Pulmonary Pharmacology & Therapeutics xxx (2013) 1e11

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Pulmonary Pharmacology & Therapeutics

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Review

Long-acting muscarinic receptor antagonists for the treatment of respiratory disease

Mario Cazzola a, b, *, Clive Page c, Maria Gabriella Matera d
a

Unit of Respiratory Clinical Pharmacology, Department of System Medicine, University of Rome Tor Vergata, 00133 Rome, Italy Department of Pulmonary Rehabilitation, San Raffaele Pisana Hospital, IRCCS, Rome, Italy c Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, Kings College London, London, SE1 9NH, UK d Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Naples, Italy
b

a r t i c l e i n f o
Article history: Received 6 September 2012 Received in revised form 2 December 2012 Accepted 3 December 2012 Keywords: Anticholinergic COPD LAMA Novel

a b s t r a c t
The use of muscarinic receptor antagonists in the treatment of chronic obstructive pulmonary disease (COPD) is well established. More recently, the potential for long-acting muscarinic receptor antagonists (LAMAs) in the treatment of asthma has also been investigated. While LAMAs offer advantages over short-acting muscarinic receptor antagonists, in terms of a reduced dosing frequency, there remains a need for therapies that improve symptom control throughout both the day and night, provide better management of exacerbations and deliver improved health-related quality of life. Furthermore, the potential for unwanted anticholinergic side effects, particularly cardiovascular effects, remains a concern for this class of compounds. Novel LAMAs in clinical development for the treatment of respiratory disease include: aclidinium bromide, NVA237 (glycopyrronium bromide), GP-MDI, EP-101, CHF-5259, umeclidinium bromide, CHF-5407, TD-4208, AZD8683 and V-0162. These compounds offer potential advantages in terms of onset of action, symptom control and safety. In addition, a number of LAMAs are also being developed as combination treatments with long-acting b2-agonists (LABAs) or inhaled glucocorticosteroids, potentially important treatment options for patients who require combination therapy to achieve an optimal therapeutic response as their disease progresses. More recently, compounds such as GSK961081 and THRX-198321 have been identied that combine LAMA and LABA activity in the same molecule, and have the potential to offer the benets of combination therapy in a single compound. Here, we review novel LAMAs and dual action compounds in clinical development, with a particular focus on how they may address the current unmet clinical needs in the treatment of respiratory disease, particularly COPD. 2013 Elsevier Ltd. All rights reserved.

1. Introduction Many factors contribute to the airow limitation seen in chronic obstructive pulmonary disease (COPD), including hyperresponsiveness to spasmogens and pathological structural changes throughout the airways and lung [1,2]. A key aspect contributing to many of the symptoms and clinical features of COPD and asthma is a dysfunction in autonomic nerve regulation of airway smooth muscle tone [3]. Therefore, bronchodilators (muscarinic receptor antagonists or b2-agonists) are recommended for the maintenance treatment of stable COPD [4] and are commonly used alongside anti-inammatory therapies in the treatment of asthma [5]. However, the use of long-acting muscarinic receptor antagonists (LAMAs) is not currently included in the Global Initiative for Asthma (GINA) guidelines for the management of asthma [6]. Cholinergic parasympathetic nerves contribute to the elevated airway smooth muscle tone in COPD [3], and this primary reversible

Abbreviations: Ach, acetylcholine; AE, adverse event; AUC, area under the curve; BID, twice daily; Cmax, maximum observed plasma concentration; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; ECG, electrocardiogram; EXACT, Exacerbations of Chronic Pulmonary Disease Tool; FEV1, forced expiratory volume in 1 s; GINA, Global Initiative for Asthma; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; Koff, rate constant of dissociation; LABA, long-acting b2-agonist; LAMA, long-acting muscarinic receptor antagonist; MABA, a single drug having muscarinic antagonist and b2-agonist activity; MCID, minimal clinically important difference; MDI, metered dose inhaler; PK, pharmacokinetic; QD, once daily; SAMA, short-acting muscarinic receptor antagonist; SGRQ, St Georges Respiratory Questionnaire; t, half-life; TDI, transitional dyspnoea index; Tmax, time to reach maximal plasma concentration. * Corresponding author. Unit of Respiratory Clinical Pharmacology, Department of System Medicine, University of Rome Tor Vergata, 00133 Rome, Italy. Tel.: 39 06 2090 0633. E-mail addresses: mcazzola@qubisoft.it, mario.cazzola@uniroma2.it (M. Cazzola), clive.page@kcl.ac.uk (C. Page), mariagabriella.matera@unina2.it (M.G. Matera). 1094-5539/$ e see front matter 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pupt.2012.12.006

