anti colinergicos in copd (1).pdf

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Drug Discovery Today Volume 18, Numbers 21/22 November 2013 REVIEWS

Novel anti-cholinergics in COPDA. Prakash 1 , K.S. Babu 2 and J.B. Morjaria 1

1 Department of Academic Respiratory Medicine, Hull York Medical School, University of Hull, Castle Hill Hospital, Castle Road, Cottingham HU16 5JQ, UK 2 Department of Respiratory Medicine, Queen Alexandra Hospital, Southwick Road, Cosham, Portsmouth PO6 3LY, UK

Anti-cholinergics have been considered the rst-choice bronchodilator therapy in the routinemanagement of stable COPD. Muscarinic cholinergic receptors are expressed on most cell types andmediate cellular signalling via the natural ligand, acetylcholine. Antagonising cholinergic receptorsmay not only result in bronchodilation, but also have associated localised activity. Until recently thelicensed anti-cholinergics were limited to ipatropium bromide, oxitropium bromide and tiotropiumbromide; the latter being the only once-daily anti-cholinergic. With the patents expired or due to expireshortly several companies have reinitiated efforts to develop safer, long-acting agents potentiallyimproving concordance and pharmaceutical marketing opportunities. The present article reviews anumber of novel anti-cholinergics that have been recently licensed and those undergoing development,some in innovative delivery devices.

IntroductionChronic obstructive pulmonary disease (COPD) is characterised byprogressive airow limitation caused by chronic airway inamma-tion and lung parenchymal injury which is commonly due tosustained inhalation of cigarette smoke [1]. The main goals of pharmacotherapy in COPD are to prevent and control symptoms,reduce the frequency and severity of exacerbations, improvehealth status, and increase exercise capacity. Global initiativefor chronic Obstructive Lung Disease (GOLD) recommends theuse of long-acting bronchodilators as rst-line maintenance ther-apy in moderate-to-severe COPD [2].

The choice of bronchodilator therapy depends on availabilityand individual response in terms of symptom relief and tolerabil-ity. Currently available bronchodilators for COPD include b 2 -agonists, anti-cholinergics or a combination of these drugs [3].In COPD, parasympathetic activity leads to increased broncho-constriction, mucus secretion and airways hyperresponsiveness tonoxious agents [4]. Hence, antagonising cholinergic receptorsprovides a realistic intervention in COPD treatment.

Inhaled anti-cholinergics have been used as bronchodilator ther-apy for centuries. However, initially they were dogged by systemicside effects (atropine) and later their short duration of action (DoA)

(ipratropium bromide (IB) and oxitropium bromide) [57] . Tiotro-pium bromide (TB), a true second-generation quaternary anti-cho-linergic represented a breakthrough in pharmacological COPDmanagement due to its 24-hours bronchodilator activity [8]. Itpossesses a higher afnity for muscarinic receptors than IB and,more importantly, dissociates gradually from M3 receptors, explain-ing its prolonged action. Although in moderate-to-very-severeCOPD subjects Understanding Potential Long-Term Impacts onFunction with Tiotropium (UPLIFT) trial failed to demonstrate acessation in the rate of forced expiratory volume in 1 s (FEV1 ) declinecompared placebo, at all time points subjects receiving TB hadsignicant improvements in lung function, health-related qualityof life (HRQoL), reduced risk for exacerbations, episodes of respira-tory failure and COPD-related hospitalisations [9]. Despite thesepositive improvements with TB use, it has some limitations includ-ing delayed bronchodilation, localised adverse effects and an immi-nent patent expiry. Moreover there remain unmet clinical needs toimprove patients symptoms, exacerbation management andHRQoL [10] . Night-time and early-morning symptoms can be pro-found and may subsequently have effects lung function, exacerba-tion frequency, HRQoL, cognition, depression and possiblymortality [11,12] . Additionally, inadequate concordance to inhaledtherapy, due to complex procedures in inhaler use as well astedious frequent dosing, is a major cause of poor clinical outcomes.Corresponding author: Morjaria, J.B. ( [email protected] )

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Consequently, features of rapid onset and prolonged DoA areimportant in treating COPD, enabling both long-lasting efcacyanda simple dosing regimen improving compliance [3].The presentarticle reviews new anti-cholinergics that have been recentlylicensed or are currently being evaluated as long-acting muscarinicreceptor antagonists (LAMAs).

Muscarinic

receptors

and

methodology

of

the

reviewIn humans and most mammals, cholinergic parasympatheticnerves provide the dominant innervation to the lungs and exerttheir bronchoconstriction, mucous secretory and other localised

effects via the activation of muscarinic ACh receptors (mAChRs)[5]. There are ve subtypes of mAChRs M15 , though only receptorsM13 are expressed in humans [13,14] . M 3 is the primary muscari-nic receptor that mediates bronchial and tracheal smooth musclecontraction, and has been implicated in mucus secretion as well asvascular smooth muscle cell vasodilatation [1518] . Figure 1 repre-sents the human pulmonary mAChRs and their interactions

[5,19] .The ideal anti-cholinergic agent in COPD should antagonise M1

and M3 receptors, with little afnity for the M2 receptor [20] . Inview of this, novel anti-cholinergic drugs are under development

