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Milestones in Drug Therapy

Series Editors: Michael J. Parnham Jacques Bruinvels

AlexandreTrifilieff Editor

Indacaterol

The First Once-daily Long-acting Beta2


Agonist for COPD

Milestones in Drug Therapy

Series Editors
Michael J. Parnham, Fraunhofer IME & Goethe University Frankfurt, Germany
Jacques Bruinvels, Bilthoven, The Netherlands

Advisory Board
J.C. Buckingham, Imperial College School of Medicine, London, UK
R.J. Flower, The William Harvey Research Institute, London, UK
A.G. Herman, Universiteit Antwerpen, Antwerp, Belgium
P. Skolnick, National Institute on Drug Abuse, Bethesda, MD, USA

For further volumes:


http://www.springer.com/series/4991

Alexandre Trifilieff
Editor

Indacaterol
The First Once-daily Long-acting Beta2
Agonist for COPD

Editor
Alexandre Trifilieff
Respiratory Diseases Area
Novartis Institutes for BioMedical Research
Basel, Switzerland

ISBN 978-3-0348-0708-1
ISBN 978-3-0348-0709-8 (eBook)
DOI 10.1007/978-3-0348-0709-8
Springer Basel Heidelberg New York Dordrecht London
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Springer Basel 2014
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Preface

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease


(including emphysema and chronic bronchitis which may or may not coexist in
the same individual) leading to a disease state characterized by poorly reversible
airflow limitation that is usually progressive and associated with an abnormal
inflammatory response of the lung. This disease constitutes a major public health
burden worldwide, and the World Health Organization estimates COPD to be the
worlds fifth most common disease and fourth leading cause of death. Very few
effective therapies are available, and bronchodilatator therapy, such as long-acting
inhaled 2-agonists or inhaled anticholinergic agents, is the mainstay of the management of this disease. Onbrez Breezhaler is a newly approved once-daily inhaled
2-agonist for the treatment of COPD.
This book has been put together in order to provide the reader with a comprehensive review of the development of Onbrez Breezhaler from the chemical design
of the molecule up to the clinical program that was performed for registration.
A review of current pharmacotherapy for COPD is covered by J. Donohue and
colleagues. R Fairhurst et al. summarized the chemical design and the preclinical
pharmacology of the molecule. The early clinical development of Onbrez is
reviewed by J. Beier and K-M Beeh. D. Lawrence et al. described the INHANCE
study that provides a successful example of the use of an adaptive design in the
confirmatory setting. The phase III clinical efficacy is presented by R. Dahl and
D. Mahler, while D Young et al. described the history and performance of the
Breezhaler device. Finally, P. Barnes has put together a list of emerging targets that
could well be the future treatments for COPD. I would like to express my gratitude
to all the contributors and hope the reader will benefit from reading this special
issue on COPD.
Basel, Switzerland

Alexandre Trifilieff

Contents

Current Pharmacotherapy for COPD . . . . . . . . . . . . . . . . . . . . . . . . . .


James F. Donohue, Matthew C. Miles, and Jill A. Ohar

The Preclinical Pharmacology of Indacaterol . . . . . . . . . . . . . . . . . . . . .


Alexandre Trifilieff, Steven J. Charlton, and Robin A. Fairhurst

25

The Design of the Indacaterol Molecule . . . . . . . . . . . . . . . . . . . . . . . . .


Robin A. Fairhurst, Steven J. Charlton, and Alexandre Trifilieff

39

The Early Clinical Development of Indacaterol . . . . . . . . . . . . . . . . . . .


Jutta Beier and Kai M. Beeh

67

INHANCE: An Adaptive Confirmatory Study with Dose Selection


at Interim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
David Lawrence, Frank Bretz, and Stuart Pocock
Phase 3 Clinical Efficacy Studies: Lung Function . . . . . . . . . . . . . . . . .
Ronald Dahl

77
93

Phase III Clinical Efficacy of Indacaterol: Patient-Centered


Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Donald A. Mahler
The History and Performance of the Breezhaler Device . . . . . . . . . . . . . 117
David Young, Lee Wood, Dilraj Singh, and Juergen Dederichs
What Does the Future Hold for the Therapy of COPD? . . . . . . . . . . . . 129
Peter J. Barnes

vii

Current Pharmacotherapy for COPD


James F. Donohue, Matthew C. Miles, and Jill A. Ohar

Abstract In this chapter, we are reviewing the current pharmacotherapy available


for the treatment of chronic obstructive pulmonary disease (COPD). Both shortacting and long-acting bronchodilators have been used for many years for the
treatment of COPD. Use of long-acting beta-agonists/long-acting muscarinic agents
alone or together, often with inhaled corticosteroids, is commonplace in COPD.
Long-acting anticholinergics are more effective in COPD because they improve the
airflow and reduce air trapping at the same time. Oral methylxanthines, the
precursors of phosphodiesterase type 4 (PDE4) inhibitors, also have a therapeutic
role and are widely used in developing nations. PDE4 inhibitors (roflumilast being
the only currently available agent) have a role limited to the severe and very severe
patient with frequent exacerbations. Recent evidence suggests that maintenance
antibiotic therapy may be additive to the effect of bronchodilators in reducing
exacerbation frequency. The choice of agents may be based primarily on individual
response, cost, side-effect profile, and availability.

