory affairs
6.
Expert opinion
Once-daily glycopyrronium bromide (Seebri Breezhaler®) for the treatment of chronic obstructive pulmonary disease (COPD) Charlotte Suppli Ulrik Department of Pulmonary Medicine, Hvidovre Hospital, Hvidovre, Denmark
Introduction: Long-acting bronchodilators are the mainstay of pharmacological therapy for patients with chronic obstructive pulmonary disease (COPD). The choice of optimal bronchodilator therapy for COPD is increasingly difficult for clinicians as new treatments are marketed. Areas covered: Inhaled glycopyrronium bromide (Seebri Breezhaler®) is a well-tolerated long-acting anti-muscarinic agent (LAMA) with a fast onset of action. In patients with moderate to severe COPD, glycopyrronium bromide has clinically important effects on level of FEV1, use of relief medication, day-time dyspnea scores, and probably also on health status. Furthermore, glycopyrronium bromide also has beneficial effects on dynamic hyperinflation and, probably by that, exercise tolerance. Glycopyrronium bromide has been shown to reduce the rate of exacerbations in patients with moderate to severe COPD, although as a secondary outcome only. Expert opinion: Once-daily inhaled glycopyrronium bromide has positive impact on important COPD outcomes, comparable to the effects of other marketed LAMAs. Once-daily administration may improve adherence, and glycopyrronium bromide has the potential for a role in the future management of COPD similar to that of other long-acting anti-muscarinic agents, including tiotropium. Studies of glycopyrronium bromide with exacerbation rate as the primary outcome of interest is needed. Keywords: Breezhaler, COPD, glycopyrronium bromide, long-acting bronchodilators, Seebri Expert Opin. Pharmacother. [Early Online]
1.
Introduction
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and poor health worldwide.[1] The goals for the management of COPD include best possible symptom control, better exercise tolerance, reduction in exacerbations, prevention of disease progression and, by that, a reduction in mortality.[1] The Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD strategy document) recommends long-acting bronchodilators as first-line maintenance therapy for patients with symptomatic COPD.[1,2] Furthermore, studies of patients with moderate-to-severe COPD have shown that long-acting bronchodilators have an effect not only on symptom control, but also on severity and rate of exacerbations, quality of life, and exercise capacity.[1,3,4] Long-acting bronchodilators, including antimuscarinic agents and β2-agonists, are, therefore, of key importance for the best possible symptom control in patients with COPD. Long-acting anticholinergic agents may be the most effective class of bronchodilators for COPD.[1,5–7] For more than a decade, the only marketed long-acting antimuscarinic agent (LAMA) was tiotropium, but in the last few years several 10.1517/14656566.2015.1100171 © 2015 Taylor & Francis. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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others have emerged on the market, including aclidinium, glycopyrronium and umeclidinium.[8,9] Of these LAMAs, glycopyrronium has been in use for years, administered as injections or tablets, to diminish secretions and block cardiac vagal reflexes before surgery, but has now been marketed as an inhaled agent for the treatment of COPD. This short review describes the available clinical studies addressing the safety and clinical efficacy of inhaled glycopyrronium bromide, also compared to other marketed LAMAs, in patients with moderate-to-severe COPD.
Box 1. Drug summary
Activity profile and safety of glycopyrronium bromide
Drug name
glycopyrronium bromide
Phase Indication Pharmacology Route of administration Chemical structure
III and IV Maintenance therapy for COPD Antimuscarinic receptor antagonist Inhaled
2.
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2.1
Pharmacodynamic and pharmacokinetic profile
Glycopyrronium bromide (NVA237) is a synthetic quaternary ammonium compound that acts as a competitive antagonist through binding to the muscarinic receptors (MR) in the bronchial smooth muscle leading to an inhibition of acetylcholine-induced bronchoconstriction [10] (FIGURE 1). The chemical name of glycopyrronium is (3(2-cyclopentyl-2-hydroxy-2-phenylacetyloxy)-1,1-dimethylpyrrolidinium bromide (FIGURE 1; Box 1). Glycopyrronium binds to all subtypes of MR (M1 – M5), of which M3R is primarily involved in smooth muscle contraction. Based on the previous studies, the optimal antimuscarinic agent for use in COPD has high affinity for M1 and M3R and low affinity for M2R.[10–12] Glycopyrronium has, like tiotropium, higher selectivity for M3R than for M2R, and dissociates, like tiotropium and aclidinium, faster from M2R than M3R.[12,13] Glycopyrronium, therefore, provides bronchodilatation via M3 blockage long after its less desirable M2 effects, such as an increase in heart rate.[11–14] In vitro studies have shown that glycopyrronium has a faster onset of action than tiotropium, which has been confirmed in clinical studies.[13,15] Glycopyrronium equilibrates much faster with M3R than with both tiotropium and aclidinium,[13,15] which is assumed to underlie the faster onset of action of glycopyrronium compared with tiotropium [13] and probably also aclidinium.
Figure 1. Glycopyrronium bromide.
2
Pivotal trials
Synthetic quaternary ammonium compound, that is, (3-(2-cyclopentyl-2-hydroxy-2-phenylacetyloxy)-1,1-dimethylpyrrolidinium bromide The GLOW studies [31,33,38,41]
2.2
Safety
Findings reported from early studies suggest a favorable safety profile for inhaled glycopyrronium. A study by Sechaud et al. [11] showed that the pharmacokinetics of glycopyrronium after single and repeated once-daily inhalation in patients with mild-to-moderate COPD were consistent between doses and with limited systemic accumulation at steady state after repeated once-daily inhalation. Compared to other antimuscarinic agents, glycopyrronium has a lower oral bioavailability and by that reduced systemic absorption.[16] The overall incidence of adverse events was, apart from the frequency of dry mouth, similar in patients on glycopyrronium and placebo. No serious adverse events were reported, and no clinically relevant effects were observed on vital signs, ECG or physical examinations.[11] Van de Maele et al. [17] reported from a controlled trial of 257 patients with moderate-to-severe COPD randomized to indacaterol plus glycopyrronium, indacaterol or placebo, the change from baseline in 24-h mean heart rate versus placebo. The safety analysis comprised 255 patients, and revealed no clinically significant differences in 24-h mean heart rate or QTc interval, suggesting a cardiovascular safety profile of both long-acting bronchodilators similar to placebo. A possible association between inhaled antimuscarinic agents and risk of major cardiovascular events has been much debated. A meta-analysis of previous studies published in 2008 reported an increased risk of cardiovascular death, myocardial infarction and stroke in COPD patients treated with inhaled LAMAs.[18–21] However, recently published controlled trials have not reported a higher risk of major cardiovascular events in COPD patients treated with the LAMA, tiotropium, irrespective of the inhaler device.[22– 24] However, it is still important to acknowledge that, similar to other clinical trials of antimuscarinic agents in COPD, patients with a number of concomitant diseases, including symptomatic prostatic hyperplasia and narrowangle glaucoma, have not been eligible for the clinical trials of inhaled glycopyrronium.