REVIEWS Drug Discovery Today Volume 18, Numbers 21/22 November 2013

A C h

M1receptor A C

h

Ganglionicsynapse

PreganglionicPostganglionic

Parasympathetic nerve

M2 receptor

Submucosalgland

Smooth muscle

Anticholinergic drug

E p i t h e l i u m

M3receptor

Negative feedback loop

Drug Discovery Today

M3receptor

FIGURE 1

The human mAChRs subtypes M1, M2, and M3 in the vagal nerve, submucosal gland, and bronchial smooth muscle in the airway [5,19]. mAChRs are metabotropicreceptors that belong to the superfamily of rhodopsin-like, 7-transmembrane domains, single-glycoprotein receptors united by intra- and extracellular loopsand maybe linked to ion (K + or Ca2+ ) channels. Muscarinic receptors initiate a cascade of intracellular responses via interaction with GTP-binding proteins through the ligandACh. Typically in the target tissue this involves activation of adenyl cyclase, activation of phospholipase C, and opening of the potassium channels. In most mammals

cholinergic

parasympathetic

nerves

provide

the

dominant

innervation

to

the

lungs.

Release

of

ACh

from

these

nerves

regulates

airway

tone,

airway

smooth

musclecontraction, mucus secretion, and vasodilatation through interaction with mAChRs found on airway smooth muscle, glands, and pulmonary vasculature. In COPDthere is an augmented parasympathetic activity that may be a reversible component of the airway obstruction with anti-cholinergic therapy.Some of airow limitationin turn may be associated with hyperination which may be reversedwith ACh antagonism. There are ve subtypes of mAChRs, M15 , though only receptors M13 areexpressed in the human lung. M1 receptors have been found in the bronchus, broblasts, bronchial epithelial cells and parasympathetic ganglia. The M2 receptorspreferentially couple to the G protein Gxo/i and function to counteract the b 2 adrenoreceptor-mediated relaxant pathway by antagonising the synthesis andaccumulation of cAMP. These channels are coupled to b 2 receptors via the Gs signalling protein coupled to the G i signalling protein in the airway smooth muscle. Thisinteraction may result in airway smooth muscle contraction via reversal of hyperpolarisation mediated by the b 2 receptor and maxi-K + channels. M2 receptors arelocated on pre-synaptic parasympathetic nerve endings at the neuromuscular junction with feedback inhibition of ACh release and inuence bronchial smoothmuscle to counteract bronchodilation by inhibiting b 2-receptor-mediated cAMP production. The M3 receptor preferentially couple to the heterotrimeric G proteinGq11 , resulting in the stimulation of phospholipase C and an elevation in intracellular Ca2+ . It is the primary muscarinic receptor that mediates bronchial and trachealsmooth muscle contraction despite its markedly lower expression than M2 receptors. Moreover, M3 receptors are implicated in mucus secretion as well asvasodilatation in vascular smooth muscle cells via the diffusion of nitricoxide synthesised in vascular endothelialcells. Akin to M1 receptors, M2 and M3 receptors mayalso be seen in broblasts and epithelial. Abbreviations : Ach, acetylcholine; mAChR, muscarinic acetylcholine receptors; K + , potassium ions; Ca2+ , calcium ions; GTPproteins, guanosine triphosphate proteins (also called G proteins); cAMP, cyclic adenosine monophosphate; b 2, beta 2.

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or have recently acquired licensing for use in COPD. Their primaryaims are not only to antagonise specic mAChRs, but also toenhance the safety prole. Here we discuss a number of thesenovel agents. Tables 1 and 2 provide some of the pharmcodynamicand pharmacokinetic activity of these molecules. Some of theseagents have a vast amount of published pre-clinical and clinicaldata, whereas others have very limited information. We report in

this review

available

relevant

information

pertaining

to

these

newagents. Relevant literature searches were conducted from PubMed,abstracts presented at international Respiratory conferences,namely American Thoracic (20092012) and European RespiratorySocieties (20062012), and early stage compounds from the clin-ical trials websites such as ClincalTrials.gov.

LAMA compounds licensed and in developmentGlycopyrronium bromide (GB)GB is a quaternary ammonium compound endowed with potentanti-muscarinic activity and is currently used as a gastric anti-secretory agent, pre-anaesthetic medication and to attenuate sali-vary secretions. Work with GB in COPD patients conducted by

Novartis, using a dry powder formulation in a novel low resistanceinhaler device called the Breezehaler 1 , has efcacious outcomesleading to its licensing in Europe and Japan for once-daily use.

In vitro studies on electrical eld stimulation (EFS)-inducedcholinergic neurotransmission demonstrated that GB was 34-foldmore potent than IB in inhibiting cholinergic neural responses inguinea-pig and human airways [21] . Importantly, both GB and IB(t 1/2 onset: 919.8 min) had similar times for onset of action whichwas faster than TB (t 1/2 onset: 3443 min). Moreover, GB had alonger DoA in human airways compared to IB. GB showedno selectivity in binding to the M1 M3 receptors, although hada 35-fold higher afnity at M3 receptors compared to IB. In ananesthetised rabbit model, GB and TB dose-dependently inhibitedmethacholine (MCh)-induced bronchoconstriction and at theequivalent efcacy doses inhibited bronchoconstriction for6 hours [22] . TB, but not GB, inhibited MCh-mediated bradycardiaand hypotension, indicating a systemic pharmacological effect forthis drug. Moreover, it has been demonstrated that GB has a DoAcompatible with once-daily dosing and a reduced potential forsystemic side-effects when compared to TB. A Phase I study com-paring inhaled versus intravenous GB reported that the former hadfewer adverse events [23] .