J.F. Donohue (*)


University of North Carolina at Chapel Hill, CB# 7020, 130 Mason Farm Road, 4125
Bioinformatics Building, Chapel Hill, NC 27599, USA
e-mail: jdonohue@med.unc.edu
M.C. Miles
Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157,
USA
e-mail: mmiles@wakehealth.edu
J.A. Ohar
Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA
e-mail: johar@wakehealth.edu
A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy,
DOI 10.1007/978-3-0348-0709-8_1, Springer Basel 2014

J.F. Donohue et al.

1 Introduction
Both short-acting and long-acting bronchodilators have been used for many years
for the treatment of chronic obstructive pulmonary disease (COPD). Use of longacting beta agonists (LABAs)/long-acting muscarinic agents (LAMAs) alone or
together, often with inhaled corticosteroids (ICS), is commonplace in COPD. The
role of the beta-receptor genotype in affecting beta-agonist response is unclear but
could hold promise in the future for optimal patient management. Long-acting
anticholinergics are more effective in COPD because of their so-called volume
dominant response [1] which means that they are as apt to improve FVC as FEV1
(Fig. 1). Bronchodilators improve FEV1 by improving airflow but improve FVC by
reducing air trapping. Oral methylxanthines, the precursors of PDE4 inhibitors, also
have a therapeutic role and are widely used in developing nations. PDE4 inhibitors
(roflumilast being the only currently available agent) have a role limited to the
severe and very severe patient with frequent exacerbations. Recent evidence
suggests that maintenance antibiotic therapy may be additive to the effect of
bronchodilators in reducing exacerbation frequency [2]. This review focuses on
the LABAs, LAMAs, ICS, theophylline, roflumilast, and their combinations when
used in COPD (Tables 1 and 2).

2 Beta2-Adrenoceptor Agonists
2.1

Pharmacology

2-adrenergic receptor (2-AR) agonists act through binding to the 2-adrenergic


receptor which is a member of the seven transmembrane domains, G-proteincoupled family of receptors. Adenyl cyclase is activated via the signal-transducing
Gs protein, which results in a rise in cellular cyclic AMP (cAMP) levels and
activation of protein kinase A (PKA) when ligand binds to the 2-AR. The precise
PKA phosphorylation targets mediating bronchial smooth muscle relaxation are not
fully understood but are likely to include myosin light-chain kinase and Ca++dependent K+ (Kca) channels [3]. Although 2-ARs are present in high density in
airway smooth muscle cells, they are also present in submucosal glands; vascular
endothelium; ciliated epithelium; mast cells; circulating inflammatory cells, such as
eosinophils and lymphocytes; Clara cells; type II pneumocytes; and cholinergic
ganglia. 2-AR agonists are delivered through the inhaled or oral route, although
use of the latter is limited because of the increased risk of adverse effects.
There are several important pharmacological differences among the existing
agents [3, 4]. The onset of action is short (15 min) with albuterol and formoterol,
while it is more prolonged with salmeterol (3045 min). The difference in onset of
action is related to the lipophilicity of each of these agents and their ability to
activate the 2-AR in the aqueous phase (albuterol and formoterol). Albuterol has a

Current Pharmacotherapy for COPD


Fig. 1 Rationale for the use
of bronchodilators in COPD

1) Physiologic Effects
a) Airway smooth muscle relaxation
Bronchodilation: Improve FEV1, lung volumes
Decreased air trapping and dynamic hyperinflation
b) Non-bronchodilator Effects
2) Clinical Effects
Breathlessness ( airway resistance, hyperinflation)
Exercise tolerance ( dynamic hyperinflation)
Sleep quality ( nocturnal bronchospasm)
Health-related quality of life
Frequency of acute exacerbations

Table 1 Summary of the effects of commonly used bronchodilators on clinical outcomes in


COPD
Bronchodilator
FEV1 Lung volume Dyspnea HRQoL Exercise endurance
Short-acting 2-AR agonist Yesa
Yesb
Yesa

Yesb
a
b
a
b
Ipratropium bromide
Yes
Yes
Yes
No
Yesb
a
a
a
a
Long-acting 2-AR agonist Yes
Yes
Yes
Yes
Yesb
a
a
a
a
Tiotropium
Yes
Yes
Yes
Yes
Yesb
Theophylline
Yesa
Yesb
Yesa
Yesb
Yesb
Adapted from [64]
a
Randomized clinical trial, substantial numbers of studies with large study populations
b
Randomized clinical trial, few studies or studies with small study populations

short duration of action lasting less than 6 h, while the duration of action of
salmeterol and formoterol is approximately 12 h. These agents also differ significantly in their ability to active the 2-AR (intrinsic efficacy) which is dependent on
their affinity and potency [3]. While formoterol has a high intrinsic efficacy (strong
agonist), albuterol and salmeterol have a very low intrinsic efficacy (weak
agonists). The clinical relevance of this difference needs to be further explored in
future trials.