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Once-daily glycopyrronium bromide (Seebri Breezhaler®) for the treatment of COPD
3.
Clinical studies of glycopyrronium bromide
3.1
Lung function
In one of the first trials of glycopyrronium for COPD, Verkindre et al. [25] enrolled 83 patients with stable moderate-to-severe COPD (mean FEV1 53%predicted). Patients were randomized to glycopyrronium 12.5, 25, 50 or 100 μg, open-label tiotropium 18 μg or placebo once daily for 7 days. The primary end point was mean trough (23–24 h post-dose) FEV1 on day 7. As expected, mean trough FEV1 on day 7 was significantly higher with all active treatments versus placebo (p < 0.05). Furthermore, clinically relevant improvements in trough FEV1 were observed for the glycopyrronium doses of 50 and 100 μg and for tiotropium on day 1 (treatment differences 121, 135 and 112 ml, respectively, p < 0.0001) and day 7 (differences 131, 142 and 127 ml, respectively, p < 0.0001). Although a statistically significant difference in FEV1 was reported in favor of glycopyrronium, no clinically significant differences in improvements in FEV1 were observed between glycopyrronium 50 and 100 μg, and tiotropium. This early study, therefore, revealed that inhaled glycopyrronium once daily provides rapid and sustained 24-h bronchodilatation, and in clinical terms the latter is similar to that of tiotropium. In a similar group of patients with stable COPD (mean FEV1 53% predicted), Vogelmeier et al. [26] studied the bronchodilator efficacy of two doses of glycopyrronium, 100 μg (n = 92) and 200 μg (n = 98) versus placebo (n = 91) for 28 days. The primary objective was safety, but efficacy was included as secondary objectives. Compared with placebo, the treatment difference was 131 and 161 ml, respectively (p < 0.05), for glycopyrronium 100 μg, and 146 and 151 ml, respectively, for glycopyrronium 200 μg (p < 0.05) on days 1 and 28. Further, significant higher values for both doses of glycopyrronium were also observed for peak FEV1, FEV1 at all time-points up to 24 h postdosing, and FEV1 area under the curve (AUC) during 5 min to 5 h post-dosing compared with placebo. Although no active comparator was included, these observations support the bronchodilator efficacy of glycopyrronium in patients with moderate-to-severe COPD. In a small randomized, double-blind, placebo-controlled, two-period, cross-over trial, Fogarty et al. [27] studied the bronchodilator effects of glycopyrronium versus placebo in 33 patients with mild COPD (mean FEV1 70%predicted). Of notice is that only patients with a positive response to inhaled ipratropium bromide (≥5% increase in FEV1) were eligible for the study. The treatment arms were glycopyrronium 50 μg once daily followed by placebo or vice versa for 14 days (separated by a 7–14 days wash-out period). The primary outcome variable was the FEV1AUC between 0 and 24 h post-dosing on day 14. A significant improvement in the FEV1AUC0 – 24 h values on day 14 was, as expected, observed for glycopyrronium compared with placebo (p < 0.001) (least square mean
treatment difference of 163 ml). For all AUCs evaluated, the FEV1 was significantly higher for glycopyrronium compared with placebo (p < 0.001). Treatment difference on day 14 was 198 ml (p < 0.001), 165 ml (p = 0.001) and 161 ml (0 < 0.001), respectively, for mean FEV1AUC0 – 5 h, FEV1AUC0 – 12 h and FEV1AUC12 – 24 h versus placebo. All comparisons with placebo of trough FEV1 revealed a clinically significant effect of glycopyrronium (predefined threshold of 120 ml), except on day 7 (91 ml). Furthermore, mean treatment difference in peak FEV1 values was 208 ml (p < 0.001) on day 14 and 173 ml (p = 0.011) on day 7, respectively, for glycopyrronium versus placebo. Although limited by the small size, this study [27] supports the notion that glycopyrronium provides 24-h bronchodilatation in patients suffering from COPD similar to the effect of tiotropium.[28] The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) is one of the largest clinical trials investigating the effects of glycopyrronium.[29] Patients with stable COPD (mean FEV1 54%predicted) were randomized to glycopyrronium 50 μg once-daily (n = 552) or placebo (n = 270) for 26 weeks. Patients currently participating in a pulmonary rehabilitation program were not eligible for the trial. Trough FEV1 at week 12 was the primary outcome. Patients treated with glycopyrronium had significantly higher mean trough FEV1 at week 12 compared with placebo (1.41 and 1.30 l, respectively), and the treatment difference was 108 ± 15 ml (p < 0.001). Significant improvements in trough FEV1 was seen from day 1 until the end of the study period (week 26); in line with this, significant improvements in FEV1 were observed at all time-points for patients treated with glycopyrronium compared with placebo. In the GLOW 2 study, Kerwin et al. [30] also investigated the effect of glycopyrronium in patients with stable COPD (mean FEV1 56%predicted). The enrolled patients were assigned to glycopyrronium 50 μg once-daily (n = 525), open-label tiotropium 18 μg once-daily (n = 267) or placebo (n = 268) for 52 weeks; primary outcome was, again, trough FEV1 at week 12. At week 12, mean trough FEV1 was higher for patients treated with both glycopyrronium and tiotropium compared with placebo (treatment difference was 97 ml (p < 0.001) and 83 ml (p < 0.001), respectively). Furthermore, the trough FEV1 values at weeks 26 and 52 were higher for both patients treated with glycopyrronium and tiotropium compared to placebo (treatment difference for glycopyrronium – 134 and 108 ml, respectively (p < 0.001), and for tiotropium – 84 and 89 ml, respectively (p < 0.001). On day 1, the mean FEV1 treatment difference from placebo was 87 and 45 ml at 5 min, respectively, and 143 and 78 ml at 15 min, respectively (p < 0.001) for glycopyrronium and tiotropium. The latter observations, therefore, support the faster onset of action of glycopyrronium compared with other long-acting anti-cholinergic drugs, including tiotropium bromide. The observations regarding changes in lung function from GLOW1 and
