Drug Profile
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
Umeclidinium for the treatment of chronic obstructive pulmonary disease Expert Rev. Respir. Med. Early online, 1–7 (2014)
Andrea Segreti1, Luigino Calzetta2, Paola Rogliani1 and Mario Cazzola*1 1 Department of System Medicine, University of Rome Tor Vergata, Rome, Italy 2 Department of Pulmonary Rehabilitation, IRCCS, San Raffaele Pisana Hospital, Rome, Italy *Author for correspondence: Tel.: +39 06 2090 0631;0633 [email protected]
Umeclidinium is a novel inhaled long-acting muscarinic receptor antagonist (LAMA) approved for treatment of chronic obstructive pulmonary disease (COPD). It provides a bronchodilation of at least 24 h, is well tolerated and has a safe profile. In this article, we describe its pharmacokinetic and pharmacodynamic characteristics. Moreover, we present a meta-analysis of randomized clinical trials carried out in COPD patients, in which the change of forced expiratory volume in 1 s (FEV1) induced by umeclidinium has been compared with that elicited by placebo or the active compound tiotropium. The data generated by the pivotal trials indicate that umeclidinium bromide delivered once-daily via the ElliptaTM inhaler is an effective and well-tolerated treatment for COPD. Therefore, it could to be used as an alternative to LAMAs already in the market, although substantial information is still lacking. It is likely that in the future, umeclidinium will be used frequently, mainly in combination with vilanterol, which is a new once-daily long-acting b2-agonist (LABA). KEYWORDS: bronchodilators • COPD • ElliptaTM inhaler • LAMA • umeclidinium bromide
Background
Parasympathetic activity is increased in patients with chronic obstructive pulmonary disease (COPD), and this appears to be the major reversible component of airway obstruction [1]. Therefore, treatment with muscarinic receptor antagonists, inhibiting muscarinic receptor activation, is an effective bronchodilator therapy in COPD [1]. As a consequence of the important role of the cholinergic system in the pathophysiology of COPD, muscarinic receptor antagonists are central to the treatment of COPD [2]. In fact, all COPD guidelines recommend longacting muscarinic receptor antagonists (LAMAs) as a first-line therapy for a broad range of COPD patients with moderate to very severe disease [3–6]. The importance of tiotropium bromide, the only LAMA approved for maintenance therapy in COPD until recently, in the maintenance treatment of COPD has promoted further research to identify new LAMAs [7,8].
designed as an inhaled once-daily LAMA for use as monotherapy and in combination with the long-acting b2-agonist (LABA) vilanterol. It has recently been licensed in Canada, Europe [9] and the USA [10] for the long-term, once-daily, maintenance treatment of COPD and is under review in several other countries. Chemistry
Umeclidinium bromide (diphenyl-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl] methanol bromide) was identified as a very potent M3 antagonist through optimizing the connectivity of a diphenyl moiety to the quinuclidine core as well as the nature and substitution of the ring nitrogen side chain [11]. The [2.2.2] quinuclidine ring is a known muscarinic pharmacophore [12]. The molecular formula of umeclidinium bromide is C29H34NO2·Br and its molecular weight is 508.5 (GSK573719A) as a quaternary ammonium bromide compound or 428.6 (GSK573719) as a free cation. The structure of umeclidinium bromide is shown in FIGURE 1.
Introduction to the compound
Umeclidinium bromide, also known as GSK573719, is a potent and competitive antagonist of muscarinic M3 receptors that has been informahealthcare.com
10.1586/17476348.2014.962519
Pharmacological activity
The pharmacological activity of umeclidinium has been well characterized [12]. In vitro,
2014 Informa UK Ltd
ISSN 1747-6348
1
Drug Profile
Segreti, Calzetta, Rogliani & Cazzola
OH
N+
Br
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
O
Figure 1. Chemical structure of umeclidinium bromide.