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component of airway limitation is sensitive to muscarinic receptor antagonists [7]. Acetylcholine (Ach) and other bronchoconstrictor mediators can also be released from non-neuronal cells to act on airway smooth muscle cells and other cells involved in the chronic inammatory response in COPD and in airway remodelling [8,9]. The effects of Ach are mediated by a family of ve G-protein coupled receptors (M1eM5), which have distinct anatomical distribution and functions. Only the M1eM3 subtypes are expressed in airways [10]; M1 receptors are found in parasympathetic ganglia where they facilitate neurotransmission; M2 receptors are found presynaptically and act as autoreceptors to modulate Ach release; and M3 receptors are expressed on airway smooth muscle, submucosal mucus glands and vascular endothelium in the lung [10]. Studies in M3R/ knockout mice have shown that the contraction of airway smooth muscle cells in response to Ach is predominantly mediated via M3 receptors [11,12]. 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 [13,14]. More recent evidence from patients with uncontrolled asthma [15], patients with asthma who have polymorphisms predicting an impaired response to b2-agonists [16], and patients with concomitant COPD and asthma [17] also supports a role for LAMAs in the treatment of asthma. There are currently three muscarinic receptor antagonists licenced for use in the treatment of COPD; the short-acting muscarinic receptor antagonists (SAMAs) ipratropium bromide and oxitropium bromide and the LAMA tiotropium bromide. Tiotropium bromide is a once-daily (QD) treatment for COPD that provides 24-h bronchodilation and improves symptoms and health-related quality of life in patients with COPD [18,19]. LAMAs offer distinct advantages over SAMAs in terms of maintaining 24-h bronchodilation. However, while tiotropium bromide provides 24-h bronchodilation, it takes 2e8 days to achieve maximal bronchodilation and 2e3 weeks to reach steady-state plasma levels [20]. Over this period there is a slow linear accumulation of tiotropium bromide and tiotropium bromide administered via HandiHaler (single-dose dry powder inhaler [DPI]) is not recommended for twice-daily (BID)dosing [20,21]. Tiotropium bromide administered via HandiHaler is also associated with typical anticholinergic adverse events (AEs), such as dry mouth [18,19], a consequence of reduced M1/M3 receptor-mediated salivary secretion in response to parasympathetic stimulation [22]. A number of novel LAMAs have been identied which address some of the current unmet clinical needs in COPD, including improved symptom control, better management of exacerbations and improved health-related quality of life [23]. Night-time and early-morning symptoms are prevalent in patients with COPD [24,25]. The presence of night-time symptoms impacts not only on lung function, but potentially also on exacerbation frequency, cognition, depression, health-related quality of life and mortality [24]. A compound suitable for BID administration may benet patients in terms of symptom control during the night-time and early-morning period, when symptoms are most troublesome to patients [25,26]. Here, we review LAMAs currently in development for the treatment of respiratory disease, with an emphasis on the current unmet clinical need and their safety prole. Compounds were identied by searching the Thomson Reuters database (search terms: muscarinic M3 receptor antagonist and muscarinic receptor antagonist). Relevant literature was identied from PubMed searches using the name of each compound; when necessary these search terms were combined with COPD or asthma to rene the search strategy. In addition, abstracts presented at both the American Thoracic Society (available for 2010e2012) and the European Respiratory Society (2007e2011) were searched

using the name of each compound. Furthermore, we have included other interesting compounds still at the discovery stage, and ClinicalTrial.gov (http://clinicaltrials.gov/) and the European Clinical Trials register (www.clinicaltrialsregister.eu/) were also searched for details of clinical trials.

2. Muscarinic receptor antagonists in the treatment of respiratory disease The bronchodilator properties of atropine, derived from the deadly nightshade plant (Atropa belladonna), have been known for many years, and drugs related to atropine have become one of the standard treatments for respiratory disease [13]. Atropine is a tertiary ammonium compound, which is readily absorbed and can cross the bloodebrain barrier. As a consequence, atropine and its derivatives have multiple, characteristic, anticholinergic systemic side effects, such as dry mouth and tachycardia, that limit their clinical usefulness. Chemical modications of atropine, in particular quaternization of the tertiary amino function, have yielded a number of synthetic congeners formulated as bromide salts (Fig. 1) that are poorly absorbed across membranes, including the bloodebrain barrier, resulting in reduced systemic exposure and, as a consequence, fewer side effects. While the use of LAMAs is well established in the treatment of COPD [4], this class of drugs has been suggested to be associated with systemic side effects, including an increased risk of cardiovascular AEs [27]. Stimulation of M2 receptors, the predominant muscarinic receptor subtype in the heart, mediates negative chronotropic and inotropic effects [28] and inhibition of M2 receptors by muscarinic receptor antagonists is responsible for the characteristic tachycardia seen with this class of compound. In vitro, tiotropium bromide has kinetic selectivity for M3 muscarinic receptors vs M2 receptors, with an almost 10-fold lower dissociation half-life at M2 vs M3 receptors [29] (Table 1 [29e32]). This selectivity should confer a reduced propensity for M2 receptor-mediated AEs, such as tachycardia, on tiotropium bromide [13]. While recent reports suggest that QD tiotropium bromide (5 and 10 mg) administered via Respimat (a propellant-free inhaler that delivers a slow-moving mist of aerosolized solution) is associated with a 52% increased risk of mortality over placebo [33], results from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial showed that patients treated with tiotropium bromide, via HandiHaler, have a lower overall mortality and a lower risk of serious cardiac AEs, congestive heart failure or myocardial infarction compared with placebo [34]. The increase in mortality seen with tiotropium bromide administered via Respimat may be a consequence of more effective drug delivery to the lungs with increased absorption, and therefore greater systemic exposure, when using this device. Respimat improves lung deposition compared with standard DPIs and metered DPIs [35e 37] and it has been hypothesized that Respimat provides higher lung deposition compared with HandiHaler [38]. Although data directly comparing the two devices in this respect are lacking, a large, long-term prospective trial is being undertaken to compare the safety and efcacy of tiotropium bromide delivered by Respimat and HandiHaler in patients with COPD (NCT01126437).

3. LAMA compounds in development A number of LAMAs are in clinical development as mono- or combination therapy with existing or novel b2-agonists for the treatment of COPD (Table 2); however, the use of some of these compounds in asthma is also being investigated.

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Br N H O OH O OH O H O

Br O

Ipratropium bromide
Br N O H O O S

Oxitropium bromide

O O S Br

S HO S

HO

N O

Tiotropium bromide

Aclidinium bromide

O O N Br O

O S

H N O

H N

O N H N OH

HO

OH

Glycopyrronium bromide

Umeclidinium bromide

F O N F O N H Br S N S F F O N H

CHF5407

V-0162

Fig. 1. Muscarinic receptor antagonists approved or in clinical development for the treatment of COPD.