2.2

Clinical Benefits

Because of their rapid onset of action, short-acting beta2-adrenoceptor agonists are


very effective for rescue from symptoms of COPD. Albuterol is the most commonly
used agent. In addition to their bronchodilatory properties, these agents are

J.F. Donohue et al.

Table 2 Commonly used bronchodilators in COPD


Short-acting agents
2-AR agonists
Albuterol (MDI, NS)
Terbutaline
Levalbuterol (MDI, NS)
Pirbuterol (MDI)
Anticholinergic
Ipratropium bromide (MDI, NS)
Fixed combination
Albuterol/ipratropium (MDI, NS)

Long-acting agents
2-AR agonists
Salmeterol (DPI)
Formoterol (DPI)
Arformoterol (NS)

Anticholinergic
Tiotropium bromide (DPI)
Fixed combination
Salmeterol/fluticasonea(DPI, MDI)
Formoterol/budesonideb(DPI, MDI)
Methylxanthines
Theophylline (PO)
MDI metered-dose inhaler, DPI dry powder inhaler, NS nebulized solution, PO oral preparation
a
Only one dose formulation (250/50) approved for COPD in the USA
b
Not currently approved for COPD in the USA

effective in increasing mucociliary clearance. A systematic review showed that


regular use of short-acting 2-AR agonists in COPD was associated with improvement in lung function and dyspnea [5]. Both salmeterol and formoterol were
initially introduced and approved for use in asthma. The COPD indications came
at a later date. These two currently available LABAs have been shown in most
COPD studies to significantly improve lung function, health status, and symptom
reduction, compared with both placebo [69] and ipratropium [10, 11]. These
agents also extend the duration of exercise and reduce hyperinflation, but effects
can be modest. However, a recent Cochrane meta-analysis concluded that while
salmeterol is more effective in improving lung function variables than ipratropium,
there was no significant difference in these agents effect on quality of life,
exacerbation frequency, or symptoms [12]. Because of formoterols fast onset of
action, it has a potential role as monotherapy or in combination with another
bronchodilator in the management of acute COPD exacerbations [1315] and for
use as both a rescue and maintenance medication [16]. A recent study demonstrated
a superior effect of formoterol compared to tiotropium bromide in improving FEV1
in the first 2 h after administration; however, the area under the curve (AUC) FEV1
over 12 h was similar between these two agents [17]. Several systematic reviews of
LABAs reveal that these agents can reduce the rate of COPD exacerbations [18,
19]. This has been confirmed by a recent Cochrane systematic review and metaanalysis of 27 trials [20]. This study went on to show that LABAs had significant
benefits on airflow limitation measures, quality of life, and use of rescue medication
[20]. In a study of 634 patients with COPD, the administration of salmeterol for
12 months improved health outcomes including exacerbations especially in patients
who complied with therapy [21]. The effect of LABAs on all-cause mortality is
contradictory with salmeterol being responsible for most of the LABA/ICS survival
advantage in TORCH, while other meta-analyses conclude the opposite.

Current Pharmacotherapy for COPD

2.3

Role of Stereoisomers

The majority of currently used 2-AR agonists are racemic compounds which
contain a 5050 mixture of the R and S-enantiomers of the agonist. Recently, the
R-enantiomer of albuterol (levalbuterol) [22, 23] and the R,R-enantiomer of
formoterol (arformoterol) were approved for clinical use in the management of
COPD [24]. Much of the pharmacological activity of the agonist usually resides in
the effects of the (R)-enantiomer, the (S)-enantiomer is believed to have no
bronchodilator effects but in fact may induce deleterious effects. An in vitro
study suggests that S,S formoterol is not biologically inert, such that in racemic
mixtures, it inhibited the beneficial effects of R,R (formoterol) on proliferation,
anti-inflammatory cellular surface marker expression, and cytokine secretion
[25]. The effectiveness and cost-effectiveness of isomeric vs. racemic 2-AR
agonists in the management of airway diseases such as COPD remain controversial
and need to be further explored [26, 27]. A recent trial investigating the efficacy and
safety of different dose formulations of arformoterol nebulization solution
administered over 12 weeks to patients with moderate to severe COPD
demonstrated a significant sustained improvement in FEV1 compared to placebo
but comparable to salmeterol [28]. Carmoterol is a similar LABA.

