Bronchodilating Drugs for Chronic Obstructive Pulmonary Disease

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Bronchodilating Drugs for Chronic Obstructive Pulmonary Disease: Current Status and Future Trends Paolo Montuschi, and Giovanni Ciabattoni J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm5013227 • Publication Date (Web): 14 Jan 2015 Downloaded from http://pubs.acs.org on January 19, 2015

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Journal of Medicinal Chemistry

Bronchodilating Drugs for Chronic Obstructive Pulmonary Disease: Current Status and Future Trends

Paolo Montuschi*, Giovanni Ciabattoni† Department of Pharmacology, Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy

Running head: Bronchodilators for COPD

Keywords: inhaled anticholinergic antimuscarinic drugs, muscarinic receptors, inhaled muscarinic receptor antagonists, tiotropium bromide, ipratropium bromide, long-acting antimuscarinic agents, long-acting beta-agonists, beta2-adrenoceptors, inhaled corticosteroids, chronic obstructive pulmonary disease

Conflict of interest disclosure: The authors declare no competing financial interest.

Author for correspondence: Paolo Montuschi, M.D. Department of Pharmacology, Faculty of Medicine Catholic University of the Sacred Heart Largo Francesco Vito, 1 00168 Rome, Italy Tel: 39-06-30156092; fax: 39-06-30506292 e-mail: [email protected]

†

This article is dedicated to the loving memory of Professor Giovanni Ciabattoni, Master of Pharmacology, Science, and Life.

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Abstract Inhaled bronchodilators, including long-acting muscarinic receptor antagonists (LAMA) and longacting beta2-adrenoreceptor agonists (LABA), are the mainstay of pharmacological treatment of stable chronic obstructive pulmonary disease (COPD). Among approved LAMA, tiotropium bromide, glycopyrronium bromide and umeclidinium bromide, are administered once daily, whereas aclidinium bromide is administered every 12 hours. New LAMA are under development for COPD. Among the approved LABA, indacaterol has a 24-h duration of action, whereas salmeterol and formoterol require twice-daily administration. New once-daily LABA, including vilanterol, olodaterol, milveterol, carmoterol, and abediterol, are in development. LAMA/LABA fixed dose combinations (FDC) provide the convenience of two bronchodilators with different mechanism of action in a single inhaler. Indacaterol/glycopyrronium, umeclidinium/vilanterol and olodaterol/tiotropium FDC, have been approved or are under approval and are likely to become a standard pharmacological strategy for COPD. Dual-pharmacology compounds, combining muscarinic antagonism and beta2-agonism (MABA) in a single molecule, potentially provide additive or synergistic bronchodilation over either inhaled antimuscarinic or beta2-agonist monotherapy.

Introduction Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the world, is characterised by persistent airflow limitation that is generally progressive and associated with increased chronic inflammation in the airways and the lung caused by noxious particles or gases.1 The persistent airflow limitation is due to peripheral airways disease (obstructive bronchiolitis) and/or parenchymal destruction (emphysema).1 Pharmacological treatment of COPD can prevent and decrease symptoms (especially dyspnoea), reduce the frequency and severity of exacerbations, improve health status, and improve exercise capacity.1


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Drugs for maintenance treatment of stable COPD are shown in Figure 1. Bronchodilators administered by inhalation, which maximizes their direct effect on the airways, while minimizing their systemic effects, are the mainstay of pharmacological treatment of COPD.1,2 . Bronchodilator drug devices include pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), or nebulizers.1 pMDIs and DPIs simplify therapy, improve pharmacological compliance, and may reduce extra medication requirement and patient cost. When used correctly, the bronchodilator response is equivalent to that achieved with a nebulizer.1 However, for some patients, a nebulizer may be easier to use and may be necessary when proper pMDI technique is not possible.1 Bronchodilators include inhaled muscarinic acethylcholine receptor (mAcChR) antagonists and selective beta2-adrenoreceptor agonists.1,3,4 They are both available in short-acting and long-acting inhaled formulations.1,3,4 Inhaled mAcChR antagonists approved for the pharmacological maintenance treatment of stable COPD include ipratropium bromide [(1R,5R)-3-[(3-hydroxy-2-phenylpropanoyl)oxy]-8-methyl-8(propan-2-yl)-8-azabicyclo[3.2.1]octan-8-ium; C20H30BrNO3] (Figure 2A),3 oxitropium bromide (1R,2R,4S,5S,7s,9s)-9-ethyl-7-{[(2S)-3-hydroxy-2-phenylpropanoyl]oxy}-9-methyl-3-oxa-9azoniatricyclo[3.3.1.02,4]nonane bromide; C19H26BrNO4] (Figure 2B),3 tiotropium bromide [1a,2b,4b,5a,7b)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9azoniatricyclo[3.3.1.02,4]nonane bromide; C19H22BrNO4S2] (Figure 2C),3 aclidinium bromide [(3R)3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide; C26H30BrNO4S2] (Figure 3A),5 and glycopyrronium bromide (1,1-dimethylpyrrolidin-1-ium-3-yl) 2cyclopentyl-2-hydroxy-2-phenylacetate bromide; C19H28BrNO3) (Figure 3B).6

Ipratropium

bromide, the prototype of anticholinergic bronchodilators, is short-acting.3 Tiotropium bromide and glycopyrronium bromide, which are long-acting muscarinic receptor antagonists (LAMA), are administered once a day,3,6 whereas aclidinium bromide is administered every 12 hours.5 Umeclidinium

bromide

(4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-



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azoniabicyclo[2.2.2]octane bromide) (Figure 3C), has recently been approved for the maintenance treatment of COPD.7 New LAMA are in development for pharmacological treatment of COPD. The short-acting beta2-adrenoreceptor agonists (SABA), including salbutamol [alpha-[(tertButylamino)methyl]-4-hydroxy-m-xylene-alpha,alpha-diol; C13H21NO3] (Figure 4A), terbutaline [5(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol; C12H19NO3] (Figure 4B), and fenoterol [5[1-Hydroxy-2-[[2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-1,3-benzenediol;

C17H21NO4]

(Figure 4C), have a rapid onset of action and a bronchodilating effect which lasts 3-6 h.4 Twice daily long-acting beta2-adrenoreceptor agonists (LABA) licensed for COPD include salmeterol [2(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl] (Figure

5A)

and

formoterol

phenol;

C25H37NO4]

[N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-

ylamino]ethyl] phenyl]formamide; C19H24N2O4] (Figure 5B).1,4 Salmeterol, which is available as a racemic mixture of salmeterol xinafoate, has lower intrinsic activity than salbutamol and delayed onset of action, but its bronchodilating effect persist for 12 h and is dose-independent.1,4 Formoterol, which is available as formoterol fumarate in a single racemic diastereoisomer (RR, SS), has high intrinsic activity with rapid onset of action (similar to salbutamol), but its duration of action is dose-dependent.1,4 Due to their 12-hour duration of action, formoterol and salmeterol are used with a twice-daily dosing regimen.1,4 Arformoterol [N-[2-hydroxy-5-[(1R)-1-hydroxy-2[[(2R)-1-(4-methoxyphenyl) propan-2-yl]amino]ethyl] phenyl]formamide; C19H24N2O4] (Figure 5C), the active (R,R)-enantiomer of formoterol, is another LABA approved by the United States Food and Drug Administration (FDA) for treatment of COPD.1,4 Indacaterol [5-[(1R)-2-[(5,6diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one; C24H28N2O3] (Figure 5D), a once-daily third generation LABA, has been approved for long-term treatment of COPD in Europe and in the USA.4,8 Indacaterol is administered as inhalation powder through a DPI, has a 24-h duration of action and a once-daily dosing regimen.8 Newer ultra-LABA, including

vilanterol

[4-[(1R)-2-[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexylamino]-1

hydroxyethyl]-2-(hydroxymethyl) phenol; C24H33Cl2NO5] (Figure 6A), olodaterol [6-hydroxy-8ACS Paragon Plus Environment

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[(1R)-1-hydroxy-2-[[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino]ethyl]-4H-1,4-benzoxazin3-one;

C21H26N2O5]

(Figure

6B),

abediterol

[5-[(1R)-2-{[6-(2,2-difluoro-2-

phenylethoxy)hexyl]amino}-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one; m.w. C25H30F2N2O4] (Figure 6C), milveterol [N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[2-[4-[[(2R)-2-hydroxy-2-phenylethyl] amino]phenyl]ethylamino]ethyl]phenyl]formamide hydrochloride; C25H30ClN3O4] (Figure 6D), and carmoterol [8-hydroxy-5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]1H-quinolin-2-one; C21H24N2O4] (Figure 6E), are in development.4 Classification of COPD severity according to Global Obstructive Lung Disease (GOLD) guidelines includes four classes (A-D), based on intensity of symptoms, as measured by the modified Medical Research Council (mMRC) dyspnoea scale and/or the COPD Assessment Test, and risk of poor outcomes [identified by the degree of airflow limitation (class I-IV) and/or the frequency of exacerbations] in a three-dimensional evaluation.1 As regular long-term treatment with bronchodilators does not modify the natural history of COPD, no treatment is required in asymptomatic patients. In symptomatic patients, relief of dyspnoea and improvement in exercise tolerance and quality of life are the main achievable outcomes of therapy.1 Current guidelines suggest that all symptomatic patients with COPD should be prescribed a shortacting bronchodilator to be used on an as-needed basis.1 If symptoms are not adequately controlled with short-acting bronchodilator therapy, particularly in patients who have more advanced disease (GOLD stage II and higher), regular treatment with LAMA and/or LABA should be started.1 Inhaled LAMA and LABA, the principal drugs used in the chronic treatment of COPD, are the first choice in COPD patients with low risk for exacerbations, more symptoms, and forced expiratory volume in one second (FEV1) ≥ 50% predicted value (GOLD class B).1 In patients with severe lung function impairment (FEV1 ≤ 50% predicted value) and high risk for exacerbations, independently of symptom severity (GOLD patient category C and D), either treatment with a fixed dose combination (FDC) of LABA/inhaled corticosteroids (ICS) or tiotropium alone, a LAMA, is considered first choice.1 However, long-term treatment with ICS, as required by patients ACS Paragon Plus Environment


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with severe COPD, is associated with adverse effects including increased risk of fractures and pneumonia.1 For this reason, the risk/benefit ratio for combinations containing ICS should be carefully evaluated in patients with COPD. Anticholinergics act as competitive mAcChR antagonists, play an important role in the management of COPD and are frequently preferred over beta2-agonists for their minimal cardiac stimulatory effects and greater efficacy in most studies.1,4 Their therapeutic efficacy is based on the fact that vagally mediated bronchoconstriction is the major reversible component of airflow limitation in patients with COPD,9 which by definition is limited, as COPD is characterized by a fixed or poorly reversible airflow limitation.1 However a mixed phenotype, known as asthma-COPD overlap syndrome (ACOS), which can be characterized by a higher response to bronchodilators, has been recently identified.10 This COPD phenotype is defined by the presence of two major diagnostic criteria (history of asthma, sputum eosinophilia, very positive response to bronchodilators) or one major criterion and two minor criteria (high serum total IgE concentrations, history of atopy, positive response to bronchodilators).10 This review presents the current status of COPD treatment with mAcChR antagonists and beta2adrenegic receptor agonists, the most used bronchodilators in COPD, particularly focusing on the recently approved medicines, and new therapeutic perspectives for these drugs.

Pharmacological modulation of airway receptors Pharmacological modulation of the airway smooth muscle cell and mechanism of action of bronchodilators are shown in Figure 7.

Muscarinic acethylcholine receptors At least five subtypes of mAcChR, which belong to the superfamily of G-protein coupled 7transmembrane receptors, have been identified.11 Three receptor subtypes are expressed in the lung.11 M1 receptors, which are present on peribronchial ganglion cells, are responsible for “tonic” or slow response of these cells.9 Pre-synaptic M2 receptors on the postganglionic vagal nerve ACS Paragon Plus Environment

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endings are inhibitory autoreceptors and their activation leads to reduction in acethylcholine release from the nerve ending.9,11 M2 receptors are also expressed on airway smooth muscle cells.9 Activation of post-synaptic M2 mAcChR, through interaction with an inhibitory G-protein (Gi), reduces beta2 receptor-induced stimulation of adenylyl cyclase activity and the resulting airway smooth muscle relaxant effect (Figure 7).9 M3 receptors are expressed on effector cells including airway smooth muscle cells and submucosal gland cells.11 M3 receptor activation by acetylcholine and mAcChR agonists on airway smooth muscle and gland cells causes bronchoconstriction and increased tracheobronchial gland secretion, respectively.11 The parasympathetic bronchoconstrictor effect of the vagus nerve is directly mediated by M3 receptor activation on effector cells and indirectly mediated by activation of M1 mAcChR subtypes on ganglion cells (Figure 7).9 Vagal fibers synapse and activate nicotinic and M1 mAcChR in parasympathetic ganglion cells within the airway wall.9 Acetylcholine released by parasympathetic vagal nerve endings causes airway smooth muscle contraction by activating post-synaptic M3 mAcChR (Figure 7).9,11 Agonist/receptor complex activates a Gq protein which, in turn, enhances phospholipase(s) C (PLC) β activity. This enzyme catalyzes the production of the second messengers inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) (Figure 7).9,11 DAG activates protein kinase C, whereas IP3, by interacting with specific receptors on the endoplasmic reticulum mobilizes calcium ions (Ca2+) from intracellular stores into the cytoplasm (Figure 7).9,11 Both events ultimately facilitate actin-myosin interaction with consequent airway smooth muscle contraction (Figure 7).9,11 SAMA and LAMA cause bronchodilation principally by blocking post-synaptic M3 mAcChR (Figure 7).9 M3 mAcChR antagonists, competing with acetylcholine released from postganglionic vagal efferent nerves, which make synapse with airway smooth muscle cells in central airways, or from non-neuronal sources in the distal airways, inhibit bronchomotor tone thus causing airway



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relaxation.4,9 Blockade of M3 mAcChR on airway gland cells inhibits airway secretions, an effect which contributes to reduction in airflow limitation induced by SAMA and LAMA.11 As activation of M2 receptors has a pre-synaptic inhibitory effect that limits further release of acetylcholine and protects against parasympathetic-mediated bronchoconstriction,9,11 an ideal mAcChR antagonist would selectively block M1 and M3 receptors sparing M2 receptors (Figure 7). More selective inhaled muscarinic M3 mAcChR antagonists (e.g., aclidinium bromide and glycopyrronium bromide) might avoid increase in acetylcholine released due to pre-synaptic M2 blockade, but the lack of post-synaptic M2 antagonism might increase the M2-mediated inhibitory effect on beta2-induced bronchodilation (Figure 7).9 Whether selective inhaled M3 receptor antagonists are preferable over non-selective antimuscarinic brochodilators is controversial.9 M2 receptor antagonism enhances beta2-induced airway relaxation in in vitro human airways.12 By inhibiting cyclic adenosine monophosphate (cAMP) production, activation of post-synaptic M2 receptor subtypes, which are more numerous than M3 receptors on airway smooth muscle cells, might reduce by beta2 receptor-induced airway relaxation (Figure 7), an effect that would limit the therapeutic efficacy of inhaled selective M3 receptor antagonists as brochodilators in patients with COPD.9 On the other hand, with non-selective antimuscarinic bronchodilators, the increased acethylcholine release from vagal fibers caused by M2 inhibitory pre-synaptic receptor blockade would be counteracted by concomitant M3 receptor antagonism (Figure 7).9 However, the implications of M2 receptor modulation for the bronchodilatating effect in patients with COPD is mostly unknown as data on the functional role of M2 receptors have been principally obtained in in vitro and in vivo animal studies.