umeclidinium displayed subnanomolar affinity for all the cloned human M1–M5 muscarinic receptors, which ranged from 0.05 to 0.16 nM. Umeclidinium showed kinetic selectivity for M3 receptors over M2 and dissociation from the M3 muscarinic receptors, which was slower than that of the M2 muscarinic receptors (half-life [t1/2] values: 82 and 9 min, respectively). Of note is the finding that umeclidinium dissociates from the M2 and M3 receptors more readily than does tiotropium (about four- and threefold, respectively). In isolated human bronchial strips, umeclidinium was potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol and was slowly reversible in a concentration-dependent manner (1–100 nM). The time to 50% restoration of contraction at 10 nM was about 381 min (vs 413 min for tiotropium bromide). In conscious guinea pigs, intratracheal administration of umeclidinium dosedependently blocked acetylcholine (ACh)-induced bronchoconstriction with a long duration of action and was comparable to tiotropium; 2.5 mg elicited 50% bronchoprotection for >24 h. Pharmacokinetics
In healthy ipratropium-responsive subjects, umeclidinium was quickly absorbed following the administration of a single dose (10–350 mg), with a Tmax of 5–15 min, followed by a rapid clearance and elimination, as demonstrated by a decline to below the lower limit of quantification by 6 h [13]. After repeat-dose administration (250–1000 mg), the Cmax was reached in 5–7 min and steady state was achieved after 4 days of dosing, consistent with steady state being achieved after 4–5 half-lives of the drug. The geometric plasma elimination halflife (t1/2) was approximately 27 h. Urinary excretion of unchanged umeclidinium was 1–1.5% of the total dose on day 1 and 3.9–4.5% at steady state. A pharmacokinetic study in patients with COPD demonstrated that Cmax was reached rapidly (Tmax: after single dose, ~5–15 min; repeat doses, 5–7 min) [14]. Following repeat dosing, the geometric mean plasma elimination t1/2 was approximately 27 h, and statistically significant accumulation was observed for the area under the plasma concentration-time curve, Cmax and cumulative amount of unchanged drug excreted into the urine at 24 h (range 1.5- to 4.5-fold). doi: 10.1586/17476348.2014.962519
The effects of patient demographics, including age, body weight and creatinine clearance, on umeclidinium systemic exposure are minimal, and therefore no dose adjustment is necessary [15]. Umeclidinium may potentially be metabolized by cytochrome P450 2D6 (CYP2D6), with some contribution of CYP3A4 [16]. However, in a randomized study evaluating the effects of inhaled single and repeat doses for 7 days of umeclidinium in healthy volunteers who were normal CYP2D6 metabolizers or poor CYD2D6 metabolizers, there were no differences in plasma and urine pharmacokinetics between groups. These data suggest that umeclidinium has favorable safety and pharmacokinetic profiles in both normal and poor CYP2D6 metabolizers [17]. Moreover, umeclidinium is a P-glycoprotein substrate and has inhibitory activities of both CYP2D6 and CYP3A4 enzymes. However, the coadministration of umeclidinium, alone or combined with vilanterol, with oral verapamil, a moderate P-glycoprotein transporter and a moderate CYP3A4 inhibitor frequently used in patients with cardiovascular comorbidities, was well tolerated and safe, with no clinically relevant increase of the systemic exposure for either drugs [18]. Inhaler
Umeclidinium is delivered via a novel, single-step activation, multidose, dry powder inhaler (DPI) for oral inhalation, ElliptaTM [19]. Ellipta delivers consistent doses within the respirable range over the lifetime of the product. In adult subjects with obstructive lung disease and severely compromised lung function (i.e., COPD with forced expiratory volume in 1 s/ forced vital capacity [FEV1/FVC] 100 bpm, >30 beats) findings were noted with umeclidinium 125 mg (5%) compared with placebo (2%), although ECG and Holter findings of ventricular arrhythmias were similar to placebo [29].
COPD patients
The most common adverse reactions in randomized clinical trials (incidence ‡3% and more common than placebo) with umeclidinium were headache, nasopharyngitis, upper doi: 10.1586/17476348.2014.962519
Expert commentary
We are definitely convinced that LAMAs represent a cornerstone in the treatment of COPD because they not only improve Expert Rev. Respir. Med.
Umeclidinium for the treatment of COPD
A Studies
Estimate (95% CI)
Tal–singer 2013 [14] Donohue 2012 [21]
–0.010 (–0.187, 0.167) –0.013 (–0.055, 0.029)
Overall (p = 0.536)
–0.013 (–0.054, 0.028)
Drug Profile
Mean difference
–0.2
–0.1
0
0.1
0.2
0.3
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
B Studies
Estimate (95% CI)
Tal–singer 2013 [14] Donohue 2012 [21]
0.067 (–0.114, 0.248) –0.077 (–0.119, –0.035)
Overall (p = 0.620)
–0.033 (–0.163, 0.097) –0.2 –0.1 Favors tiotropium
0
0.1
0.2 0.3 Favors inmeclidinium
Figure 3. Meta-analysis of the forced expiratory volume in 1 s (l) adjusted mean difference (95% CI) of umeclidinium (A) 250 mg and (B) 500 mg vs tiotropium (18 mg).
bronchodilation but also concomitantly improve symptom control and health-related quality of life in these patients [7]. However, as we have recently stated [8], we believe that there are important questions that still need definite answers. In particular, we do not yet know whether LAMAs are the best initial choice among bronchodilators for all patients suffering from COPD, whether the once- or twice-daily dosing is preferable when we choose to prescribe a LAMA and whether new muscarinic receptor antagonists are really as long lasting as tiotropium bromide or whether they have a longer duration of action simply as a consequence of increasing the dose to overcome their shorter duration of action, possibly through a mechanism implying the generation of a drug depot in the lungs. Moreover, it is now critical to understand whether it is more beneficial to start broncholytic treatment in patients with COPD by associating the LAMA to a LABA instead of using the LAMA as monotherapy. In fact, studies of LABA/LAMA combinations, to date, indicate that combining different classes of bronchodilators results in significantly greater improvements in lung function and other meaningful outcomes such as inspiratory capacity, dyspnea, symptom scores, rescue medication use and health status in comparison with individual drugs [31]. The data generated by the pivotal trials indicate that umeclidinium bromide delivered once daily via the Ellipta inhaler is an effective and well-tolerated treatment for COPD. Therefore, it could be used as an alternative to LAMAs already in the market. Our meta-analysis suggests that there is no statistical difference between the effectiveness of umeclidinium and tiotropium when umeclidinium is administered at high doses. However, the strength that has been approved by the US FDA and the EMA is 62.5 mg. A Phase III study has evaluated the efficacy and safety of umeclidinium 125 mg and tiotropium via HandiHaler administered once daily over a 24-week treatment period in subjects with COPD [32]. Apparently, the results of this trial informahealthcare.com
have not yet been published, but they are available on the ClinicalTrials.gov website [33]. Changes from baseline in trough FEV1 at day 169 were 0.186 ± 0.0178 ml with umeclidinium and 0.149 ± 0.0176 ml with tiotropium. The impact of the two LAMAs on the shortness of breath assessed by using the Mean Shortness of Breath With Daily Activities (SOBDA) score did not show substantial differences (–0.19 ± 0.041 with umeclidinium and –0.21 ± 0.040 with tiotropium). Although these results seem to indicate effectiveness comparable between umeclidinium and tiotropium, it is now mandatory to perform a long-term trial that will compare umeclidinium 62.5 mg and tiotropium and will be focused not only on lung function but also on different patient-centered outcomes (dyspnea, healthrelated quality of life, exacerbations). This study is unquestionably needed to establish whether umeclidinium and tiotropium are really interchangeable, although our meta-analysis has documented that there is no very clear link between the once-daily doses of this LAMA and its broncholytic efficacy, a finding that was previously highlighted by the results of a meta-analysis performed by J. P. Morgan Cazenove’s Europe Equity Research on umeclidinium Phase II studies [34].