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GLOW2 studies have recently been published in a pooled analysis by D’Urzo et al.[31] In the GLISTEN study, Frith et al. [32] compared the efficacy of glycopyrronium (50 μg once daily) with tiotropium (18 μg once daily) when combined with salmeterol/ fluticasone propionate (SAL/FP; 50/500 μg twice daily) in patients with moderate-to-severe COPD (mean FEV1 57% predicted). Of 773 patients, 85% completed the 12-week trial, and the primary outcome was trough FEV1 at week 12. One of the secondary outcomes of interest was whether adding glycopyrronium to SAL/FP was better than SAL/FP alone. At week 12, no difference in trough FEV1 was found between the two groups treated with glycopyrronium and tiotropium (least square mean treatment difference − 7 ml). As expected, glycopyrronium added to SAL/FP improved lung function significantly compared to SAL/FP alone. This study, therefore, also supports the beneficial effect of triple therapy in this group of patients. In contrast to other comparisons with tiotropium, Chapman et al. [33] in the GLOW5 study performed a blinded comparison of glycopyrronium and tiotropium in patients with moderate-to-severe COPD (mean FEV1 53% predicted). No difference in the primary end point (trough FEV1 at week 12) was found between the two treatment groups, and likewise, the other reported effects of the two treatments were similar to the findings in previous comparisons. From the GLOW7 study of predominantly Chinese patients, Wang et al. [34] reported findings in line with the above-mentioned studies. 3.2
Hyperinflation and exercise capacity
The GLOW1 study [29] also revealed a significant treatment difference in inspiratory capacity [IC] comparable to what has previously been reported from the studies of indacaterol and tiotropium [35,36] and aclidinium.[37] Patients treated with glycopyrronium had higher IC at all time-points on day 1, weeks 12 and 26 (all p < 0.001) versus placebo with a treatment difference of 104, 97, and 113 ml, respectively (all p < 0.001). Similar to other long-acting bronchodilators, glycopyrronium, therefore, have a beneficial effect on dynamic hyperinflation in patients with COPD. The GLOW2 study [30] also showed a higher IC in patients treated with glycopyrronium compared with placebo, and with a treatment effect similar to that of tiotropium. In the GLOW3 trial,[38] Beeh et al. investigated the effect of inhaled glycopyrronium on exercise tolerance in stable patients with COPD (mean FEV1 57%predicted) in a cross-over study where patients (n = 108) were allocated to once-daily glycopyrronium 50 μg followed by placebo or vice versa for 3 weeks (2 weeks wash-out). Exercise tolerance on glycopyrronium versus placebo after 3 weeks of treatment was the primary outcome. The exercise endurance time during a submaximal constant-load cycle-ergometry test (SMET) 4
was used to assess exercise endurance. The IC at isotime (i.e., last time-point in the SMET at which each patient had a valid test result for both treatment periods) and at rest were also included as outcome variables. Compared with placebo, exercise endurance time was improved by glycopyrronium, treatment difference of 89 s (p < 0.001). In line with this, significant treatment differences were also observed in IC, respectively, at isotime (p < 0.001) and at rest (p < 0.05). The effect of glycopyrronium on exercise tolerance in patients with COPD, therefore, is comparable to that of other long-acting bronchodilators.[35–37,39] Health status, symptom relief and use of rescue medication 3.3
Compared to placebo, patients treated with glycopyrronium (100 or 200 μg once-daily) used less recue medication (p < 0.05) during the 28-day treatment period in the study by Vogelmeier et al. [26] Mean change in puffs per day from baseline was −0.6 and −0.3, respectively, in the glycopyrronium-treated groups versus +0.5 in the placebo group. Similar findings were reported from the GLOW1 study [29] (−0.5 puffs/day), the GLOW2 study [30] (−0.4 puffs/ day and −0.6 puffs/day (p = 0.003), respectively, in the glycopyrronium and tiotropium groups) and the GLISTEN study [32] (treatment difference between glycopyrronium and placebo – 0.7 puffs/day). In the GLOW1 study,[29] glycopyrronium improved the transition dyspnea index (TDI) focal score at week 26 (1.84) compared with placebo (0.80), treatment difference of 1.04 (minimal clinical important difference [MCID] 1 point). This study also showed that patients treated with glycopyrronium had a significantly lower (i.e., better) St. George Respiratory Questionnaire (SGRQ) score at week 26 (39.50) compared with placebo (42.31). However, the treatment difference (−2.8) did not reach MCID (≥4 points); although the proportion of patients achieving MCID in SGRQ score was significantly higher for the glycopyrronium group (57% and 46%, respectively, odds ratio 1.58, p = 0.006). Comparable observations with regard to TDI focal score and SGRQ score were reported from the GLOW2 trial,[30] but the treatment difference in TDI focal score did not reach MCID; likewise for SGRQ score in the GLISTEN study.[32] 3.4
Exacerbations
In the GLOW1 trial,[29] acute exacerbations of COPD were in line with the previously published studies,[40] defined as moderate if requiring treatment with systemic corticosteroids and/or an antibiotic, and as severe if they require hospitalization. Patients enrolled in the study were not required to have acute exacerbations previously (79% of the patients had no history of exacerbations in the year prior to enrolment). It is important to notice that time to first moderate or severe
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Once-daily glycopyrronium bromide (Seebri Breezhaler®) for the treatment of COPD
COPD exacerbation was one of the secondary outcome measures. During the study period (26 weeks), 93 of 532 patients (17.5%) treated with glycopyrronium had at least one moderate or severe COPD exacerbation, compared to 63 of 260 patients (24.2%) in the placebo group. Treatment with glycopyrronium reduced the risk of moderate or severe COPD exacerbations by 31% compared with placebo (hazard ratio [HR]: 0.69, confidence interval [CI]: 0.50– 0.95, p = 0.023). In line with this, a reduction was also observed in the risk of hospitalization for a COPD exacerbation (HR: 0.35, CI: 0.14–0.86, p = 0.022) for glycopyrronium versus placebo. Furthermore, a reduction was also observed in the proportion of hospitalizations due to an exacerbation of COPD (1.7% and 4.2%, respectively, odds ratio 0.34, p = 0.024) with glycopyrronium versus placebo. In the GLOW2 trial,[30] treatment with glycopyrronium reduced the risk of exacerbations (defined as in the GLOW1 trial) by 34% compared with placebo (HR: 0.66, 95% CI: 0.52–0.85: p = 0.001) over 52 weeks, and by that showed results similar to tiotropium (39% risk reduction; HR: 0.61, 95% CI: 0.46–0.81, p = 0.001). Furthermore, a reduction was observed in the rate of moderate-to-severe COPD exacerbations in the glycopyrronium group compared to placebo (0.54 versus 0.80 per year, rate ratio 0.66, CI: 0.50–0.87, p = 0.003). The post hoc pooled analysis of the GLOW1 and GLOW2 trials,[31] not surprisingly, reported a significant improvement in time to first moderate or severe exacerbation with glycopyrronium compared with placebo. However, so far no controlled trials have been published with effect of glycopyrronium on exacerbation rate in patients with COPD as the primary outcome variable. 4.