2.4

Non-bronchodilator Effects of 2-AR Agonists

Although the major action of 2-AR agonists on airways is relaxation of airway


smooth muscles, they also exert several effects mediated through the activation of
2-ARs expressed on resident airway cells such as epithelial cells and mast cells
and circulating inflammatory cells such as eosinophils and neutrophils [29,
30]. These effects include inhibition of airway smooth muscle cell proliferation
and inflammatory mediator release, as well as non-smooth muscle effects, such as
stimulation of mucociliary transport [31], cytoprotection of the respiratory mucosa,
and attenuation of neutrophil recruitment and activation [30]. Recently both
formoterol and salmeterol have been shown to inhibit LPS (lipopolysaccharide)stimulated release of tumor necrosis factor (TNF) and granulocyte/monocyte
colony-stimulating factor (GMCSF) but not CXCL-8 from monocyte-derived
macrophages in culture [32]. Budesonide inhibited the release of all three cytokines
and when combined with formoterol inhibited TNF release in an additive manner.
However, many of these effects have been described by in vitro studies, and in vivo
studies are still needed to fully explore these effects.

2.5

J.F. Donohue et al.

Novel Beta2-Adrenoceptor Agonists

A variety of 2-AR agonists with longer half-lives are currently under development
with the hopes of achieving once-daily dosing [33]. These include carmoterol,
indacaterol, GSK-159797, GSK-597901, GSK-159802, GSK-642444, and
GSK-678007. These compounds are mainly (R,R)-enantiomers and have high
intrinsic efficacy and quick onset of action. While a quick onset of action and a
prolonged 24-h effect are desirable in the management of COPD, the use of agonists
with high intrinsic efficacy may theoretically be associated with a rapid onset of
tolerance, the fact that may limit their clinical use [3]. This needs to be taken in
consideration in the evaluation of new agents under development. However, it is
likely that once-daily dosing of a LABA will lead to enhancement of compliance
with therapy and may have advantages leading to improved overall clinical
outcomes in patients with COPD.

3 Anticholinergics
3.1

Pharmacology

Parasympathetic activity in the large- and medium-size airways is mediated through


the muscarinic receptors (M1 and M3) and results in airway smooth muscle contraction, mucus secretion, and possibly increased ciliary activity. M2 receptors
inhibit acetylcholine release from nerve terminals. Increased cholinergic tone is
important in the pathogenesis of COPD, contributing both to increased bronchial
smooth muscle tone and to mucus hypersecretion [34, 35]. Thus, anticholinergics
reduce airway tone and improve expiratory flow limitation, hyperinflation, and
exercise capacity in patients with COPD.
Two anticholinergic bronchodilators are currently available in the USA for
clinical use. These are ipratropium bromide and tiotropium. The short-acting
anticholinergic agent, ipratropium bromide, acts on all three muscarinic receptors.
Its short duration of action requires dosing every 6 h, and its delayed onset of action
(peak at 45 min) precludes its use as rescue therapy. Tiotropium also binds to all
three receptor subtypes; however, it dissociates rapidly from M2 receptors. In
contrast, its dissociation half-life from M3 receptors is close to 35 h which results
in a prolonged bronchodilatory effect. Its peak bronchodilatory effect is in 13 h
and continues for up to 32 h with a dip between 16 and 24 h related to circadian
change. However, its bronchoprotective effect against a bronchospastic agent
continues up to 48 h [36].