Table 1. Summary of on-treatment adverse events reported by 3% of subjects or more. Any adverse event
Headache Nasopharyngitis Cough URTI Back pain
% of subjects Placebo 10 9 4 4 4
Umeclidinium 62.5 mg
Umeclidinium 125 mg
8 7 4 5 2
10 7 5 4 4
URTI: Upper respiratory tract infection.
doi: 10.1586/17476348.2014.962519
Drug Profile
Segreti, Calzetta, Rogliani & Cazzola
Moreover, it is fundamental to know whether and how umeclidinium differs not only from tiotropium bromide but also from aclidinium bromide and glycopyrronium bromide. These novel LAMAs achieve maximal bronchodilation on the first day of dosing or have a faster onset of action than tiotropium bromide, which may offer advantages in terms of improving symptom control [7]. A comparison of umeclidinium with these two LAMAs is, therefore, essential.
cannot, therefore, predict great success for this bronchodilator, at least as monotherapy in COPD. Nevertheless, we are confident that in the future this LAMA will be used frequently in combination with vilanterol, which is a new once-daily LABA. In fact, the information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD [35]. Financial & competing interests disclosure
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
Five-year view
To speculate whether umeclidinium will be able to gain significant market share in the coming years is extremely difficult. Although it is a bronchodilator with an interesting pharmacological and clinical (effectiveness and safety) profile, we cannot omit to affirm that umeclidinium is entering a market that is currently quite crowded and very competitive. We honestly
M Cazzola is a member of an international advisory board of GSK and a consultant at GSK Italia. 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. No writing assistance was utilized in the production of this manuscript.
Key issues • Parasympathetic activity is increased in patients with chronic obstructive pulmonary disease (COPD), and this appears to be the major reversible component of airway obstruction. • The importance of tiotropium bromide, the only long-acting muscarinic receptor antagonist (LAMA) approved for maintenance therapy in COPD until recently, in the maintenance treatment of COPD has promoted further research to identify new LAMAs. • Umeclidinium bromide is a potent and competitive antagonist of muscarinic M3 receptors that has been designed as an inhaled oncedaily LAMA for use as monotherapy and in combination with the long-acting b2-agonist vilanterol. • Umeclidinium showed kinetic selectivity for M3 receptors over M2 and dissociation from the M3 muscarinic receptors, which was slower than that of the M2 muscarinic receptors. • The pharmacokinetic steady state of umiclidinium is achieved after 4–5 half-lives of the drug. • Umeclidinium is delivered via a novel, single-step activation, multidose, dry powder inhaler for oral inhalation, ElliptaTM , which delivers consistent doses within the respirable range over the lifetime of the product. • The data generated by the pivotal trials indicate that umeclidinium bromide delivered once daily via the ElliptaTM inhaler is an effective and well-tolerated treatment for COPD. • Additional trials to assess advantages over other LAMAs already in the market are required to allow the place of umeclidinium bromide to be fully elucidated.
Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
••
4.
Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev 2012;64: 450-504 A review that examines in-depth the different pharmacological and clinical aspects of bronchodilators.
2.
Cazzola M, Matera MG. Bronchodilators: current and future. Clin Chest Med 2014; 35(1):191-201
3.
National Institute for Health and Clinical Excellence. CG101 Chronic Obstructive Pulmonary Disease (update): full guideline
doi: 10.1586/17476348.2014.962519
stable COPD. Arch Bronconeumol 2012;48:247-57
23 June 2010. Available from: www.nice.org [Last accessed 30 April 2014]
References
5.
6.
Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med 2011;155:179-91 Global initiative for chronic Obstructive Lung Disease.Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Revised 2014. Available from: www. goldcopd.org/ [Last accessed 30 April 2014] Miravitlles M, Soler-Cataluna˜ JJ, Calle M, et al. Spanish COPD Guidelines (GesEPOC): pharmacological treatment of
7.
Cazzola M, Page C, Matera MG. Long-acting muscarinic receptor antagonists for the treatment of respiratory disease. Pulm Pharmacol Ther 2013;26:307-17
8.
Matera MG, Rogliani P, Cazzola M. Muscarinic receptor antagonists for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother 2014;15:961-77
•
An updated review that describes the role of muscarinic receptor antagonists for the treatment of COPD.
9.