3.1. Aclidinium bromide Aclidinium bromide (LAS 34273; Fig. 1), delivered by a novel multiple-dose DPI (Genuair1; Pressair1), has been indicated in Europe for maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.2 Aclidinium bromide will be marketed by Forest Laboratories in the USA, Kyorin in Japan, Daewoong in Korea and Almirall will co-market in the EU with Menarini. Genuair is a breath-actuated inhaler containing 60

1 Registered trademarks of Almirall, S.A., Barcelona, Spain for use within the European Union, Iceland, and Norway as Genuair and within the USA as Pressair. 2 Indicated in the USA for long-term maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema.

doses for a 1-month supply, which is ready to use. Novel features include an audible and a visual feedback signal to reassure patients that inhalation was successful, an over-dosing prevention system, and a lock-out mechanism to ensure that patients cannot use the inhaler after the last dose has been taken. Development of aclidinium bromide initially focused on QD treatment for COPD; three Phase II and three Phase III studies were completed with this dosing regimen. More recently, aclidinium bromide has been evaluated for a BID regimen, and two Phase II and seven Phase III studies have been completed. In vitro, aclidinium bromide displays subnanomolar afnity for all ve muscarinic receptors, kinetic selectivity for M3 receptors over M2 (Table 1) and rapidly associates at recombinant M3 receptors [30]. Preclinical data suggest that aclidinium bromide has a shorter duration of action and a faster onset compared with

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Table 1 Dissociation half-lives for muscarinic receptor antagonists against the human M2 and M3 receptor subtypes. hM2 Koff (min1) Tiotropium bromide Aclidinium bromide Glycopyrronium bromide CHF-5407 n/a 0.15 0.031 0.022 t (h) 3.6 0.5 4.7 0.3 0.37 0.5 0.1 hM3 Koff (min1) n/a 0.02 0.002 0.004 t (h) 34.7 2.9 29.2 0.6 6.1 2.8 0.2 9.6 6.2 16.5 5.6 Disse et al. [29] Gavald et al. [30] Casarosa et al. [31] Villetti et al. [32] t M3/M2 Reference

Koff, rate constant of dissociation of radiolabelled antagonist; n/a, not available in reference; t, residence half-life.

tiotropium bromide [30]. Aclidinium bromide is also rapidly hydrolyzed in vitro in human plasma (half-life [t] 2.4 min) to two inactive metabolites [39,40]. The kinetic selectivity and rapid plasma hydrolysis of aclidinium bromide suggests a reduced potential for systemic side effects. The Phase II QD studies showed that aclidinium bromide maintained bronchodilation over 24 h [41,42] and initial Phase III studies were conducted to investigate a QD dosing regimen. Results from two 1-year Phase III studies (AClidinium CLinical trial Assessing efcacy and safety In Moderate to severe COPD patients [ACCLAIM] COPD I and II) demonstrated that while aclidinium bromide 200 mg QD signicantly improved trough forced expiratory volume in 1 s (FEV1) in patients with COPD vs placebo [43], the improvement (59e67 ml) was below the suggested minimal

clinically important difference (MCID) of 100 ml [44]. However, in both studies signicantly more patients achieved an MCID of 4 units from baseline in St Georges Respiratory Questionnaire (SGRQ) at all timepoints vs placebo (with the exception of Week 52 in ACCLAIM COPD I) [43]. Similarly, a higher percentage of patients achieved a MCID of 1 unit from baseline [45] in Transitional Dyspnoea Index (TDI) vs placebo; this was signicantly greater at all timepoints in ACCLAIM COPD I. Furthermore, exacerbation rates and time to rst moderate or severe exacerbation were signicantly improved vs placebo in ACCLAIM COPD II [43]. Subsequently, studies investigating higher doses and alternative dosing regimens were conducted. In a double-blind, placebo- and active-controlled crossover Phase IIa study (n 30), aclidinium bromide 400 mg BID provided bronchodilation over 24 h that was equivalent to

Table 2 Long-acting muscarinic receptor antagonists in clinical development (monotherapy and combination therapy). Key features Monotherapy Aclidinium bromide Indicated in Europe for maintenance bronchodilator treatment to relieve symptoms in adult patients with COPDy. 24-h bronchodilation equivalent to tiotropium with maximal bronchodilation on Day 1. Night-time symptoms also signicantly improved. Low propensity for anticholinergic side effects Suitable for once-daily dosing. More rapid onset of action than tiotropium bromide. Safety prole comparable to placebo Improvements in bronchodilation comparable to tiotropium bromide with a comparable safety prole Statistically signicantly improved FEV1 compared with placebo. Safety prole comparable to placebo No data available Being developed as a once-daily treatment for COPD. Potent antagonist of Ach in vitro, with a longer duration of action than tiotropium bromide. Statistically signicantly improved FEV1 compared with placebo. Drug-related AEs increased with dose Potent antagonist with a dissociation half-life at M3 receptors comparable to tiotropium bromide, and a more rapid dissociation from M2 receptors No data available No data available No data available Developed as a once-daily treatment. Rapid onset of action. Sustained clinically meaningful improvements in bronchodilation compared with indacaterol alone. Incidence of cardiovascular side effects was comparable to placebo or indacaterol alone Signicantly improved trough FEV1 compared with tiotropium bromide alone. No safety issues identied Signicantly improved trough FEV1 AUC0-12 compared with glycopyrronium bromide, formoterol or tiotropium bromide alone. Incidence of dry mouth was comparable to tiotropium bromide Improved trough FEV1 compared with placebo. Well tolerated with no serious AEs reported No data available Current status Approved in Europe and the USA Company Almirall/Forest Laboratories

Glycopyrronium bromide NVA237 GP-MDI EP-101 CHF-5259 Umeclidinium bromide

Approved in Europe and Japan Phase II Phase II Phase II Phase III

Novartis Pearl Therapeutics Elevation Pharmaceuticals /PARI Pharma Chiesi Farmaceutici GlaxoSmithKline

CHF-5407 TD-4208 AZD8683 V-0162 Combination therapy Glycopyrronium bromide/indacaterol (QVA149) Tiotropium bromide/olodaterol Glycopyrronium bromide/formoterol Umeclidinium bromide/vilanterol Aclidinium bromide/formoterol

Phase I Phase II Phase II Phase II Phase III

Chiesi Farmaceutici Theravance AstraZeneca Pierre Fabre Novartis

Phase III Phase II

Boehringer Ingelheim Pearl Therapeutics

Phase III Phase III

GlaxoSmithKline Almirall/Forest Laboratories

Ach, acetylcholine; AE, adverse event; AUC0-12, area under the curve from time zero to 12 h; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s. y Indicated in the USA for long-term maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema.