Beta2-adrenergic receptors SABA and LABA induce bronchodilation by activating beta2-adrenergic receptors on airway smooth muscle cells (Figure 7).13 Binding of endogenous agonists (e.g., cathecolamines), SABA, or LABA to the beta2-adrenergic receptor causes a conformational receptor change, stimulatory GACS Paragon Plus Environment

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protein (Gs) activation and subsequent enhanced adenylyl cyclase activity which catalyzes the production of cAMP from adenosine triphosphate (Figure 7).13 Increased intracellular cAMP concentrations activates protein kinase A triggering a cascade of intracellular events, including myosin light chain kinase inhibition, which ultimately leads to airway smooth muscle relaxation.13 Formoterol and salmeterol have a different pharmacodynamic profile, the main differences being their rate of onset of action and efficacy.14 Formoterol is much faster as about 70% of maximum bronchodilation is observed within 5 min of inhalation compared with nearly an hour for salmeterol.14 In vitro efficacy of LABA is expressed as intrinsic activity which is the maximal response of the test compound, relative to the maximum effect of the high efficacy agonist isoprenaline whose intrinsic activity, by definition, is 1.15 Salmeterol is a partial agonist while formoterol is a full agonist.14 A partial agonist has a lower intrinsic activity than a full agonist and requires greater receptor occupancy for a maximal response. Formoterol is significantly more effective than salmeterol.14,15 Intrinsic activity for formoterol is 0.97, that of salmeterol is 0.37.15 Emax (the maximal relaxant effect expressed as a percentage of the maximal relaxant effect induced by theophylline) of salmeterol on isolated human bronchus at resting tone is 70 ± 4% versus 93 ± 1% for formoterol.14 Indacaterol, a third-generation once-daily LABA approved by the European Medicines Association in December 2009 and by the US FDA in July 2011 for maintenance bronchodilator treatment in patients with COPD,4,8 has fast onset of action and its bronchodilation effect is clinically significant over 24 h.16 The debate on the mechanism for the long clinical bronchodilating effect exhibited by inhaled beta2adrenoreceptor agonists has been ongoing since the discovery and clinical use of salmeterol and formoterol in the early 1990s. Persistent airway smooth muscle relaxation by LABA after washout, the rapid disappearance of this effect following exposure to beta-receptor antagonists and its recovery after antagonist removal (“reassertion”) has been demonstrated in in vitro experiments.17 The microkinetic model, the exosite ACS Paragon Plus Environment


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model, and the rebinding model have been proposed for explaining the persistent bronchodilating effect of LABA.17 In the diffusion microkinetic model, which implies that LABA are constantly partitioned between the membrane and the surrounding aqueous phase depending on their degree of lipophilicity,18 the plasma membrane would act as a depot/reservoir for the LABA rather than merely providing an inert structural substratum for the receptor. Formoterol is continuously released from the lipid bilayer depot into the aqueous phase to interact with the active site of the beta2adrenergic receptor.19 The concentration of formoterol determines the initial size of the depot,19 which, in turn, determines the duration of action, that is the time lag during which a sufficient amount of this agonist can be released in the aqueous phase to cause effective airway smooth muscle relaxation in vitro.17 Because of its very high partitioning in synthetic plasma membranes and slow release from such membranes [half-life (t1/2) value of 25 min],18 salmeterol is thought to reach the receptor by lateral diffusion through the membrane and reach the central core of the receptor by lateral diffusion between the receptor’s membrane spanning hydrophobic alpha helices.20 Consistent with the microkinetic model, an even slower release of salmeterol from tracheal strips (t1/2 of 3 h) has been reported.21 The diffusion microkinetic model is sufficient to explain the persistent beta2-activation and reassertion observed at high concentrations of salmeterol.17 However, at lower concentrations of salmeterol, “exosite” binding and “rebinding” might be the most important mechanisms.17 The exosite model implies that the lipophilic phenylalkoxyalkyl side chain of salmeterol would be tightly bound to an accessory site (the exosite), located either close to the beta2-adrenergic receptor or even within the receptor molecule itself.17 This would keep the agonist in the immediate vicinity of the active site of the beta2-adrenergic receptor and cause its persistent activation. However, the existence of an exosite at the beta2-adrenergic receptor has not been demonstrated. The “rebinding” model assumes that dissociated salmeterol can reassociate to the same or other receptor molecules. The continuous shuffling of salmeterol between nearby beta2-adrenergic receptors would delay its escape from the membrane, thus, maintaining the pharmacological effect.17 ACS Paragon Plus Environment

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Structure-activity relationships Muscarinic receptor antagonists Inhaled mAcChR antagonists used as bronchodilators are generally quaternary ammonium synthetic derivatives of the natural tertiary ammonium compounds such as atropine, the prototype of mAcChR antagonists.9 Nevertheless, a novel tertiary amine series of potent M3 mAcChR antagonists have been described as potential inhaled long-acting bronchodilators for the pharmacological treatment of COPD.22 Quaternary ammonium compounds include ipratropium bromide, derived by the introduction of an isopropyl group to the N atom of atropine (Figure 2A),23 oxitropium bromide (Figure 2B), a derivative of scopolamine formed by the introduction of an ethyl group, and tiotropium bromide (Figure 2C).23 The structures of quaternary ammonium compounds (Figure 2) make them water soluble, but lipid-insoluble. Therefore, unlike the lipid-soluble tertiary ammonium compounds, these compounds do not easily cross biological barriers. Most of the pharmacological characteristics that distinguish quaternary ammonium compounds from atropine are due to lipid solubility.23 Being lipid-soluble, tertiary ammonium compounds are easily absorbed, and can cause significant systemic side effects, including effects on the central nervous system.23 In contrast, quaternary ammonium compounds are poorly absorbed after oral administration, do not cross blood-brain barrier and, for these reasons, are better tolerated.23 As quaternary mAcChR antagonist bronchodilators are administered topically by inhalation, the possible interference with neuromuscular transmission due to their greater nicotinic receptor selectivity, at doses that more closely approximate to those that cause muscarinic antagonism, has little, if any, relevance.23 From the structural point of view, mAcChR antagonist bronchodilators are characterized by an aromatic group, attached to an ester moiety (like in atropine and scopolamine) and a positively charged center, generally a protonated or quaternized nitrogen (Figure 2 and Figure 3).23 The optimal distance between the nitrogen and the carbonyl oxygen of 2,2-diphenylpropionate mAcChR ACS Paragon Plus Environment


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antagonists is estimated to be 4.4-5.9 Å.24 The long half-life of tiotropium (more than 24 h) is potentially due to interactions in the binding site; in particular, a highly directed interaction of the ligands' hydroxy group with an asparagine (N508(6.52)) prevents rapid dissociation via a snap-lock mechanism.25 Searching for novel antagonist bronchodilators, structures incorporating nitrogen containing rings (e.g., piperidine, pyrrolodine, or tropane) and an aromatic moiety (e.g., phenyl, thiophene, or biphenyl) separated by 4 to 6 carbon-carbon bonds have been identified.26,27 Lainé et al at GlaxoSmithKline characterized a novel series of tropane derivatives starting from compound 1a (Figure 8A) which has a hydroxyethyl group linking the tropane and the aromatic region.26 Initial results, leading to compound 1h (Figure 8B), showed that the C-3 endo configuration, a quaternary ammonium salt, and a two-carbon linker were preferred features around the tropane template.26 Structure-activity relationship (SAR) studies, undertaken by preparing a series of quaternary ammonium salts derived from compound 1h, suggest that the nature of the linker between the tropane ring and the aromatic rings is important for potency and in vivo efficacy.26 On this basis, the effect of substituting the linker at the C-20 position was explored.26 SAR optimization around the tropane scaffold lead to the identification of the quaternary ammonium salt 34 as a very potent M3 mAcChR antagonist (Figure 8C). This compound is functionally active and displays a duration of action greater than 24 h in a mouse model of bronchoconstriction.26 In another study, Lainé et al discovered novel 1-azoniabicyclo[2.2.2]octane mAcChR antagonists from structural changes of the [2.2.2] quinuclidine ring which has a positive center and two aromatic groups.28 The general strategy was based on the exploration of the linker length and connectivity point, substitution of the phenyl ring and nitrogen substituents, the ring size and the replacement of the hydroxyl group.28 SARs of the various compounds were explained by computational docking studies using a homology model of the M3 mAcChR.28 Among the identified compounds, compound 14o (GSK573719)28 (umeclidinium bromide) (Figure ACS Paragon Plus Environment

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3C) is a very potent, slow reversible M3 mAcChR antagonist with a very long in vivo duration of action (greater than 50% of bronchoprotection observed at 48 h) in a mouse bronchoconstriction model.28 3-Quinuclidinol esters are potent mAcChR antagonists.29,30 Quaternarization of the tertiary amino function, a common chemical manipulation of 3-quinuclidinol esters, minimizes absorption, resulting in low oral bioavailability and blood-brain barrier permeability.31 Revatropate, a (3R)quinuclidinol ester with a M3 and M1 selective antagonist activity (Figure 8D), entered phase II clinical trials for COPD, but its development was stopped likely due to its short duration of action.32 Quaternary ammonium derivatives of quinuclidinyl benzylate with aliphatic chains of different length on the N+ of the azoniabicyclo ring have antagonist activity at mAcChR.33 Prat et al at Almirall discovered a series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters.31 Among these compounds, aclidinium bromide was initially developed as once-daily maintenance treatment of COPD (Figure 3A).31 Two 2-thienyl substituents at R1 and a phenethyl chain or phenoxypropyl chain at R2 provide the highest affinity for the M3 mAcChR (0.18-1.62 nM).31 Quaternarization maintains or even improves the duration of action of these compounds.31 The presence of two 2-thienyl substituents on the R1 group and quaternarization of the (3R)quinuclidinol ester (aclidinium bromide) (Figure 3A) decrease compound stability in human plasma.31 Compounds with a hydroxyl substituent were less stable in human plasma than compounds with a methyl substituent.29 Aclidinium bromide is approved for pharmacological treatment of COPD. This potent mAcChR antagonist is rapidly hydrolyzed in human plasma, with minimal potential risks for class-related systemic side effects.31 In guinea pigs in vivo, its duration of action [defined as the time taken to reduce the maximal acethylcholine-induced bronchoconstriction achieved at 1 h by 50% (t1/2)] is 29 h.34 This duration of action is considerably longer than that of ipratropium (t1/2 of 8 h) and shorter than that of tiotropium (t1/2 of 64 h).34 However, as a single dose of aclidinium does not have a clinically significant brochodilating effect over 24 h, twice daily administration is required in patients with COPD.35 Interestingly, airway ACS Paragon Plus Environment


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antiremodelling effects of aclidinium bromide have been reported in in vitro and in vivo experimental models.36-38 In vitro studies show that aclidinium bromide inhibits human carbachol, transforming growth factor-beta and cigarette smoke-induced lung fibroblast-to-myofibroblast transition,36,37 a key step in peribronchiolar fibrosis formation which is part of lung remodelling in asthma and COPD and contributes to airflow limitation.37 Airway antiremodelling effects of aclidinium have also been observed in vivo as this drug inhibits smooth muscle enlargement in small airways and, to a lesser extent, airspace enlargement in guinea-pigs chronically exposed to cigarette smoke, an experimental model of COPD.38 Glossop et al at Pfizer identified compound 47 (PF-3635659)22 (Figure 9A) as a phase II clinical candidate from a novel tertiary amine series.22 Compound 47 is characterized by geminal dimethyl functionality which confers very long dissociative half-life from the M3 mAcChR in vitro.22 In vivo studies have confirmed that compound 47 has slow off-rate binding kinetics from M3 mAcChR making it potentially suitable for inhaled once-daily treatment of COPD.22 Combination of rapid oxidative clearance with targeted introduction of a phenolic moiety to enable rapid glucuronidation minimizes systemic exposure after inhalation and the consequent side effects.22 Searching for novel inhaled LAMA, Lainé et al identified a new series of N-substituted tropane derivatives which were characterized as potent M3 mAcChR antagonists.39 SAR at the M3 mAcChR of a N-substituted series of analogs of compound 1 (darotropium) (Figure 9B) have been studied.39 Quaternary salts 3-15 derived from darotropium were obtained as a mixture of two isomers.39 The N-endo derivatives possessing the pending chain on the same side as the C-3 substituent were more potent than N-exo isomers having the chain on the oposite side as the C-3 substituent.39 Initial results, indicating the importance of the stereochemistry at the tropan nitrogen, suggested that testing of the compounds as diasteroisomeric mixtures was not the best strategy.39 Therefore, subsequent SAR studies were focused on N-endo derivatives with linear alkyl chains of up to 7 carbon atoms that can be tolerated at the receptor pocket.39 Among the N-endo derivatives, compound 24 (Figure 9C) was selected for further evaluation based on its ability to form a stable ACS Paragon Plus Environment

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crystalline form with a high melting point (> 200°C), a desirable characteristics for a DPI drug as it can increase compound stability during the manufacturing processes.39 In kinetic washout studies at the human M3 cloned receptor and in human airway kinetic studies, the N-endosubstituted analog 24 displayed a very long off rate at the M3 mAcChR (off t50 > 600 min) that was considerably longer than the methyl-substituted parent molecule 1 darotropium (85 min).39 This profile translated into a much more persistent in vivo duration of action of compound 24 (> 96 h) compared with darotropium (about 48 h) as shown in a mouse plethysmography model.39 Longer duration of bronchoprotection observed with compound 24 is most likely due to its slower target off-rate.39 From a pharmacokinetic stanpoint, compound 24 has a very high systemic clearance and low bioavailability. These properties are required for a drug delivered by inhalation. Therefore, the introduction of alkyl chains on the tropane nitrogen of darotropium has enabled the identification of a novel class of mAcChR antagonists with a better potential for long-lasting duration of bronchodilation in humans.39 Nagashima et al at Astella Pharma have recently described the synthesis and pharmacological profiles of novel quinuclidinyl heteroarylcarbamate derivatives.40 Among them, the quinuclidin-4-yl thiazolylcarbamate derivative compound 43a (ASP9133)40 (Figure 9D) was identified as a promising LAMA showing more selective inhibition of bronchoconstriction versus salivation and more rapid onset of action than tiotropium bromide in a rat model.40 Peretto et al at Chiesi Farmaceutici reported the synthesis of diaryl imidazolidin-2-one derivatives.41,42

The

novel

quaternary

ammonium

salt

(3R)-3-[[[(3-fluorophenyl)[(3,4,5-

trifluorophenyl)methyl]amino]carbonyl]oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1azoniabicyclo[2.2.2]octane bromide, compound 50 (CHF5407)41 (Figure 9E), which initiated clinical development in 2007, shows a prolonged antibronchospastic activity, both in vitro and in vivo, caused by a very slow dissociation from M3 receptors, whereas is markedly short-acting at M2 receptors, a behavior not shared by tiotropium.43 This compound is being developed both as a single agent and in combination with compounds of other classes for the treatment of COPD. ACS Paragon Plus Environment