Anonymous. GSK receives EU marketing authorisation for Incruse (umeclidinium) for the treatment of COPD. Available from: www.gsk.com/media/press-releases/2014/gskreceives-eu-marketing-authorisation-for-
Expert Rev. Respir. Med.
Umeclidinium for the treatment of COPD
randomized clinical trial. Clin Drug Investig 2013;33:653-64
incruse–umeclidiniu.html [Last accessed 12 May 2014]
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
10.
Anonymous. GSK receives approval for IncruseTM Ellipta (umeclidinium) in the US for the treatment of COPD. Available from: www.gsk.com/media/press-releases/ 2014/gsk-receives-approval-for-incruseellipta—umeclidinium–in-the.html [Last accessed 15 May 2014]
11.
Laine´ DI, McCleland B, Thomas S, et al. Discovery of novel 1-azoniabicyclo[2.2.2] octane muscarinic acetylcholine receptor antagonists. J Med Chem 2009;52: 2493-505
12.
Salmon M, Luttmann MA, Foley JJ, et al. Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther 2013;345:260-70
••
A fundamental study to understand the pharmacological profile of umeclidinium.
13.
Cahn A, Tal-Singer R, Pouliquen IJ, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects: two randomized studies. Clin Drug Investig 2013;33:477-88
14.
Tal-Singer R, Cahn A, Mehta R, et al. Initial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: two randomised studies. Eur J Pharmacol 2013;701:40-8
15.
16.
17.
Goyal N, Beerahee M, Kalberg C, et al. Population pharmacokinetics of inhaled umeclidinium and vilanterol in patients with chronic obstructive pulmonary disease. Clin Pharmacokinet 2014;53(7):637-48 Laine´ DI, Luttmann MA, Foley JJ, et al. The pre-clinical pharmacology of the inhaled muscarinic antagonist GSK573719 predicts once-daily clinical dosing [abstract]. Eur Respir J 2011; 38(Suppl 5):613s Cahn A, Mehta R, Preece A, et al. Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a double-blind,
informahealthcare.com
18.
Mehta R, Kelleher D, Preece A, et al. Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: a randomized and open-label study. Int J Chron Obstruct Pulmon Dis 2013;8:159-67
19.
Svedsater H, Dale P, Garrill K, et al. Qualitative assessment of attributes and ease of use of the ELLIPTATM dry powder inhaler for delivery of maintenance therapy for asthma and COPD. BMC Pulm Med 2013;13:72
20.
Church A, Beerahee M, Brooks J, et al. Dose response of umeclidinium administered once or twice daily in patients with COPD: a randomised cross-over study. BMC Pulm Med 2014;14:2
21.
22.
23.
Donohue JF, Anzueto A, Brooks J, et al. A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD. Respir Med 2012;106:970-9 Decramer M, Maltais F, Feldman G, et al. Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients. Respir Physiol Neurobiol 2013;185:393-9 Trivedi R, Richard N, Mehta R, Church A. Umeclidinium in patients with COPD: a randomised, placebo-controlled study. Eur Respir J 2014;43:72-81
24.
Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/ 25 mcg in COPD: a randomized, controlled study. Chest 2014. [Epub ahead of print]
25.
Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med 2013;107:1538-46
26.
Wallace BC, Dahabreh IJ, Trikalinos TA, et al. Closing the Gap between Methodologists and End-Users: R as a Computational Back-End. J Stat Software 2012;49:1-15
27.
Turner JR, Durham TA. Metamethodology: conducting and reporting meta-analyses. J Clin Hypertens (Greenwich) 2014;16:91-3
Drug Profile
28.
Viechtbauer W. Conducting Meta-Analyses in R with the metafor Package. J Stat Software 2010;36:1-48
29.
FDA Advisory Committee Briefing Document. ANOROTM ELLIPTATM (Umeclidinium Bromide/Vilanterol Inhalation Powder) For Treatment of Chronic Obstructive Pulmonary Disease. Available from: www.fda.gov/downloads/ AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ PulmonaryAllergyDrugsAdvisoryCommittee/ UCM367414.pdf [Last accessed 15 May 2014]
30.
Matera MG, Page CP, Cazzola M. Novel bronchodilators for the treatment of chronic obstructive pulmonary disease. Trends Pharmacol Sci 2011;32:495-506
31.
van der Molen T, Cazzola M. Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. Prim Care Respir J 2012;21:101-8
32.
24-week Trial Comparing GSK573719/ GW642444 With GSK573719 and With Tiotropium in Chronic Obstructive Pulmonary Disease. Available from: http:// clinicaltrials.gov/show/NCT01316913
33.
ClinicalTrials.gov. 24-week Trial Comparing GSK573719/GW642444 With GSK573719 and With Tiotropium in Chronic Obstructive Pulmonary Disease. Available from: https://clinicaltrials.gov/ct2/ show/NCT01316913?term=umeclidinium +tiotropium&rank=1 [Last accessed 15 May 2014]
34.
Gordon J. GlaxoSmithKline. Upgrading to Neutral, upside from upcoming catalysts balances out earnings risk. Available from: https://markets.jpmorgan.com/research/ email/eevpt8pp/GPS-1190044-0.pdf [Last accessed 12 May 2014]
35.