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tiotropium bromide 18 mg QD [46]. Improvements in FEV1 area under the curve (AUC) were signicantly greater with aclidinium bromide than with tiotropium bromide for all time intervals on Day 1 (P < 0.05 aclidinium bromide 400 mg vs tiotropium bromide 18 mg), consistent with aclidinium bromide providing maximal bronchodilation from Day 1 [46]. Based on patient diaries, night-time and early-morning symptoms were also signicantly improved with aclidinium bromide (P < 0.05 vs placebo), but not with tiotropium bromide [46], which may suggest that the evening dose of aclidinium bromide offers advantages in terms of the management of troublesome symptoms. However, this remains to be established using validated tools. Two randomized, doubleblind, placebo-controlled, Phase III studies (AClidinium in Chronic Obstructive Respiratory Disease [ACCORD] COPD I and Aclidinium To Treat Airway obstruction In COPD patieNts [ATTAIN]) conrmed that aclidinium bromide BID provided clinically meaningful improvements in bronchodilation over 24 h (124 ml at Week 12 and 128 ml at Week 24, respectively; both P < 0.0001) [47,48]. In both studies, peak FEV1 improvements seen on Day 1 were maintained throughout the duration of the trial. Furthermore, in the 12-week ACCORD COPD I study (n 561), aclidinium bromide 200 mg and 400 mg BID signicantly reduced the frequency of night-time COPD symptoms, reduced the severity and impact of early-morning breathlessness, reduced daily sputum production and reduced the need for daily relief medication based on a Night-time Symptoms Questionnaire (all P < 0.05 for both doses vs placebo) [48]. Similar improvements in COPD symptoms were reported in the 24-week ATTAIN study (n 828). A higher percentage of patients achieved an MCID in TDI focal scores with aclidinium bromide 200 mg and 400 mg compared with placebo (53.3% [P < 0.05], 56.9% [P < 0.01], and 45.5%, respectively) [47] and both doses improved Exacerbations of Chronic Pulmonary Disease Tool (EXACT)-Respiratory Symptoms domain and total scores (P < 0.05 for both doses of aclidinium bromide vs placebo) [49]. Patients receiving the higher dose reported a signicant reduction in both night-time and earlymorning symptoms (P < 0.01) and a reduced need for daily relief medication (P < 0.0001) compared with placebo [47,49]. Clinically meaningful improvements in health-related quality of life were also seen, with a clinically signicant improvement in SGRQ total score at Week 24 with aclidinium bromide 400 mg and signicantly more patients achieving a clinically signicant improvement in SGRQ total score with both doses at Weeks 12 and 24 (P < 0.05 for all comparisons) [47]. In ATTAIN, the exacerbation rate was also signicantly lower with both doses of aclidinium bromide compared with placebo [47]. In a double-blind, randomized Phase III study designed to assess the long-term (52-week) efcacy of aclidinium bromide 200 mg and 400 mg BID (n 600, intent-to-treat population), improvements in trough FEV1 were maintained during ongoing treatment with both doses of aclidinium bromide [50]. Furthermore, clinically signicant improvements in health-related quality of life were sustained at Week 52 with both doses [50]. Similar benets on lung function and health status were also observed in a long-term (52-week) extension study of ACCORD COPD I [51]. At rest, patients with COPD show variable degrees of pulmonary hyperination; with exercise, incomplete emptying of the lungs and subsequent air trapping results in dynamic hyperination and worsening of dyspnoea and exercise tolerance. Furthermore, inspiratory capacity, as an indirect measure of hyperination, has been shown to correlate with subjective measures of quality of life [52,53] as well as with exercise tolerance and dyspnoea [53e55], all of which are factors important to patients daily living. Aclidinium bromide 200 mg QD signicantly improved exercise endurance time compared with placebo (P < 0.001) in patients with moderate to severe COPD in a 6-week randomized, double-blind, placebo-

controlled Phase II study (n 181) [56]. Inspiratory capacity was also signicantly improved with aclidinium bromide at Day 1 and Week 3 (both P < 0.05 vs placebo) and the likelihood of patients stopping exercise due to breathing discomfort was signicantly lower compared with placebo (P < 0.05) [56]. Aclidinium bromide has been tested in healthy volunteers at doses up to 6000 mg and was found to convert rapidly to two major inactive metabolites [57,58]. Maximum observed plasma concentration (Cmax) values were reached rapidly (time to Cmax [Tmax] 57 min) and were dose-dependent up to 4800 mg (greatly exceeding the clinical dose) [58]. In healthy volunteers, steadystate plasma concentrations of aclidinium bromide following BID dosing were achieved at Day 7, with no accumulation [59]. The effective t in healthy volunteers was 4.6e7 h [59]. A study in patients with impaired renal function showed no change in pharmacokinetic (PK) parameters after a single dose of aclidinium bromide 400 mg [60]; a similar observation was made in elderly patients compared with younger patients with 200 mg and 400 mg doses [61]. Aclidinium bromide also has no effect on heart rate or QTc interval at doses up to 800 mg [62]. The safety prole of aclidinium bromide BID has generally been very favourable and the incidence of anticholinergic AEs in patients receiving aclidinium bromide is comparable to placebo [47,48]. Furthermore, tolerability was maintained over the long term (52e64 weeks) [50,51], with a low incidence of cardiac AEs (<5%) reported [51]. These data suggest a promising safety prole for aclidinium bromide. The Genuair inhaler can be used for various monotherapy and combination inhalation drugs for COPD and asthma [63,64]. No apparent cardiovascular safety issues have been associated with aclidinium bromide delivered via Genuair in Phase III studies [47,48]. In two randomized, double-blind, double-dummy, crossover studies (n 109 total), more patients found Genuair easier to use than Aerolizer or HandiHaler and reported that dose preparation with Genuair was very easy compared with the other two inhalers (65% vs 24% for Genuair vs Aerolizer; 80% vs 53% for Genuair vs HandiHaler) [65]. Overall, more patients expressed a preference for Genuair compared with Aerolizer or HandiHaler (63% vs 6% for Genuair vs Aerolizer; 30% vs 7% for Genuair vs HandiHaler) [65]. Furthermore, in a study including 48 patients with COPD, chronic bronchitis or emphysema, the overall success rate (including opening the inhaler, preparing the dose and closing/cleaning the inhaler) was highest for Genuair (69%), followed by Diskus (67%), HandiHaler (35%) and Respimat (23%) [63]. 3.2. Glycopyrronium bromide Glycopyrronium bromide is in clinical development in a number of different formulations and by a number of pharmaceutical companies. A DPI formulation of glycopyrronium bromide (NVA237; Fig. 1) administered using Vecturas PowderHale technology (Seebri Breezhaler) is being developed as a QD treatment for COPD by Novartis, under licence from Sosei/Vectura. This compound has recently been approved in Europe and Japan as a QD inhaled maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD; ling with the US Food and Drug Administration is planned pending additional clinical data. To date, there are four Phase II and four Phase III (GLOW 1, 2, 3 and 4) studies in patients with COPD completed, plus an ongoing longterm safety and tolerability study. Glycopyrronium bromide has high, non-selective afnity for all ve muscarinic receptor subtypes [31,66]. The dissociation t at the M3 receptor is shorter than that of aclidinium bromide and glycopyrronium bromide demonstrates kinetic selectivity for M3 over