A number of small clinical studies (Phase II) have shown ef-cacy, safety and tolerability of GB in COPD and have been sum-marised in Table 3 [2428] , which have been conrmed in largerstudies described below [2931] . There have been three Phase IIIstudies namely GLOW (GB in COPD airways clinical study) 1, 2and 3 so far. The GLOW1 was a double-blind, placebo-controlled(DBPC) study randomising patients with stable, moderate-to-severe COPD to either GB 50 mg once daily or placebo for 26 weeks[29] . Not only was it reported that the mean FEV1 was signicantlyhigher in patients receiving GB ( P < 0.001), but signicantimprovements in trough FEV1 and throughout the 24 hours periodwere apparent at the end of day 1 and sustained through to week-26. Subjects on GB had a clinically and statistically signicantenhancement in transitional dyspnoea score index (TDI) score atweek-26, however only a statistically signicant reduction in St.Georges Respiratory Questionnaire (SGRQ) score. Of note, more

subjects achieved a clinically meaningful improvement in SGRQwith the use of GB than with placebo (56.8% vs 46.3%; odds ratio1.58; P = 0.006). Additionally GB signicantly reduced the risk ofCOPD exacerbation in terms of time to rst moderate or severeCOPD exacerbations, the total number of moderate-to-severeexacerbations, hospitalisation due to COPD exacerbations as wellas the use of rescue medications. There were no safety concerns

with

the

use

of

GB

compared

to

placebo.GLOW2 was a 3-arm 52-week DBPC randomised study compar-

ing GB with placebo and open-labelled (OL) TB [30] . Akin toGLOW1, GB achieved the same primary end-points demonstratingsuperior 24 hours bronchodilation compared to placebo at 12weeks (97 ml vs placebo; P < 0.001) and so did OL TB (83 ml vsplacebo; P < 0.001). On day 1, mean FEV1 treatment difference forGB/placebo and TB/placebo was 87 ml and 45 ml at 5 min, and143 ml and 78 ml at 15 min, respectively ( P < 0.001), supportingthe pre-clinical data of the rapid onset of action of GB compared toTB. Also, there were signicant improvements risk reduction ofexacerbation in terms of time to rst moderate or severe exacer-bation (34% vs placebo, P = 0.001), comparable to TB (39% vs

placebo, P = 0.001). Subjective parameters of TDI ( P = 0.002) andSGRQ scores ( P < 0.001), reduction in rescue medication use( P = 0.039) and increased proportion of days with no daytimesymptoms ( P < 0.05) compared to placebo over 52 weeks tooshowed signicant improvements. Moreover, the incidence ofserious adverse events was marginally less with GB use (12.6%)than with either placebo (15.4%) or OL TB (15.0%). More recently,GLOW3 assessed the effect of once daily GB or placebo on exercisetolerance in 108 patients with moderate-to-severe COPD for 3weeks [31] . It was reported that treatment with GB was superiorto placebo in the exercise endurance time, with associated sig-nicant treatment differences in inspiratory capacity at isotime(isotime refers to the last time point in the sub-maximal constant load cycle ergometry test (SMET) at which the patient had a validtest result for both treatment periods) ( P < 0.001) and inspiratorycapacity at rest ( P < 0.05). From these ndings, the effect of GB onexercise tolerance in COPD patients appears to be comparable withthat of other long-acting bronchodilators.

Other GB productsTwo new inhaled aerosolised metered-dose formulations of GBhave been developed by Pearl Therapeutics (GP-MDI) and ChiesiFarmaceutici (CHF-5259) which are in Phase I/II of development.Elevation Pharmaceuticals and Pari Pharma have produced anebulised solution (EP-101) that can be administered usingthe eFlow 1 nebuliser system which is in a Phase II developmentstage as well. There is limited literature on GP-MDI [32,33] andEP-101 [34,35] which is summarised in Table 4 , while data onCHF-5259 is only mentioned on the ClinicalTrials.gov website(NCT01176903).

Aclidinium bromide (AB) licensed ( Table 4 )Aclidinium bromide (AB) ((3R)-3-y-l-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane bromide) is a quaternary ammonium com-pound with a high binding afnity to M3 receptors was developedby Almiral SA1 . AB has a low oral bioavailability and poor bloodbrain barrier permeability but can be safely used by inhalationroute.