Cazzola M, Segreti A, Matera MG. New developments in the combination treatment of COPD: focus on umeclidinium/ vilanterol. Drug Des Devel Ther 2013;7: 1201-8
doi: 10.1586/17476348.2014.962519
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
Umeclidinium for the treatment of chronic obstructive pulmonary disease Expert Rev. Respir. Med. Early online, 1–7 (2014)
Andrea Segreti1, Luigino Calzetta2, Paola Rogliani1 and Mario Cazzola*1 1 Department of System Medicine, University of Rome Tor Vergata, Rome, Italy 2 Department of Pulmonary Rehabilitation, IRCCS, San Raffaele Pisana Hospital, Rome, Italy *Author for correspondence: Tel.: +39 06 2090 0631;0633 [email protected]
Umeclidinium is a novel inhaled long-acting muscarinic receptor antagonist (LAMA) approved for treatment of chronic obstructive pulmonary disease (COPD). It provides a bronchodilation of at least 24 h, is well tolerated and has a safe profile. In this article, we describe its pharmacokinetic and pharmacodynamic characteristics. Moreover, we present a meta-analysis of randomized clinical trials carried out in COPD patients, in which the change of forced expiratory volume in 1 s (FEV1) induced by umeclidinium has been compared with that elicited by placebo or the active compound tiotropium. The data generated by the pivotal trials indicate that umeclidinium bromide delivered once-daily via the ElliptaTM inhaler is an effective and well-tolerated treatment for COPD. Therefore, it could to be used as an alternative to LAMAs already in the market, although substantial information is still lacking. It is likely that in the future, umeclidinium will be used frequently, mainly in combination with vilanterol, which is a new once-daily long-acting b2-agonist (LABA). KEYWORDS: bronchodilators • COPD • ElliptaTM inhaler • LAMA • umeclidinium bromide
Background
Parasympathetic activity is increased in patients with chronic obstructive pulmonary disease (COPD), and this appears to be the major reversible component of airway obstruction [1]. Therefore, treatment with muscarinic receptor antagonists, inhibiting muscarinic receptor activation, is an effective bronchodilator therapy in COPD [1]. As a consequence of the important role of the cholinergic system in the pathophysiology of COPD, muscarinic receptor antagonists are central to the treatment of COPD [2]. In fact, all COPD guidelines recommend longacting muscarinic receptor antagonists (LAMAs) as a first-line therapy for a broad range of COPD patients with moderate to very severe disease [3–6]. The importance of tiotropium bromide, the only LAMA approved for maintenance therapy in COPD until recently, in the maintenance treatment of COPD has promoted further research to identify new LAMAs [7,8].
designed as an inhaled once-daily LAMA for use as monotherapy and in combination with the long-acting b2-agonist (LABA) vilanterol. It has recently been licensed in Canada, Europe [9] and the USA [10] for the long-term, once-daily, maintenance treatment of COPD and is under review in several other countries. Chemistry
Umeclidinium bromide (diphenyl-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl] methanol bromide) was identified as a very potent M3 antagonist through optimizing the connectivity of a diphenyl moiety to the quinuclidine core as well as the nature and substitution of the ring nitrogen side chain [11]. The [2.2.2] quinuclidine ring is a known muscarinic pharmacophore [12]. The molecular formula of umeclidinium bromide is C29H34NO2·Br and its molecular weight is 508.5 (GSK573719A) as a quaternary ammonium bromide compound or 428.6 (GSK573719) as a free cation. The structure of umeclidinium bromide is shown in FIGURE 1.
Introduction to the compound
Umeclidinium bromide, also known as GSK573719, is a potent and competitive antagonist of muscarinic M3 receptors that has been informahealthcare.com
10.1586/17476348.2014.962519
Pharmacological activity
The pharmacological activity of umeclidinium has been well characterized [12]. In vitro,
2014 Informa UK Ltd
ISSN 1747-6348
1
Drug Profile
Segreti, Calzetta, Rogliani & Cazzola
OH
N+
Br
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
O
Figure 1. Chemical structure of umeclidinium bromide.