Current Pharmacotherapy for COPD

3.2

Clinical Benefits

The short-acting ipratropium has for a long time been used as monotherapy or in
combination with albuterol in the maintenance therapy of COPD [12, 37, 38]. Like
ipratropium monotherapy, the fixed combination is available in both metered-dose
inhaler and nebulizer solution. Unlike ipratropium monotherapy, the fixed combination can be used as rescue therapy because of the rapid onset of action of the
albuterol component. Several studies have now shown that the use of long-acting
bronchodilators is superior in improving health outcomes. The use of tiotropium in
patients with COPD results in improved health status, dyspnea, and exercise
capacity and reduced hyperinflation and COPD exacerbation rate in patients with
moderate to severe COPD relative to placebo [3941] and ipratropium [42]. Data
from large long-term trials showed that trough FEV1 increased by 100150 mL and
the peak FEV1 increased by 150200 mL above trough level after inhalation of
18 g of tiotropium. No loss of efficacy was seen over the course of 1 year of regular
treatment with tiotropium. Furthermore, in a multicenter Veterans Administration
trial involving 1,829 patients with severe COPD, the addition of tiotropium to other
COPD therapies significantly reduced acute COPD exacerbations and reduced
COPD hospitalizations when compared to placebo [43]. Data from three more
recent studies, specifically designed to explore the potential differences between
tiotropium and salmeterol, seem to indicate a greater efficacy of tiotropium [1, 44,
45]. A meta-analysis that contained these studies and others concluded that
tiotropium reduced the odds of a COPD exacerbation, related hospitalizations but
not pulmonary or all-cause mortality compared with ipratropium and placebo
[46]. It yielded greater increases in FEV1 and FVC than ipratropium, placebo,
and LABAs. The effect of tiotropium on odds of a COPD exacerbation and related
hospitalizations in this meta-analysis was not different from LABAs [46]. In a
conflicting analysis, Rodrigo and colleagues concluded that tiotropium did decrease
the incidence of severe COPD exacerbations compared with LABAs [20]. This has
been confirmed by a recent trial where tiotropium was more effective than
salmeterol in preventing exacerbations in patients with moderate to very severe
COPD [47]. In this study a total of 7,376 patients were randomly assigned to
tiotropium (3,707 patients) or salmeterol (3,669 patients). Tiotropium increased
the time to the first exacerbation (187 days vs. 145 days) with a 17 % reduction in
risk (hazard ratio, 0.83; 95 % confidence interval [CI], 0.770.90; P < 0.001). The
study was enriched with subjects that had suffered an exacerbation within the past
year but included not only those with those with very severe COPD but also those
with moderate (~48 %) and severe (~43 %) COPD.
The UPLIFT trial designed to evaluate the effect of tiotropium on the decline of
lung function over a 4-year period failed to meet its primary endpoint; however, this
study did show a significant mortality benefit at the end of treatment that was lost at
the end of the study [48]. This is in conflict with the results of the recent Ontario
cohort study trial referenced above that differs from UPLIFT which was a

J.F. Donohue et al.

randomized controlled prospective design with spirometrically defined entry


criteria [49].

3.3

Non-bronchodilator Effects of Anticholinergics

Some non-bronchodilator effects for the existing anticholinergics have been


reported [50]. Furthermore, results from a recent study performed on sputum cells
obtained from COPD patients demonstrate that muscarinic receptors may be
involved in airway inflammation in subjects with COPD through acetylcholineinduced ERK1/2-dependent leukotriene B4 release [51]. These results suggest that
anticholinergic therapy may contribute to reduced neutrophilic inflammation in
COPD; however, these findings need to be further evaluated.

3.4

Novel Anticholinergics

Several new long-acting anticholinergic agents are under development, and these
include LAS-34273, LAS-35201, GSK656398, GSK233719, and NVA-237
(glycopyrrolate). Although clinical details are still not available, potential
advantages of such agents over tiotropium may include a quicker onset of action
and a better safety profile.

4 Methylxanthines
4.1

Pharmacology

Methylxanthines nonselectively inhibit phosphodiesterase (PDE) to act as a weak


bronchodilator and respiratory stimulant. It has been shown to improve diaphragmatic contractility and has some anti-inflammatory properties [52]. The classic
agent in this class is theophylline, which has been limited in clinical use due to a
narrow therapeutic index when traditional dosing is utilized. Of note, recent studies
[5355] have demonstrated the ability of low-dose theophylline to restore activity
of histone deacetylase, suggesting its ability to restore and/or enhance corticosteroid sensitivity. Theophylline may have the ability of enhancing the effects of
inhaled corticosteroids in patients with COPD.

Current Pharmacotherapy for COPD

4.2

Clinical Benefits

Relative to other available agents such as LABAs and tiotropium, the


bronchodilatory effect of theophylline is weak. Several studies have demonstrated
the additive effect for theophylline when used in combination with other treatments
in patients with COPD [53, 54, 56]. Analysis of a large (n 36,492) health
administration database revealed that users of theophylline were less likely than
users of LABAs but more likely than users of inhaled glucocorticoids to suffer an
exacerbation [57]. Several past studies have shown beneficial effects from the
addition of theophylline to other therapies for COPD [53, 54, 56], but it cannot
be recommended as a first-line agent.

4.3

Non-bronchodilator Effects of Methylxanthines

The salutary effects of theophylline may be due as much to its non-bronchodilator


as to its bronchodilator activity [52, 5861]. In addition to its steroid-sparing effects
on histone deacetylase, theophylline has both inotropic and chronotropic cardiac
effects. It enhances mucociliary sweep, diaphragmatic contractility, and central
respiratory drive.

4.4

Roflumilast

Selective phosphodiesterase-3 and -4 inhibitors have been developed to ameliorate


the side-effect profile of methylxanthines, but significant gastrointestinal side
effects remain clinically apparent. One PDE4i, roflumilast, was recently approved
by the FDA to reduce exacerbations in patients with severe COPD [62,
63]. Roflumilast is a selective PDE4 inhibitor approved for reducing exacerbation
rates in severe COPD patients with chronic bronchitis who experience
exacerbations. It has modest bronchodilator properties but can be safely combined
with either LABA or LAMA. Side effects include weight loss, diarrhea, and
possible suicidal ideation.