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M2, similar to other LAMAs in development (Table 1) [31,67]. In vitro, it has a shorter duration of action than both aclidinium bromide and tiotropium bromide [31,68]. Results from two Phase II, randomized, double-blind, placebocontrolled, crossover studies show that glycopyrronium bromide QD provides sustained and clinically signicant bronchodilation in patients with stable COPD [69,70]. In the study by Verkindre et al. (n 83), which included an open-label tiotropium bromide arm, glycopyrronium bromide (25e100 mg QD via a low resistance single-dose DPI) statistically signicantly (P < 0.0001) and dosedependently improved mean trough FEV1 compared with placebo; the effect was clinically signicant on Day 7 with the 50 mg and 100 mg doses [70]. Improvements in trough FEV1 were significantly greater with glycopyrronium bromide 100 mg compared with tiotropium bromide (P < 0.05) from 5 min to 4 h post-dose on Day 1, suggesting a faster onset of action for glycopyrronium bromide [70]. In the 26-week, randomized, double-blind, placebocontrolled Phase III (GLOW 1) study of glycopyrronium bromide 50 mg QD, administered via a low-resistance single-dose DPI (Concept1 device) (n 822), statistically signicant and clinically meaningful improvements in trough FEV1 were seen on Day 1, and at Weeks 12 and 26 with glycopyrronium bromide compared with placebo (all P < 0.001) [71]. Similarly, in the long-term (52-week) Phase III GLOW2 study (n 1066), glycopyrronium bromide 50 mg QD, administered via the Breezhaler device, provided statistically signicant improvements in trough FEV1 on Day 1, and at Weeks 26 and 52 compared with placebo (all P < 0.001) [72]. In both GLOW1 and GLOW2, glycopyrronium bromide 50 mg QD signicantly improved COPD symptoms (P < 0.05), reduced relief medication use (P < 0.05) and improved quality of life as assessed by SGRQ total score (P < 0.001) compared with placebo at the end of treatment [71,73]. The risk of rst moderate/severe COPD exacerbation and the time to the rst severe exacerbation requiring hospitalization were also signicantly reduced by glycopyrronium bromide (both P < 0.05 vs placebo) in both studies [71,74]. In GLOW3 (n 108), glycopyrronium bromide, from the rst dose, signicantly improved exercise endurance time compared with placebo (P < 0.001) [75]. To date, there are no reports describing the impact of glycopyrronium bromide on night-time symptoms. A randomized, double-blind, parallel-group Phase II PK study (n 40), showed that Cmax for glycopyrronium bromide was reached 5e6.5 min post-inhalation and the mean elimination t was 13e22 h [76]. Steady-state plasma concentrations were reached within 1 week of treatment [76]. No clinically relevant changes in electrocardiogram (ECG) parameters, vital signs or haematological prole were reported with therapeutic doses of glycopyrronium bromide [70]. In the studies reported to date, the safety prole of glycopyrronium bromide 50 mg (therapeutic dose) is comparable to placebo [70,74,77]. Pearl Therapeutics is developing an inhaled aerosol form of glycopyrronium bromide, GP-MDI, delivered by a pressurized metered dose inhaler (MDI); to date one Phase I and three Phase II studies have been completed. In a randomized, double-blind, placebo-controlled, crossover Phase II study (n 33), improvements compared with placebo in peak FEV1 and FEV1 AUC from time zero to 24 h (AUC0-24) with single doses of GP-MDI 72 mg or 144 mg were comparable to tiotropium bromide delivered by DPI [78]. A second Phase II study showed that GP-MDI 36 mg BID provides statistically signicant improvements in bronchodilation (P < 0.0001 vs placebo), comparable to tiotropium bromide delivered by DPI [79]. In both studies, GP-MDI was well tolerated and had a safety prole comparable to tiotropium bromide. Elevation Pharmaceuticals and PARI Pharma have an inhalation solution formulation of glycopyrronium bromide (EP-101) optimized for administration via PARI Pharmas investigational eFlow