umeclidinium displayed subnanomolar affinity for all the cloned human M1–M5 muscarinic receptors, which ranged from 0.05 to 0.16 nM. Umeclidinium showed kinetic selectivity for M3 receptors over M2 and dissociation from the M3 muscarinic receptors, which was slower than that of the M2 muscarinic receptors (half-life [t1/2] values: 82 and 9 min, respectively). Of note is the finding that umeclidinium dissociates from the M2 and M3 receptors more readily than does tiotropium (about four- and threefold, respectively). In isolated human bronchial strips, umeclidinium was potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol and was slowly reversible in a concentration-dependent manner (1–100 nM). The time to 50% restoration of contraction at 10 nM was about 381 min (vs 413 min for tiotropium bromide). In conscious guinea pigs, intratracheal administration of umeclidinium dosedependently blocked acetylcholine (ACh)-induced bronchoconstriction with a long duration of action and was comparable to tiotropium; 2.5 mg elicited 50% bronchoprotection for >24 h. Pharmacokinetics
In healthy ipratropium-responsive subjects, umeclidinium was quickly absorbed following the administration of a single dose (10–350 mg), with a Tmax of 5–15 min, followed by a rapid clearance and elimination, as demonstrated by a decline to below the lower limit of quantification by 6 h [13]. After repeat-dose administration (250–1000 mg), the Cmax was reached in 5–7 min and steady state was achieved after 4 days of dosing, consistent with steady state being achieved after 4–5 half-lives of the drug. The geometric plasma elimination halflife (t1/2) was approximately 27 h. Urinary excretion of unchanged umeclidinium was 1–1.5% of the total dose on day 1 and 3.9–4.5% at steady state. A pharmacokinetic study in patients with COPD demonstrated that Cmax was reached rapidly (Tmax: after single dose, ~5–15 min; repeat doses, 5–7 min) [14]. Following repeat dosing, the geometric mean plasma elimination t1/2 was approximately 27 h, and statistically significant accumulation was observed for the area under the plasma concentration-time curve, Cmax and cumulative amount of unchanged drug excreted into the urine at 24 h (range 1.5- to 4.5-fold). doi: 10.1586/17476348.2014.962519
The effects of patient demographics, including age, body weight and creatinine clearance, on umeclidinium systemic exposure are minimal, and therefore no dose adjustment is necessary [15]. Umeclidinium may potentially be metabolized by cytochrome P450 2D6 (CYP2D6), with some contribution of CYP3A4 [16]. However, in a randomized study evaluating the effects of inhaled single and repeat doses for 7 days of umeclidinium in healthy volunteers who were normal CYP2D6 metabolizers or poor CYD2D6 metabolizers, there were no differences in plasma and urine pharmacokinetics between groups. These data suggest that umeclidinium has favorable safety and pharmacokinetic profiles in both normal and poor CYP2D6 metabolizers [17]. Moreover, umeclidinium is a P-glycoprotein substrate and has inhibitory activities of both CYP2D6 and CYP3A4 enzymes. However, the coadministration of umeclidinium, alone or combined with vilanterol, with oral verapamil, a moderate P-glycoprotein transporter and a moderate CYP3A4 inhibitor frequently used in patients with cardiovascular comorbidities, was well tolerated and safe, with no clinically relevant increase of the systemic exposure for either drugs [18]. Inhaler
Umeclidinium is delivered via a novel, single-step activation, multidose, dry powder inhaler (DPI) for oral inhalation, ElliptaTM [19]. Ellipta delivers consistent doses within the respirable range over the lifetime of the product. In adult subjects with obstructive lung disease and severely compromised lung function (i.e., COPD with forced expiratory volume in 1 s/ forced vital capacity [FEV1/FVC] 100 bpm, >30 beats) findings were noted with umeclidinium 125 mg (5%) compared with placebo (2%), although ECG and Holter findings of ventricular arrhythmias were similar to placebo [29].
COPD patients
The most common adverse reactions in randomized clinical trials (incidence ‡3% and more common than placebo) with umeclidinium were headache, nasopharyngitis, upper doi: 10.1586/17476348.2014.962519
Expert commentary
We are definitely convinced that LAMAs represent a cornerstone in the treatment of COPD because they not only improve Expert Rev. Respir. Med.
Umeclidinium for the treatment of COPD
A Studies
Estimate (95% CI)
Tal–singer 2013 [14] Donohue 2012 [21]
–0.010 (–0.187, 0.167) –0.013 (–0.055, 0.029)
Overall (p = 0.536)
–0.013 (–0.054, 0.028)
Drug Profile
Mean difference
–0.2
–0.1
0
0.1
0.2
0.3
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
B Studies
Estimate (95% CI)
Tal–singer 2013 [14] Donohue 2012 [21]
0.067 (–0.114, 0.248) –0.077 (–0.119, –0.035)
Overall (p = 0.620)
–0.033 (–0.163, 0.097) –0.2 –0.1 Favors tiotropium
0
0.1
0.2 0.3 Favors inmeclidinium
Figure 3. Meta-analysis of the forced expiratory volume in 1 s (l) adjusted mean difference (95% CI) of umeclidinium (A) 250 mg and (B) 500 mg vs tiotropium (18 mg).
bronchodilation but also concomitantly improve symptom control and health-related quality of life in these patients [7]. However, as we have recently stated [8], we believe that there are important questions that still need definite answers. In particular, we do not yet know whether LAMAs are the best initial choice among bronchodilators for all patients suffering from COPD, whether the once- or twice-daily dosing is preferable when we choose to prescribe a LAMA and whether new muscarinic receptor antagonists are really as long lasting as tiotropium bromide or whether they have a longer duration of action simply as a consequence of increasing the dose to overcome their shorter duration of action, possibly through a mechanism implying the generation of a drug depot in the lungs. Moreover, it is now critical to understand whether it is more beneficial to start broncholytic treatment in patients with COPD by associating the LAMA to a LABA instead of using the LAMA as monotherapy. In fact, studies of LABA/LAMA combinations, to date, indicate that combining different classes of bronchodilators results in significantly greater improvements in lung function and other meaningful outcomes such as inspiratory capacity, dyspnea, symptom scores, rescue medication use and health status in comparison with individual drugs [31]. The data generated by the pivotal trials indicate that umeclidinium bromide delivered once daily via the Ellipta inhaler is an effective and well-tolerated treatment for COPD. Therefore, it could be used as an alternative to LAMAs already in the market. Our meta-analysis suggests that there is no statistical difference between the effectiveness of umeclidinium and tiotropium when umeclidinium is administered at high doses. However, the strength that has been approved by the US FDA and the EMA is 62.5 mg. A Phase III study has evaluated the efficacy and safety of umeclidinium 125 mg and tiotropium via HandiHaler administered once daily over a 24-week treatment period in subjects with COPD [32]. Apparently, the results of this trial informahealthcare.com
have not yet been published, but they are available on the ClinicalTrials.gov website [33]. Changes from baseline in trough FEV1 at day 169 were 0.186 ± 0.0178 ml with umeclidinium and 0.149 ± 0.0176 ml with tiotropium. The impact of the two LAMAs on the shortness of breath assessed by using the Mean Shortness of Breath With Daily Activities (SOBDA) score did not show substantial differences (–0.19 ± 0.041 with umeclidinium and –0.21 ± 0.040 with tiotropium). Although these results seem to indicate effectiveness comparable between umeclidinium and tiotropium, it is now mandatory to perform a long-term trial that will compare umeclidinium 62.5 mg and tiotropium and will be focused not only on lung function but also on different patient-centered outcomes (dyspnea, healthrelated quality of life, exacerbations). This study is unquestionably needed to establish whether umeclidinium and tiotropium are really interchangeable, although our meta-analysis has documented that there is no very clear link between the once-daily doses of this LAMA and its broncholytic efficacy, a finding that was previously highlighted by the results of a meta-analysis performed by J. P. Morgan Cazenove’s Europe Equity Research on umeclidinium Phase II studies [34].