5 Combination Therapies
The use of combination therapy is supported by multiple clinical trials and by
guidelines from the European Respiratory Society and American Thoracic Society
[64], as well as the Global Initiative for Chronic Obstructive Lung Disease
[65]. These guidelines reflect the most well-established combinations of

10

J.F. Donohue et al.

Table 3 Potential combinations of scheduled pharmacotherapy for COPD (short-acting agents


are excluded due to their recommended use only on an as-needed basis)
LABA
LABA
LAMA
ICS
ULABA
PDE3/4i
Methylxanthines

LAMA

ICS

ULABA

PDE3/4i

Methylxanthines

pharmacotherapy, but other dual combinations can be conceived (Table 3). Most
studies of combination inhalers have been powered to detect changes in FEV1
between 75 and 100 mL [66, 67].
Initial trials on combination therapy focused on combining LABA with ICS,
based on the dual-effect hypothesis of bronchoconstriction and inflammation common to COPD and asthma. Indeed, significant benefit from this combination was
noted in the TORCH trial [68], as well as a subsequent systematic review from the
Cochrane Collaboration. A meta-analysis [69] of the combination LABA/ICS
vs. placebo noted reduction in exacerbation rates of roughly 25 % and a significant
reduction in all-cause mortality (3-year number needed to treat: 36). The effects
seen were dominated by the large TORCH trial, but studies of both salmeterol/
fluticasone and formoterol/budesonide were included for analysis. This metaanalysis also noted an increased risk of pneumonia, with a 3-year number needed
to harm of 13. The combination of LABA with ICS has now become well
established in clinical practice; the reader is referred to the Cochrane review [69]
for a detailed analysis of those trials results. More recent trials have examined
different combinations of therapy, addressing many potential dual combinations
noted in Table 3.

5.1

LAMA + LABA

Pertinent features of recent clinical trials evaluating the combination of LAMA +


LABA discussed below are included in Table 4. Ichinose evaluated the combination of the unique transdermal LABA tulobuterol and the inhaled LAMA
tiotropium compared with tiotropium alone in subjects with GOLD stages II and
III COPD [70]. Subjects were not allowed to continue any other long-acting
bronchodilator. The investigators found statistically significant improvements in
respiratory-related quality of life as measured by the St. George Respiratory
Questionnaire. However, a baseline imbalance in the SGRQ scores limits the
impact of this finding.
Tashkin [71] evaluated the combination of nebulized arformoterol and
tiotropium compared with either therapy alone in subjects with GOLD stages II

Current Pharmacotherapy for COPD

11

Table 4 LAMA + LABA trial characteristics


Statistically significant
outcomes
SGRQ: 6.48 U
vs. 1.90 U
234
Mean FEV1 AUC: +0.22 L
vs. 0.10 L vs. 0.08 L
IC: 0.15 L vs. 0.07 L
vs. 0.02 L
TDI: +3.1 vs. +2.3 vs +1.8
Van
71
6 weeks
Tiotropium plus QD
Predose FEV1: 1.134 L
vs. 1.091 L vs. 1.127 L
Noord
formoterol vs. BID
[72]
formoterol vs. tiotropium Use of rescue salbutamol:
1.81 puffs/day vs. 2.37
puffs/day vs. 2.41
puffs/day
Van
95
6 weeks
Tiotropium plus QD
Average FEV1 increase
over 24 h: 0.142 L
Noord
salmeterol vs. tiotropium
vs. 0.185 L vs. 0.045 L
[73]
plus BID salmeterol
vs. 0.070 L
vs. BID salmeterol
TDI: +2.56 vs. +2.71
vs. tiotropium
vs. +0.97 vs. +1.18
Wang
1,868
224 weeks Tiotropium plus formoterol Average FEV1 increase
over 24 h: 105 mL
[74]
(pooled)
vs. tiotropium
with combination
Average FVC increase
over 24 h: 135 mL
with combination
Trough FEV1 increase:
53.4 mL with combination
Mean improvement in
TDI: 1.50 U with
combination
Rabe [75] 605
6 weeks
Tiotropium plus formoterol FEV1 AUC012: 1.64 L
vs. 1.56 L
vs. salmeterol plus
Peak FEV1: 1.78 L
fluticasone
vs. 1.67 L
FVC AUC012: 3.14 L
vs. 2.97 L
Peak FVC: 3.38 L
vs. 3.16 L
Predose FVC: 2.95 L
vs. 2.87 L
Table includes pertinent features of recent trials evaluating the combination of LAMA + LABA

Trial
Ichinose
[70]
Tashkin
[71]