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TABLE 1

Summary pharmacokinetic and pharmacodynamic data on LAMAs licensed and undergoing investigation

Drug name Binding afnityto muscarinic

receptors

Dissociation kinetics Functional propeM2 receptors

hM 1 hM 2 hM 3 hM 1 hM 2 hM 3 T 1/2 ratioM3 /M 2

Gi signalling

K off (h 1 ) t 1/2 (h) K off (h 1 ) t 1/2 (h) K off (h 1 ) t 1/2 (h) pA 2muscarine

Ipratropium bromide 9.4 9.53 9.58 6.75 0.15 0.1 17.7 0.3 0.03 3.09 0.09 0.22 7.33 9.62

Tiotropium bromide 10.8 10.69 11.02 0.066 0.01 10.5 0.26 0.05 2.6 0.026 0.005 27 10.38 11.15

Glycopyrronium bromide 10.09 9.67 10.04 0.35 0.07 2 1.84 0.1 0.37 0.11 0.02 6.1 16.49 10.01

Aclidinium bromide 10.78 10.68 10.74 0.11 0.007 6.4 0.39 0.03 1.8 0.071 0.01 10.7 5.94 11.25

GSK573719/umeclidinium 9.6 10.1 10.6 4.44 0.24 0.16 0.534 0.072 1.37

GSK233705/darotropium

CHF5407 0.096 0.036 5.91 1.344 0.402 0.53 0.246 0.018 2.77 5.23

TD-4208 0.115 1.35 11.74

AZD9164 9 9.8

RBx 343E48F0 9.6

PF4522791

ALKS 27/trospium

Denitions: Binding afnity to muscarinic receptors binding afnity of differentLAMAsto three human muscarinic receptor subtypes as calculatedby their dissociation constants basedonrate constant, which refers to the rate at which the drug receptor complex dissociates; pA 2 values of the different antagonists were determined in the CHO-hM 2 cell line with the cAMP assthe presence of adenylate cyclase activator forskolin, whereas, to monitor the G s component, cells were pre-treated with PTX (overnight, 80 ng/ml). Values were obtained experimentally by eshifts, according to Schild analysis. Abbreviations : CHO, Chinese hamster ovary; cAMP, cyclic adenosine monophosphate; hM 1 , human muscarinic receptor 1; hM 2 , human muscarinic receptor 2; hM 3 , human muscarinic recrefers to the rate at which the drug receptor complex dissociates; t 1/2 , dissociation half-life; PTX, Pertussis toxin.

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AB is a potent inhibitor of all muscarinic receptor subtypes(M 15 ), but dissociates more slowly from M3 [36,37] . Thereforethe bronchodilatory effects of AB through M3 blockade is longlasting compared to after the less desirable effects on M 2 receptors.The half-life of AB was approximately 7 hours in healthy volun-teers [38] . In vitro AB attenuated human broblast to myobroblasttransition following exposure to carbachol, transforming growthfactor (TGF)-b , cigarette smoke extract and suppressed carbachol-induced MUC5AC expression in human bronchial tissues [39] . ABis a dry powder inhaler delivered by a novel multi-dose breathactivated device named Genuair 1 inhaler. The inspiratory ow foradequate aerosolisation of the powder is 45 L/min [40] with 34%of the delivered dose distributed to the lungs in healthy indivi-duals [41] . In a Phase I study AB was well tolerated in a singleinhaled dose of 400 mg with no dose adjustments required inpatients with renal impairment [42] . AB has a low systemic sideeffect prole due to its rapid hydrolysis in the plasma.

The therapeutic efcacy of AB 400 mg twice daily administeredby inhalation has been evaluated in various randomised con-trolled trials (RCTs) (Table 4). In a Phase IIa DBPC trial in subjectswith COPD, AB 400 mg bid improved 24 hours bronchodilationand the results were comparable to tiotropium 18 mg daily [43] . APhase IIb study assessed the efcacy and safety of AB in COPDsubjects. A twice daily dosing regimen produced meaningfulimprovements in FEV1 compared to placebo [44] . Another PhaseIIb dose-varying study (AB doses of 25 mg, 50 mg, 100 mg, 200 mgand 400 mg), placebo and OL TB reported that the 200 mg and400 mg AB doses compared to placebo improved trough FEV1 [45] .In the ACCLAIM/COPD I (n = 843) and ACCLAIM/COPD II(n = 804) in contrast to placebo 200 mg AB administered once dailyimproved FEV1 in subjects with moderate-to-severe COPD and inthe latter study delayed time to moderate-to-severe exacerbation[46] . Additionally AB has been shown to improve exercise toler-ance and lung hyperination compared to placebo in a 6-weekstudy in subjects with moderate-to-severe COPD [47] . In theACCORD COPD I and ATTAIN studies AB signicantly improved

both peak and trough FEV1 compared to placebo [48,49] . Further-more there were objective improvements in trough FVC, peak FVCand trough inspiratory capacity, and subjective improvements inSGRQ and TDI compared to placebo. Although these studies werenot designed to look at exacerbation frequency, the rates ofexacerbations were signicantly lower in favour of AB. Thesendings have been mirrored in the ACCORD COPD II except thatthere were no differences when compared to placebo in the SGRQscores or the use of rescue medications. In a long-term safety studythe bronchodilator effect of AB persisted over the course of 52weeks and this was also associated with improvements in SGRQtotal scores [39] . Pooled results from the 3 phase III trials (ACCORDCOPD I, ACCORD COPD II and ATTAIN) showed that AB was welltolerated with a side effect prole similar to placebo and drymouth was the most commonly encountered side effect [39] .