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Beta2-adrenergic receptor agonists Development of once daily bronchodilators is a priority in the LABA research programmes as these drugs would likely improve patient outcomes and compliance with pharmacological treatment. Unlike salbutamol, which is hydrophilic and has a rapid onset and short duration of action, salmeterol has an aryl alkyl group with a chain length of 11-atoms from the amine (Figure 4A). This bulkiness makes the compound more lipophilic and selective at the beta2-receptor. Similarly, formoterol is highly selective for the beta2 receptor and its lipophilicity contributes to its long duration of action. Due to their lipophilic properties, both formoterol and salmeterol remain in the airway tissues as a depot in close vicinity of the beta2-receptors and is postulated for their long duration of action (diffusion microkinetic model).17 From the structural point of view, salmeterol is about 25 Å long and preferentially accumulates in the outer monolayer of synthetic membranes wherein it assumes a highly specific orientation similar to the phospholipids.18,19 Salmeterol has a saligenin (arylethanolamine) head that is responsible for beta2-adrenergic receptor activation and an extended lipophilic phenylalkoxyalkyl side chain (Figure 10) that is not generally present in most LABA. SAR studies show that the position of the oxygen atom in the side chain does not affect the lipophilicity of salmeterol, but that it is essential for its long duration of action.19 These findings are consistent with the exosite model in which phenylalkoxyalkyl side chain of salmeterol would anchor the drug to an accessory site (the exosite) located either close to or even within the beta2-adrenergic receptor itself. The exosite’s ability to keep the phenylalkoxyalkyl side chain in place would enable the active saligenin head of salmeterol to continuously sneak in- and out of the active receptor site. The position of the oxygen atom in the alkyloxalkyl side chain would not affect the average depth of penetration of the whole salmeterol molecule in the membrane, but it could determine the depth of the “hinge” and, therefore, the efficiency of the docking process.44 Pharmacological characteristics required by novel inhaled LABA include 24 h bronchodilator effect in vivo which would make them suitable for once daily administration, high potency and selectivity ACS Paragon Plus Environment

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for beta2-adrenoceptors, low oral bioavailability (< 5%) after inhalation, high systemic clearance, and lipophilicity as compounds with a log D > 2 generally have a longer duration of action.45 From a pharmacokinetic point of view, increased lipophilicity could result in increased cell permability and subsequent increased oral absorption following inhalation, but also in high first pass metabolism, which would decrease oral bioavailability after inhalation.45 A homology model was built to facilitate the understanding of the SAR for LABA. Computational docking of compounds to the homology model was undertaken, by identifying “interacting” residues by receptor mutagenesis and molecular modelling studies.15,46 Based on this model, catechol mimic interacts with the serine residues 204 and 207 on the fifth transmembrane spanning domain (TM5), the benzyl alcohol interacts with the chirally discriminating Asn-293 on TM6 and the protonated amine with Asp-113 on TM3.15 Interaction between the methylene groups near the protonated amine of salmeterol and Tyr-308 on TM7 would be responsible for salmeterol beta2 selectivity.47 Moreover, Tyr-308 is the residue which defines the interactions of the amine substituents of carmoterol and formoterol.48 The ether oxygen in the phenylalkoxyalkyl side chain of salmeterol interacts with Tyr-31648 and, consequently, its 4-phenylbutyl ether group would interact with the exosite binding pocket which is defined by the amino acids at positions 149-158 on TM4.49 Baur et al at Novartis Pharma synthesized an 8-hydroxyquinolinone 2-aminoindan derived series of beta2-adrenergic receptor agonists which were assessed as inhaled once-daily long-acting bronchodilators.16 Determination of their activities at the human beta2-adrenergic receptor showed that symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta2-agonists.16 The 5,6-diethylindan analogue indacaterol (Figure 5D) possesses a unique profile which combines a rapid onset of action with a long duration of action in vitro.16 Further in vivo studies of indacaterol confirmed the sustained duration of action and showed a wide therapeutic index following pulmonary administration. For these reasons, this compound was selected as a ACS Paragon Plus Environment


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development candidate.16 Indacaterol is synthesized by combining the dihydroindeneamine region and the quinolinol region of the molecule.50 Beattie et al at Novartis Pharma described the synthesis of a series of indacaterol analogues, in which each of the three structural regions of indacaterol are modified in a systematic manner.51 Evaluation of the affinity of these analogues for the beta2-adrenoceptor identified the 3,4dihydroquinolinone and 5-n-butylindanyl analogues to demonstrate the most similar profiles to indacaterol.51 An α-methyl aminoindane analogue was discovered to be 25-fold more potent than indacaterol.51 Functional studies revealed an atypical beta2-adrenoceptor activation profile for this compound consistent with that of a slowly dissociating 'super agonist'.51 By incorporation of the arylsulfonamide groups on the right hand side phenyl ring of (R)salmeterol, Procopiou et al at GlaxoSmithKline obtained a series of very potent saligenin alkoxyalkylphenylsulfonamide beta2-adrenoceptor agonists.15 The (S)-enantiomer of metasubstituted primary sulfonamide was more potent than the para and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues.15 The onset and duration of action of selected compounds in vitro was assessed on isolated superfused guinea pig trachea. The primary sulfonamide at the meta-position (29b) (Figure 11) was identified as the analogue that fulfilled all the criteria of potency, selectivity, rapid onset, and long duration of action in vivo, low oral bioavailability, and higher therapeutic index than salmeterol.15 The cinnamate salt of 29b, which was found to have suitable properties for inhaled administration, was selected as a candidate for further development.15 The following interactions between sulfonamide 29b groups and beta2-adrenoceptor amino acid residues were found when sulfonamide 29b was docked in the model described previously: phenolic hydroxyl with Ser-207, benzylic hydroxyl with Ser-204 and Ser-203, asymmetric benzylic hydroxyl and Asn-293, ether oxygen in the side chain with Asn-318 (TM7), meta-sulfamido group with Ser-120 (TM3) and Asn-322 (TM7) (Figure 12).15 The sulfonamide tail was found to project down toward the exosite binding pocket, but no direct interaction was described.15 Postulated ACS Paragon Plus Environment

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interactions of the meta-sulfonamide 29b with the beta2-receptor derived from modeling studies were confirmed by crystal structure studies.52,53 Procopiou et al identified a series of saligenin beta2-adrenoceptor agonist antedrugs which possess high metabolic clearance by incorporation of an oxygen atom at the homobenzylic position of the right-hand side phenyl ring of (R)-salmeterol.54 Antedrugs act locally at the site of application, but, once absorbed into the systemic circulation, are transformed into inactive metabolites.54 This approach reduces potential systemic side effects, while maintaining efficacy. The compounds were screened for beta2, beta1, and beta3 agonist activity in CHO cells.54 The onset and duration of action of selected compounds in vitro were assessed on isolated superfused guinea pig trachea.54 The 2,6dichlorobenzyl analogue 13f, vilanterol (Figure 6A), fulfilled all the criteria of potency, selectivity, rapid onset of action on guinea pig trachea, long duration of action, rapid metabolism, and in vivo efficacy with a long duration that increased with increasing dose.54 The R-phenylcinnamate and triphenylacetate salts of vilanterol were found to have suitable properties for inhaled administration. For this reason, they were selected as candidates for further development.54 As they have never been used in marketed inhaled products, these salts underwent further toxicological investigation.54 Vilanterol trifenatate (compound 13f triphenylacetate) is currently undergoing clinical trials for the maintenance treatment of COPD and asthma, as a combination with umeclidinium bromide (approved for COPD) or fluticasone furoate or both.7,54 Due to its bronchodilating effect which lasts over 24 h in patients with asthma, vilanterol is potentially suitable for once daily administration.55 All interactions between vilanterol groups and beta2-receptor amino acid residues, derived from modeling studies and confirmed by crystal structure studies, were similar to those reported for compound 29b.15,54 The benzylic ether oxygen on vilanterol, which is not present on 29b, shows the same interaction with Ser-120 (TM3) and Asn-322 (TM7) as the meta-sulfonamido group on 29b.15,54 The hypothesis for the persistence and reassertion profile of vilanterol is more than likely based on the microkinetic model17,18 as the calculated log P value for vilanterol (3.2) is similar to that of salmeterol (3.1).56 However, dissociation kinetics in a recombinant expression system is not ACS Paragon Plus Environment


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sufficiently slow to explain the duration of action of vilanterol.56 Further studies combining radioligand binding, mutagenesis/receptor modelling (based on the crystal structure determined for the beta2-adrenoceptor-G protein αs complex exposed to a range of structurally distinct LABA), and functional studies in basic and more complex physiological systems are required to clarify the mechanism(s) of action which explain the long-lasting bronchodilating effect of vilanterol and other LABA.56 Searching for new ultra-LABA, Brown et al at Pfizer synthesized and characterised a novel series of saligenin analogues.45,57,58 Compound 5 belongs to a series of indole compounds (Figure 13A).58 In compounds 11, the indole linker has been replaced by a phenyl acetic group (Figure 13B),45 whereas in compound 7, an adamantyl group has replaced the dichlorophenyl group of compound 11 (Figure 13C).57 Compound 5 has equivalent, whereas compound 7 and 11 have greater potency and duration of action than salmeterol in guinea pig trachea in vitro.45,57,58 All compounds are potentially safer than salmeterol due to their lower oral bioavailability after inhalation.45,57,58 This was achieved by introducing amide functionality with high hydrogen bonding potential to reduce oral absorption while maintaining high hepatic metabolism through phase I cytochrome P450 enzymes.45,57,58 For optimum potency the saligenin template required R,R-stereochemistry, αmethyl substitution and N-H indole bearing amide substituion at the 2-position.58 As these compounds are iso-lipophilic with salmeterol, their long duration of action could be explained by the diffusion microkinetic hypothesis.45,57,58 Although indole derivatives have less conformational flexibility, their structural similarity to salmeterol would also be compatibile with the exosite hypothesis.45,58 Based on “inhalation by design” strategy, that includes searching for compounds combining oncedaily LABA (ultra-LABA) characteristics with the solid form attributes required by delivery in a DPI device, Glossop et al at Pfizer identified of a novel series of selective and potent sulfonamide derived beta2-adrenergic receptor agonists.59 The key design feature is the incorporation of a sulfonamide group in the headgroup of target compounds structurally similar to a previous saligenin ACS Paragon Plus Environment

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series.59 The identified compounds elicit very long-lasting smooth muscle relaxation in guinea pig trachea strips.59 From this series, compound 38 (PF-610355) was identified as a clinical candidate (Figure 13D). As compound 38 is isolipophilic with salmeterol, its long duration of action could be explained, at least partially, by the diffusion microkinetic model.59 Compound 38 might also access the proposed beta2-receptor exosite and this might explain its long lasting effect on airway smooth muscle. Although the sulfonamide template has less conformational flexibility than salmeterol, when the beta2-adrenergic receptor agonist headgroups are superimposed, the aromatic tail residues occupy similar regions of space (Figure 14).59 From a SAR point of view, the position of the amide group in compound 38 (Figure 13D) could have a similar significance to the ether oxygen atom in the salmeterol tail (Figure 10).59 Introduction of a phenolic moiety optimizes the pharmacokinetic profile, including a rapid phase II clearance through glucuronidation,59 which minimizes systemic exposure after inhalation, thus, reducing systemic adverse effects. In vivo studies confirm that compound 38 has long duration of action which makes it potentially suitable for once-daily administration.59 In phase Ib clinical trials, compound 38 provides a 24 h bronchodilating effect in healthy subjects, confirming compound 38 as a once-daily LABA.59 Compound 38 has achieved positive proof-of-concept for the treatment of asthma and COPD and is currently in phase II clinical studies.59 Bouyssou et al and Hoencke et al at Boehringer Ingelheim Pharma identified novel beta2-agonists with a 5-hydroxy-4H-benzo[1,4]oxazin-3-one moiety as head group (Figure 15).60-62 The template compound 1 has a 5-hydroxy-4H-benzo[1,4]oxazin-3-one moiety at its left-hand side and a phenethylamine residue with two geminal methyl groups at the carbon atom next to the amine at its right-hand side (Figure 15A).61 This structure is similar to the amine portion of formoterol.61 Systematic chemical variations at the phenethylamine group of these compounds lead to the discovery of compound 6m, a potent, beta2-adrenoceptor full agonist with a high beta2/beta1selectivity (Figure 15B).61 Molecular modeling revealed an interaction between the carboxylic acid group of 6m and a lysine residue (K305) at the extracellular end of the beta2-receptor TM7 as ACS Paragon Plus Environment


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putative explanation for its high selectivity.61 In a guinea pig in vivo model, compound 6m demonstrated a bronchodilating effect lasting over the complete study period of 5 h.61 However, a significant increase in heart rate (> 10%) was observed at doses of 10 µg/kg, required for achieving maximal bronchodilation. By contrast, the first dose required for reaching the maximal effect observed with formoterol was 10-fold lower (≥ 1 µg/kg) than that required to cause tachycardia (10 µg/kg).61 Development of compound 6m was stopped because of its inferior safety margin compared with formoterol.61 Shifting the phenolic hydroxyl group of the beta2-agonist from the para- to the meta-position with respect to the ethanolamine substituent provides a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones with a considerably optimized profile.62 Compound (R)-4p (olodaterol) (Figure 6B), which was identified from a series of 6-hydroxy-4Hbenzo[1,4]oxazin-3-ones (Figure 15C), is a highly potent and selective beta2-agonist.62,63 Olodaterol causes dose-dependent bronchodilation in a guinea pig in vivo model.62 Up to 10-fold above the first dose required for reaching maximal bronchodilation, no cardiovascular side effects are observed.62 Olodaterol and formoterol have a similar therapeutic index.62 The (R) enantiomer of olodaterol has a duration of action over 24 h in dog and guinea pig in vivo models of bronchoprotection with no systemic effects including decrease in serum potassium concentrations and increase in serum glucose and lactate concentrations.62 Despite a log D value of 1.2 (at pH 7.4), olodaterol has a long lasting bronchodilating effect,62 indicating that lipophilicity is not necessarily a requirement for inhaled once-daily LABA.62 In a model of bronchoprotection in dogs, olodaterol showed a superior safety margin compared with formoterol, as equally effective doses of olodaterol were not associated with systemic metabolic effects and tachycardia was less pronounced than that observed with formoterol.62 Olodaterol has favourable pharmacokinetic properties. Olodaterol systemic availability is low as suggested by the lack of metabolic side effects after inhalation. This was confirmed by pharmacokinetic data showing low permeability in vitro and low oral bioavailability (3 ± 2%) after ACS Paragon Plus Environment

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oral administration in rats.62 The physical-chemical properties of a crystalline hydrocholride salt of (R)-olodaterol are compatible with a formulation in a DPI and in a Soft Mist Inhaler as an aqueous solution.62 Olodaterol is currently approved for the once-daily maintenance treatment of COPD in Canada and Russia and under approval evaluation in other countries including EU and USA.63 Connelly et al at AstraZeneca synthesized and characterised a new potential once-daily LABA by modifying the dual DA2/beta2-agonist sibenadet structure (Figure 16A).64 Addition of a benzylic hydroxyl group increases selectivity at the dopamine receptor, potency, and intrinsic activity.64 Incorporation of a second base along the chain improves pharmacokinetic profile.64 Plasma half-life was optimized by modifying lipophilicity.64 Due to its bronchoprotection effect in guinea pig in vivo which lasts 24 h, compound 16 is potentially suitable for once daily administration (Figure 16B).64 A di-hydrobromide salt of compound 16, which has acceptable inhaled characteristics, is currently in development.64 Compound 31 (Figure 16C), a potent, effective, and selective beta2adrenoreceptor agonist, has been identified from a similar series of novel dibasic compounds.65 Compound 31 has a duration of action longer than that of salmeterol and formoterol and similar to that of indacaterol in a bronchoconstriction guinea pig model.65 Based on these results, compound 31 was progressed into development for further studies as the bis-malonate salt.65