N
103

Intervention
duration
Comparison
8 weeks
Tiotropium plus tulobuterol
vs. tiotropium
2 weeks
Tiotropium plus
arformoterol
vs. arformoterol
vs. tiotropium

and III COPD. No other LABA or anticholinergic could be used, nor could
leukotriene modifiers or methylxanthines. Oral or inhaled corticosteroids were
permitted, provided the dose had been stable over 14 days prior to the study period.
Roughly 20 % of subjects in each group were using corticosteroids. The primary
study outcome, mean FEV1 area under the curve, improved above baseline for each

12

J.F. Donohue et al.

individual drug group, with a greater increase seen in the combined therapy group.
Among secondary endpoints, the inspiratory capacity also increased significantly
greater with combination therapy than with individual therapy, as did the improvement in mean transitional dyspnea index.
In 2005, van Noord [72] examined the combination of formoterol and tiotropium
once daily compared with either daily tiotropium or twice daily formoterol in
subjects with mostly GOLD stage III COPD. Subjects were allowed to continue
inhaled or oral steroid use up to a daily dose equivalent of 10 mg prednisone, and
theophylline use was not allowed. Ninety percent of subjects were using
corticosteroids (63 inhaled, 2 oral). As the primary outcome, the predose morning
FEV1 was significantly higher in subjects treated with combination therapy than
when they received formoterol alone but was similar to when they received
tiotropium alone. As a secondary outcome, evaluation of 24-h FEV1 profiles was
performed. This revealed that combination therapy produced superior FEV1
between hours 812 and again at hour 24 (trough). Use of rescue salbutamol was
also lower during the daytime among patients taking the combination tiotropium
plus formoterol.
Van Noord later evaluated the combination of salmeterol (daily or BID) and
tiotropium compared with either agent alone (tiotropium daily or salmeterol BID)
in subjects with GOLD stage II or III COPD [73]. Prior to randomization, subjects
could not have used tiotropium and theophylline preparations for 4 weeks, but
inhaled or oral steroid use was permitted up to a daily dose equivalent of 10 mg
prednisone. Again, 90 % of subjects were using corticosteroids (81 inhaled, 5 oral).
The primary endpoint of average FEV1 over 24 h was significantly higher when
subjects were receiving the combination of tiotropium and salmeterol once daily
than with tiotropium alone or salmeterol alone. The addition of an additional
evening salmeterol dose resulted in similar daytime bronchodilation but superior
nighttime bronchodilation. In this study, transitional dyspnea index was also noted
to improve more with once-daily combination therapy than with tiotropium or
salmeterol alone. The addition of the second-daily dose of salmeterol in combination with tiotropium did not increase the TDI significantly more than with
salmeterol once daily.
Recently, the combination of formoterol and tiotropium was compared to
tiotropium alone in a meta-analysis by Wang et al. [74]. The authors concluded
that treatment with the combination of tiotropium and formoterol resulted in
significantly greater improvements in average FEV1, average FVC, and trough
FEV1. The mean improvement in transitional dyspnea index was also greater
with the combination. There was a nonsignificant trend toward fewer adverse
events (including COPD exacerbations) with combination therapy, but this did
not reach statistical significance.
Rabe [75] compared the combination of tiotropium qd plus formoterol bid to the
combination of salmeterol plus fluticasone bid in subjects with GOLD stages IIIII
COPD. During the study, inhaled corticosteroids other than study medication were
not permitted, and oral steroids were only allowed to control acute exacerbations.
The primary study endpoints were FEV1 area under the curve for hours 012 (FEV1

Current Pharmacotherapy for COPD

13

AUC012) and peak FEV1. There was a statistically significant higher FEV1
AUC012 and peak FEV1 with tiotropium plus formoterol than with salmeterol
plus fluticasone. Statistically significant increases with the tiotropium plus
formoterol combination compared with the salmeterol plus fluticasone combination
were also seen in the secondary endpoints of FVC AUC012, Peak FVC, and
predose FVC.
In summary, the trials above that have evaluated the combination of LABA plus
LAMA have found consistently greater improvements in markers of lung function
(FEV1, FVC) with combination therapy compared with monotherapy. Additionally,
transitional dyspnea index has consistently shown improvement with combination
therapy, a change that has been both statistically (P < 0.05) and clinically
(MCID + 1 U) meaningful. In the large study by Rabe and colleagues [75], greater
improvement in spirometry was seen with the combination of LAMA + LABA
vs. the combination of LABA + ICS, supporting guideline recommendations that
for patients where a single bronchodilator does not suffice, the addition of two
separate classes of bronchodilators is superior to bronchodilator monotherapy plus
ICS. Adverse effects have not been observed statistically more often with combination therapy, but the small populations of these studies leave open the possibility
of type II error, and larger, longer duration trials would be necessary to increase
confidence in the safety of this approach.