Umeclidinium (umeclidinium bromide GSK573719)Umeclidinium is a M 3 antagonist developed by GlaxoSmithK-line 1 . In vitro and in vivo studies have shown umeclidinium tohave potent competitive antagonistic activity at the M3 receptoras well as reduced functional reversibility on cloned and endo-genous isolated human bronchi [50] . Furthermore, compared toTB, umeclidinium has an extended DoA in human bronchialstrips (413 min vs > 600 min to 50% restoration of contraction,respectively). In healthy volunteers single and repeated doseinhalations of umeclidinium via DPI demonstrated a T max of 515 min [51,52] . With repeated inhalations the mean t 1/2 at day-14was 2628 hours and a steady state achieved at 68 days of doseinitiation [52] . Urinary excretion of unchanged drug was 11.5%of total dose on day-1 and 3.94.5% at steady state. Absorption,distribution, metabolism and elimination of umeclidinium fol-lowing single oral and intravenous doses indicate negligible oralumeclidinium bioavailability, low gut absorption, signicanttissue distribution, biliary elimination of the parent drug andits metabolites, andto a minimal extent urinary excretion [53] . InDBPC observations of IB-responsive healthy and COPD subjects,


TABLE 2

Onset, duration of action (DoA) and potency of LAMAs licensed and undergoing investigation

Drug name Onset of action (mins) t 1/2 (hrs) % recovery (at 6 hrs) pIC50 Refs

Ipratropium bromide 14.9 2.8 3 0.2 110 10 9.5 0.04 Villetti et al. 2006 [17]

Tiotropium bromide > 6 27 3 9.5 0.1 Villetti et al. 2006 [17]

Glycopyrronium bromide 19.7 3.5 3.7 0.2 101 10 10.4 0.02 Villetti et al. 2006 [17]

Aclidinium bromide 30 7 9.5 0.1 Frampton et al. 2012 [39]

GSK573719 (Umeclidinium)

GSK233705 (Darotropium)

CHF5407 > 6 25 2 9.5 0.04 Villetti et al. 2010 [17]

TD-4208

AZD9164 15 Bjermer et al. 2012 [65]

RBx 343E48F0

PF-4522971

ALKS 27/Trospium 15 Oleson et al. 2010 [70]

Abbreviations : mins, minutes; t 1/2 , is thetime taken forresponse to carbachol to return to 50% recovery after washout of the test antagonist in human bronchus; hrs, hours; % recovery:percentage of responseto carbachol obtained 6 hours after thewashout of thetestantagonist. Alldataare mean ( standard error of themean{SEM})of at least four observations; pIC 50represents the -log molar concentration of the test antagonist producing a 50% reversal of carbachol induced tonic contraction in human isolated bronchus.



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TABLE 3

Glycopyrronium bromide clinical studies

Study [Refs] Patientnumber

Glycopyrroniumbromide (GB) dose

Durationof study

Comparator Study outcomes

Novartis GB/NVA237 studiesVerkindre et al. [24] 83 12.5 mg, 25 mg, 50 mg,

100 mg NVA2377 days Placebo and

OL Tiotropium18 mg

GB 50 mg and 100 mg showed clinically relevantimprovement versus placebo on day 1 and day 7

Vogelmeier et al. [25] 281 100 mg, 200 mg NVA237 28 days Placebo FEV 1 signicantly higher with GB Signicantly less use of rescue medications with GB Frequency and distribution of AE similar to placebo

Fogarty et al. [26] 33 50 mg NVA237 14 days Placebo FEV 1 AUC024 hours signicantly higher for GB on day 14Arievich et al. [27] 385 12.5 mg, 25 mg, 50 mg,

100 mg NVA23728 days Placebo GB 50 mg OD provides signicant bronchodilation over

a 24 hours periodSingh et al. [28] 45 20 mg, 125 mg, 250 mg,

400 mg NVA237Single dose Placebo Signicant improvement in FEV 1 at 24 hours

(> 125 mg GB) Majority of AE were mild or moderate; incidenceunrelated to dose

DUrzo et al. (GLOW1)[29]

822 50 mg NVA237 26 weeks Placebo Signicant improvement in: Trough FEV 1 on day 1 and sustained through week 26 FEV 1 throughout 24 hours period TDI focal scoreSGRQ score

Signicant reduction in: Risk of COPD exacerbation in terms of time to rstmoderate or severe exacerbation

Percentage of hospitalisations due to exacerbation of COPD

Lower incidence of AEKerwin et al. (GLOW2) [30] 1066 50 mg NVA237 52 weeks Placebo

OL Tiotropium18 mg

Signicant improvement in: Trough FEV 1 at week-12 TDI focal scoreSGRQ score

Signicant reduction in: Risk of COPD exacerbation Use of rescue medication

Similar AE prole to placeboBeeh et al. (GLOW3) [31] 108 50 mg NVA237 3 weeks Placebo Signicant improvement in:

Exercise

tolerance

(exercise

endurance

time)

at

3weeks IC at isotime and IC at rest TDI focal scoreBorg CR10 score

Safety prole similar to that of placebo

Other GB products (not by Novartis)Rennard et al. [32] 33 18 mg, 36 mg, 72 mg,

144 mg GP MDISingle dose Placebo

OL Tiotropium All four doses of GB demonstrated superior efcacy compared to placebo in terms of

Peak FEV 1 FEV 1 AUC024 hours

72 mg, 144 mg doses of GB demonstrated non-inferiorbronchodilator efcacy relative to OL TiotropiumNo differences in terms of safety