nebulizer system in Phase II. Single doses of EP-101 (50e400 mg) statistically signicantly improved trough FEV1 compared with placebo in a Phase IIa randomized, double-blind, placebocontrolled, dose-nding study in patients (n 42) with moderate to severe COPD [80]. The incidence of AEs with EP-101 was similar to that with placebo and there were no clinically relevant changes in vital signs or ECG parameters. GOLDEN-1 (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer), a Phase IIb study, has been completed. Chiesi Farmaceutici is developing CHF-5259, an inhaled formulation of glycopyrronium bromide, also delivered using a pressurized MDI. A Phase I/II study (NCT01176903) was started in August 2010 to assess the safety and efcacy of single and repeated increasing doses of CHF-5259 compared with tiotropium in patients with moderate to severe COPD. No data from this study are available to date. 3.3. Umeclidinium (umeclidinium bromide) Umeclidinium, an inhaled powder formulation of umeclidinium bromide, is currently in Phase III clinical development for the treatment of COPD. To date, ve Phase II studies (NCT00515502, NCT01372410, NCT01030965, NCT01372410 and NCT00950807) of umeclidinium QD in patients with COPD have been completed; four studies compared umeclidinium monotherapy with tiotropium. A Phase III clinical trial investigating umeclidinium 62.5 mg QD and 125 mg QD has recently been completed (NCT01387230). In vitro, umeclidinium is a potent, competitive antagonist at recombinant M3 receptors and has a longer duration of action than tiotropium bromide in isolated bronchial strips (time to 50% restoration of contraction >600 min vs 413 min with 10 nM tiotropium bromide) [81]. In a Phase I PK study (n 36), the Tmax for umeclidinium delivered by DPI was 5e15 min and t at Day 14 was 26e28 h [82]. In a separate Phase I study (n 20), specic airway conductance was signicantly higher with umeclidinium 350 mg compared with placebo at 12 h and 24 h post-dose in ipratropium bromide-responsive healthy volunteers (n 36; delivery devices not stated) [83]. Umeclidinium QD provided statistically signicant improvements in trough FEV1 after 28 days compared with placebo (P < 0.001) in a randomized, double-blind, placebo-controlled Phase II study [84]. In a second, randomized, double-blind, placebocontrolled Phase II study (n 176), umeclidinium QD (62.5e 1000 mg) signicantly improved trough FEV1 compared with placebo after 14 days of treatment (P < 0.01) [85]. Improvements in lung function with umeclidinium QD were comparable to those seen with umeclidinium BID (62.5e250 mg) and tiotropium bromide. Umeclidinium QD also signicantly reduced the need for rescue medication compared with placebo [85]. Umeclidinium is well tolerated [85]; however, the incidence of drug-related AEs was shown to be dose related in a randomized, double-blind, Phase II study in patients with COPD (n 38) [86]. Umeclidinium 1000 mg QD produced larger increases in heart rate in the 4 h post-dose compared with umeclidinium 250 mg QD or placebo; there was no dose effect on heart rate when assessed over 24 h. 3.4. CHF-5407 Chiesi Farmaceutici is developing an aerolized formulation of CHF-5407 under licence from Laboratorios SALVAT. Similar to other LAMAs in development, CHF-5407 has subnanomolar afnity for human M1-3 receptors and no selectivity across receptor subtypes [32]. In vitro, the dissociation t of CHF-5407 at M3 receptors is comparable to tiotropium bromide (2.8 vs 2.7 h), but CHF-5407 dissociates from M2 receptors much more rapidly (0.5 vs 6.0 h). CHF-5407 produces long-lasting inhibition of carbachol-induced

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contractions in isolated human bronchus with a similar potency and duration of action as tiotropium bromide and a longer duration of action than glycopyrronium bromide [32]. In vivo, the bronchodilator prole of CHF-5407 is comparable to tiotropium bromide [32]. Phase I clinical trials of CHF-5407 are reported to be underway, although no development has been reported since 2007. 3.5. Other muscarinic receptor antagonists in development for respiratory disease TD-4208, an inhaled muscarinic receptor antagonist, is undergoing Phase II clinical development by Theravance; no study details are currently available. AZD8683 is being developed as a solution for inhalation by nebulization by AstraZeneca. Two Phase I studies and one Phase II study (NCT01205269) of AZD8683 in patients with COPD have been completed; no data are available. Pierre Fabre is developing V-0162 (Fig. 1) for the potential treatment of respiratory disease and a Phase I/II study of V-0162 in patients with COPD has been started (NCT01348555). LAMAs currently in the discovery phase include Theron Pharmaceuticals TRN-157, Ranbaxys RBx343E48FD and Pzers PF-4522971. 4. Combination therapies Combination therapy is recommended for patients with persistent COPD symptoms not controlled with monotherapy [4]. Fixed-dose combination formulations of both novel and established LAMAs with long-acting b2-agonists (LABAs) are being developed by a number of companies (Table 2). 4.1. QVA149 (glycopyrronium bromide/indacaterol) QVA149, a QD inhaled xed-dose formulation of glycopyrronium bromide (NVA237) and the LABA indacaterol, is being developed by Novartis, under licence from Vectura and Sosei. Two Phase II trials in patients with COPD are complete. At the time of writing, four Phase III trials have been completed and a further three Phase III studies are ongoing (NCT01490125, NCT01285492 and NCT0112061). Results from the rst randomized, double-blind, placebo-controlled, crossover Phase II study (n 154), showed that QVA149 (glycopyrronium bromide 50 mg/indacaterol 300 mg QD), via a single-dose DPI, provides sustained statistically signicant improvements in bronchodilation compared with either placebo or indacaterol alone (P < 0.001 vs placebo or indacaterol). The improvements in mean trough FEV1 exceeded predened MCIDs (100e140 ml) for QVA149 vs placebo and indacaterol [87]. The onset of action of QVA149 is rapid, and improvements in trough FEV1 over both placebo and indacaterol alone are seen as early as 5 min post-dose on the rst day of treatment [87]. In this study, QVA149 was well tolerated, although the incidence of AEs was slightly higher compared with indacaterol 300 mg or placebo (27.5%, 22% and 21.7%, respectively) [87]. No signicant differences in 24-h heart rate were seen for any dose of QVA149 (glycopyrronium bromide/indacaterol 100/300 mg, 300/100 mg or 100/150 mg) compared with placebo or indacaterol 300 mg alone in a 2-week randomized, double-blind, placebo-controlled, Phase II study (n 257) [88]. Similarly, there were no clinically relevant differences in mean QTc interval between treatment groups. Dry mouth was reported only in patients receiving QVA149. 4.2. Tiotropium bromide/olodaterol

