The effective treatment of COPD: Anticholinergics and what else?

THERAPEUTICSTRATEGIES

DRUG DISCOVERY

TODAY

Drug Discovery Today: Therapeutic Strategies Vol. 3, No. 3 2006

Editors-in-Chief

Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK

Eliot Ohlstein – GlaxoSmithKline, USA

Respiratory diseases

The effective treatment of COPD:Anticholinergics and what else?Mario Cazzola1,*, Maria Gabriella Matera2

1University of Rome Tor Vergata, Department of Internal Medicine, Unit of Respiratory Diseases, Via Montpellier 1, 00133 Rome, Italy2Second University of Naples, Department of Experimental Medicine Unit of Pharmacology and Toxicology, Piazza Miraglia 4, 80123 Naples, Italy

Long-acting bronchodilator therapy should be consid-

ered when a COPD patient is symptomatic. For patients

whose conditions are not sufficiently controlled by

monotherapy, combining medications of different

classes seems a convenient treatment for obtaining

better results. The current opinion is that it is advanta-

geous to develop inhalers containing several classes of

long-acting bronchodilator drugs in an attempt to sim-

plify treatment regimes as much as possible and to serve

as a basis for improved ‘triple therapy’ combinations

through co-formulation with novel anti-inflammatory

compounds, such as inhaled PDE4 inhibitors, that could

deliver three complementary therapeutic effects.

*Corresponding author: M. Cazzola ([email protected])

1740-6773/$ � 2006 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddstr.2006.09.009

Section Editors:Roy Goldie – Faculty of Health Sciences, Flinders University,Adelaide, AustraliaPeter Henry – School of Medicine & Phamacology, TheUniversity of Western Australia, Nedlands, Australia

Introduction

National and international guidelines [1–4] suggest that long-

acting bronchodilator therapy should always be considered

when patients with COPD are symptomatic, but no distinction

is made as to which class of drugs should be considered first,

althoughanticholinergics agents areofnoteworthyvalue since

parasympathetic cholinergic pathways arising from the vagus

nerveare implicated in the pathophysiology ofairflowobstruc-

tion in COPD [4–6]. In effect, a systematic review with meta-

analysis of current evidence about the effectiveness of tiotro-

pium bromide compared with placebo, ipratropium bromide

or long-acting b2-adrenoceptor (AR) agonists [LABAs], for the

treatment of stable COPD patients [7] has documented that

increases in FEV1 and FVC from baseline were significantly

larger with tiotropium than with placebo, ipratropium and

LABAs. Also, tiotropium reduced COPD-related exacerbations

and hospital admissions compared with placebo and led to

30% reduction in COPD-related admissions compared with

LABAs. Moreover, Adams et al. [8] have recently observed that

tiotropium provided significant improvement in lung func-

tion, health status and dyspnea when used as maintenance

treatment in undertreated COPD patients who were not

previously receiving maintenance bronchodilator therapy.

For patients whose conditions are not sufficiently con-

trolled by monotherapy, combining medications of different

classes, in particular an inhaled anticholinergic with a b2-AR

agonist, seems a convenient way of delivering treatment and

obtaining better results [1–3]. This includes better lung func-

tion and improved symptoms. Specifically, as airflow obstruc-

tion becomes more severe, both a long-acting anticholinergic

plus a long-acting b2-agonist are advocated, although data

supporting this therapeutic approach are still scarce [9].

The aim of this article is to illustrate newer and potential

options that could be considered when monotherapy appears

to be ineffective.

Pharmacological rationale for combining b2-agonists

and anticholinergic agents

Postganglionic, parasympathetic-cholinergic nerves inner-

vate the airways. When activated, these nerves are capable

277

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http://dx.doi.org/10.1016/j.ddstr.2006.09.009

Drug Discovery Today: Therapeutic Strategies | Respiratory diseases Vol. 3, No. 3 2006

of obliterating the lumen of small bronchi and bronchioles,

and markedly increasing airway resistance in larger, cartilagi-

nous airways, by secretion of the bronchoconstricting media-

tor acetylcholine (ACh), which causes activation of muscarinic

receptors at the level of the target cells, such as bronchial

smooth muscle and goblet cells [9]. Conversely, sympathetic

nerves may control tracheobronchial blood vessels, but no

innervation ofhuman airway smoothmuscle has been demon-

strated. b2-ARs, however, are abundantly expressed on human

airway smooth muscle and activation of these receptors causes

its relaxation [9].