Orevillo et al. [33] 36 mg GP-MDI 7 days Placebo

OL

Tiotropium

FEV 1 AUC012 hours signicantly better with GB and OL

Tiotropium

on

day7 GB has comparable safety and efcacy to OLTiotropium

Fogarty et al. (GOLDEN-1)[35]

140 25 mg, 50 mg, 100 mg,200 mg EP-101

7 days PlaceboOL Tiotropium

All doses well tolerated with similar AE rates betweenplacebo and EP-101

All doses demonstrated dose related improvement inFEV 1 AUC compared to placebo

Singh et al. [34] 42 12.5 mg, 50 mg, 100 mg,200 mg, 400 mg EP-101

Single dose Placebo All treatments were well tolerated with similar AE rate Signicant improvement in mean change of troughFEV 1 at 24 hours at doses 50 mg compared toplacebo

Abbreviations : AE, Adverse events; AUC, Area under the curve; COPD, chronic obstructive pulmonary disease; EP 101, nebulisedglycopyrrolate; GLOW, glycopyrronium bromide in COPDairways clinical study;NVA 237,once-daily dry-powder formulation of glycopyrroniumbromideby Novartis;FEV 1, forcedexpiratoryvolume in1 s; TDI,transition dyspnoea index; SGRQ, St.Georges respiratory questionnaire; OL, open-label; IC, inspiratory capacity; GB, glycopyrronium bromide; OD, once-daily; IV, intravenous; GP-MDI, glycopyrrolate metered dose inhaler;GOLDEN: Glycopyrrolate for Obstructive Lung Disease via Electronic Nebuliser.



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umeclidinium had a signicantly higher specic airway conduc-tance (sG aw ) and FEV 1 improvement in the latter compared toplacebo [51,54] . To exclude potential increase in drug levels asresult of co-administration of verapamil (an inhibitor of P-glyco-protein and Cyp3a4) or its enhanced metabolism by the cyto-chrome p450 isoenzyme 2D6 (CYP2D6) in healthy subjects,umeclidinium was noted not to have any relevant drug interac-tion and remained unaltered [55] .

Phase II dose-ranging studies (15.61000 mg) have shown sig-nicant improvements in FEV1 and were well tolerated at 14- and28-days in comparison to placebo in varying severities of COPD

[56,57] . Only with 1000 mg were there minor drug-related adverseevents noted in the 04 hours post-dose period, but no dose effectat 24 hours [57] . At all tested doses there was rapid absorption witha T max of 515 min akin to healthy volunteers. Improvements inlung function and reduction in rescue medication use with ume-clidinium QD were comparable to umeclidinium BID and open-labelled tiotropium [57] . Presently umeclidinium is being inves-tigated in a number of Phase III studies as QD administration atdoses of 62.5 mg and 125 mg for use individually or in combinationwith an ultra-LABA, vilanterol, which is also marketed by Glax-oSmithKline 1 .


TABLE 4

Aclidinium bromide(AB) clinical studies

Study Patientnumber

Aclidinium dose Duration Othertreatmentscompared

Study outcomes

Singh et al. [44] 79 100 mg, 200 mg, 400 mg 7 days Placebo orformoterol12 mg

AB (all doses) and formoterol resulted asignicantly improved FEV

1 normalised AUC0

12 compared t placebo AB (all doses) had signicantly improved FEV1normalised AUC1224 , normalised AUC024 andmorning pre-dose FEV 1 compared to placebo

400 mg versus 100 mg was signicantly betterFEV 1 normalised AUC1224 , normalised AUC024and morning pre-dose FEV 1

AB was well tolerated

Chanez et al. [45] 464 25 mg, 50 mg, 100 mg,200 mg or 400 mg OD

4 weeks Placebo orTB 18 mg

AB 200 mg and 400 mg improved trough FEV1 AB was well tolerated

Maltais et al. [47] 181 200 mg OD 6 weeks Placebo AB improved exercise tolerance compared toplacebo

AB signicantly improved FEV 1, FVC, IC and ICTLC at week 3 and 6

Jones et al. (ACCLAIMCOPD I, ACCLAIMCOPD II) [46]

843, 804 200 mg OD 52 weeks Placebo AB improved trough FEV 1 at weeks 12 and 28 Signicant improvement in SGRQ at 52 weeksin ACCLAIM COPD I (P = 0.025)

Improvement in SGRQ at 52 weeks in ACCLAIMCOPD II (P = 0.07)

Time to rst exacerbation signicantly delayedin ACCLAIM COPD I

Fuhr et al. [43] 30 400 mg BD 2 weeks Placebo orTB 18 mg

Mean change in FEV 1 was signicantly greaterin AB and TB over placebo

Symptoms of COPD (breathlessness and nighttime symptom score) signicantly improvedfrom baseline in the AB group but not inplacebo or TB group

Kerwin et al. (ACCORD

COPD

I)

[48]

561 200 mg or 400 mg BD 12 weeks Placebo Compared to placebo mean trough FEV 1

improved

signicantly

(86

and

124

ml

in

the200 mg and 400 mg group respectively) Both doses signicantly improved SGRQ, TDIand COPD symptom scores

Incidence of adverse effects were similar acrossgroups

Jones et al. (ATTAIN) [49] 828 200 mg or 400 mg BD 24 weeks Placebo Signicant improvement in trough FEV 1 in AB200 mg and 400 mg group

Both doses of AB signicantly improved meanSGRQ over placebo

The incidence of anti-cholinergic side effectswere low

Abbreviations : ACCLAIM, AClidinium CLinical Trial Assessing Efcacy and Safety In Moderate to Severe COPD Patients; ACCORD, AClidinium in Chronic Obstructive Respiratory Disease I;ATTAIN: Aclidinium To Treat Airway obstruction In COPD patients.