Conclusions
The overall safety profile of inhaled glycopyrronium is, based on the available studies, comparable to the safety profile of other marketed LAMAs, including tiotropium. Furthermore, it has been documented that glycopyrronium has the profile of a once-daily drug. In patients with COPD, inhaled glycopyrronium has been shown to have beneficial effects on level of FEV1, use of rescue medication, daytime dyspnea and statistically significant impact on quality of life. In keeping with this, inhaled glycopyrronium also improves exercise tolerance, as assessed by exercise endurance time, and IC, which is likely due to a positive effect on dynamic hyperinflation, in patients with moderate-to-severe COPD, with an effect-estimate comparable to tiotropium, indacaterol and aclidinium. Glycopyrronium bromide has also been reported to reduce the rate of exacerbations in patients with moderate-to-severe COPD. In conclusion, once-daily inhaled glycopyrronium has positive impact on important COPD outcomes, including sustained 24-h bronchodilatation and improvement in exercise tolerance, comparable to the effects of other marketed LAMAs.
5.
Regulatory affairs
Inhaled glycopyrronium bromide is indicated as once-daily maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. 6.
Expert opinion
Long-acting bronchodilators, including both long-acting β2agonists and LAMAs, constitute the cornerstone of pharmacological management of stable moderate-to-severe COPD. However, although several treatment options are available, there is an unmet need for bronchodilators with a combination of fast onset of action and long duration of action that are delivered effectively by a simple, easy-to-use device. The available studies, including the GLOW trials, document that inhaled glycopyrronium leads to rapid and sustained improvements in lung function, symptoms and exercise endurance comparable to that of tiotropium with an acceptable safety profile. The post hoc pooled analysis of the GLOW1 and GLOW2 data further documented that the fast onset of action of glycopyrronium, compared to tiotropium, was sustained over 26 weeks. Several controlled trials have reported positive impact of glycopyrronium on health status. However, it is important to notice that the treatment differences observed have not reached the MCID. In all previous comparisons between glycopyrronium and tiotropium (the current gold standard – LAMA therapy for COPD), tiotropium has been administered as open-label therapy, which might introduce bias. However, the double-blind comparison of glycopyrronium and tiotropium in the GLOW5 study has documented similar efficacy and safety of the two drugs, apart from the difference in the onset of action. Nonadherence with maintenance therapy is an important challenge in the management of COPD, and it should be acknowledged that characteristics of COPD medications and treatment regimens may contribute to nonadherence. These aspects should, therefore, be considered when selecting the appropriate therapy for each individual patient with COPD. Suboptimal adherence may be improved by choosing more simple drug regimens and also by the use of medication with a fast onset of action as the patient may feel an immediate beneficial effect. The latter not least, when administered in the morning, as most patients with COPD have the most troublesome symptoms during the morning hours. The oncedaily administration of glycopyrronium together with the fast onset of action, compared with tiotropium, may, therefore, improve adherence, and by that probably the clinical outcome for the COPD patients. Glycopyrronium has also been shown to have an effect on exacerbation rate, but it is noteworthy that controlled clinical trials with the effect of glycopyrronium on exacerbation rate as the primary outcome is necessary to document the drug’s effect on exacerbation rate in patients with COPD.
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Currently, the goal of pharmacological therapy for COPD is a reduction in symptoms and frequency, and not least, severity, of exacerbations together with an improvement in quality of life and exercise capacity. In recent years, several new drugs have been developed for COPD, including drugs with a fast onset of action, for example, glycopyrronium and indacaterol, and as many patients with COPD remain symptomatic on one long-acting bronchodilator it is likely that fixed combination therapy with glycopyrronium and indacaterol will become an increasingly important option as maintenance therapy for stable COPD. However, there is still clearly a need for COPD drugs that can reduce the annual decline of lung function. Although long-acting bronchodilators are expected to continue to be the cornerstone of the pharmacological management of stable COPD, the focus
should probably be more on the drugs that can improve the overall outcome of the disease, including level of lung function.
Declaration of interest C Ulrik has received fees from Novartis, Merck, AstaZeneca, GlaxoSmithKline, Stallergenes, Pfizer, Boehringer Ingelheim, Mundipharma and Sandoz. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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of death in COPD. N Engl J Med. 2013;369(16):1491–1501. 23.
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24.
Wise RA, Anzueto A, Calverley P, et al. The tiotropium safety and performance in respimat trial (TIOSPIR), a large scale, randomized, controlled, parallel-group trial-design and rationale. Respir Res. 2013;14:40. Burgel PR, Paillasseur JL, Dusser D, et al. Tiotropium might improve survival in subjects with COPD at high risk of mortality. Respir Res. 2014;15:64.
25.
Verkindre C, Fukuchi Y, Flemale A, et al. Sustained 24-h efficacy of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients. Respir Med. 2010;104(10):1482–1489.
26.
Vogelmeier C, Verkindre C, Cheung D, et al. Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients. Pulm Pharmacol Ther. 2010;23(5):438–444.
27.
28.
29.
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Fogarty C, Hattersley H, Di Scala L, et al. Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients. Respir Med. 2011;105(3):337–342. Casaburi R, Conoscenti CS. Lung function improvements with once-daily tiotropium in chronic obstructive pulmonary disease. Am J Med. 2004;117(Suppl 12A):33s–40s.
31.
D’Urzo A, Kerwin E, Overend T, et al. Once daily glycopyrronium for the treatment of COPD: pooled analysis of the GLOW1 and GLOW2 studies. Curr Med Res Opin. 2014;30(3):493–508.
36.
O’Donnell DE, Casaburi R, Vincken W, et al. Effect of indacaterol on exercise endurance and lung hyperinflation in COPD. Respir Med. 2011;105(7):1030– 1036.
•
Pooled analysis of two large trials (approximately 2000 patients) showing that glycopyrronium provides early (5 minutes) and sustained (24 hours) bronchodilation.
37.
Maltais F, Celli B, Casaburi R, et al. Aclidinium bromide improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. Respir Med. 2011;105(4):580–587.
32.
Frith PA, Thompson PJ, Ratnavadivel R, et al. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/ fluticasone in patients with COPD: the GLISTEN study – a randomised controlled trial. Thorax. 2015;70(6):519– 527.
38.
Beeh KM, Singh D, Di Scala L, et al. Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis. 2012;7:503– 513.
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Casaburi R. Factors determining constant work rate exercise tolerance in COPD and their role in dictating the minimal clinically important difference in response to interventions. Copd. 2005;2 (1):131–136.
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Jones PW, Rennard SI, Agusti A, et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res. 2011;12:55.