Bronchodilation may be obtained either by stimulating the

b2-ARs with b2-AR agonists, or by inhibiting the action of

ACh at muscarinic receptors with anticholinergic agents. In

any case, anticholinergics are more likely to decrease central

airway resistance, although there are muscarinic receptors

that are expressed in the smooth muscle of small airways,

which do not appear to be innervated by cholinergic nerves,

and b2-AR agonists have a greater effect on peripheral airway

resistance in patients with COPD [9]. It is reasonable to

postulate that attempts to reduce bronchoconstriction

through two distinct mechanisms (anticholinergic and sym-

pathomimetic) with a different prevalent site of action may

maximize bronchodilator response [9].

Interestingly, the presence of small dense-cored vesicles

containing adrenergic nerve varicosities, occasionally in close

Figure 1. Schematic presentation of the potential alternative role of b2-adren

parasympathetic nerve endings. Bronchodilation may be obtained either by stim

airway smooth muscle, with b2-adrenoceptor agonists, or by inhibiting the actio

with anticholinergic agents. A prejunctional b2-adrenoceptor is present on cho

that its activation can increase acetylcholine release in a concentration-depend

b2-ARs inhibits cholinergic neurotransmission, Abbreviations: A, circulating adr

muscarinic M1 or M3 receptors; , neuronal activity; !, stimulatory effect; ,

278 www.drugdiscoverytoday.com

proximity to morphologically characteristic cholinergic

nerve-endings, has been identified in human airways, sug-

gesting that catecholamines might modulate cholinergic

neurotransmission (Fig. 1) [9]. However, different studies

have led to dissimilar conclusions. Early research papers

based on force measurement alone suggested that stimula-

tion of b2-ARs inhibits cholinergic neurotransmission, most

probably by the release of inhibitory prostaglandins from the

airway mucosa [9]. However, interpretation of these data is

seriously hampered by the large postjunctional effects of

b2-AR agonists. On the contrary, other studies have docu-

mented that activation of b2-ARs can increase ACh release in

a concentration-dependent manner [9]. Whatever the type of

interaction between the two systems may be, combining b2-

AR agonists and anticholinergic agents is pharmacologically

useful. In fact, in the first case, the addition of a b2-AR agonist

decreases the release of ACh because of the modulation of

cholinergic neurotransmission by prejunctional b2-AR and,

consequently, amplifies the bronchial smooth muscle relaxa-

tion directly induced by the anticholinergic agent. On the

contrary, in the second circumstance, the addition of an

anticholinergic agent can reduce the peripheral bronchocon-

strictor effects of ACh, whose release has been facilitated by

the b2-AR agonist, and in this manner can amplify the

bronchodilation elicited by the b2-AR agonist through the

direct stimulation of smooth muscle b2-ARs.

oceptor in the pre-synaptic control of acetylcholine release from airway

ulating the b2-adrenoceptors, which are abundantly expressed on

n of acetylcholine at muscarinic receptors on bronchial smooth muscle

linergic nerves in airways smooth muscle. It has been documented

ent manner, but some papers have suggested that stimulation of

enaline; ACh, acetylcholine; b2-AR, b2-adrenoceptor; M1 and M3,

inhibitory effect.