Developing new bronchodilators: “inhalation by design” strategies “Inhalation by design” has been implemented in the development of new bronchodilators in order to improve their pharmacokinetic/pharmacodynamics profile.22,54,59,66 This drug discovery strategy aims at identifying molecules with high potency to achieve a low inhaled drug dose (≤ 1 mg), a clinically significant duration of bronchodilating effect, high clearance and low oral absorption to minimise systemic exposure and consequently potential side effects, multiple routes of clearance to minimise the effect of drug interactions, and characteristics of physical form suitable for a DPI including high crystallinity and compatibility with lactose, the commonly used excipient,59 and good long-term stability and high degree of delivered dose reproducibility.66 Complying with the ACS Paragon Plus Environment


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latter two features is technically more challenging for low-dose highly potent compounds including formoterol.66 For this reason, beta2-agonists with intermediate potency facilitate manufacturing of formulations suitable for a final drug product.66 This is particularly relevant as beta2-agonists are frequently co-formulated in FDC with other drug classes (e.g., LAMA and/or ICS).66 Inhalation by design has been used for developing novel tertiary amine muscarinic M3 receptor antagonists with slow off-rate binding kinetics22 and novel ultra-long-acting β2-adrenoreceptor agonists which utilise a sulfonamide agonist headgroup.59 Introduction of alkyl chains on the tropane nitrogen led to the discovery of a novel class of mAChR antagonists with a better likelihood to achieve long-lasting bronchodilation in humans.39 Moving from the lipophilicity and metabolism based hypotheses, which are part of the inhalation by design strategy, Beattie et al firstly described the chiral synthesis of a 4-hydroxybenzothiazolone based series of beta2-adrenoceptor agonists which were used for preparing a library of N-substituted analogues.66 This approach led to the identification of beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents with the potential to be fast onset and long-acting beta2-agonist inhaled bronchodilators with improved therapeutic margins.66 Development of new bronchodilators relying on antedrugs which are active in the airways, but once absorbed are inactivated, has been proposed to synthesize a series of beta2-adrenoceptor agonists prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of hydroxyl-protecting group, alkylation, and final deprotection.54

Approved muscarinic receptor antagonists for COPD: pharmacological and clinical aspects Short-acting muscarinic antagonists (SAMA) Ipratropium bromide Ipratropium bromide is a polar non-lipophilic quaternary ammonium SABA (Figure 2). Unlike atropine, which is a non-polar lipophilic tertiary amine, ipratropium bromide is poorly absorbed from the lungs or the gastrointestinal tract and does not inhibit mucociliary clearance.23 For this ACS Paragon Plus Environment

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reason, treatment with ipratropium bromide in patients with COPD avoids the increased accumulation of lower airway secretions and the antagonism of beta-agonist-induced enhancement of mucociliary clearance that occurs with atropine.23 Even at doses much higher than those recommended, ipratropium bromide causes little or no change in heart rate, blood pressure, bladder function, intraocular pressure, or pupillary diameter.3,23 This selectivity reflects the very low absorption of the drug from airway or gastrointestinal mucosa.23 Ipratropium bromide was first introduced in a pMDI form and then in a solution for nebulized administration.3 Each puff of the pMDI with hydrofluoroalkane as a propellent provides 21 µg of ipratropium bromide (delivered dose from the valve equivalent to 17 µg of ipratropium bromide from the mouthpiece). The recommended dose from the pMDI is 2 puffs 4 times a day, but the medication is well tolerated at much higher doses.3 Each 2.5 ml unit dose of the nebulized solution contains 500 µg of ipratropium, the recommended dose to be given 3 to 4 times per day.3 Ipratropium bromide does not seem to induce tachyphylaxis, and, therefore, its efficacy is not blunted over years of regular use.3 Ipratropium bromide improves dyspnoea, increases exercise tolerance, and improves pulmonary function and gas exchange in patients with COPD.3 However, ipratropium bromide does not possess anti-inflammatory properties and does not modify the natural history of COPD in terms of lung function or mortality.3,67 The Lung Health Study prospectively evaluated the effect of smoking cessation with or without ipratropium bromide treatment on the decline of lung function in 5887 smokers with COPD.68 In this study, ipratropium bromide was the bronchodilator of choice due to its low frequency of side effects, relatively long duration of action, and demonstrated bronchodilator efficacy in patients with COPD.3,68,69 Regular treatment with inhaled ipratropium bromide produced increased FEV1, an effect that was evident at the end of the first year and maintained for the succeeding 4 years. However, improvement in lung function did not increase over time and appeared to reverse within a few weeks of suspension of treatment with ipratropium bromide.68 These results reflect the ACS Paragon Plus Environment


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relatively short-term, pharmacologically mediated change in lung function attributable to the ipratropium bromide. As this effect is presumably available at any time during the course of COPD, these results support the treatment with bronchodilators for symptomatic benefit, including improvement in dyspnoea and exercise tolerance. Ipratropium bromide was found to be superior to a beta-agonist in a randomized, double-blind, multicenter study in 260 patients with COPD which showed ipratropium bromide had higher efficacy and longer duration of action than metaproterenol.69 Moreover, ipratropium bromide can produce significant bronchodilation in patients who do not respond to inhaled beta2-agonists.70 In a randomized, double-blind, trial conducted in 183 patients with moderate to severe COPD who received either ipratropium alone (80 µg, 3 times per day), formoterol, or placebo for 12 weeks, ipratropium bromide improved pulmonary function, increased exercise capacity, and decreased dyspnoea and cough compared to placebo. 71 Treatment with ipratropium bromide may also improve the quality of life in patients with COPD. In a multicenter, double-blind, randomized study conducted in 223 patients with COPD, the efficacy of nebulized ipratropium bromide (500 µg) was compared with nebulized salbutamol (2.5 mg) (each taken 3 times daily for up to 85 days).72 Clinical improvement was noted in both groups, but treatment with ipratropium bromide was associated with a greater symptomatic benefit and higher score on quality of life questionnaires.72 The rationale of combination therapy with ipratropium and beta2-agonists relies on the fact that the degree of bronchodilation achieved with SABA and anticholinergics is additive. In fact, mAcChR antagonists act predominantly on the proximal large airways, whereas beta2-agonists act on the more distal small airways. Moreover, the two classes of drugs cause bronchodilation via complementary mechanisms. Beta2-agonists cause bronchodilation by activating beta2-adrenergic receptors on airway smooth muscle cells with subsequent binding to Gs protein, increased adenylyl cyclase activity and increased intracellular cAMP concentrations. Ipratropium bromide causes bronchodilation principally by antagonizing the effects of acethylcholine released by vagal fibers ACS Paragon Plus Environment

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on M3 mAcChR on airway smooth muscle cells with subsequent binding to Gq protein, PLC activation, increased synthesis of IP3 and DAG, and increased intracellular calcium concentrations and PKC activation.

Combination treatment with ipratropium bromide and salbutamol Concomitant treatment with ipratropium bromide and SABA provides the relatively persistent effect of the former and the rapid onset of action of the latter. The efficacy of their combined effect is exploited at intermediate times. When bronchodilators with different mechanisms of action are used at the recommended doses in patients with COPD, combination treatment generally provides more pronounced bronchodilation than does the administration of single drugs.73,74 In one crossover trial conducted in 863 patients, combination treatment with ipratropium bromide and salbutamol resulted in peak FEV1 that was 24% higher than that achieved by salbutamol monotherapy and 37% greater than that achieved with ipratropium bromide monotherapy.74 In another large randomized trial conducted in 534 patients with COPD who were assigned to receive either salbutamol alone, ipratropium bromide alone, or salbutamol plus ipratropium, combination treatment resulted in mean peak FEV1 increase greater than that obtained with either drug alone, but did not change the frequency of COPD exacerbations.73 In contrast, a similar study reported that ipratropium bromide plus salbutamol decreased the frequency of COPD exacerbation compared with salbutamol alone, but not ipratropium bromide alone.75 Due to availability of LAMA such as tiotropium bromide and glycopyrronium bromide which provide 24 h bronchodilation,3,6 regular use of ipratropium bromide alone for long-term maintenance treatment of stable COPD is not common and not recommended by GOLD guidelines.1 However, pMDIs containing a FDC of ipratropium bromide and salbutamol are commercially available and are the short-acting bronchodilator standard of care for COPD treatment.



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Once daily long-acting muscarinic antagonists (LAMA) Tiotropium Tiotropium bromide is about 15-fold more potent [dissociation constant (KD) = 0.014 nM) than ipratropium bromide (KD = 0.204) at the human M3 mAcChR, and dissociates more slowly from the M3 receptor (t1/2 = 34.7 h) than from the M2 (t1/2 = 3.6 h) and the M1 receptor (t1/2 = 15 h), resulting in a “kinetic” selectivity.76 This mechanism explains the much more prolonged duration of action of tiotropium bromide, which produces sustained bronchodilation for as long as 24 h with once-daily dosing,77 as opposed to 6–8 h after each dose of ipratropium bromide. Tiotropium bromide is a LAMA that was initially introduced in a dry powder formulation (delivered in single doses via the Handihaler, one puff once daily, single capsules each containing 18 µg of tiotropium) and, more recently, in a novel, multidose micronebulizer device for delivering drug as a soft mist in single doses of 3.124 µg, equivalent to 2.5 µg of tiotropium, two puffs once daily (Respimat).4 Efficacy and safety of tiotropium bromide in patients with COPD have been shown in a systematic review and meta-analysis of nine trials of at least 12 weeks duration including 8000 patients.78 Tiotropium bromide has a longer duration of action than ipratropium bromide and enables a more convenient dosing schedule for patients with COPD.79 In one randomized study including 288 patients with severe COPD who received either tiotropium bromide once daily or ipratropium bromide four times per day, significantly greater bronchodilation was achieved and significantly less rescue salbutamol was used in the tiotropium bromide group.80 Continuous treatment with tiotropium bromide seems to be well tolerated and is associated with fewer acute COPD exacerbations and hospitalizations,81 decreased dyspnoea,82 reduction in lung hyperinflation at rest and during exercise,83 and improved overnight arterial oxygen saturation compared with placebo.84 The lack of an immediate bronchodilator response does not correlate with long-term outcome measures as reported in a large 1-year randomized placebo-controlled trial with tiotropium


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bromide,85 in which patients with COPD who were treated with tiotropium bromide had improved pulmonary function and less dyspnoea than patients who received placebo. Understanding Potential Long-term Impacts of Function with Tiotropium (UPLIFT) study, the largest and longest randomized placebo controlled trial with tiotropium bromide, included 5993 patients with moderate to severe COPD who were followed for up to 4 years.86 Patients were allowed to use concomitant respiratory medication, including LABA, ICSs and theophylline, throughout the trial, but not SAMA.86 The trial primary endpoints, that is annual rate of decline in pre-bronchodilator and post-bronchodilator FEV1, were not achieved.86 However, sustained improvement in pre-bronchodilator and post-bronchodilator trough FEV1 (87–103 and 47–65 ml, respectively) and trough forced vital capacity (170–204 and 32–65 ml, respectively) over placebo was observed with tiotropium bromide at each time point (30 days and every 6 months thereafter) throughout the 4 year-trial.86 Importantly, whereas treatment with tiotropium bromide did not modify the rate of decline in FEV1, it did result in persistent improvement in pulmonary function so that mean pre-bronchodilator FEV1 at the end of the 4 years of the study was not inferior to that observed at baseline.86 These beneficial effects on pulmonary function tests were achieved in spite of the fact that more 70% of the patients with COPD were being treated with a LABA and an ICS and 35% used theophylline concomitantly during the trial.86 These results imply that tiotropium bromide provides additional benefits to these commonly used maintenance respiratory pharmacological treatments. A subgroup analysis conducted in the 2739 patients with GOLD stage II (moderate) COPD included in the UPLIFT study showed persistent tiotropium-minus-placebo improvements over the 4-year trial in pre- and post-bronchodilator FEV1 (100–118 and 52–81 ml, respectively; p < 0.0001 at all time points) which were numerically greater than those achieved in those patients with more severe COPD.87 These results provide a strong rationale for treating GOLD stage II COPD patients with tiotropium bromide. The same subgroup analysis reported a modest, but significant, lower rate of decline in the post-bronchodilator FEV1 in the tiotropium bromide group than in the placebo group ACS Paragon Plus Environment


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(43 ± 2 ml vs 49 ± 2 ml, respectively; p = 0.02).87 A further analysis of the UPLIFT study showed that, compared with placebo, the benefits of tiotropium bromide in terms of pre- and postbronchodilator FEV1, COPD exacerbation risk, and quality of life were present irrespective of smoking status.88 However, the effect size varied among current smokers, intermittent smokers, and continuing ex-smokers.88 In another post-hoc analysis of the UPLIFT study, a lower risk of mortality was observed in the tiotropium group [hazard ratio (HR), 0.84; 95% confidence interval (CI), 0.73–0.97] at the end of the protocol-defined treatment period (p = 0.034), but not 30 days thereafter (p = 0.086).89 Treatment with tiotropium bromide reduces COPD exacerbation rate as reported in several studies. In a 12-month multicenter trial including more than 1000 COPD patients, tiotropium bromide increased the time to the first exacerbation expressed in months by approximately 100 days, reduced the proportion of patients with at least one COPD exacerbation by 17% and decreased the number of exacerbations by 35% compared with placebo.90 In the UPLIFT study, compared with placebo (median 12.5 months, 95% CI, 11.5 to 13.8), treatment with inhaled tiotropium bromide [18 µg once daily through a DPI] for 4 years delayed the time to the first exacerbation (median 16.7, 95% CI, 14.9 to 17.9) (HR 0.86, 95% CI 0.81–0.91).86 Tiotropium bromide also caused a significant delay in the time to the first hospitalization for a COPD exacerbation (HR 0.86, 95% CI, 0.78 to 0.95) and a reduction in the mean number of exacerbations of 14% (p < 0.001).86 In a study assessing the effect of a 12-month treatment with tiotropium bromide vs placebo on exacerbations and sputum and serum inflammatory markers in 142 patients with COPD, tiotropium bromide was associated with a 52% reduction in the rate of exacerbations per patient year (1.17 ± 2.25) compared with placebo (2.46 ± 3.82; p = 0.007).91 Treatment with tiotropium bromide also caused a significant delay in the time to the first COPD exacerbation (236 ± 143 days) compared with placebo (157 ± 124 days; p = 0.009).91 There were no differences in sputum interleukin (IL)6, IL-8, and myeloperoxydase, or serum IL-6 and C-reactive protein measured as inflammatory markers between the two treatment arms.91 These findings suggest that the decreased exacerbation ACS Paragon Plus Environment