41.
Vincken W, Aumann J, Chen H, et al. Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study. Int J Chron Obstruct Pulmon Dis. 2014;9:215–228.
••
First study with blinded tiotropium to investigate the effect of add-on glycopyrronium vs. tiotropium (and placebo) to salmeterol+fluticasone dipropionate (tripple-therapy).
33.
Chapman KR, Beeh KM, Beier J, et al. A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study. BMC Pulm Med. 2014;14:4.
34.
D’Urzo A, Ferguson GT, van Noord JA, et al. Efficacy and safety of once-daily NVA237 in patients with moderate-tosevere COPD: the GLOW1 trial. Respir Res. 2011;12:156. Kerwin E, Hebert J, Gallagher N, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J. 2012;40(5):1106–1114.
35.
Wang C, Sun T, Huang Y, et al. Efficacy and safety of once-daily glycopyrronium in predominantly Chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 study. Int J Chron Obstruct Pulmon Dis. 2015;10:57–68. O’Donnell DE, Fluge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J. 2004;23(6):832–840.
Expert Opin. Pharmacother. (2015) 16(17)
Affiliation Charlotte Suppli Ulrik MD DMSc†1,2 † Author for correspondence 1 Department of Pulmonary Medicine, Hvidovre Hospital, DK-2650 Hvidovre, Denmark E-mail: [email protected] 2 Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
7
ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
Once-daily glycopyrronium bromide (Seebri ® Breezhaler ) for the treatment of chronic obstructive pulmonary disease (COPD) Charlotte Suppli Ulrik To cite this article: Charlotte Suppli Ulrik (2015): Once-daily glycopyrronium bromide (Seebri ®
Breezhaler ) for the treatment of chronic obstructive pulmonary disease (COPD), Expert Opinion on Pharmacotherapy, DOI: 10.1517/14656566.2015.1100171 To link to this article: http://dx.doi.org/10.1517/14656566.2015.1100171
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Date: 09 December 2015, At: 18:34
Drug Evaluation
1.
Introduction
2.
Activity profile and safety of
3.
Clinical studies of glycopyrro-
glycopyrronium bromide
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nium bromide 4.
Conclusions
5.
Regulatory affairs
6.
Expert opinion
Once-daily glycopyrronium bromide (Seebri Breezhaler®) for the treatment of chronic obstructive pulmonary disease (COPD) Charlotte Suppli Ulrik Department of Pulmonary Medicine, Hvidovre Hospital, Hvidovre, Denmark
Introduction: Long-acting bronchodilators are the mainstay of pharmacological therapy for patients with chronic obstructive pulmonary disease (COPD). The choice of optimal bronchodilator therapy for COPD is increasingly difficult for clinicians as new treatments are marketed. Areas covered: Inhaled glycopyrronium bromide (Seebri Breezhaler®) is a well-tolerated long-acting anti-muscarinic agent (LAMA) with a fast onset of action. In patients with moderate to severe COPD, glycopyrronium bromide has clinically important effects on level of FEV1, use of relief medication, day-time dyspnea scores, and probably also on health status. Furthermore, glycopyrronium bromide also has beneficial effects on dynamic hyperinflation and, probably by that, exercise tolerance. Glycopyrronium bromide has been shown to reduce the rate of exacerbations in patients with moderate to severe COPD, although as a secondary outcome only. Expert opinion: Once-daily inhaled glycopyrronium bromide has positive impact on important COPD outcomes, comparable to the effects of other marketed LAMAs. Once-daily administration may improve adherence, and glycopyrronium bromide has the potential for a role in the future management of COPD similar to that of other long-acting anti-muscarinic agents, including tiotropium. Studies of glycopyrronium bromide with exacerbation rate as the primary outcome of interest is needed. Keywords: Breezhaler, COPD, glycopyrronium bromide, long-acting bronchodilators, Seebri Expert Opin. Pharmacother. [Early Online]
1.
Introduction
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and poor health worldwide.[1] The goals for the management of COPD include best possible symptom control, better exercise tolerance, reduction in exacerbations, prevention of disease progression and, by that, a reduction in mortality.[1] The Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD strategy document) recommends long-acting bronchodilators as first-line maintenance therapy for patients with symptomatic COPD.[1,2] Furthermore, studies of patients with moderate-to-severe COPD have shown that long-acting bronchodilators have an effect not only on symptom control, but also on severity and rate of exacerbations, quality of life, and exercise capacity.[1,3,4] Long-acting bronchodilators, including antimuscarinic agents and β2-agonists, are, therefore, of key importance for the best possible symptom control in patients with COPD. Long-acting anticholinergic agents may be the most effective class of bronchodilators for COPD.[1,5–7] For more than a decade, the only marketed long-acting antimuscarinic agent (LAMA) was tiotropium, but in the last few years several 10.1517/14656566.2015.1100171 © 2015 Taylor & Francis. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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others have emerged on the market, including aclidinium, glycopyrronium and umeclidinium.[8,9] Of these LAMAs, glycopyrronium has been in use for years, administered as injections or tablets, to diminish secretions and block cardiac vagal reflexes before surgery, but has now been marketed as an inhaled agent for the treatment of COPD. This short review describes the available clinical studies addressing the safety and clinical efficacy of inhaled glycopyrronium bromide, also compared to other marketed LAMAs, in patients with moderate-to-severe COPD.
Box 1. Drug summary
Activity profile and safety of glycopyrronium bromide
Drug name
glycopyrronium bromide
Phase Indication Pharmacology Route of administration Chemical structure
III and IV Maintenance therapy for COPD Antimuscarinic receptor antagonist Inhaled
2.
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2.1
Pharmacodynamic and pharmacokinetic profile
Glycopyrronium bromide (NVA237) is a synthetic quaternary ammonium compound that acts as a competitive antagonist through binding to the muscarinic receptors (MR) in the bronchial smooth muscle leading to an inhibition of acetylcholine-induced bronchoconstriction [10] (FIGURE 1). The chemical name of glycopyrronium is (3(2-cyclopentyl-2-hydroxy-2-phenylacetyloxy)-1,1-dimethylpyrrolidinium bromide (FIGURE 1; Box 1). Glycopyrronium binds to all subtypes of MR (M1 – M5), of which M3R is primarily involved in smooth muscle contraction. Based on the previous studies, the optimal antimuscarinic agent for use in COPD has high affinity for M1 and M3R and low affinity for M2R.[10–12] Glycopyrronium has, like tiotropium, higher selectivity for M3R than for M2R, and dissociates, like tiotropium and aclidinium, faster from M2R than M3R.[12,13] Glycopyrronium, therefore, provides bronchodilatation via M3 blockage long after its less desirable M2 effects, such as an increase in heart rate.[11–14] In vitro studies have shown that glycopyrronium has a faster onset of action than tiotropium, which has been confirmed in clinical studies.[13,15] Glycopyrronium equilibrates much faster with M3R than with both tiotropium and aclidinium,[13,15] which is assumed to underlie the faster onset of action of glycopyrronium compared with tiotropium [13] and probably also aclidinium.