Vol. 3, No. 3 2006 Drug Discovery Today: Therapeutic Strategies | Respiratory diseases

Evidence from clinical studies showing benefits of

LABA and tiotropium combination therapy in COPD

Considering that formoterol provides a greater degree of early

bronchodilation (in the first 2 h) than tiotropium and

comparable bronchodilation over 12 h [10], the possibility

of combining these two agents was examined in stable COPD

patients. Formoterol 12 mg and tiotropium 18 mg appeared

complementary not only after their acute administration

[11], but also after a regular treatment [12,13]. In fact

tiotropium ensured prolonged bronchodilation; formoterol

added fast onset and greater peak effect. In particular, van

Noord et al. [12] documented that 6 weeks of treatment with

tiotropium 18 mg + formoterol 12 mg once daily (od) in the

morning in patients suffering from moderate-to-severe COPD

had a greater bronchodilator effect compared with individual

agents (tiotropium 18 mg od in morning, formoterol 12 mg

bid), over 24 h (with the greatest differences during the first

12 h) and was significantly better for daytime (but not night-

time) rescue salbutamol use. In any case, the numerical

differences suggested that patients would have benefited

from an evening dose of formoterol. In effects, the results

of 2-week treatments with tiotropium alone or tiotropium

plus formoterol once or twice daily following a 2-week

pretreatment period with tiotropium, have documented that,

although the investigators appear to favour the od combina-

tion in their discussion, the evening dose of formoterol added

clear benefit [13].

Interestingly, the additive effect of a second long-acting

bronchodilator in patients receiving a first long-acting

bronchodilator does not depend on which type of broncho-

dilator is given first [14].

Also the combination of tiotropium 18 mg + salmeterol

50 mg had a greater bronchodilator effect compared with

individual agents, but results excluded the once-daily co-

administration of the two drugs [15]. It was also observed

that the onset of action of the two drugs was faster when they

were combined. This effect is worthy of attention because

both agents elicit a slow onset of action.

It has also been documented that for patients suffering

from a mild-to-moderate acute exacerbation of COPD, com-

bination therapy with formoterol and tiotropium provides

faster and greater peak and overall bronchodilation, with

improved oxygen saturation [16]. In this study, both single

agents had a shorter duration than expected, perhaps because

of increased airways inflammation during an exacerbation –

however, the combination improved FEV1 for 24 h.

Anti-inflammatory approaches in COPD

Unfortunately, COPD is a multicomponent disease with

inflammation and the development of extensive tissue remo-

delling during the course of the disease process at its core, in

which patients experience progressively worsening lung

function, disease symptoms and quality of life (QoL), as well

as increasing exacerbations [4]. Bronchodilators improve the

airflow limitation by only producing airway smooth-muscle

relaxation. Therefore, there is an absolute need to also target

other components of the disease, mainly inflammation.

Corticosteroids are highly effective as an anti-inflamma-

tory treatment in asthma, but in COPD their role is contro-

versial, as the inflammatory phenotype differs from that seen

in asthma [17] and, moreover, COPD has been reported to

respond less favourably in the short term to inhaled corti-

costeroids (ICS) [18]. Nonetheless, regular treatment with ICS

is recommended for symptomatic patients who suffer from

frequent exacerbations, and whose FEV1 is<50% of predicted

[4]. This recommendation is also supported by the observa-

tion that in a pooled analysis of seven randomised studies

involving 5085 patients, ICSs reduced all-cause mortality by

about 25% relative to placebo in patients with stable COPD

[19].

In any case, in severe COPD patients, combinations of ICS

and LABA show an additive effect, suggesting an interaction

between the two moieties that can have a positive effect and

bring to significant improvement of important clinical out-

comes [20]. In effect, LABA + ICS therapy causes a rapid

improvement in lung function, which is sustained for at least

12 months. In addition, greater improvements in cough and

breathlessness are seen with combination treatment, com-

pared to monotherapy with the individual agents alone.

Importantly, the number and severity of exacerbations

experienced by patients is reduced by LABA + ICS combina-

tion therapy, compared with monotherapy, in severe COPD

[21]. However, in patients with mild to moderate COPD, no

additional benefit of LABA + ICS combination therapy has

been shown thus far [23]. Moreover, there are concerns about

the increased risk of side effects and cost of using LABA + ICS

therapy in COPD [22].