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rate does not seem to be related to a reduction in airway or systemic inflammation as reflected by the inflammatory markers included in this study.91 Data from 13 randomised controlled trials including 6078 subjects showed that treatment with tiotropium bromide reduced COPD-related exacerbations [odds ratio (OR) 0.76, 95% CI 0.68– 0.87] and hospital admissions (OR 0.59, 95% CI: 0.47–0.73) compared with placebo.92 In a randomized, controlled, multicenter, international trial, 7376 patients with moderate to very severe COPD who had experienced at least 1 exacerbation in the previous year, were treated with either tiotropium bromide or salmeterol for 12 months.93 Tiotropium bromide was more effective than salmeterol in increasing the time to first COPD exacerbation (trial primary outcome measure) (tiotropium: 187 days; salmeterol: 145 days, corresponding to a 17% reduction in risk with tiotropium (HR, 0.83; 95% CI, 0.77 to 0.90; p < 0.001), in increasing the time to first severe exacerbation, and in reducing the number of moderate or severe exacerbations during the 12month study period.93 No significant differences in mortality or adverse events were observed between the treatment groups.92 Data on pulmonary function were not provided in this study.93 In the INSPIRE study, the relative efficacy of tiotropium bromide [18 µg once daily trough a DPI] vs a LABA/ICS FDC [salmeterol/fluticasone propionate, 50/500 µg twice daily through a DPI (Diskus)] in preventing exacerbations and related outcomes in severe and very severe patients with COPD was compared.94 Tiotropium bromide monotherapy was as effective as salmeterol/fluticasone FDC on the exacerbation rate, as the modeled annual exacerbation rate was not significantly different between the salmeterol/fluticasone group and the tiotropium group (1.28 vs 1.32, respectively; p = 0.656).94 On the other hand, treatment with salmeterol/fluticasone FDC was associated with significantly lower mortality (p = 0.032), but a higher number of pneumonias relative to tiotropium (p = 0.008).94 These results reinforce data derived from the UPLIFT study in which treatment with tiotropium bromide was not associated with an increased incidence of pneumonia.86



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Tiotropium bromide improves health-related quality of life as assessed by the St. George’s Respiratory Questionnaire (SGRQ). In a meta-analysis, a higher proportion of patients with COPD exhibiting an improvement of at least 4 units (which is considered clinically significant) has been reported with tiotropium bromide compared with placebo and ipratropium bromide, but not salmeterol.78 A 1-year study including 913 patients with COPD confirmed these results as treatment with tiotropium bromide significantly improved the SGRQ total score compared with placebo (40.9 units vs 43.7 units, respectively; p < 0.01).95 The difference in the proportion of tiotropium bromide vs placebo patients with COPD who had at least 4-unit improvement in SGRQ total score (53% vs 44%, respectively) approached statistical significance (p = 0.052).95 In another study, more tiotropium-treated (59.1%) than placebo-treated patients with moderate to severe COPD (48.2%, p = 0.029) achieved a reduction of at least 4 units in the SGRQ total score after 9 months of treatment.96 In the UPLIFT study, the proportion of COPD patients with at least 4 units improvement in the SGRQ total score at 4 years was 45% with tiotropium bromide and 36% with placebo (p < 0.001).86 In a 12-week study evaluating the effect of tiotropium bromide on dyspnoea in a small sample of patients with moderate to severe COPD, tiotropium resulted in a clinically meaningful numeric improvement in Transition Dyspnoea Index (TDI) compared with placebo, but statistical significance was not achieved due to the small sample size.97 Treatment with tiotropium bromide also improved exercise tolerance measured by the incremental shuttle walking test (36 ± 14 m increased walking distance compared with placebo; p < 0.05).97 In patients with stable COPD, tiotropium bromide as well ipratropium bromide seems to provide greater bronchodilation and improvement in dyspnoea than LABA.98,99 Moreover, in a large parallel group study comparing tiotropium bromide, salmeterol and placebo in over 1200 patients with COPD, tiotropium treatment resulted in a significant delay in the time to first exacerbation and fewer exacerbations per year than treatment with salmeterol or placebo.98


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Although further studies are required for verifying these results and extending the observations of the above mentioned trials to all the subgroups of COPD patients, the available evidence provides important information to clinicians regarding the choice of an initial inhaled long-acting bronchodilator for patients with moderate to very severe COPD.

Glycopyrronium bromide Glycopyrronium bromide (NVA237) (Seebri) (Figure 3B) is a once daily, fast-acting LAMA which is approved in several countries, including the EU, as a maintenance bronchodilator for the symptomatic pharmacological treatment of patients with COPD.6 It is delivered as capsules for inhalation through a SDDPI (Breezehaler).6 Each capsule contains 63 µg of glycopyrronium bromide, equivalent to 50 µg of glycopyrronium, the active principle, and each delivered dose, that is the amount of drug that leaves the inhaler, contains 55 µg of glycopyrronium bromide, equivalent to 44 µg of glycopyrronium.6 The pharmacological profile of glycopyrronium bromide has been recently reviewed.6 Glycopyrronium bromide is a competitive mAcChR antagonist which has higher affinity for human M1 and M3 receptors than for the human M2 receptor under in vitro physiological conditions (equilibrium binding affinity constants of 9.60 and 9.59 vs 8.70, respectively).100 Its M3 selectivity ratio, that is ratio of the affinity constant for the M3 receptor vs that for the M2 receptor, is 7.76-fold, which is higher that that reported for tiotropium bromide (2.09-fold).100 However, selectivity ratios lower than 10 are generally of limited pharmacological significance and may have little, if any, clinical relevance. Dissociation half-life of glycopyrronium bromide from the M3 (11.4 min; kinetic off rate 0.061 per min) and M1 receptors (13.9 min; kinetic off rate 0.05 per min) is slower that that from the M2 receptor (1.07 min; kinetic off rate 0.646).100 M3 kinetic selectivity ratio, that is the ratio of the area under the simulated association and dissociation curves for the M3 receptor vs that for the M2 receptor, reported for glycopyrronium bromide is 11.41-fold, whereas that reported for tiotropium bromide is 4.30fold.100 ACS Paragon Plus Environment


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Onset of action of glycopyrronium bromide in vitro is 2.5-4.8-fold faster than that of tiotropium.100 The fast bronchodilating action of glycopyrronium bromide was confirmed in a phase II study in which patients with moderate to severe COPD who were treated with glycopyrronium bromide (50 µg) had post-dose FEV1 values from 5 min to 2 h on the first day of treatment significantly higher than those observed in patients who were receiving tiotropium bromide [18 µg through a DPI].101 However, no between group difference was observed after 7 days of treatment.101 In one in vivo experimental animal study, tiotropium bromide provided more effective inhibition of acetylcholine-induced bronchospasm than aclidinium bromide and glycopyrronium bromide 24 h after administration of each drug at equivalent doses.101 Bronchoprotection was 35% with tiotropium bromide, 21% with aclidinium bromide, whereas no bronchoprotection was observed with glycopyrronium bromide at 24 h.102 In another pre-clinical study, tiotropium bromide caused 70.6% inhibition of acetylcholine-induced bronchospasm 24 after drug administration, whereas the inhibitory effect of glycopyrronium bromide was 29.7%.103 The clinically significant bronchodilating effect of glycopyrronium bromide and tiotropium bromide has been attributed to their long residency time at the M3 mAcChR.102 However, recent in vitro experiments performed under more physiological conditions reported much shorter dissociation half-lives for glycopyrronium bromide (11.4 min) and tiotropium bromide (46.2 min)100 than those previously reported under non-physiological conditions (at room temperature, in the absence of sodium ions) (glycopyrronium bromide: 173 min; tiotropium bromide: 462 min).102 There results are in contrast with the hypothesis that the clinically observed 24 h bronchodilating action of LAMA is directly related to the residency time at the receptor, pointing out that in vitro receptor binding kinetics are only one variable in the complex pulmonary pharmacology and cannot reliably predict the duration of effect of inhaled drugs.104 The “rebinding” model, based on restricted diffusion of free drug molecules away from the airway vagal cholinergic neuroeffector junction, which would allow freshly dissociated ligands to “rebind” to the same receptor and/or


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receptors nearby,105 might explain how glycopyrronium bromide and tiotropium bromide maintain their 24 h duration of bronchodilating effect, despite their rapid kinetic off rates.100 Phase II studies showed that inhaled glycopyrronium bromide administered via DPI at doses of 100 and 200 µg once daily provides clinically significant 24 h bronchodilation with a rapid onset of action and a favourable safety and tolerability profile.106 Phase III clinical trials using a singledose DPI showed that glycopyrronium bromide has low systemic absorption resulting in a low potential for systemic side effects, including inhibition of salivary secretion,106 and confirmed its long duration of action, which makes it suitable for once daily dosing, as well as a rapid onset of bronchodilation.101,104,106 Effects of glycopyrronium bromide on pulmonary function seem to be similar to those of tiotropium bromide.106 In a randomized, double-blind, placebo-controlled, twoperiod, crossover, multicenter trial, 33 patients with COPD received glycopyrronium bromide 50 µg once daily followed by placebo or placebo followed by glycopyrronium bromide 50 µg for 14 days.104 Treatment with glycopyrronium bromide was well tolerated and resulted in significant and sustained 24-h bronchodilation.104 Efficacy and safety of glycopyrronium bromide were also assessed in a randomized, double-blind, placebo-controlled, four-period, incomplete block crossover study, with open-label tiotropium bromide as active comparator, conducted in 83 patients with stable moderate-to-severe COPD.101 Patients received glycopyrronium bromide at a dose of 12.5 µg, 25 µg, 50 µg or 100 µg, placebo, or tiotropium bromide at a dose of 18 µg once daily for 7 days.101 The primary endpoint was mean trough (23-24 h post-dose) FEV1 on day 7. Mean trough FEV1 on day 7 and day 1 was significantly higher with all active treatments compared with placebo (p < 0.05).101 Glycopyrronium bromide 50 µg, 100 µg and tiotropium bromide provided clinically relevant improvements over placebo on day 7 and day 1.101 On day 1, but not day 7, FEV1 was significantly higher (p < 0.05) with glycopyrronium 50 µg and 100 µg vs tiotropium from 5 min up to 2 and 4 h post-dose, respectively.101 All doses of glycopyrronium bromide and tiotropium bromide were well tolerated. These results confirm that glycopyrronium



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once-daily is effective and well tolerated versus placebo, and has a rapid and sustained 24-h bronchodilator effect.101 In the randomized, controlled, phase III GLOW (GLycopyrronium bromide in chronic Obstructive pulmonary disease airWays clinical study)-1 and GLOW-2 studies, including 822 and 1066 patients, respectively, treatment with inhaled glycopyrronium bromide at a dose of 50 µg once daily was associated with a significant improvement in pulmonary function over placebo in patients with moderate to severe COPD as reflected by increased trough FEV1 at 12 weeks (primary endpoint).107,108 This effect was maintained for up to 52 weeks.108 Secondary outcome measures including dyspnoea scores, health status and exacerbation rates were also improved to a greater extent in the inhaled glycopyrronium bromide group than in the placebo group.107,108 In the randomized, controlled, phase III GLOW3 trial, treatment with inhaled glycopyrronium bromide induced a significantly longer exercise endurance time than placebo after 3 weeks’ treatment in patients with moderate to severe COPD.109 The drug was generally well tolerated over the 26-week (GLOW1) or 52-week (GLOW2) study duration,107,108 and had a tolerability profile that was similar to that of tiotropium bromide.110 Serious adverse events were consistent with those expected in patients with moderate to severe COPD.110

Twice daily LAMA Aclidinium bromide A novel series of (3R)-quinuclidinol esters were synthesized and characterized as mAcChR antagonists.31 Aclidinium bromide, a potent and selective mAcChR antagonist, interacts rapidly with muscarinic receptors31 and its association rate for the M3 mAcChR is similar to that of ipratropium bromide and 2.6 times faster than that of tiotropium bromide.111 Aclidinium bromide dissociates slightly faster from M2 and M3 mAcChR than tiotropium, but much more slowly than ipratropium bromide.111 Residence half-life of [3H]aclidinium at the M2 mAcChR was shorter than that at the M3 mAcChR, indicating kinetic selectivity for the M3 receptor.111 A potent ACS Paragon Plus Environment

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bronchodilatory effect has been observed after inhalation of aclidinium bromide.111 Clinical trials have demonstrated that aclidinium bromide provides a sustained bronchodilation similar to that observed with tiotropium bromide and confirmed the positive safety profile of aclidinium bromide, particularly in terms of a very low propensity to cause antimuscarinic adverse events.5 Aclidinium bromide, administered in a multidose DPI (Genuair), is rapidly hydrolysed once absorbed into the plasma,31 which enhances its safety profile.112 However, as its duration of action at the doses employed in phase III clinical trials does not provide a clinically significant bronchodilation over 24 h, inhaled aclidinium bromide has been proposed for registration and approved with a twice daily regimen.5 The pre-determined dose of aclidinium bromide is 400 µg (equivalent to 343 µg of aclidinium), whereas each delivered dose, that is the amount of drug that leaves the inhaler, contains 375 µg of aclidinium bromide, equivalent to 322 µg of aclidinium.5 The long-term efficacy and safety of aclidinium bromide were recently investigated in patients with moderate to severe COPD in two double-blind, placebo-controlled 52-week studies.113 At 12 and 28 weeks, aclidinium bromide significantly improved trough FEV1 compared placebo, an effect which was maintained over the 52-week study period.113 A higher number of patients with COPD in the aclidinium group than in the placebo group had a SGRQ improvement (greater than or equal to 4 units) at 52 weeks.113 The time to first COPD exacerbation was significantly delayed by aclidinium bromide. Adverse events were minor in both studies, more frequently nasopharyngitis and headache.113 In another randomised, placebo-controlled study aclidinium bromide significantly improved exercise tolerance, airflow obstruction and lung hyperinflation, and was safe and well tolerated.113

Safety and potential risks In spite of the minimal impact of ipratropium bromide and tiotropium bromide on heart rate and blood pressure, possible adverse cardiovascular effects of inhaled antimuscarinic drugs in patients



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with COPD have raised concern. Conflicting results have been reported in multiple studies and meta-analyses.86,115-117 The UPLIFT study randomized patients to either tiotropium bromide delivered through a DPI or placebo in addition to other, unrestricted respiratory medications for 4 years.86 In this study, treatment with tiotropium bromide was associated with a significantly lower rate of cardiac adverse events (risk ratio (RR) 0.84; 95% CI, 0.73-0.98)86 and reduced cardiac mortality (relative risk 0.81; 95% CI, 0.60-1.10 as established by a mortality adjudication committee; relative risk 0.80; 95% CI, 0.76-0.99 as established by site investigator).118 The risk of cardiovascular events was further examined using the clinical trial safety database for tiotropium, which monitored 19545 patients with moderate to severe patients with COPD (including the UPLIFT data).117 Patients were randomly assigned to tiotropium or placebo group in a total of 30 trials.117 No increase in all-cause mortality, cardiovascular mortality, or cardiovascular events was observed in the tiotropium group.117 Data from two cohorts of patients with COPD, a cohort including patients prescribed tiotropium bromide and a historic cohort including patients seen before the introduction of tiotropium, suggested that treatment with tiotropium was associated with a reduced all-cause mortality risk when combined with ICS plus LABA versus a medication regimen of ICS plus LABA (HR 0.60; 95% CI, 0.45–0.79), but with an increased all-cause mortality risk when tiotropium was combined with other medication regimens, including ipratropium bromide and theophylline (HR, 1.38; 95% CI, 1.06-1.81).119 Nevertheless, data from this observational study must be considered with caution as they could be confounded by differences in COPD severity and smoking status. In contrast, in a prior meta-analysis of 17 randomized trials (12 tiotropium and 5 ipratropium trials) including nearly 15000 patients with COPD, but not those enrolled in the UPLIFT trial, treatment with ipratropium bromide or tiotropium for more than 30 days significantly increased the risk of myocardial infarction (RR 1.53; 95% CI, 1.05-2.23) and cardiovascular death (RR 1.80; 95% CI, 1.17-2.77).115 However, the possibility that ipratropium bromide and tiotropium bromide ACS Paragon Plus Environment