Figure 1. Glycopyrronium bromide.
2
Pivotal trials
Synthetic quaternary ammonium compound, that is, (3-(2-cyclopentyl-2-hydroxy-2-phenylacetyloxy)-1,1-dimethylpyrrolidinium bromide The GLOW studies [31,33,38,41]
2.2
Safety
Findings reported from early studies suggest a favorable safety profile for inhaled glycopyrronium. A study by Sechaud et al. [11] showed that the pharmacokinetics of glycopyrronium after single and repeated once-daily inhalation in patients with mild-to-moderate COPD were consistent between doses and with limited systemic accumulation at steady state after repeated once-daily inhalation. Compared to other antimuscarinic agents, glycopyrronium has a lower oral bioavailability and by that reduced systemic absorption.[16] The overall incidence of adverse events was, apart from the frequency of dry mouth, similar in patients on glycopyrronium and placebo. No serious adverse events were reported, and no clinically relevant effects were observed on vital signs, ECG or physical examinations.[11] Van de Maele et al. [17] reported from a controlled trial of 257 patients with moderate-to-severe COPD randomized to indacaterol plus glycopyrronium, indacaterol or placebo, the change from baseline in 24-h mean heart rate versus placebo. The safety analysis comprised 255 patients, and revealed no clinically significant differences in 24-h mean heart rate or QTc interval, suggesting a cardiovascular safety profile of both long-acting bronchodilators similar to placebo. A possible association between inhaled antimuscarinic agents and risk of major cardiovascular events has been much debated. A meta-analysis of previous studies published in 2008 reported an increased risk of cardiovascular death, myocardial infarction and stroke in COPD patients treated with inhaled LAMAs.[18–21] However, recently published controlled trials have not reported a higher risk of major cardiovascular events in COPD patients treated with the LAMA, tiotropium, irrespective of the inhaler device.[22– 24] However, it is still important to acknowledge that, similar to other clinical trials of antimuscarinic agents in COPD, patients with a number of concomitant diseases, including symptomatic prostatic hyperplasia and narrowangle glaucoma, have not been eligible for the clinical trials of inhaled glycopyrronium.
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3.
Clinical studies of glycopyrronium bromide
3.1
Lung function
In one of the first trials of glycopyrronium for COPD, Verkindre et al. [25] enrolled 83 patients with stable moderate-to-severe COPD (mean FEV1 53%predicted). Patients were randomized to glycopyrronium 12.5, 25, 50 or 100 μg, open-label tiotropium 18 μg or placebo once daily for 7 days. The primary end point was mean trough (23–24 h post-dose) FEV1 on day 7. As expected, mean trough FEV1 on day 7 was significantly higher with all active treatments versus placebo (p < 0.05). Furthermore, clinically relevant improvements in trough FEV1 were observed for the glycopyrronium doses of 50 and 100 μg and for tiotropium on day 1 (treatment differences 121, 135 and 112 ml, respectively, p < 0.0001) and day 7 (differences 131, 142 and 127 ml, respectively, p < 0.0001). Although a statistically significant difference in FEV1 was reported in favor of glycopyrronium, no clinically significant differences in improvements in FEV1 were observed between glycopyrronium 50 and 100 μg, and tiotropium. This early study, therefore, revealed that inhaled glycopyrronium once daily provides rapid and sustained 24-h bronchodilatation, and in clinical terms the latter is similar to that of tiotropium. In a similar group of patients with stable COPD (mean FEV1 53% predicted), Vogelmeier et al. [26] studied the bronchodilator efficacy of two doses of glycopyrronium, 100 μg (n = 92) and 200 μg (n = 98) versus placebo (n = 91) for 28 days. The primary objective was safety, but efficacy was included as secondary objectives. Compared with placebo, the treatment difference was 131 and 161 ml, respectively (p < 0.05), for glycopyrronium 100 μg, and 146 and 151 ml, respectively, for glycopyrronium 200 μg (p < 0.05) on days 1 and 28. Further, significant higher values for both doses of glycopyrronium were also observed for peak FEV1, FEV1 at all time-points up to 24 h postdosing, and FEV1 area under the curve (AUC) during 5 min to 5 h post-dosing compared with placebo. Although no active comparator was included, these observations support the bronchodilator efficacy of glycopyrronium in patients with moderate-to-severe COPD. In a small randomized, double-blind, placebo-controlled, two-period, cross-over trial, Fogarty et al. [27] studied the bronchodilator effects of glycopyrronium versus placebo in 33 patients with mild COPD (mean FEV1 70%predicted). Of notice is that only patients with a positive response to inhaled ipratropium bromide (≥5% increase in FEV1) were eligible for the study. The treatment arms were glycopyrronium 50 μg once daily followed by placebo or vice versa for 14 days (separated by a 7–14 days wash-out period). The primary outcome variable was the FEV1AUC between 0 and 24 h post-dosing on day 14. A significant improvement in the FEV1AUC0 – 24 h values on day 14 was, as expected, observed for glycopyrronium compared with placebo (p < 0.001) (least square mean
treatment difference of 163 ml). For all AUCs evaluated, the FEV1 was significantly higher for glycopyrronium compared with placebo (p < 0.001). Treatment difference on day 14 was 198 ml (p < 0.001), 165 ml (p = 0.001) and 161 ml (0 < 0.001), respectively, for mean FEV1AUC0 – 5 h, FEV1AUC0 – 12 h and FEV1AUC12 – 24 h versus placebo. All comparisons with placebo of trough FEV1 revealed a clinically significant effect of glycopyrronium (predefined threshold of 120 ml), except on day 7 (91 ml). Furthermore, mean treatment difference in peak FEV1 values was 208 ml (p < 0.001) on day 14 and 173 ml (p = 0.011) on day 7, respectively, for glycopyrronium versus placebo. Although limited by the small size, this study [27] supports the notion that glycopyrronium provides 24-h bronchodilatation in patients suffering from COPD similar to the effect of tiotropium.[28] The glycopyrronium bromide in COPD airways clinical study 1 (GLOW1) is one of the largest clinical trials investigating the effects of glycopyrronium.