Recently, it has been suggested to use antioxidants, iNOS

inhibitors and theophylline for increasing histone deacety-

lase (HDAC) activity because of the reduction in HDAC

activity, owing to a selective reduction in HDAC-2 expres-

sion as a consequence of the increased oxidative and nitra-

tive stress in lungs of smokers, which may account for the

increased pulmonary inflammation and resistance to corti-

costeroids [23]. Nonetheless, this proposal seems to be more

theoretic than practical. In fact, it was documented that both

salmeterol + fluticasone propionate and theophylline + flu-

ticasone propionate combination significantly improved

FEV1, with no difference between the two therapeutic

regimes, and, in addition, fluticasone propionate in combi-

nation with salmeterol was more effective in reducing dys-

pnea and use of salbutamol as rescue medication after 4

months of treatment [24]. Furthermore, the results of the

BRONCUS study suggested that the exacerbation rate might

be reduced with N-acetylcysteine only in patients not treated

with ICS [25].

www.drugdiscoverytoday.com 279

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Table 1. Ultra long-acting b-agonists under development

Pros Cons Latest developments Who is working on this strategy Refs

Arformoterol It has a longer duration of action than currently

marketed LABAsa

It is unlikely that the drug will be approved as a

once-daily dosing regime

A new drug application

submitted to the U.S.

Food and Drug

Administration

Sepracor (http://www.sepracor.com/) [27]

The potential association between LABA and rare,

but potentially serious, respiratory adverse events

Indacaterol It offers a quick onset of action and true

24-hour control.



Phase III Novartis (http://www.novartis.com/) [27]

It behaves as a potent b2-ARb agonist with

high intrinsic efficacy that, in contrast to salmeterol,

does not antagonize the bronchorelaxant effect

of a short-acting b2-AR agonist.

Carmoterol It displays a fast onset and long

duration (30 h) of activity.



Phase III Chiesi (http://www.chiesigroup.com/2006/) [27]

GSK159797 It produces clinically significant increases

in FEV1c through 24 hours, with little

change in heart rate.



Phase IIb Theravance (http://www.theravance.com/)/

GlaxoSmithKline (http://www.gsk.com/)

[27]

GSK159802 Detailed status not disclosed The potential association between LABA and rare,


Phase II GlaxoSmithKline (http://www.gsk.com/)



Phase II GlaxoSmithKline (http://www.gsk.com/) [27]



Phase IIa GlaxoSmithKline (http://www.gsk.com/) [27]



Phase II GlaxoSmithKline (http://www.gsk.com/) [27]

a Long-acting b-agonist.b b2-Adrenoceptor.c Forced expiratory volume in one second.

280

ww

w.d

rugd

iscoveryto

day.co

m

http://www.altanapharma.com/

http://www.gsk.com/

http://www.gsk.com/

http://www.gsk.com/

http://www.ivax.com/

http://www.novartis.com/


http://www.gsk.com/

http://www.almirall.es/


Future directions

Regrettably, the existing therapy of COPD is far from ideal

because no currently available agent has been shown to slow

the relentless progression of this disease but, with a better

understanding of the inflammatory and destructive process,

several targets have been identified and new treatments are in

development. We do not know, however, if all these new

therapies will reach the market because the therapeutic ratio-

nale behind many of these treatments is mainly speculative

and, moreover, they are fraught with important safety issues

[26].

In any case, there is a pressing need to develop new treat-

ments for this disease. The current opinion is that it will be

advantageous to develop inhalers containing several classes

of long-acting bronchodilator drugs in an attempt to simplify

treatment regimes as much as possible. A once daily inhaler

with a once daily b2-AR agonist and anticholinergic as well as

a once daily inhaler with a once daily b2-AR agonist and a

once daily ICS would, therefore, be ideal.

New bronchodilators

Once-daily b2-AR agonists such as carmoterol, indacaterol,

GSK-159797, GSK-597901, GSK-159802, GSK-642444 and

GSK-678007 are under development for the treatment of

COPD [27] (Table 1), despite the recent FDA public health

advisory that has highlighted the concerns raised by the

SMART study [28]. The majority of these compounds are

(R,R)-isomers to control desensitisation and accumulation.