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have different effects on cardiovascular events should be considered. The potential effect of ipratropium bromide on cardiovascular events was examined in a cohort study of 82717 United States veterans with COPD who were followed from 1999 to 2002.116 The HR for cardiovascular events among patients with COPD who had 4 or fewer 30-day prescriptions for ipratropium bromide was 1.40 (95% CI, 1.30-1.51), and the HR among those with more than 4 30-day prescriptions for ipratropium bromide was 1.23 (95% CI, 1.13-1.36).116 However, the case cohort design results in several limitations on data interpretation. Further data on the safety of ipratropium bromide are needed to draw definitive conclusions. Randomized trials in which cardiovascular endpoints are specifically sought and pre-defined are required. In the meantime, any potential for cardiovascular risk should be balanced against the known benefits of inhaled mAcChR antagonists which include reduction in frequency of exacerbations and hospitalizations for COPD, and improvement in dyspnoea. In a systematic review and mixed treatment comparison meta-analysis of 42 randomised controlled trials including 52516 patients with COPD, tiotropium bromide soft mist inhaler was associated with increased risk of overall death compared with placebo (OR 1.51; 95% CI, 1.06 to 2.19), tiotropium DPI (OR 1.65; 95% CI, 1.13 to 2.43), LABA (OR 1.63; 95% CI, 1.10 to 2.44) and LABA/ICS (OR 1.90; 95% CI, 1.28 to 2.86).120 The risk was more pronounced for cardiovascular death, in patients with severe COPD, and at a higher tiotropium soft mist inhaler daily dose.120 Treatment with LABA/ICS was associated with the lowest risk of death among all treatments.120 No excess risk was observed with tiotropium DPI or LABA.120 In a systematic review and metaanalysis of 5 randomized clinical trials, treatment with tiotropium soft mist inhaler was associated with increased risk of mortality (RR 1.52; 95% CI, 1.06 to 2.16; P = 0.02). Both 10 µg (RR 2.15; 95% CI, 1.03 to 4.51; p = 0.04) and 5 µg (RR 1.46; 95% CI, 1.01 to 2.10; p = 0.04) doses of tiotropium bromide mist inhaler were associated with an increased risk of mortality.121 To formally address this safety issue, a randomized, double-blind, parallel-group trial (Tiotropium Safety and Performance in Respimat, TIOSPIR) involving 17135 patients with COPD was undertaken to ACS Paragon Plus Environment


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evaluate the risk of death of tiotropium soft mist inhaler at a once-daily dose of 2.5 µg or 5 µg, as compared with tiotropium DPI at a once-daily dose of 18 µg.122 During a mean follow-up of 2.3 years, tiotropium soft mist inhaler was noninferior to tiotropium DPI with respect to the risk of death (tiotropium soft mist inhaler at a dose of 5 µg vs tiotropium DPI: HR, 0.96; 95% CI, 0.84 to 1.09; tiotropium soft mist inhaler at a dose of 2.5 µg vs tiotropium DPI: HR, 1.00; 95% CI, 0.87 to 1.14).122 Causes of death and incidences of major cardiovascular adverse events were similar in the three groups.122 This study shows that tiotropium soft mist inhaler at a dose of 5 µg or 2.5 µg has a safety profile similar to that of tiotropium DPI at a dose of 18 µg in patients with COPD.122 However, considering overall mortality or composite cardiovascular endpoints might mask differences in cause-specific mortality.123 The significant association between the use of tiotropium soft mist inhaler at a dose of 5 µg once daily and fatal myocardial infarction among patients with COPD in the TIOSPIR trial, as reported by a recent post-hoc analysis,123 raised further concerns about the cardiac safety of tiotropium soft mist inhaler. However, analysis of nonfatal and fatal myocardial infarction did not yield definitive evidence for an elevated risk among patients in each tiotropium soft mist inhaler group in isolation.123 Reasons for apparent increased risk of mortality associated with tiotropium soft mist inhaler as compared with tiotropium DPI are unknown.122 Lung deposition of tiotropium delivered through soft mist inhaler is likely higher than that of tiotropium delivered through DPI as shown by the fact that a daily dose of the former (5 µg) is more than 3 times lower than that of the latter (18 µg). The potential increased risk of mortality, particularly cardiovascular,123 with tiotropium soft mist inhaler compared with tiotropium DPI120,121 might suggest that a daily dose of tiotropium soft mist inhaler of 5 µg once daily might be too high and/or that COPD patients with cardiovascular comorbidities (e.g., ischemic heart disease, arrhythmias) might be more susceptible to tiotropium soft mist inhaler.123 Adverse events other than cardiovascular effects are reported in some studies. A pooled clinical trial analysis of tiotropium safety, including 4435 patients who were treated with tiotropium bromide and 3384 patients who received placebo, revealed dry mouth (RR 3.60; 95% CI, 2.56– ACS Paragon Plus Environment

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5.05) as one of the most commonly reported adverse events.124 Urinary retention was a rare event (incidence rate of 0.78 per 100-patient years in tiotropium-treated patients), but the RR for this event was 10.93 (95% CI, 1.26–94.8).124 Other known side effects of muscarinic receptor antagonists, including constipation and visual blurring, occurred infrequently.124 The type and frequency of adverse events reported in the UPLIFT trial86 are similar to those reported in the pooled analysis of previous clinical trials.124

Approved beta2-adrenoceptor agonists for COPD: pharmacological and clinical aspects Short-acting beta2-agonists (SABA) Salbutamol Salbutamol, the prototype of SABA, has a rapid onset of bronchodilating effect (within 5 minutes) which generally peaks within 30 minutes and start decreasing after 2 h. Duration of action of salbutamol is 3 to 6 h.4 Salbutamol is a partial agonist with a mean Emax of 47% of the maximal effect of isoprenaline at human beta2-adrenoceptors in vitro.

Twice daily LABA LABA alone or in combination with LAMA are effective drugs in patients with stable COPD (see reference 1 for individual studies).1 Efficacy of LABA has been assessed principally through the impact of these drugs on pulmonary function, although the bronchodilating response in patients with COPD is limited by definition.1 As spirometry is currently recognised as a poor predictor of disability and quality of life, therapeutic efficacy should also be assessed by other variables and outcomes of importance to the patient including symptoms, quality of life, frequency of exacerbations, COPD progression and mortality.1 In most of the randomized clinical trials, LABA monotherapy has been compared with LABA/ICS combination.1



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All LABA approved for COPD (salmeterol, formoterol, indacaterol) improve pulmonary function.1,125-132 LABA improve pre-bronchodilator FEV1 compared with placebo, with an effect size that ranges from 50 to 90 mL.130-131 In patients with COPD, formoterol and salmeterol improve symptom control as assessed by a reduction in diary card symptom scores and requirement for rescue bronchodilator treatment.1,125,130,131 However, less consistent results are reported when validated scales of dyspnoea are used.1 Studies evaluating the effect of LABA on exercise tolerance are relatively few. However, both formoterol and salmeterol significantly improve exercise tolerance through amelioration of dynamic hyperinflation,133,134 an exercise-induced air trapping which significantly contributes to exercise limitation caused by intolerable dyspnoea. LABA improve peripheral airway patency and, as a consequence, the rate of lung emptying, thus reducing the functional residual capacity (FRC). Breathing at a lower FRC, in turn, decreases the work of breathing while placing the respiratory muscle in a more favourable geometric arrangement for their pressure generating capacity. The combination of the reduced work of breathing with improved respiratory muscle performance results in increase of exercise tolerance and reduction of dyspnoea. LABA-induced bronchodilation, independently of the FEV1 changes, is associated with a significant reduction in FRC resulting in increased inspiratory capacity (IC).134 IC is inversely correlated with dyspnoea as assessed by the Visual Analog Scale or the Borg scale and positively correlated with exercise capacity.135 Therefore, the improvement in the exercise capacity in patients with COPD does not seem to depend principally on changes in FEV1, but on improvement in IC as a consequence of decreased FRC.135 As it may reflect COPD severity more accurately than FEV1, general health status is an important summary endpoint. Treatment with inhaled formoterol130 or salmeterol131 has been reported to significantly improve health-related quality of life, as assessed by the SGRQ, compared with placebo.1 On the contrary, other studies have not shown a significant effect of formoterol and salmeterol on quality of life.1,136 ACS Paragon Plus Environment

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In a meta-analysis comprising 14 randomized clinical trials including 6453 patients with COPD, salmeterol or formoterol significantly reduced exacerbations requiring study withdrawal or hospitalization compared with placebo [relative risk 0.78; 95% CI, 0.67-0.91; number needed to treat, that is the average number of patients who need to be treated to prevent one additional exacerbation: 30 (95% CI, 20 to 52)].137 Combination with ICS was not associated with a further risk reduction.137 In another meta-analysis including 23 randomized controlled trials of twice-daily LABA (16 trials comparing salmeterol vs placebo, 4 formoterol vs placebo, 3 salmeterol vs tiotropium and 1 formoterol vs tiotropium), treatment with a LABA was associated with a significant reduction in the risk of a COPD exacerbation compared with placebo (odds ratio [OR] 0.84; 95% CI, 0.76-0.92), whereas tiotropium bromide significantly reduced the exacerbation risk compared with a LABA (OR 0.82; 95% CI, 0.72-0.93).138 There was no difference between LABA/ICS combination or LABA monotherapy in reducing the risk of a COPD exacerbation (OR 0.90; 95% CI, 0.80-1.01).138 In a systematic review and meta-analysis of 27 trials including 30495 patients with COPD, treatment with ICS/LABA combination was associated with reduced total mortality compared with placebo (RR, 0.80; p = 0.005).139 Neither tiotropium (RR, 1.08; p = 0.61) nor LABA monotherapy (RR, 0.90; p = 0.21) was associated with reduced mortality.139 Based on these results, the authors conclude that, unlike LABA and tiotropium monotherapy, ICS/LABA combination seems to be effective in reducing mortality by approximately 20% and prolong survival in patients with COPD.139 However, definitive conclusions on the effect of ICS/LABA combination on mortality in patients with COPD cannot be drawn because of high heterogeneity of drugs and doses used in the various trials, lack of assessment of COPD-related mortality, and lack of access to individual data. In a Cochrane systematic review, which examined 10 randomised, double-blind controlled trials including 10680 patients with severe COPD, treatment with ICS/LABA combination or LABA monotherapy was reported to have similar effects on mortality for COPD (OR 0.92; 95% CI 0.76 to 1.11) with a moderate quality evidence.140 ACS Paragon Plus Environment


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Salmeterol Treatment with inhaled salmeterol at a dose of 50 µg twice daily significantly increases FEV1 as compared to baseline values, but limited to an average effect size of 51 mL.141 In the Toward a Revolution in COPD Health (TORCH) study, the largest trial with salmeterol, a randomized, double blind, parallel group, placebo controlled study, 6112 patients mostly with severe COPD (mean FEV1 44 % predicted), were assigned to one of four groups: salmeterol alone [50 µg twice daily delivered through a DPI], fluticasone alone [500 µg twice daily delivered through a DPI, salmeterol/fluticasone FDC [50/500 µg twice daily delivered through a DPI], or placebo. Study duration was 3 years.142 Salmeterol and, to a greater extent, salmeterol/fluticasone FDC significantly reduced the decline in pulmonary function, reduced COPD exacerbation rate, and improved healthrelated quality of life compared with placebo.142 In a post-hoc analysis of TORCH data, FEV1 declined at a similar rate in all active treatment groups (salmeterol/fluticasone: 39 mL/year; salmeterol: 42 mL/year; fluticasone: 42 mL/year), but at a significantly slower rate than placebo (55 mL/year).143 Either salmeterol or fluticasone were effective, but there was no additional effect of the salmeterol/fluticasone FDC over salmeterol alone.143 In the INSPIRE trial, salmeterol/fluticasone and tiotropium bromide had a similar effect on the mean number of COPD exacerbations/year (1.28 and 1.32, respectively).94 In the TORCH study, salmeterol, fluticasone and salmeterol/fluticasone FDC were all superior to placebo in reducing the rate of moderate and severe COPD exacerbations.142 However, the mean number of such exacerbations was small (0.85-0.97 per patient per year in the active treatment groups and 1.13 per patient per year in the placebo group).142 A Cochrane meta-analysis including trials of duration ranging from 12 to 52 weeks showed that COPD exacerbation rate was significantly reduced with salmeterol (50 µg twice daily) compared with placebo.141 The TORCH study failed to demonstrate reduction in all cause mortality, the primary study endpoint, following treatment with salmeterol/fluticasone FDC for 3 years (HR = 0.825, CI 0.681 to ACS Paragon Plus Environment

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1.002; p = 0.052).142 In the same study, monotherapy with either salmeterol or fluticasone had no effect on all cause mortality in patients with COPD.142 In the INSPIRE study, salmeterol/fluticasone FDC provided a 52% reduction in risk of mortality vs tiotropium at all time points during treatment (HR = 0.476; 95% CI, 0.267–0.848; p = 0.012).94 In a meta-analysis, a significant reduction in mortality with salmeterol/fluticasone FDC vs placebo (OR, 0.79; 95% CI, 0.65–0.98),144 but not vs LABA alone, was reported.140

Formoterol In a 6-month double blind placebo-controlled study, formoterol improved FEV1 compared with placebo, showing that this drug is an effective maintenance treatment for patients with COPD.145 In a

12-month

randomised,

double

blind,

placebo-controlled

trial,

treatment

with

formoterol/budesonide FDC (two puffs of 4.5/160 µg twice daily), budesonide alone (two puffs of 200 µg twice daily), and formoterol alone (two puffs of 4.5 µg twice daily) increased FEV1 compared with placebo in patients with moderate to severe COPD.146 In terms of changes in postbronchodilator FEV1, efficacy of formoterol/budesonide FDC (15% increase compared with placebo, p < 0.001) and formoterol alone (14% increase compared with placebo, p < 0.001) was similar.146 In contrast, formoterol/budesonide FDC was more effective than individual treatments (formoterol or budesonide alone) in another randomised, multicentre study in which patients with COPD were enrolled on the basis of FEV1 ≤ 50% of predicted values, smoking history ≥ 10 pack years and ≥ 1 COPD exacerbation in the previous 2–12 months.130 In two studies, formoterol monotherapy was not associated with reduced frequency or delayed time to the first severe COPD exacerbation.130,146 However, combined pharmacological treatment with formoterol and budesonide reduced COPD exacerbation rate compared with formoterol monotherapy and placebo.130,140,144,146



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Once daily LABA Indacaterol Indacaterol (Onbrez), a novel, inhaled, once-daily LABA approved in the EU at doses of 150 µg or 300 µg and in the USA at a dose of 75 µg for the maintenance treatment of COPD,8,147 is administered once daily by means of a single-dose dry powder inhaler (SDDPI).8 Indacaterol is a partial agonist with higher intrinsic activity than salmeterol and salbutamol.147 Reported mean Emax for indacaterol at human beta2-adrenoceptors in vitro is 73% of the maximal effect of isoprenaline, whereas mean Emax values for formoterol, salmeterol and salbutamol are 90%, 38% and 47%, respectively.147 Like formoterol, indacaterol is a very weak agonist at the beta1-adrenoceptor (mean Emax 16%).147 Indacaterol has beta2-adrenoceptor agonist activity which causes airway smooth muscle relaxation and bronchodilation, a long duration of action and a fast onset of action in both in vitro and in vivo animal models.8 The faster onset of action and longer duration of action of indacaterol compared with some other beta2-adrenoceptor agonists may be due to its intrinsic efficacy and lipid membrane interactions.8 In randomized controlled trials including more than 400 patients, indacaterol at a dose of 150 or 300 µg once-daily improved pulmonary function compared with placebo after 12 weeks of treatment.126129