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Darotropium (GSK233705)Darotropium is another LAMA developed by GlaxoSmithKline 1 .Data on in vitro and early safety studies are scanty. In a DBPC PhaseII dose-ranging 28-day study (12.5200 mg) it was reported that thevarying doses were not only well tolerated but also reported asignicant improvement in FEV1 compared to placebo [58] .Importantly, only the 200 mg dose achieved the clinically signi-

cant

FEV1 improvement

threshold

of

130

ml.

Peak

bronchodila-tion was reported at around 2 hours though declined toinsignicant levels at 2324 hours. In a 7-day study evaluatingthe addition of darotropium to salmeterol or placebo and compar-ing to tiotropium and salmeterol individually, darotropium wassafe and resulted in a signicant improvement in FEV1 comparedto placebo as well as salmeterol and tiotropium alone [59] .

Despite these positive ndings, we assume that the lack of 24 hours bronchodilation and delayed onset of action may havehalted further studies and instead umeclidinium, with its rapidonset and > 24 hours efcacy is being pursued.

CHF-5407 Chiesi Farmaceutici 1 have developed a novel aerosolised quatern-ary salt which has demonstrated sub-nanomolar afnities for thehuman M13 receptors [17] . In vitro, CHF-5407 compared to TBactivity resulted in a more rapid dissociation t 1/2 at the M2 (31 minvs 297 min) receptor but a comparable dissociation t 1/2 at the M3receptor (166 min vs 163 min). In anesthetised guinea pigs ACh-induced bronchospasm was dose-dependently attenuated by intra-tracheal (i.t.) administration of CHF-5407 23 times more potentlycompared to TB and IB, with the former two having unchangedactivity at 24 hours. In fact CHF-5407 had 57% inhibitory activityat 48 hours post-administration. Moreover i.t. administration of CHF5407 in anaesthetised dogs produced maximal inhibition of 30% (180 min post-dose) and 66% (60 min post-dose) after twodoses. From the safety perspective CHF-5407, akin to TB, had nosignicant cardiovascular effects.

From this preclinical data it is evident that CHF-5407 has greatpotential as an anti-bronchospastic anti-cholinergic agent with nomajor safety concerns. It is reported that CHF-5407 is beinginvestigated in Phase I studies [60] , however there is no availabledata of this or any other development on this molecule in theliterature for the last half decade.

TD-4208Theravance 1 , through the application of a multivalent design hasdeveloped a novel inhaled LAMA, TD-4208. Preclinical in vitrocharacterisation has demonstrated that TD-4208 has a t 1/2 at M2and M3 receptors of 6.9 min and 81 min respectively, and anestimated intrinsic half-life DoA after washout in tracheal ringpreparation EFS contractions of > 16 hours [61] . In anaesthetisedMCh-challenged rats and ACh-challenged dogs, nebulised TD-4208, caused dose-dependent potent bronchoconstriction antag-onism maintained at 7 days repeat dosing as well as persistent> 75% inhibition of bronchoconstriction at 24 hours post-dosing[62] . Moreover, repeated dosing had no effect on further bronch-odilation or antisialagogue activity.

Although there is sparse information on Phase I studies, anebulised dose-ranging DBPC (including IB) 4-way crossover PhaseII study in moderate-to-severe COPD subjects has reported that

TD-4208 was well tolerated, had similar onset of action to IB,however unlike IB had sustained bronchodilatory activity as mea-sured by FEV1 at 12 hours and 24 hours [63] . Theravance 1 havefurther studies underway on TD-4208 not only for individual usebut also in combination with other agents [64] .

AZD9164

AZD9164

stemmed

from

the

collaboration

of

AstraZeneca1

Dis-covery and Pulmogen Therapeutics Ltd 1 [65] . In vitro and in vivo(anaesthetised i.t. MCh-challenged) guinea pig studies haveshown about a 10-fold selectivity for the M3 compared to M 2receptors and prolonged DoA, increased human plasma proteinbinding and human liver microsomal intrinsic clearance, andimproved systemic side effect prole in a pilocarpine-inducedsalivation model [66] .

Although there is a lack of information on Phase I analyses,recently a Phase II single-dose, dose-ranging DBPC double-dummy5-arm study (including 3 nebulised doses of AZD9164 or placeboand inhaled TB) by Bjemer et al. reported an initial rapid dose-dependent dip in FEV1 (within 15 min) lasting up to 60120 min

followed by marked and sustained increase at 2226 hours in theAZD9164-treated subjects [65] . The TB and placebo arms had noinitial dips and the improvement in FEV1 with tiotropium wasmaintained for 114 hours post-dose, which then declined slowlythereafter. Overall AZD9164 and TB had statistically signicantimprovements in average, maximal and assessments at 2226 hours in FEV1 compared to placebo, and also betweenAZD9164 and TB. Due to the early dips in lung function therewas increased use of rescue medication in the AZD9164 armsthough there were no overall safety concerns with its use.