It is likely that once-daily dosing of an ultra LABA will lead to

increased convenience for the patients, which may also lead

Table 2. Long-acting antimuscarinic agents under development

Pros Cons

NVA237 At doses showing similar efficacy,

NVA237 demonstrated a significantly

lower effect on cardiovascular

parameters than tiotropium.

OrM3 It has been formulated as an oral

tablet, a potentially more convenient

formulation, particularly for less

compliant patients and those who

have difficulty using aerosol therapy.

At a dose that provided effi

less than that of ipratropium

the incidence of dose-relat

mechanism-based side effec

OrM3 exceeded those obs

for ipratropium.

GSK656398 Detailed status not disclosed. Detailed status not disclos

GSK233705 Its long duration of action when

administered via inhalation in

animal models supports the

potential for use as a once-daily

bronchodilator for COPD.

Detailed status not disclos

LAS 34273 Detailed status not disclosed. Detailed status not disclos

LAS 35201 Detailed status not disclosed. Detailed status not disclos

to enhancement of compliance, and may have advantages

leading to improved overall clinical outcomes in patients

with COPD. In any case, the results of a recent study that

has evaluated the bronchodilating activity of the ultra LABA

carmoterol and the muscarinic M3-antagonist tiotropium,

given intratracheally alone or in combination in anaesthe-

tized artificially ventilated normal and actively sensitized

guinea-pigs, provide a clear evidence of a positive interaction

between these two bronchodilators in controlling the

bronchoconstriction elicited by different challenges, anaphy-

lactic reaction included [29]. In particular, in the presence of

doses of tiotropium ineffective per se, the ED50 values of

carmoterol were significantly reduced by 5 to over 30 times,

depending on the challenge.

Also some new long-acting antimuscarinic agents (LAMAs)

such as LAS-34273, LAS-35201, GSK656398 (formerly known

as TD-5742), GSK233705, NVA-237 (glycopyrrolate) and OrM3

are under development (Table 2). In particular, it has been

documented in an experimental setting that at doses showing

similar efficacy, NVA237 demonstrated a significantly lower

effect on cardiovascular parameters than tiotropium, which

may indicate a potential clinical benefit in man [30]. In effect,

inhaled NVA237 has low systemic absorption, and therefore

should not be expected to be associated with typical systemic

antimuscarinic adverse effects. This is supported by the

observed lack of dry mouth (a classic antimuscarinic adverse

effect) with inhaled NVA237, and suggests a favourable safety

profile for this once-daily antimuscarinic bronchodilator [31].

Single doses of NVA237 480 mg demonstrated bronchodilatory

efficacy up to 32 h post-dose in patients with reversible

Latest

developments

Who is working on this strategy Refs

Phase IIb Vectura (www.vectura.com)/Novartis

(http://www.novartis.com/)

[30–33]

cacy

,

ed,

ts for

erved

Phase IIb Merck Research Laboratories

(http://www.merck.com/mrl/)

[34]

ed. Phase I Theravance (www.theravance.com)/


ed. Phase II GlaxoSmithKline (http://www.gsk.com/)

ed. Phase II/III Almirall (http://www.almirall.es/)

ed. Phase I/II Almirall (http://www.almirall.es/)



http://www.gsk.com/

http://www.gsk.com/

http://www.gsk.com/




http://www.gsk.com/


Table 3. Combination of LABAa + LAMAb under development

Pros Cons Latest

developments

Who is working on this strategy Refs

Formoterol +

tiotropium

The combination of a LABA with

tiotropium is superior to either

single agent alone

Once-daily

administration is

not really possible.

Development of

unit dose oral

inhalation products

for nebulization

Novartis (http://www.novartis.com/),

Boehringer-Ingelheim

(http://www.boehringer-ingelheim.com/),

Dey (http://www.dey.com/)

[11–14,16]

Salmeterol +

tiotropium

The combination of a LABA with

tiotropium is superior to either

single agent alone

Once-daily

administration is

not really possible.