[29] Patients with stable COPD (mean FEV1 54%predicted) were randomized to glycopyrronium 50 μg once-daily (n = 552) or placebo (n = 270) for 26 weeks. Patients currently participating in a pulmonary rehabilitation program were not eligible for the trial. Trough FEV1 at week 12 was the primary outcome. Patients treated with glycopyrronium had significantly higher mean trough FEV1 at week 12 compared with placebo (1.41 and 1.30 l, respectively), and the treatment difference was 108 ± 15 ml (p < 0.001). Significant improvements in trough FEV1 was seen from day 1 until the end of the study period (week 26); in line with this, significant improvements in FEV1 were observed at all time-points for patients treated with glycopyrronium compared with placebo. In the GLOW 2 study, Kerwin et al. [30] also investigated the effect of glycopyrronium in patients with stable COPD (mean FEV1 56%predicted). The enrolled patients were assigned to glycopyrronium 50 μg once-daily (n = 525), open-label tiotropium 18 μg once-daily (n = 267) or placebo (n = 268) for 52 weeks; primary outcome was, again, trough FEV1 at week 12. At week 12, mean trough FEV1 was higher for patients treated with both glycopyrronium and tiotropium compared with placebo (treatment difference was 97 ml (p < 0.001) and 83 ml (p < 0.001), respectively). Furthermore, the trough FEV1 values at weeks 26 and 52 were higher for both patients treated with glycopyrronium and tiotropium compared to placebo (treatment difference for glycopyrronium – 134 and 108 ml, respectively (p < 0.001), and for tiotropium – 84 and 89 ml, respectively (p < 0.001). On day 1, the mean FEV1 treatment difference from placebo was 87 and 45 ml at 5 min, respectively, and 143 and 78 ml at 15 min, respectively (p < 0.001) for glycopyrronium and tiotropium. The latter observations, therefore, support the faster onset of action of glycopyrronium compared with other long-acting anti-cholinergic drugs, including tiotropium bromide. The observations regarding changes in lung function from GLOW1 and
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GLOW2 studies have recently been published in a pooled analysis by D’Urzo et al.[31] In the GLISTEN study, Frith et al. [32] compared the efficacy of glycopyrronium (50 μg once daily) with tiotropium (18 μg once daily) when combined with salmeterol/ fluticasone propionate (SAL/FP; 50/500 μg twice daily) in patients with moderate-to-severe COPD (mean FEV1 57% predicted). Of 773 patients, 85% completed the 12-week trial, and the primary outcome was trough FEV1 at week 12. One of the secondary outcomes of interest was whether adding glycopyrronium to SAL/FP was better than SAL/FP alone. At week 12, no difference in trough FEV1 was found between the two groups treated with glycopyrronium and tiotropium (least square mean treatment difference − 7 ml). As expected, glycopyrronium added to SAL/FP improved lung function significantly compared to SAL/FP alone. This study, therefore, also supports the beneficial effect of triple therapy in this group of patients. In contrast to other comparisons with tiotropium, Chapman et al. [33] in the GLOW5 study performed a blinded comparison of glycopyrronium and tiotropium in patients with moderate-to-severe COPD (mean FEV1 53% predicted). No difference in the primary end point (trough FEV1 at week 12) was found between the two treatment groups, and likewise, the other reported effects of the two treatments were similar to the findings in previous comparisons. From the GLOW7 study of predominantly Chinese patients, Wang et al. [34] reported findings in line with the above-mentioned studies. 3.2
Hyperinflation and exercise capacity
The GLOW1 study [29] also revealed a significant treatment difference in inspiratory capacity [IC] comparable to what has previously been reported from the studies of indacaterol and tiotropium [35,36] and aclidinium.[37] Patients treated with glycopyrronium had higher IC at all time-points on day 1, weeks 12 and 26 (all p < 0.001) versus placebo with a treatment difference of 104, 97, and 113 ml, respectively (all p < 0.001). Similar to other long-acting bronchodilators, glycopyrronium, therefore, have a beneficial effect on dynamic hyperinflation in patients with COPD. The GLOW2 study [30] also showed a higher IC in patients treated with glycopyrronium compared with placebo, and with a treatment effect similar to that of tiotropium. In the GLOW3 trial,[38] Beeh et al. investigated the effect of inhaled glycopyrronium on exercise tolerance in stable patients with COPD (mean FEV1 57%predicted) in a cross-over study where patients (n = 108) were allocated to once-daily glycopyrronium 50 μg followed by placebo or vice versa for 3 weeks (2 weeks wash-out). Exercise tolerance on glycopyrronium versus placebo after 3 weeks of treatment was the primary outcome. The exercise endurance time during a submaximal constant-load cycle-ergometry test (SMET) 4
was used to assess exercise endurance. The IC at isotime (i.e., last time-point in the SMET at which each patient had a valid test result for both treatment periods) and at rest were also included as outcome variables. Compared with placebo, exercise endurance time was improved by glycopyrronium, treatment difference of 89 s (p < 0.001). In line with this, significant treatment differences were also observed in IC, respectively, at isotime (p < 0.001) and at rest (p < 0.05). The effect of glycopyrronium on exercise tolerance in patients with COPD, therefore, is comparable to that of other long-acting bronchodilators.[35–37,39] Health status, symptom relief and use of rescue medication 3.3
Compared to placebo, patients treated with glycopyrronium (100 or 200 μg once-daily) used less recue medication (p < 0.05) during the 28-day treatment period in the study by Vogelmeier et al. [26] Mean change in puffs per day from baseline was −0.6 and −0.3, respectively, in the glycopyrronium-treated groups versus +0.5 in the placebo group. Similar findings were reported from the GLOW1 study [29] (−0.5 puffs/day), the GLOW2 study [30] (−0.4 puffs/ day and −0.6 puffs/day (p = 0.003), respectively, in the glycopyrronium and tiotropium groups) and the GLISTEN study [32] (treatment difference between glycopyrronium and placebo – 0.7 puffs/day). In the GLOW1 study,[29] glycopyrronium improved the transition dyspnea index (TDI) focal score at week 26 (1.84) compared with placebo (0.80), treatment difference of 1.04 (minimal clinical important difference [MCID] 1 point). This study also showed that patients treated with glycopyrronium had a significantly lower (i.e., better) St. George Respiratory Questionnaire (SGRQ) score at week 26 (39.50) compared with placebo (42.31). However, the treatment difference (−2.8) did not reach MCID (≥4 points); although the proportion of patients achieving MCID in SGRQ score was significantly higher for the glycopyrronium group (57% and 46%, respectively, odds ratio 1.58, p = 0.006). Comparable observations with regard to TDI focal score and SGRQ score were reported from the GLOW2 trial,[30] but the treatment difference in TDI focal score did not reach MCID; likewise for SGRQ score in the GLISTEN study.[32] 3.4
Exacerbations
In the GLOW1 trial,[29] acute exacerbations of COPD were in line with the previously published studies,[40] defined as moderate if requiring treatment with systemic corticosteroids and/or an antibiotic, and as severe if they require hospitalization. Patients enrolled in the study were not required to have acute exacerbations previously (79% of the patients had no history of exacerbations in the year prior to enrolment). It is important to notice that time to first moderate or severe
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Once-daily glycopyrronium bromide (Seebri Breezhaler®) for the treatment of COPD