completed, with seven Phase III studies ongoing. In vitro, olodaterol reverses airway contractions induced by a variety of stimuli and in vivo provides long-lasting bronchoprotection [89]. In vivo, the bronchoprotective effect and the duration of action of olodaterol against histamine-induced airway obstruction and the reversal of allergen-induced hyperresponsiveness in guinea pigs are markedly enhanced by co-treatment with tiotropium bromide [90,91]. A xed-dose combination of tiotropium bromide (5 mg) and olodaterol (10 mg), via Respimat, signicantly increased (P < 0.05) trough FEV1 compared with tiotropium bromide (5 mg) alone in a 4-week randomized, double-blind, parallel-group Phase II study (n 360) [92]; no safety or tolerability issues were identied. 4.3. Glycopyrronium bromide/formoterol PT003 (GFF-MDI) is an inhaled combination of PT001 (glycopyrronium bromide) and formoterol fumarate (PT005), delivered via hydrouroalkane-suspension MDI, being developed by Pearl Therapeutics. A Phase I study and three Phase II studies of GFF-MDI in patients with COPD have been completed. In the double-blind, single-dose, Phase I study, GFF-MDI was safe and well tolerated with a prole similar to that of glycopyrronium bromide or formoterol fumarate alone [93]. In a Phase II study (n 118), both doses of GFF-MDI assessed (glycopyrronium bromide/formoterol fumarate 36/9.6 mg and 72/9.6 mg BID) provided signicantly greater improvements in FEV1 AUC0-12 compared with placebo, glycopyrronium bromide 36 mg, formoterol fumarate 9.6 mg or 7.2 mg, or tiotropium bromide 18 mg alone (P < 0.001 for all comparisons) [94,95]. Both doses also signicantly improved trough and peak inspiratory capacity compared with tiotropium bromide (P < 0.05 for all comparisons) [94]. Mean home peak expiratory ow rate was signicantly improved with GFF-MDI 36/ 9.6 mg and 72/9.6 mg BID vs tiotropium bromide or formoterol fumarate, and the use of rescue medication was reduced with GFFMDI, compared with placebo and the active comparators [96]. The incidence of dry mouth with GFF-MDI was comparable to that in patients receiving tiotropium bromide [95]. 4.4. Umeclidinium/vilanterol An inhaled formulation combining umeclidinium and the LABA vilanterol is being investigated as a QD treatment for COPD by GlaxoSmithKline and Theravance. One Phase III study has recently been completed (NCT01313637) and three Phase III studies are ongoing (NCT0131690, NCT01316913 and NCT01313650). In a multicentre, randomized, double-blind, placebo-controlled, Phase II study (n 51), umeclidinium/vilanterol improved trough and serial FEV1 over 0e6 h compared with placebo [97]. Umeclidinium/ vilanterol was rapidly absorbed, with a median tmax of w6 min for both drugs and no evidence of accumulation on Day 28 vs Day 1 [97]. Furthermore, the umeclidinium/vilanterol combination was well tolerated with no serious AEs reported. In this study, umeclidinium/vilanterol was shown to be non-inferior to placebo for the primary endpoint of change from baseline in postdose (0e6 h) weighted mean pulse rate over 28 days. Furthermore, there were no clinically signicant differences between umceclidinium/vilanterol and placebo in terms of blood pressure, minimum and maximum heart rate, and QT interval corrected for Fridericias formula, and no apparent difference between treatments for abnormal ECGs [97]. 4.5. Other combination therapies in development

An inhaled combination of tiotropium bromide and the b2agonist olodaterol (BI-1744) is being developed by Boehringer Ingelheim. Three Phase II and two Phase III studies have been

A BID combination of aclidinium bromide/formoterol fumarate (LAS40464) is being developed by Almirall and Forest Laboratories.

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Two Phase II studies in patients with COPD are complete with four Phase III studies ongoing: NCT01437397 and NCT01462942 are 24week randomized, double-blind, placebo-controlled studies designed to assess the efcacy, safety and tolerability of two xeddose combinations of aclidinium bromide/formoterol fumarate compared with monotherapy and placebo in patients with stable moderate or severe COPD; NCT01437540 is a randomized, doubleblind, placebo-controlled study to assess the long-term safety and tolerability of a xed-dose aclidinium bromide/formoterol fumarate combination compared with formoterol fumarate alone; and NCT01572792 is a 28-week long-term extension study of NCT01439397. Boehringer Ingelheim is developing a xed-dose combination of inhaled tiotropium bromide plus BI 54903 (an inhaled corticosteroid [ICS]) delivered via Respimat; a 21-day Phase I trial (NCT01309139) has recently been completed. A number of companies, including Chiesi, have combination therapies at the discovery stage. In addition to dual combination therapies, triple therapies are being developed. Chiesis LABA/LAMA/ICS is in clinical development for the treatment of COPD, while Pearl Therapeutics is reported to be developing a combined formulation of glycopyrronium bromide/formoterol fumarate/ICS. No data are currently available for these triple therapies. 5. Bifunctional muscarinic receptor antagonists and b2adrenoreceptor agonists (MABAs) In addition to selective LAMAs, for use in mono- or combination therapy, novel pharmacophores with dual muscarinic receptor antagonist and b2-agonist activity combined within the same molecule are undergoing clinical development (Table 3).