Phase III Boehringer-Ingelheim

(http://www.boehringer-ingelheim.com/),


[15]

Carmoterol +

tiotropium

In the presence of doses of

tiotropium ineffective per se,

the ED50c values of

carmoterol were significantly

reduced by 5 to over 30 times,

depending on the challenge.

Human data are

still lacking.

Preclinical phase. Chiesi (http://www.chiesigroup.com/2006/) [29]

Indacaterol +

NVA237

(QVA149)

Detailed status not disclosed Detailed status

not disclosed.

In preparation

for Phase II.

Novartis (http://www.novartis.com/)

GSK159797 +

GSK233705

Detailed status not disclosed. Detailed status

not disclosed.

Preclinical phase. Theravance (http://www.theravance.com/)/


GSK-961081 It is both a muscarinic

antagonist and a b2-ARd agonist.

Detailed status

not disclosed.

Phase I GlaxoSmithKline (http://www.gsk.com/)

a Long-acting b-agonist.b Long-acting antimuscarinic agent.c Effective dose 50%.d b2-Adrenoceptor.

obstructive airways disease, supporting the potential for once-

daily dosing, and exhibited a rapid onset of action [32]. In

particular, single doses of NVA237 provided a similar degree of

bronchodilation to the short-acting b2-agonist salbutamol

over the first 40 min post-dose [33]. OrM3 is a 4-acetamidopi-

peridine derivative with a high degree of selectivity (120-fold)

for the M3 receptor over M2 receptors [34]. It has been for-

mulated as an oral tablet, a potentially more convenient for-

mulation, particularly for less compliant patients and those

who have difficulty using aerosol therapy. Dosed orally, phar-

macokinetic data demonstrated that OrM3 has a long half-life

(t1/2 = 14.20 h), which would potentially allow for a once-

daily dosing regimen. In effect, OrM3 demonstrated a signifi-

cant dose-related improvement in serial FEV1 and a trend for

Table 4. Combination therapy with an ICS and an ultra LABA

Pros Cons

Carmoterol + budesonide It is two-fold more effective

than the formoterol/

budesonide combination.

Detailed status

not disclosed.

Indacaterol + QAE397 Detailed status not disclosed. Detailed status

not disclosed.

Indacaterol + mometasone Detailed status not disclosed. Detailed status

not disclosed.

GSK159797 + GSK685698 Detailed status not disclosed. Detailed status

not disclosed.


dose-related improvement in patient-reported symptoms

compared with placebo [34]. However, at a dosage that pro-

vided efficacy less than that of ipratropium, the incidence of

dose-related, mechanism-based side effects for OrM3 exceeded

those observed for ipratropium [34].

Bronchodilators are still central in the symptomatic man-

agement of COPD [1]. For this reason, the current opinion is

that it will be advantageous to develop inhalers containing

combination of several classes of long-acting bronchodilator

drugs in an attempt to simplify treatment regimes as much as

possible. Consequently, several options for once-daily dual-

action ultra LABA + LAMA combination products are cur-

rently being evaluated (Table 3). Because combination ther-

apy with an ICS and a LABA is now considered a therapeutic

under development

Latest developments Who is working on this strategy Refs

Preclinical phase Chiesi

(http://www.chiesigroup.com/2006/)

Novartis (http://www.novartis.com/)

Novartis (http://www.novartis.com/)/

Schering-Plough

(http://www.schering-plough.com/)



http://www.gsk.com/

http://www.gsk.com/

http://www.gsk.com/




http://www.gsk.com/


http://www.elbion.de/


http://www.gsk.com/

http://www.gsk.com/

http://www.gsk.com/



option for treating patients suffering from severe to very-

severe COPD, there is a factual interest in developing a once-

daily combination therapy, again in an attempt to simplify

the treatment, and also to overcome the loss of patent pro-

tection (Table 4). The awareness that new ICS such as cicle-

sonide or GSK685698 (Table 4), which can be used as a once-

daily dosing, have been developed or are in development

have further supported the development of new ultra-LABAs

that can be used on a once-a-day basis.