Table 1. Summary of on-treatment adverse events reported by 3% of subjects or more. Any adverse event
Headache Nasopharyngitis Cough URTI Back pain
% of subjects Placebo 10 9 4 4 4
Umeclidinium 62.5 mg
Umeclidinium 125 mg
8 7 4 5 2
10 7 5 4 4
URTI: Upper respiratory tract infection.
doi: 10.1586/17476348.2014.962519
Drug Profile
Segreti, Calzetta, Rogliani & Cazzola
Moreover, it is fundamental to know whether and how umeclidinium differs not only from tiotropium bromide but also from aclidinium bromide and glycopyrronium bromide. These novel LAMAs achieve maximal bronchodilation on the first day of dosing or have a faster onset of action than tiotropium bromide, which may offer advantages in terms of improving symptom control [7]. A comparison of umeclidinium with these two LAMAs is, therefore, essential.
cannot, therefore, predict great success for this bronchodilator, at least as monotherapy in COPD. Nevertheless, we are confident that in the future this LAMA will be used frequently in combination with vilanterol, which is a new once-daily LABA. In fact, the information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD [35]. Financial & competing interests disclosure
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
Five-year view
To speculate whether umeclidinium will be able to gain significant market share in the coming years is extremely difficult. Although it is a bronchodilator with an interesting pharmacological and clinical (effectiveness and safety) profile, we cannot omit to affirm that umeclidinium is entering a market that is currently quite crowded and very competitive. We honestly
M Cazzola is a member of an international advisory board of GSK and a consultant at GSK Italia. 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. No writing assistance was utilized in the production of this manuscript.
Key issues • Parasympathetic activity is increased in patients with chronic obstructive pulmonary disease (COPD), and this appears to be the major reversible component of airway obstruction. • The importance of tiotropium bromide, the only long-acting muscarinic receptor antagonist (LAMA) approved for maintenance therapy in COPD until recently, in the maintenance treatment of COPD has promoted further research to identify new LAMAs. • Umeclidinium bromide is a potent and competitive antagonist of muscarinic M3 receptors that has been designed as an inhaled oncedaily LAMA for use as monotherapy and in combination with the long-acting b2-agonist vilanterol. • Umeclidinium showed kinetic selectivity for M3 receptors over M2 and dissociation from the M3 muscarinic receptors, which was slower than that of the M2 muscarinic receptors. • The pharmacokinetic steady state of umiclidinium is achieved after 4–5 half-lives of the drug. • Umeclidinium is delivered via a novel, single-step activation, multidose, dry powder inhaler for oral inhalation, ElliptaTM , which delivers consistent doses within the respirable range over the lifetime of the product. • The data generated by the pivotal trials indicate that umeclidinium bromide delivered once daily via the ElliptaTM inhaler is an effective and well-tolerated treatment for COPD. • Additional trials to assess advantages over other LAMAs already in the market are required to allow the place of umeclidinium bromide to be fully elucidated.
Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
••
4.
Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev 2012;64: 450-504 A review that examines in-depth the different pharmacological and clinical aspects of bronchodilators.
2.
Cazzola M, Matera MG. Bronchodilators: current and future. Clin Chest Med 2014; 35(1):191-201
3.
National Institute for Health and Clinical Excellence. CG101 Chronic Obstructive Pulmonary Disease (update): full guideline
doi: 10.1586/17476348.2014.962519
stable COPD. Arch Bronconeumol 2012;48:247-57
23 June 2010. Available from: www.nice.org [Last accessed 30 April 2014]
References
5.
6.
Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med 2011;155:179-91 Global initiative for chronic Obstructive Lung Disease.Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Revised 2014. Available from: www. goldcopd.org/ [Last accessed 30 April 2014] Miravitlles M, Soler-Cataluna˜ JJ, Calle M, et al. Spanish COPD Guidelines (GesEPOC): pharmacological treatment of
7.
Cazzola M, Page C, Matera MG. Long-acting muscarinic receptor antagonists for the treatment of respiratory disease. Pulm Pharmacol Ther 2013;26:307-17
8.
Matera MG, Rogliani P, Cazzola M. Muscarinic receptor antagonists for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother 2014;15:961-77
•
An updated review that describes the role of muscarinic receptor antagonists for the treatment of COPD.
9.