In the INHANCE trial, indacaterol improved trough FEV1 values compared with placebo more

effectively than open label tiotropium.128 Moreover, indacaterol had a greater effect on trough FEV1 values at 12 weeks than formoterol or salmeterol.126,129 Inhaled indacaterol at a dose of 150 µg128 and 300 µg126 once daily significantly reduces exacerbations, and improves COPD symptom control and health-related quality of life assessed using the SGRQ compared with placebo.126,128,129 In a randomized, double blind, placebo-controlled study (INLIGHT-2) comparing once-daily indacaterol (150 µg) and twice-daily salmeterol (50 µg) in 838 patients with moderate-to-severe COPD, indacaterol improved FEV1 compared with placebo (p < 0.001) and salmeterol (p < 0.001) after 6 months of treatment.129 Both indacaterol and salmeterol improved health status, as assessed


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by the SGRQ, and dyspnoea compared with placebo, with differences between them favouring indacaterol.129 In patients with COPD, indacaterol improves exercise tolerance, dyspnoea and dynamic lung hyperinflation.8 In studies up to one year, indacaterol was well tolerated showing a safety profile, including cardiovascular safety, similar to placebo, and comparable to tiotropium bromide, salmerterol and formoterol.126,128,129 Among COPD patients who received indacaterol at a dose of 150 µg and 300 µg in the INVOLVE and INHANCE studies, the incidence of adverse events that are typically associated with beta2-adrenoceptor activation, such as tremor (0.2–0.5%) and tachycardia (0.2– 1.2%), was low (where reported).126,128 In summary, clinical studies suggest that indacaterol provides a rapid (within 5 min) and longlasting (at least 24 hours) bronchodilation in patients with COPD. Exposure to a maximum of 28 days’ treatment with different doses of indacaterol confirmed that this drug is suitable for once daily dosing, with a favourable overall safety profile, and maintained efficacy without evidence of tolerance development.8 Open-label studies indicate that indacaterol may be at least as effective as tiotropium bromide in providing long-lasting bronchodilation.8

Safety The most common class effects of LABA include tremor and tachycardia that may limit the maximal tolerated dose, particularly in some older patients.1,14 Beta1- and beta2-adrenoceptors are both expressed in the heart, but beta1-adrenoceptor density is 3-fold higher than that of beta2adrenoceptors. Heart beta2-adrenoceptors activation could explain, at least partially, cardiac adverse effects induced by LABA.4 Cardiovascular side effects are more likely in susceptible patients. There is some risk associated with beta2-agonist treatment in patients with COPD and concomitant cardiac diseases, particularly chronic heart failure,148 a frequent comorbidity in these patients.



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Nevertheless, salmeterol and formoterol are considered generally safe1,4 and well tolerated over periods of at least 1 year.130,131,142,146 Pro-arrhythmic effects of LABA in patients with COPD were evaluated in two double blind randomised clinical trials in which patients were assigned to one of the following 5 treatment groups for 12 weeks: arformoterol 15 µg twice daily; arformoterol 25 µg twice daily; arformoterol 50 µg twice daily; salmeterol 42 µg twice daily; placebo.149 The percentage of patients with treatment emergent atrial tachycardia, that is not present at baseline, ranged from 27% to 32% and was similar in the LABA groups (2–5%) and in the placebo group.149 More serious arrhythmias were not frequent and their frequency was not increase with inhaled LABA treatment. The safety profile of the two long-acting bronchodiltators used in these studies, arformoterol and salmeterol, was similar.149 In contrast to asthma,150 LABA monotherapy in patients with COPD is not associated with increased risk of mortality for respiratory causes. In a meta-analysis including 27 studies, no significant difference between LABA and placebo in terms of risk of respiratory death was observed (relative risk 1.09, 95% CI, 0.45-2.64).137 These results were confirmed in a more recent meta-analysis including 23 trials which reported a similar risk of mortality comparing a LABA with placebo (OR 0.95, 95% CI, 0.71-1.27).138

Combination therapy Pharmacological therapy combining classes of bronchodilators with different mechanism(s) of action improves efficacy and reduces the risk of adverse events compared with increasing the dose of a single bronchodilator.1 Combination treatment with tiotropium bromide and formoterol is more effective than monotherapy in inducing bronchodilation and improvement of symptoms in patients with COPD.1 Compared with monotherapy, combination of tiotropium bromide (18 µg once daily) and formoterol (10 µg twice daily) was superior to monotherapy for FEV1 2 h post-dose at 24 weeks ACS Paragon Plus Environment

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(primary outcome measure) (P = 0.044 vs formoterol), FEV1 5 min after the first dose (P < 0.001) and at 12 weeks (P < 0.05 vs tiotropium) and mean morning peak expiratory flow rate over the first 6 weeks of treatment (P < 0.001 for both).151 The addition of nebulized arformoterol to tiotropium bromide was more effective than tiotropium alone in improving pulmonary function and dyspnoea index.152 A 6-week randomized clinical trial comparing tiotropium plus formoterol vs salmeterol plus fluticasone showed that the double-bronchodilator combination resulted in greater bronchodilation over the course of 12 h than salmeterol plus fluticasone.153 However, the short treatment period precludes definitive conclusions about the relative benefits of the two different combinations, including their effects on patient-reported outcomes. In a randomized double-blind placebo-controlled trial, 449 patients with moderate to severe COPD were assigned to one of the following treatment group: tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone/salmeterol FDC.154 The duration of pharmacological treatment was one year. The percentage of patients who experienced a COPD exacerbation that required treatment with systemic steroids or antibiotics, the primary study end point, was similar in the tiotropium plus placebo group (62.8%), in the tiotropium plus salmeterol group (64.8%) and in the tiotropium plus fluticasone/salmeterol FDC group (60.0%).154 Regarding secondary end points, treatment with tiotropium plus fluticasone/salmeterol FDC was more effective than tiotropium plus placebo in improving pulmonary function (p = 0.049) and disease-specific quality of life (p = 0.01), and reducing the number of hospitalizations for COPD exacerbation and all-cause hospitalizations.154 In contrast, treatment with tiotropium plus salmeterol and tiotropium plus placebo had a similar effect on lung function or hospitalization rates in patients with COPD.154 In small-scale, double-blind, double-dummy, 2-week cross-over study comparing combination treatment with salmeterol/fluticasone FDC plus tiotropium bromide (triple therapy) with its two major individual component (salmeterol/fluticasone FDC and tiotropium) in symptomatic patients with moderate to severe COPD, triple therapy was more effective than salmeterol/fluticasone FDC



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alone or tiotropium alone in improving lung function and dyspnoea score, and reducing rescue medication.155 In a retrospective study including two cohorts of patients with COPD, one treated with a combination of inhaled tiotropium plus LABA plus ICS, the other, a historic, matched COPD population, treated with an inhaled LABA plus ICS, triple therapy was associated with a reduced risk of mortality, COPD exacerbations, and hospitalizations, whereas tiotropium plus other medications was not associated with these effects.119 A 12-week randomized clinical trial including 660 patients with moderate to severe COPD showed that triple inhaler therapy consisting of budesonide/formoterol FDC at a dose of 320/9 µg twice daily plus tiotropium bromide at a dose of 18 µg once daily (n = 329) was more effective than inhaled tiotropium alone (n = 331) in improving pre-bronchodilator FEV1 (primary outcome), postbronchodilator FEV1, and morning symptoms, and reducing the number of severe exacerbations.156 The efficacy of the triple inhaler therapy is also supported by data obtained in the UPLIFT trial.86 In this study, patients were randomized to receive usual standard care for COPD either with or without tiotropium bromide.86 In those two-thirds of the patients who were on a LABA/ICS combination as their usual treatment, the addition of tiotropium significantly reduced COPD exacerbation rate and improved pulmonary function and health-related quality of life.86 Taken together, this evidence supports an additional benefit of combining tiotropium bromide with either a LABA (double inhaler therapy) or a LABA/ICS combination (triple inhaler therapy) which seems to be particularly useful in patients with severe COPD. Nevertheless, the role of ICS in the treatment of COPD is not clearly defined.10 Pharmacological response to these drugs is likely dependent on the COPD phenotype. To formally address this issue, future prospective randomized controlled trials should focus on phenotypes of patients with COPD more likely to respond to ICS [e.g., patients with ACOS or frequent exacerbators].


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New bronchodilators and pharmacological strategies for COPD New LAMA In patients with stable COPD in whom regular treatment with a single bronchodilator is not sufficient for disease control, the trend is moving towards combining medications in double inhaler therapy (LAMA/LABA) to achieve “maximal” bronchodilation or, limited to responders, triple inhaler therapy (LAMA/LABA/ICS) which, in addition to that, provides the potential benefits of ICS anti-inflammatory effects. In patients with COPD who require a single bronchodilator, new LAMA will have to face a tough competion with tiotropium which is well tolerated and considered the gold standard.1 As tiotropium bromide is going to be available as a generic, pharmacoeconomic considerations could also favour this drugs among the various LAMA. New LAMA will only likely to be competitive if they are developed as FDC. However, apart from their development in FDC, glycopyrronium bromide6 (Figure 3B) and aclidinium bromide5 (Figure 3A), which are both well tolerated, as well as umeclidinium bromide7 (Figure 3C) have been approved for COPD as single bronchodilators in various countries. Several novel M3 mAcChR antagonists are in various stages of development for COPD treatment.3

Umeclidinium Umeclidinium (Incruse) (Figure 3C), a potent new inhaled once-daily LAMA, has been approved for pharmacological maintenance treatment of stable COPD in several countries including Europe, USA, Australia and Canada.7 It is delivered as powder (contained in blisters) for oral inhalation through a DPI (Ellipta).7 Each blister contains 74.5 µg of umeclidinium bromide, equivalent to 62.5 µg of umeclidinium. Under standardised in vitro conditions, this device delivers 55 µg of umeclidinium per dose when tested at a flow rate of 60 L/min for 4 seconds. Umeclidinium affinity of the human M1-M5 mAcChR range from 0.05 to 0.16 nM.157 Dissociation of umeclidinium bromide from the M3 receptor in vitro is slower than that for the M2 receptor [halflife (t1/2) values: 82 min and 9 min, respectively].157 Umeclidinium bromide is a potent mAcChR ACS Paragon Plus Environment


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antagonist with slow functional reversibility at the human M3 receptor and long duration of action in animal models, a pharmacological profile which translates into a 24-h duration of bronchidilation in vivo.157 In a 14-day dose ranging efficacy study in patients with COPD, inhaled umeclidinium bromide provided clinically significant and persistent improvements in pulmonary function over 24 h with similar efficacy to twice-daily dosing.158 Similar results were obtained in a 28-day randomized, double-blind, placebo-controlled, parallel group study, including 285 patients with COPD, in which three once-daily doses of umeclinidium (125 µg, 250 µg and 500 µg) were tested.159 All drug doses significantly increased morning trough FEV1 on day 29 (primary endpoint) over placebo.159 Effect size ranged from 150 mL to 168 mL with and a clinically significant bronchodilating effect lasted over 24 h.159 Umeclidinium bromide was well tolerated with no apparent treatment-related changes in vital signs.159 Two recent trials provided initial assessment of safety, tolerability, bronchodilatory effect and pharmacokinetics following single and repeat doses of inhaled umeclidinium in patients with COPD.160 In the single-dose trial (NCT00515502), a randomized, double-blind, placebo-controlled, double-dummy, dose-ascending, cross-over study, 24 patients with COPD were randomized to receive four of the following five treatments: umeclidinium bromide (250 µg, 500 µg, and 1000 µg), tiotropium bromide 18 µg (as a positive control) or placebo. All active treatments significantly improved lung function over placebo, as reflected by increased specific airway conductance and FEV1 for up to 24 h.160 The repeat dose study (NCT700732472) assessing safety, tolerability and pharmacokinetics of inhaled umeclidinium at a dose of 250 µg or 1000 µg administered once-daily for 7 days in 31 patients with COPD, showed that most adverse events were mild-to-moderate and transient.160 No clinically significant effect on heart rate, QT interval, blood pressure and laboratory assessments was reported.160 After single and repeat doses, maximum observed plasma umeclidinium concentration (Cmax) was reached in 5-15 min and 1.5-1.9-fold accumulation was observed after repeat-dosing.160


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Although relatively limited, this evidence suggests that umeclidinium bromide can be a welltolerated and effective LAMA bronchodilator which is suitable for once-daily pharmacological maintenance treatment of COPD. However, larger clinical studies are required for assessing its efficacy and tolerability in patients with COPD. Umeclidinium bromide7 (Figure 3C) has been approved in various countries for maintenance treatment of COPD both as a single bronchodilator and in a FDC with vilanterol.7

New LABA Vilanterol Vilanterol (Figure 6A) is a novel, potent, and selective beta2-adrenoceptor agonist with 24 h activity. It displays subnanomolar affinity for beta2-adrenergic receptors similar to that of salmeterol, but higher affinity than olodaterol, formoterol or indacaterol.56 In cAMP functional activity studies, selectivity of vilanterol for beta2-adrenoreceptors was about 1000-fold higher than that for beta1- or beta3-adrenoreceptors, with a selectivity profile that was significantly superior to that of formoterol, indacaterol and salbutamol, but not to that of salmeterol.56 Based on in vitro studies, vilanterol intrinsic efficacy was similar to that of indacaterol, but significantly greater than that of salmeterol and lower than that of formoterol and isoprenaline.56 In isolated human small airways, vilanterol had a faster onset of action than salmeterol (dissociation half-life 3.1 min vs 8.3 min, respectively; p < 0.0001) and longer duration of action (only vilanterol exhibited significantly bronchodilation at 22 h; p < 0.01).56 Dissociation half-life (t1/2) was calculated from dissociation rate (koff) using the the equation dissociation t1/2 = 0.693/koff.56 Pharmacological profile of vilanterol is consistent with its once-daily dosing in the treatment of asthma and COPD. In COPD, vilanterol trifenatate has been approved in FDC with umeclidinium (double inhaler therapy) and is being developed in FDC with umeclidinium bromide and fluticasone furoate (triple inhaler therapy).7



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Olodaterol Olodaterol (Striverdi) (Figure 6B) received its first global approval for the once-daily maintenance treatment of COPD in Canada (Health Canada) in 2013 and was then approved in Russia.63 Submissions for regulatory approval have also been made in the USA, the EU and elsewhere.63 Preclinical studies suggest potential for once-daily dosing of olodaterol in humans, along with rapid onset of action and a favourable safety profile.161 Like formoterol, olodaterol reduces in vitro profibrotic cellular activity in human lung fibroblasts,162 but causes less in vitro desensitization than formoterol after repeated exposure.63 Phase III studies are based on doses of 5 µg and 10 µg once daily. However, only 5 µg dose, administered as two 2.5 µg puffs through the soft mist inhaler, was approved as 10 µg dose was not more effective in phase III or phase II trials likely because the bronchodilating effect of olodaterol reaches a plateau at 5 µg once daily.63 Olodaterol is a fast-acting LABA as shown by improved lung function 5 min after the first dose in patients with COPD.63 Single doses of olodaterol improved FEV1 for 24 h in patients with COPD making

this

bronchodilator suitable

for

once-daily administration.63

This long-lasting

bronchodilator effect is likely due to a dissociation half-life of 17.8 h of the stable drug/receptor complex.163 In four pivotal, 48-week, phase III trials in patients with moderate to very severe COPD (trials 1222.11-14), olodaterol at a dose of 5 µg once daily on top of the usual maintenance treatment improved lung function and the secondary endpoint of the SGRQ score, which assesses symptoms, activity and impact, compared with placebo.63 From the safety standpoint, like other LABA, olodaterol prolongs the QT interval in a dosedependent manner.63 However, in healthy subjects at the highest olodeterol therapeutic dose (10 µg daily), increase in QT interval was below 10 ms, the threshold of concern.63 In a pooled analysis, the incidence of any adverse events (69%-71%), serious adverse events (15%-16.4%), fatal adverse


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events (1.5%-2.2%), and treatment-related cardiac adverse events (1.4%-1.7%) seems to be similar to formoterol and placebo.63 The most common serious adverse events associated with olodaterol treatment are COPD exacerbation (4.7%) and pneumonia (1.6%) which are not different from placebo (6% and 1.5%, respectively).63 Based on the information available at http://www.clinicaltrials.gov, all phase II and III trials of olodaterol in patients with COPD have been completed.63

Abediterol Abediterol (LAS100977)164 (Figure 6C) has a preclinical profile which is suitable for once-daily dosing in humans, a fast onset of action and a favourable cardiovascular safety profile.164 Abediterol is a full agonist with a subnanomolar affinity for the human beta2-adrenoceptor and a duration of action up to 48 h which is similar to that of indacaterol.164 In dogs, abediterol has a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) (5.6) than indacaterol (0.3), formoterol (2.2) and salmeterol (3.3).164 The first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of abediterol at once daily doses of 5 µg, 10 µg, 25 µg or 50 µg shows a potent, rapid and sustained bronchodilatory effect of this drug in healthy male subjects.165 At the time of writing September 2014, lower doses of abediterol are under investigation in patients with asthma and in patients with COPD.165 In a phase IIa study, abediterol at single doses of 2.5 µg, 5 µg and 10 µg was superior to indacaterol at a dose of 150 µg in improving trough FEV1 over baseline values. Phase IIb studies with a once-daily FDC of abediterol and ICS in patients with asthma and COPD are ongoing [information available at: http://www.epgonline.org/news/2012/Jun/Abediterol-Almirall-Forest-superior-to.cfm].