New anti-inflammatory agents

Theophylline has been relegated to a second- or even third-

line therapy in the treatment of COPD, behind corticoster-

oids and b2-agonists, although it possesses anti-inflammatory

and immunomodulatory effects in addition to its well-recog-

nized effects as a bronchodilator [35]. In part, theophylline

has fallen out of favour because of its adverse side-effect

profile, and this has led to the search for more effective

and safer drugs based on the knowledge that theophylline

is orally active and that it is a nonselective phosphodiesterase

Figure 2. PDE4 Inhibitors in COPD. In contrast to asthma, the key inflammator

cells. These cells release the reactive oxygen species, chemokines, cytokines and p

The ongoing inflammatory processes lead to enlargement of the alveolar spaces

obstruction. Airway hyperresponsiveness is not a feature of COPD. Epithelial met

inhibitors can target the inflammatory processes. Abbreviations. AHR, Airway Hyp

mediates cellular adherence; GM-CSF, Granulocyte/Macrophage Colony Stimula

Interferon; LTB4, Leukotriene B4; LTC4, Leukotriene C4; MIP-1a, Macrophage

Prostaglandin D2; RANTES, Regulated on Activation Normal T Cell Expressed

Factor-a; VCAM1, Vascular Cell Adhesion Molecule 1.

(PDE) inhibitor. In view of the fact that PDE4 isoenzyme is the

predominant isoenzyme in the majority of inflammatory

cells, including neutrophils, which are implicated in the

pathogenesis of COPD [35] (Fig. 2), selective PDE4 inhibitors

have been developed or are under development for the

treatment of COPD [35] (Table 5).

Roflumilast and cilomilast are currently the most advanced

PDE4 inhibitors undergoing clinical trials for COPD. In a large

placebo-controlled trial, roflumilast 500 mg once daily pro-

duced a significant improvement in postbronchodilator

FEV1, and reduced exacerbations by 34% over placebo [36].

Roflumilast was safe and well tolerated, although the class-

associated side effects of diarrhoea, nausea, and headache

were still apparent [36]. Also cilomilast 15 mg twice daily

resulted in an improvement in FEV1 compared with placebo.

There was also a clinically significant improvement in the St

George’s respiratory questionnaire score and a greater per-

centage of exacerbation-free weeks in cilomilast-treated

patients [37]. These data demonstrate that PDE4 inhibitors

can improve clinical symptoms in patients with COPD,

y cells involved in COPD include: neutrophils, macrophages and CD8+ T

roteases that are instrumental in producing a chronic inflammatory state.

, destruction of the lung parenchyma, loss of elasticity and small airways

aplasia and mucus hypersecretion are prominent features of COPD. PDE4

erresponsiveness; CD11b, subunit of receptor on human neutrophils that

ting Factor; IL-2, -4, -5, -8, -10, -13, Interleukin-2, -4, -5, -8, -10, -13; IFN,

inflammatory protein 1a; PAF, Platelet Activating Factor; PGD2,

and Secreted; ROS, Reactive Oxygen Species; TNF-a, Tumor Necrosis


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Table 5. Antiinflammatory therapies under development

Pros Cons Latest developments Who is working on this strategy Refs

Inhaled corticosteroids

Ciclesonide (Alvesco) It can be used as a once-daily dosing. It passes through the airways tissues

too fast and splits too fast in the

airways and in the body to have a

significant impact on effect duration

and airway selectivity of its active

metabolite.

It has been approved in

37 countries and is now

available in 18 countries

Altana (http://www.altanapharma.com/)

It is inactive until it reaches the lungs,

where it is converted to its active metabolite

desisobutyryl-ciclesonide.

Other favourable pharmacokinetic and

pharmacodynamic characteristics such as high

protein binding, low oral bioavailability and

rapid clearance contribute to its efficacy and

improved systemic safety profile.