Anonymous. GSK receives EU marketing authorisation for Incruse (umeclidinium) for the treatment of COPD. Available from: www.gsk.com/media/press-releases/2014/gskreceives-eu-marketing-authorisation-for-
Expert Rev. Respir. Med.
Umeclidinium for the treatment of COPD
randomized clinical trial. Clin Drug Investig 2013;33:653-64
incruse–umeclidiniu.html [Last accessed 12 May 2014]
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Michigan University on 10/16/14 For personal use only.
10.
Anonymous. GSK receives approval for IncruseTM Ellipta (umeclidinium) in the US for the treatment of COPD. Available from: www.gsk.com/media/press-releases/ 2014/gsk-receives-approval-for-incruseellipta—umeclidinium–in-the.html [Last accessed 15 May 2014]
11.
Laine´ DI, McCleland B, Thomas S, et al. Discovery of novel 1-azoniabicyclo[2.2.2] octane muscarinic acetylcholine receptor antagonists. J Med Chem 2009;52: 2493-505
12.
Salmon M, Luttmann MA, Foley JJ, et al. Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther 2013;345:260-70
••
A fundamental study to understand the pharmacological profile of umeclidinium.
13.
Cahn A, Tal-Singer R, Pouliquen IJ, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects: two randomized studies. Clin Drug Investig 2013;33:477-88
14.
Tal-Singer R, Cahn A, Mehta R, et al. Initial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: two randomised studies. Eur J Pharmacol 2013;701:40-8
15.
16.
17.
Goyal N, Beerahee M, Kalberg C, et al. Population pharmacokinetics of inhaled umeclidinium and vilanterol in patients with chronic obstructive pulmonary disease. Clin Pharmacokinet 2014;53(7):637-48 Laine´ DI, Luttmann MA, Foley JJ, et al. The pre-clinical pharmacology of the inhaled muscarinic antagonist GSK573719 predicts once-daily clinical dosing [abstract]. Eur Respir J 2011; 38(Suppl 5):613s Cahn A, Mehta R, Preece A, et al. Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a double-blind,
informahealthcare.com
18.
Mehta R, Kelleher D, Preece A, et al. Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: a randomized and open-label study. Int J Chron Obstruct Pulmon Dis 2013;8:159-67
19.
Svedsater H, Dale P, Garrill K, et al. Qualitative assessment of attributes and ease of use of the ELLIPTATM dry powder inhaler for delivery of maintenance therapy for asthma and COPD. BMC Pulm Med 2013;13:72
20.
Church A, Beerahee M, Brooks J, et al. Dose response of umeclidinium administered once or twice daily in patients with COPD: a randomised cross-over study. BMC Pulm Med 2014;14:2
21.
22.
23.
Donohue JF, Anzueto A, Brooks J, et al. A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD. Respir Med 2012;106:970-9 Decramer M, Maltais F, Feldman G, et al. Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients. Respir Physiol Neurobiol 2013;185:393-9 Trivedi R, Richard N, Mehta R, Church A. Umeclidinium in patients with COPD: a randomised, placebo-controlled study. Eur Respir J 2014;43:72-81
24.
Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/ 25 mcg in COPD: a randomized, controlled study. Chest 2014. [Epub ahead of print]
25.
Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med 2013;107:1538-46
26.
Wallace BC, Dahabreh IJ, Trikalinos TA, et al. Closing the Gap between Methodologists and End-Users: R as a Computational Back-End. J Stat Software 2012;49:1-15
27.
Turner JR, Durham TA. Metamethodology: conducting and reporting meta-analyses. J Clin Hypertens (Greenwich) 2014;16:91-3
Drug Profile
28.
Viechtbauer W. Conducting Meta-Analyses in R with the metafor Package. J Stat Software 2010;36:1-48
29.
FDA Advisory Committee Briefing Document. ANOROTM ELLIPTATM (Umeclidinium Bromide/Vilanterol Inhalation Powder) For Treatment of Chronic Obstructive Pulmonary Disease. Available from: www.fda.gov/downloads/ AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ PulmonaryAllergyDrugsAdvisoryCommittee/ UCM367414.pdf [Last accessed 15 May 2014]
30.
Matera MG, Page CP, Cazzola M. Novel bronchodilators for the treatment of chronic obstructive pulmonary disease. Trends Pharmacol Sci 2011;32:495-506
31.
van der Molen T, Cazzola M. Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. Prim Care Respir J 2012;21:101-8
32.
24-week Trial Comparing GSK573719/ GW642444 With GSK573719 and With Tiotropium in Chronic Obstructive Pulmonary Disease. Available from: http:// clinicaltrials.gov/show/NCT01316913
33.
ClinicalTrials.gov. 24-week Trial Comparing GSK573719/GW642444 With GSK573719 and With Tiotropium in Chronic Obstructive Pulmonary Disease. Available from: https://clinicaltrials.gov/ct2/ show/NCT01316913?term=umeclidinium +tiotropium&rank=1 [Last accessed 15 May 2014]
34.
Gordon J. GlaxoSmithKline. Upgrading to Neutral, upside from upcoming catalysts balances out earnings risk. Available from: https://markets.jpmorgan.com/research/ email/eevpt8pp/GPS-1190044-0.pdf [Last accessed 12 May 2014]
35.
Cazzola M, Segreti A, Matera MG. New developments in the combination treatment of COPD: focus on umeclidinium/ vilanterol. Drug Des Devel Ther 2013;7: 1201-8
doi: 10.1586/17476348.2014.962519