COPD exacerbation was one of the secondary outcome measures. During the study period (26 weeks), 93 of 532 patients (17.5%) treated with glycopyrronium had at least one moderate or severe COPD exacerbation, compared to 63 of 260 patients (24.2%) in the placebo group. Treatment with glycopyrronium reduced the risk of moderate or severe COPD exacerbations by 31% compared with placebo (hazard ratio [HR]: 0.69, confidence interval [CI]: 0.50– 0.95, p = 0.023). In line with this, a reduction was also observed in the risk of hospitalization for a COPD exacerbation (HR: 0.35, CI: 0.14–0.86, p = 0.022) for glycopyrronium versus placebo. Furthermore, a reduction was also observed in the proportion of hospitalizations due to an exacerbation of COPD (1.7% and 4.2%, respectively, odds ratio 0.34, p = 0.024) with glycopyrronium versus placebo. In the GLOW2 trial,[30] treatment with glycopyrronium reduced the risk of exacerbations (defined as in the GLOW1 trial) by 34% compared with placebo (HR: 0.66, 95% CI: 0.52–0.85: p = 0.001) over 52 weeks, and by that showed results similar to tiotropium (39% risk reduction; HR: 0.61, 95% CI: 0.46–0.81, p = 0.001). Furthermore, a reduction was observed in the rate of moderate-to-severe COPD exacerbations in the glycopyrronium group compared to placebo (0.54 versus 0.80 per year, rate ratio 0.66, CI: 0.50–0.87, p = 0.003). The post hoc pooled analysis of the GLOW1 and GLOW2 trials,[31] not surprisingly, reported a significant improvement in time to first moderate or severe exacerbation with glycopyrronium compared with placebo. However, so far no controlled trials have been published with effect of glycopyrronium on exacerbation rate in patients with COPD as the primary outcome variable. 4.
Conclusions
The overall safety profile of inhaled glycopyrronium is, based on the available studies, comparable to the safety profile of other marketed LAMAs, including tiotropium. Furthermore, it has been documented that glycopyrronium has the profile of a once-daily drug. In patients with COPD, inhaled glycopyrronium has been shown to have beneficial effects on level of FEV1, use of rescue medication, daytime dyspnea and statistically significant impact on quality of life. In keeping with this, inhaled glycopyrronium also improves exercise tolerance, as assessed by exercise endurance time, and IC, which is likely due to a positive effect on dynamic hyperinflation, in patients with moderate-to-severe COPD, with an effect-estimate comparable to tiotropium, indacaterol and aclidinium. Glycopyrronium bromide has also been reported to reduce the rate of exacerbations in patients with moderate-to-severe COPD. In conclusion, once-daily inhaled glycopyrronium has positive impact on important COPD outcomes, including sustained 24-h bronchodilatation and improvement in exercise tolerance, comparable to the effects of other marketed LAMAs.
5.
Regulatory affairs
Inhaled glycopyrronium bromide is indicated as once-daily maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. 6.
Expert opinion
Long-acting bronchodilators, including both long-acting β2agonists and LAMAs, constitute the cornerstone of pharmacological management of stable moderate-to-severe COPD. However, although several treatment options are available, there is an unmet need for bronchodilators with a combination of fast onset of action and long duration of action that are delivered effectively by a simple, easy-to-use device. The available studies, including the GLOW trials, document that inhaled glycopyrronium leads to rapid and sustained improvements in lung function, symptoms and exercise endurance comparable to that of tiotropium with an acceptable safety profile. The post hoc pooled analysis of the GLOW1 and GLOW2 data further documented that the fast onset of action of glycopyrronium, compared to tiotropium, was sustained over 26 weeks. Several controlled trials have reported positive impact of glycopyrronium on health status. However, it is important to notice that the treatment differences observed have not reached the MCID. In all previous comparisons between glycopyrronium and tiotropium (the current gold standard – LAMA therapy for COPD), tiotropium has been administered as open-label therapy, which might introduce bias. However, the double-blind comparison of glycopyrronium and tiotropium in the GLOW5 study has documented similar efficacy and safety of the two drugs, apart from the difference in the onset of action. Nonadherence with maintenance therapy is an important challenge in the management of COPD, and it should be acknowledged that characteristics of COPD medications and treatment regimens may contribute to nonadherence. These aspects should, therefore, be considered when selecting the appropriate therapy for each individual patient with COPD. Suboptimal adherence may be improved by choosing more simple drug regimens and also by the use of medication with a fast onset of action as the patient may feel an immediate beneficial effect. The latter not least, when administered in the morning, as most patients with COPD have the most troublesome symptoms during the morning hours. The oncedaily administration of glycopyrronium together with the fast onset of action, compared with tiotropium, may, therefore, improve adherence, and by that probably the clinical outcome for the COPD patients. Glycopyrronium has also been shown to have an effect on exacerbation rate, but it is noteworthy that controlled clinical trials with the effect of glycopyrronium on exacerbation rate as the primary outcome is necessary to document the drug’s effect on exacerbation rate in patients with COPD.
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Currently, the goal of pharmacological therapy for COPD is a reduction in symptoms and frequency, and not least, severity, of exacerbations together with an improvement in quality of life and exercise capacity. In recent years, several new drugs have been developed for COPD, including drugs with a fast onset of action, for example, glycopyrronium and indacaterol, and as many patients with COPD remain symptomatic on one long-acting bronchodilator it is likely that fixed combination therapy with glycopyrronium and indacaterol will become an increasingly important option as maintenance therapy for stable COPD. However, there is still clearly a need for COPD drugs that can reduce the annual decline of lung function. Although long-acting bronchodilators are expected to continue to be the cornerstone of the pharmacological management of stable COPD, the focus
should probably be more on the drugs that can improve the overall outcome of the disease, including level of lung function.
Declaration of interest C Ulrik has received fees from Novartis, Merck, AstaZeneca, GlaxoSmithKline, Stallergenes, Pfizer, Boehringer Ingelheim, Mundipharma and Sandoz. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation Charlotte Suppli Ulrik MD DMSc†1,2 † Author for correspondence 1 Department of Pulmonary Medicine, Hvidovre Hospital, DK-2650 Hvidovre, Denmark E-mail: [email protected] 2 Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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