Fluticasone furoate

(GSK685698,

Avamys/Allermist)

It can be used as a once-daily dosing. Allergic rhinitis is its main indication. Phase III GlaxoSmithKline (http://www.gsk.com/)

GSK799943 Detailed status not disclosed Detailed status not disclosed Phase II GlaxoSmithKline (http://www.gsk.com/)

GSK870086 Detailed status not disclosed Detailed status not disclosed Phase I GlaxoSmithKline (http://www.gsk.com/)

Etiprednol

dicloacetate (BNP-166)

It is rapidly converted to an inactive form

after absorption, which reduces the

likelihood of side effects.

Detailed status not disclosed Phase II IVAX Corporation (http://www.ivax.com/)

QAE397 Detailed status not disclosed Detailed status not disclosed Phase I Novartis (http://www.novartis.com/)

PDE4a inhibitors

Roflumilast (Daxas) It is the most advanced PDE4 inhibitors

undergoing clinical trials for airways disease.

At least in asthmatic patients there are

early dose-limiting adverse events with

the 500 mg dose that abate with

longer-term treatment.

Phase III Altana (http://www.altanapharma.com/) [35,36,

38,39]

Cilomilast (Ariflo) It significantly improves lung function

and quality of life to a clinically meaningful

extent.

The results of Phase III studies

are unremarkable and disappointing,

raising doubt over the future of

cilomilast as a novel therapy for COPD.

Phase III GlaxoSmithKline (http://www.gsk.com/) [37]

Arofylline Detailed status not disclosed Detailed status not disclosed Phase II/III: Almirall (http://www.almirall.es/)

AWD12-281 It causes no side effects in animal

models in opposite to other PDE4 inhibitor.

Detailed status not disclosed Phase II Elbion AG (http://www.elbion.de/) [35]

GRC-3886 Detailed status not disclosed Detailed status not disclosed Phase I Glenmark Pharmaceuticals Ltd

(http://www.glenmarkpharma.com/)

[35]

HT0712 Detailed status not disclosed Detailed status not disclosed Phase I Inflazyme Pharmaceuticals Ltd

(http://www.inflazyme.com/)

[35]

a Phosphodiesterase4.

284

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http://www.gsk.com/

http://www.gsk.com/

http://www.gsk.com/




http://www.gsk.com/


http://www.elbion.de/

http://www.glenmarkpharma.com/

http://www.inflazyme.com/


although unlike theophylline, they have no direct broncho-

dilator activity and are therefore likely to be having a differ-

ent mechanism of action [35]. Interestingly, a significant

reduction in the amount-number of neutrophils and eosino-

phils in sputum of patients with COPD has been observed

after 4 weeks of treatment with roflumilast 500 mg once daily

[38], thus adding clinical evidence to the wide range of anti-

inflammatory effects observed in preclinical studies. In addi-

tion, in a murine model roflumilast has also been shown to

prevent the development of cigarette smoke–induced

emphysema, suggesting that it could be used as a protective

therapy in smokers to prevent deterioration of their lung

function, although this has yet to be explored clinically [39].

Conclusion

Although smoking cessation strategies are important for

reducing the incidence of COPD in the longer term, there

is clearly a need for more effective therapies for patients who

already have the disease. The investigational therapies for

COPD discussed above have shown promising results. It is

likely that the development of once-daily dual-action ultra

LABA + LAMA combination products may serve as a basis for

improved ‘triple therapy’ combinations through co-formula-

tion with novel anti-inflammatory compounds such as

inhaled PDE4 inhibitors, that could deliver three comple-

mentary therapeutic effects for patients with COPD. In any

case, the development of once-daily dual-action ultra

LABA + LAMA combination products may serve also as a

basis for improved ‘triple therapy’ combinations through

co-formulation with novel ICS. The potential for these

therapeutic strategies to be administered once daily simplifies

patient treatment regimens and therefore increases the

likelihood of compliance with therapy.

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The effective treatment of COPD: Anticholinergics and what else?