Carmoterol Carmoterol (Figure 6E) is a non-catechol beta2-adrenoceptor agonist with a p-methoxyphenyl group on the amine side chain and an 8-hydroxyl group on the carbostyril aromatic ring.166 Most of the ACS Paragon Plus Environment


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pharmacological information on carmoterol has been published in abstract form (see reference 4 for individual studies). Compared with other beta1- and beta2-adrenoceptor agonists, carmoterol has a high selectivity and affinity for the beta2-adrenoceptor.4 Carmoterol has a fast onset and long duration of action (30 h) in vitro and a long-lasting bronchodilating effect in patients with COPD.4 Development of pharmacological tolerance was not observed over two weeks of treatment.4 In a phase II study in patients with COPD, treatment with carmoterol at both doses of 2 µg and 4 µg once daily resulted in significantly higher bronchodilation over 24 hours compared with placebo and similar to that obtained with salmeterol at a dose of 50 µg twice daily.4 Preliminary data in patients with COPD suggests that carmoterol is well tolerated and has a good safety profile.4

Dual bronchodilator therapy for COPD LAMA/LABA fixed dose combinations When dual bronchodilation is indicated, new LAMA/LABA FDC provide the convenience of two bronchodilators in a single inhaler and, at the same time, a simple, once-daily dosing regimen that may improve compliance with pharmacological treatment. Combining different mechanisms of actions, LAMA/LABA FDC at full doses provide additive effects, thus increasing efficacy (maximal broncodilatation) as compared with monotherapy. On the other hand, reducing the dose of individual components with consequent reduced risk for side effects can improve drug safety and tolerability profiles while maintaining therapeutic efficacy. Therefore, LAMA/LABA FDC are a valuable pharmacological strategy in the treatment of COPD. Three LAMA/LABA FDC including indacaterol/glycopyrronium bromide, umeclidinium bromide/vilanterol and olodaterol/tiotropium bromide have been approved or are under approval in various countries.

Indacaterol/Glycopyrronium bromide


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Indacaterol/glycopyrronium bromide (QVA149)167 (Ultibro), a once daily FDC of indacaterol (inhalation powder hard capsule containing 143 µg of indacaterol maleate equivalent to 110 µg of indacaterol) and glycopyrronium bromide (inhalation powder hard capsule containing 63 µg of glycopyrronium bromide equivalent to 50 µg) in a single DPI, was approved in the EU and Japan in 2013 as a maintenance bronchodilator treatment of COPD.167 Each delivered dose contains 110 µg of indacaterol maleate equivalent to 85 µg of indacaterol and 54 µg of glycopyrronium bromide equivalent to 43 µg of glycopyrronium.167 Efficacy and safety/tolerability of indacaterol/glycopyrronium bromide FDC is being assessed in the IGNITE phase III clinical trial programme including more than 10000 patients worldwide in 11 trials.167 In patients with moderate-to-severe COPD,

indacaterol/glycopyrronium bromide FDC

significantly improved lung function compared with placebo.168-170 Bronchodilation appeared 5 minutes after the first drug dose, was clinically significant (FEV1 ≥ 100 ml, minimal clinical important difference [MCID]) at all time points, including day 1, and was maintained during treatment for up to 52 weeks. 168-170 Lung function improvement induced by indacaterol/glycopyrronium bromide FDC treatment was associated with amelioration in dyspnoea,168,169 health status,168 symptoms,168,170 rescue medication use,168 and exercise tolerance.171 In the SHINE study, indacaterol/glycopyrronium bromide FDC treatment reduced moderate-tosevere COPD exacerbation rate by 43% compared with placebo, although the primary study endpoint was trough FEV1 at week 26 for indacaterol/glycopyrronium bromide FDC versus its monocomponents.168 Compared with active treatment, indacaterol/glycopyrronium bromide FDC was more effective than monotherapy with indacaterol, glycopyrronium bromide and tiotropium bromide in improving pulmonary function in patients with COPD168,169,171,172 and non inferior to its active



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monocomponents administered concurrently.173 A recent metanalysis including 4842 patients enrolled in five trials (only one trial including patients with very severe COPD)167-170,172 suggests that indacaterol/glycopyrronium bromide FDC has higher efficacy than glycopyrronium bromide and the current standard of care tiotropium bromide in patients with COPD.174 Compared with tiotropium, indacaterol/glycopyrronium bromide FDC significantly increases trough FEV1 (effect size ranges from 60 mL to 100 mL) from day 1 to week 64, reduces COPD exacerbation rate (number need to treat for benefit = 19)168,172 and the use of rescue medication (-0.63 puffs/day) with a higher likelihood of achieving a minimal clinical important difference in TDI (19%) (number needed to treat for benefit = 11) and in health status as assessed by SGRQ score (16%) (number needed to treat for benefit = 11).174 Compared with glycopyrronium bromide, indacaterol/glycopyrronium bromide FDC significantly increases trough FEV1 (70 mL) up to 26 weeks,168,169 increases the percentage of patients who achieved a minimal clinically important difference in the SGRQ score (number needed to treat for benefit = 12), reduces COPD exacerbation rate168,172 (number needed to treat for benefit = 25), and reduces rescue medication use (-0.59 puffs/day).174 Regarding comparison between indacaterol/glycopyrronium bromide FDC and indacaterol, pooled analysis of data was not possible as only one study reported this comparison.174 Mean improvements in trough FEV1 vs tiotropium, glycopyrronium, and indacaterol were similar (70 mL) and close to those observed comparing a LABA (salmeterol, formoterol or indacaterol)/tiotropium combination vs tiotropium alone (60 mL).175 Improvement in pulmonary function with indacaterol/glycopyrronium bromide FDC treatment compared with LAMA or LABA monotherapy was rapid in onset168,169 and maintained up to 64 weeks.172 Compared with monotherapies, treatment with indacaterol/glycopyrronium FDC achieved or approched the minimal clinically significant difference in trough FEV1 of 100 ml.168,169,172 However, this threshold is used for comparisons vs placebo and a similar thershold for comparisons vs active treatments has not yet been established.


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Significant differences in health status and dyspnoea following indacaterol/glycopyrronium bromide FDC treatment as compared with its monocomponents,168 but not with tiotropium bromide,168,169 were not generally observed in patients with moderate to severe COPD at low risk for exacerbation. In contrast, treatment with glycopyrronium/indacaterol FDC was associated with improvement in health status in severe or very severe COPD patients at high exacerbation risk.172 The clinical relevance of these differences is unknown as the minimal clinically important difference in health status and dyspnoea between active treatments is not established.167 In patients with severe to very severe COPD at high risk for exacerbation, treatment with glycopyrronium/indacaterol FDC for 64 weeks was more effetive than glycopyrronium bromide alone, but not than tiotropium bromide, in reducing the annualized rate (-12%) of moderate to severe exacerbations (primary outcome).172 Annualized rate of all exacerbations (mild, moderate, and severe) was reduced by 15% compared with glycopyrronium and 14% compared with tiotropium.172 In patients with moderate to severe COPD without exacerbations in the previous year, once daily treatment with glycopyrronium/indacaterol FDC was more effective than salmeterol/fluticasone FDC at a dose of 500 µg b.i.d. in improving pulmonary function, an effect that was rapid in onset and persistent throughout the 26-week study period.176 The increase of 138 ml in the standardised area under the curve from 0 to 12 h post dose for FEV1 [FEV1 area under the curve (AUC)0-12h) over salmeterol/fluticasone FDC after 26 week treatment with indacaterol/glycopyrronium bromide FDC (primary outcome) is considered clinically meaningful.176 Improved dyspnoea and reduced

rescue

medication

over

salmeterol/fluticasone

FDC

were

reported

with

indacaterol/glycopyrronium bromide FDC.176 Indacaterol/glycopyrronium bromide FDC was generally well tolerated in patients with moderate to very severe COPD.167,168,170,172,176 COPD worsening was the most common treatment-emergent adverse event and serious adverse event.168,170,172 Other common adverse events (incidence ≥2%) include nasopharyngitis, cough, upper and lower respiratory tract infections, headache, ACS Paragon Plus Environment


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oropharyngeal pain.167 Compared with placebo, adverse events in patients with moderate to severe COPD who were being treated with indacaterol/glycopyrronium bromide FDC up to 52 weeks were generally similar.168,170 Likewise, indacaterol/glycopyrronium bromide FDC was well tolerated with no potential safety signals reported compared with tiotropium, glycopyrronium and indacaterol.174 Its overall profile of cardio-vascular safety was similar to tiotropium, glycopyrronium, and indacaterol.168,174 The FLAME study, a 52-week treatment, multi-center, randomized, double-blind, double dummy, parallel-group, active controlled study to compare the effect of indacaterol/glycopyrronium bromide FDC with salmeterol/fluticasone FDC on the rate of exacerbations in subjects with moderate to very severe COPD, is ongoing as well as other phase III studies with indacaterol/glycopyrronium bromide FDC.167

Umeclidinium bromide/Vilanterol Inhaled umeclidinium bromide/vilanterol received its first global approval in the USA in 2013 for the long-term, once-daily maintenance treatment of airflow limitation in patients with COPD.7 Umeclidinium bromide/vilanterol was then approved in Canada for the same indication and regulatory applications have been filed in the EU, Japan and elsewhere.7 In the USA, umeclidinium bromide/vilanterol FDC (Anoro) has been approved at a dose of 62.5 µg/25 µg taken once-daily through a DPI.7 Umeclidinium bromide and vilanterol are principally absorbed in the lungs with minimal oral absorption.7 Following inhalation, Cmax occurs in 5-15 min. The once daily dose of umeclidinium/vilanterol FDC used in phase III registration trials was 62.5 µg or 125 µg of umeclidinium and 25 µg of vilanterol as determined in phase II dose finding studies.7 Two pivotal 24-week, randomised, double-blind, parallel group, placebo-controlled7,177,178 and two pivotal 24-week, multicentre, randomised, blinded, double-dummy, parallel-group, active comparator-controlled studies were performed to test the efficacy and safety of once-daily 125/25 ACS Paragon Plus Environment

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µg and 62.5/25 µg doses of umeclidinium/vilanterol FDC.179 A total of 5353 patients with moderate to very severe COPD (GOLD stage II-IV) were included in the pivotal trials. Supportive evidence was provided by two 12-week, double-blind, crossover, multicentre, exercise endurance trials (NCT01328444 and NCT01323660) including a total of 657 patients with COPD.7 In the pivotal trials, the primary efficacy endpoint was the mean trough FEV1 at study end (defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on day 169).177-179 In the exercise endurance trials, the coprimary endpoints were the change from baseline to study end in exercise endurance time measured during the shuttle walk test and the trough FEV1 at study end.7 In the placebo-controlled pivotal trials, all active treatments improved trough FEV1 as compared with placebo at 24 weeks.177,178 Improvements with both 125/25 µg (ClinicalTrials.gov identifier: NCT01313637) (0.079 L and 0.114 L; both p≤0.001) and 62.5/25 µg (ClinicalTrials.gov identifier: NCT01313637) (0.052-0.095 L, p ≤ 0.004) umeclidinium/vilanterol were significantly greater than those observed with the individual drugs at the same respective doses.177,178 Additional lungfunction, symptomatic and health-related quality of life endpoints were also improved after treatment with umeclidinium/vilanterol as compared with placebo.177,178 In the two pivotal active-controlled trials, increases in trough FEV1 on day 169 for both doses of umeclidinium/vilanterol compared with tiotropium monotherapy (administered at once-daily dose of 18 µg via DPI as active control) were observed (study 1, umeclidinium/vilanterol 125/25 µg: 0.088 L [95% CI, 0.036 to 0.140; p = 0.0010]; study 1, umeclidinium/vilanterol 62.5/25 µg: 0.090 L [95% CI, 0.039 to 0.141; p = 0.0006]; study 2, umeclidinium/vilanterol 125/25 µg: 0.074 L [95% CI, 0.025 to 0.123; p = 0.0031]; study 2, umeclidinium/vilanterol 62.5/25 µg: 0.060 L [95% CI, 0.010 to 0.109; nominal p = 0.0182]).179 Both doses of umeclidinium/vilanterol improved trough FEV1 compared with vilanterol monotherapy (umeclidinium/vilanterol 125/25 µg: 0.088 L [95% CI, 0.036 to 0.140; p = 0.0010]; umeclidinium/vilanterol 62.5/25 µg: 0.090 L [95% CI, 0.039 to 0.142;

p

=

0.0006],

but

not

compared

with

umeclidinium

125

µg

monotherapy

(umeclidinium/vilanterol 125/25 µg: 0.037 L [95% CI, -0.012 to 0.087; p = 0.14]; ACS Paragon Plus Environment


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umeclidinium/vilanterol 62.5/25 µg: 0.022 L [95% CI, -0.027 to 0.072; p = 0. 38]).179 There was no statistically significant difference between the two doses of umeclidinium/vilanterol.179 All treatments improved dyspnoea and health-related quality of life. No significant differences in symptoms, health status, or risk of COPD exacerbation between umeclidinium/vilanterol FDC and tiotropium were observed.179 The most common on-treatment, severe-intensity adverse event in both studies was acute COPD exacerbation (1-4 [

Bronchodilating Drugs for Chronic Obstructive Pulmonary Disease

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