5.2. Dual compounds in preclinical development A number of MABAs are currently in preclinical development. THRX-198321 is being developed by GSK, under licence from Theravance, for the treatment of asthma and COPD. THRX-198321 has high afnity at M2 and M3 muscarinic receptors and b2 adrenoceptors (pKi 10.6, 10.1 and 9.5, respectively) [99]. It acts as a competitive antagonist at muscarinic receptors and its agonist activity at b2 receptors is inhibited by propranolol [99]. PF-3429281 is a novel MABA being investigated by Pzer. In vivo PF-3429281 caused a dose-related inhibition of Ach-induced bronchoconstriction in anaesthetized guinea pigs that was not blocked by propranolol; non-cholinergic-mediated bronchoconstriction was also reversed by PF-3429281 supporting dual pharmacology [100]. In anaesthetized dogs, PF-3429281 inhibited Achinduced bronchoconstriction with a potency similar to ipratropium bromide [101]. Pzer is also investigating PF-4348235, a compound with subnanomolar afnity for human M3 receptors (Ki 0.8 nM) and potent agonist activity at b2 receptors (3.7 nM) [102]. In vivo, PF4348235 also inhibited the bronchoconstriction induced by either Ach or b-alanine neurokinin A, an effect which was not altered by infusion of propranolol [103,104]. Almirall has LAS190792 in preclinical development and AstraZeneca and Chiesi also have dual action compounds in their early pipeline. 6. Conclusions There is extensive evidence that LAMAs improve bronchodilation in patients with COPD. There is also evidence from studies with tiotropium bromide and the most advanced drugs in clinical development (aclidinium bromide and glycopyrronium bromide) that treatment with LAMAs concomitantly improves symptom control and health-related quality of life in these patients. Managing the impact of COPD on a patients quality of life is an important goal in the pharmacological treatment of the disease. Novel LAMAs, such as aclidinium bromide and glycopyrronium bromide, achieve maximal bronchodilation on the rst day of dosing or have a faster onset of action than tiotropium bromide, which may offer advantages in terms of improving symptom control. Patients also want improved control of early-morning and nocturnal symptoms, and the availability of efcacious treatments suitable for BID dosing should improve the choice of treatments available to manage COPD symptoms throughout both the day and night. While inhaled muscarinic receptor antagonists are reported to be associated with an increased risk of serious cardiovascular effects, no issues associated with cardiovascular safety have been identied with the most advanced compounds in development, suggesting that these compounds may have an improved safety prole. The incidence of characteristic anticholinergic AEs varies between compounds and is likely to be related to the systemic exposure of compounds, as evidenced by the lack of anticholinergic side effects seen with aclidinium bromide, which is rapidly hydrolyzed in plasma. However, overall, this class of compounds is well tolerated. Monotherapy remains the rst choice for maintenance treatment in patients with stable COPD [4] and the recent Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines suggest that LAMAs are an appropriate rst-line treatment option in patients classied as GOLD B-D [105]. However, LAMA/LABA combination therapy is recommended in patients with COPD who remain breathless or have exacerbations despite treatment with a LAMA or LABA, or for whom treatment with an ICS is not possible. The need for lower doses of each individual treatment in combination therapies may translate to a reduced risk of AEs and an

5.1. Dual compounds in clinical development GSK961081 is being developed by GSK under licence from Theravance. Four Phase I and three Phase II trials in patients with COPD have been completed. In a randomized, double-blind, double-dummy, placebo-controlled crossover study (n 50), both doses of GSK961081 (400 mg and 1200 mg QD; delivery device not stated) signicantly improved trough FEV1 compared with placebo (both P < 0.05) [98]. The safety prole of GSK961081 was similar to placebo and the active comparator (salmeterol 50 mg QD tiotropium bromide 18 mg BID), with the exception of tremor, dysgeusia and dry mouth, which were seen only in the GSK961081 groups [98]. AstraZeneca is developing AZD-2115 and a Phase I trial of an inhaled nebulizer formulation is complete (NCT01283984). A second Phase I trial (NCT01445782) and a Phase II trial (NCT01498081) are currently underway.

Table 3 Dual action muscarinic receptor antagonist/b2-agonists (MABAs) in clinical development. Summary GSK961081 Signicantly improved FEV1 compared with placebo, in patients with COPD. Safety prole comparable to placebo and active comparator; tremor, dysgeusia and dry mouth were reported No data available Current status Phase II Company GlaxoSmithKline

AZD-2115

Phase II

AstraZeneca

COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s.

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improved safety prole. Data from studies of novel xed-dose LAMA/LABA formulations do not indicate any additional safety risks compared with monotherapy, although there is currently no information available on the efcacy/safety prole of the two LAMA/LABA/ICS triple combination therapies in development. In addition to single inhaler xed-dose combination treatments, the recent identication of novel compounds combining both LAMA and LABA activity in a single molecule may offer benets in terms of providing efcacy similar to combination therapies, but with the potential for a better safety prole as the likelihood of drugedrug interactions will be reduced. This is an exciting development in the eld, but results from ongoing clinical studies with these compounds are necessary to assess the potential for this class of compounds to further improve the management of COPD. Although these developments are signicant advances, increasing the potential therapeutic options for patients with COPD, muscarinic receptor antagonists are still somewhat unselective across muscarinic receptor subtypes. The development of LAMAs with even greater kinetic selectivity for M3 receptors over M2 receptors would be another step forward, potentially improving the tolerability of this class of compounds further. While this review has focused on novel compounds in development for the treatment of COPD, effective clinical management of this condition is dependent on a number of other factors associated with formulation, drug delivery method and the patients themselves. In both COPD and severe asthma, the main site of airway obstruction is the small airways. Inhalers have a signicant inuence on the effectiveness of treatment, and advances in inhaler design and drug formulation aim to improve the efciency and reproducibility of drug delivery to these areas of the lungs [106]. In addition, an efcacious drug delivered by an efcient and targeted inhaler is only of use if patients are both willing and able to use the device correctly. In the clinical setting, the end goal is an inhaler product that controls the patients COPD. As the products outlined in this review come into the clinical setting, the increased treatment options available to the physician should help them to match efcacious drugs delivered by effective and efcient inhalers with patients individual preferences and ability to use the inhaler. Disclosures M Cazzola has received honoraria for speaking and consulting and/or nancial support for attending meetings from Abbott, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dey, GlaxoSmithKline, Lallemand, Menarini Farmaceutici, Mundipharma, Novartis, Nycomed (Takeda), Pzer, Sanovel, Sigma Tau and Valeas. M G Matera has received honoraria for speaking and consulting and/or nancial support for attending meetings from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Novartis, Nycomed (Takeda) and Pzer. C Page has no conict of interest to declare. Acknowledgements We thank Deborah McGregor, PhD, of Complete Medical Communications, who provided medical writing/editing support funded by Almirall, S.A., Barcelona, Spain. References
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