This preliminary study demonstrates probable enhancedimprovements in bronchodilation with the use of AZD9164 inCOPD patients with no inevitable increase in adverse eventshowever the observed initial bronchoconstriction is undesirableand needs further assessment before entering into any largerclinical studies. This may be the reason that although the PhaseII study was reported in an AstraZeneca 1 clinical study reportsynopsis in early 2010 [67] , but no further studies have beenreported to-date. In fact another molecule AZD8683, a nebulisedLAMA, is being investigated in Phase I and II (NCT01205269)studies although there is no data available on these [60] .

RBx 343E49F0RBx 343E49F0 is a novel LAMA being developed by Ranbaxy 1 . Inanimal models in vivo and in vitro studies, it has been reported tohave potent anti-muscarnic activity, a 60-fold selectivity for theM 3 over the M 2 receptor, anda rapid onset of action with a DoA of > 24 hours [68] . Presently there is no further available clinicaldata.

PF-4522971Pzer 1 have developed a LAMA, PF-4522971, that has beenassessed preclinically in vitro [69] . It antagonised bronchoconstric-tion guinea pig trachea and dog bronchi, but was about 10 timesless potent than TB and IB, while in human bronchi was 36 timesand 10 times less potent respectively. At maximal concentrationPF-4522971 and TB had a DoA of > 16 hours. Further clinical dataon PF-4522971 are scanty due to its lack of potency.




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ALKS27 (Trospium)ALKS27 is a dry powder inhaled LAMA developed by AlkermesInc 1 for which no pre-clinical data are available. In a Phase IIDBPC dose-ranging study in COPD patients it was reported thatALKS27 was well tolerated, had a rapid onset of action of around15 min and maximal improvement in FEV1 at around 120 minwhich was maintained at 24 hours as well as improvements in the

expiratory

ratio

[70] . To-date

no

further

studies

have

been

reportedon ALKS27.

OthersThere are number of molecules that are being developed as LAMAsfor use as bronchodilators for which the data are scarce includingV-0162 by Pierre Fabre 1 (Phase I/II NCT0134855) and TRN-157 byTheron 1 .

ConclusionA cost-effectiveness analysis for subjects who were tolerant of ICS,it was reported that LAMAs were the rst-line treatment followedby LAMA + LABA/ICS and LAMA, LABA/ICS + roumilast. For ICS

intolerant subjects the order of cost-effectiveness, after LAMAs,was LAMA + LABA and LAMA + LABA + roumilast. The primarydriver of cost-effectiveness was exacerbations [71] . Key challengesin COPD are driving development. COPD is a growing market witha number of exciting pipeline products that have been recentlylicensed or are in late stages of clinical trials. Up until recently themarket leader has been TB, however with the licensing of AB andGB for COPD there is now a choice not only for the physicians butalso for the patients who were unable to tolerate TB. Importantly,the administration of AB is twice daily which may have someimplications on concordance in patients. GB is licensed in Europebut no in the USA. The future looks exciting for the LAMAs andLABAs as there are the rst choice for patients with COPD basedon the GOLD guidelines. Combination inhalers with a LAMA andLABA would add another dimension to our management of

patients with COPD. Various xed dose combinations of LABA/LAMA are being investigated and are in various stages of devel-opment including indacaterol/GB, olodaterol/TB and vilanterol/GSK573719 [72] .

Drugs with a bi-functional mechanism of action, combiningboth muscarinic antagonist and b 2 -adrenoceptor agonist pharma-cology in a single molecule, which are known as dual-acting

muscarinic

antagonist/ b 2 -adrenoceptor

agonist

(MABA)

broncho-dilators, provide an interesting alternative approach [73] . MABAshave the advantage of delivering a xed ratio into every region ofthe lung, hence reducing the complexity of combination inhalers.In preclinical models, LAS190792 from Almiral has shown to havea long DoA and bronchodilator activity when combined with b 2agonism. The molecule shows very favourable drug properties andsafety. On a similar note GSK961081 is in a Phase IIb study toevaluate efcacy and safety in patients with moderate-to-severeCOPD [72] . The future looks very promising for patients withCOPD with triple drug combinations (LAMA/LABA/ICS) beingcombined into a single inhaler. These are in various stages ofclinical trials. The combinations under evaluation include TB/

salmeterol and uticasone/ciclesonide; indacaterol/GB andmometasone; milveterol/darotropium and uticasone furoate;GSK-642444/dartropium and uticasone furoate [72] . Thoughthese exciting novel therapies may take some time to reachpatients, it is encouraging to realise that patients with COPD willbe receiving more effective, safe and user friendly treatments innear future.

Conict of interestKSB has received honoraria for speaking and nancial support toattend meetings from Chiesi, AstraZeneca, Boehringer Ingelheim,GSK/Allen & Hanburys and Wyeth. JBM has received honoraria forspeaking and nancial support to attend meetings/advisory boardsfrom Wyeth, Chiesi, Pzer, MSD, Boehringer Ingelheim, Teva,GSK/Allen & Hanburys, Napp, Almirall and Novartis.

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