5.2

Triple Therapy

In the above mentioned trials of LAMA + LABA combination therapy, the proportion of subjects using corticosteroids at baseline varied widely, from 20 % [71] to
90 % [72]. Two small randomized trials have evaluated the combination of
tiotropium and fluticasone/salmeterol for severe COPD [76, 77], and current
guidelines recommend combination therapy with inhaled LAMA, LABA, and
ICS for patients with GOLD stage III or IV COPD who suffer from frequent
exacerbations [64, 65]. Two large trials of triple therapy deserve further mention,
with pertinent details included in Table 5.
In 2007, the Canadian Thoracic Society and Canadian Respiratory Clinical
Research Consortium published the results of the Canadian Optimal Therapy of
COPD Trial [78]. Subjects with GOLD stage II or III COPD were treated with
tiotropium plus either placebo, salmeterol alone, or salmeterol plus fluticasone. The
primary outcome was the proportion of patients in each group experiencing a
COPD exacerbation. As secondary outcomes, investigators examined the mean
number of exacerbations per patient-year, the total number of exacerbations
resulting in urgent care or emergency department visits, number of hospitalizations
for COPD, number of hospitalizations in total, changes in health-related quality of
life (as determined by St. Georges Respiratory Questionnaire [79]), changes in
dyspnea (as measured by the transitional dyspnea index [80] and the dyspnea
domain of the Chronic Respiratory Questionnaire [81]), and lung function

14

J.F. Donohue et al.

Table 5 Triple therapy trial characteristics


Trial
Aaron [78]

N
449

Intervention
duration
52 weeks

Welte [82]

660

12 weeks

Comparison
Tiotropium
vs. tiotropium plus
salmeterol
vs. tiotropium plus
salmeterol/
fluticasone
Tiotropium
vs. tiotropium plus
formoterol/
budesonide

Statistically significant
outcomes
SGRQ: 4.5 vs. 6.3 vs. 8.6
Predose FEV1 increase at wk
52: zero (reference)
vs. +0.027 L vs. +0.086 L

Predose FEV1: 1.08 L


vs. 1.15 L
Postdose FEV1: 1.13 L
vs. 1.25 L
SGRQ: 1.5 vs. 3.8
Severe exacerbations: 18.5 %
vs. 7.6 %

(as measured by FEV1). There was no difference among groups in the primary
outcome; between 60 and 65 % of patients in all three groups experienced an
exacerbation. Among secondary outcomes, there was a lower rate of
hospitalizations, both all-cause and those specifically for COPD, in the triple
therapy group compared with the tiotropium plus placebo group. This benefit was
not seen in the group treated with tiotropium plus salmeterol compared to
tiotropium plus placebo. Quality of life per SGRQ was improved more with each
additional therapy. Dyspnea did not differ significantly among groups, but lung
function measured by FEV1 increased significantly more in the triple therapy group
than in the tiotropium plus salmeterol group. However, this improvement was still
less than the MCID for FEV1. There was not a significant difference from placebo
in the group assigned to tiotropium plus salmeterol. No difference in adverse
events, including death and hospitalizations, was observed.
Welte [82] performed a trial of budesonide/formoterol in addition to tiotropium
(triple therapy) vs. tiotropium alone in subjects with predominantly GOLD stage
III COPD. The primary endpoint was the change in predose FEV1 over weeks 012.
As secondary endpoints, measurement of predose FVC and IC and postdose FEV1,
FVC, and IC was also performed. Quality of life was assessed using St. Georges
Respiratory Questionnaire at each of six clinic visits. Over the treatment period,
triple therapy significantly increased pre- and postdose FEV1. This change was
more than the minimal clinically important difference (MCID) in postdose FEV1
but not in predose FEV1 [66]. Overall, the improvement in SGRQ was statistically
significant but also below the MCID of 4 U [67, 79, 80]. An improvement in SGRQ
by more than 4 U was seen in 49.5 and 40 % of subjects in the triple therapy and
tiotropium alone groups, respectively (P 0.016), but 27.6 and 29.7 % of subjects
had a deterioration in SGRQ by more than 4 U (P NS). There was a significantly
lower incidence of severe exacerbations in the triple therapy group compared with
the tiotropium alone group.

Current Pharmacotherapy for COPD

15

The trial by Welte et al. of triple therapy compared with LAMA alone thus
demonstrated improvements in lung function and dyspnea roughly equivalent to
those seen in the aforementioned trials of LAMA + LABA therapy. The reduction
in severe exacerbations seen in this trial was not seen in trials of LAMA + LABA,
suggesting that the reduction in exacerbations is attributable to the addition of ICS.
However, the 52-week Canadian Optimal Trial [78] found no difference in the
number of patients experiencing exacerbations, although there was a numerically
longer median time to first exacerbation in the triple therapy group and the trial was
underpowered to detect a true difference. Based on this data, one could postulate
that the true benefit of ICS in triple therapy is less than that seen in the shortduration trial by Welte et al. or alternatively that the small significant improvement
in lung function measures seen in the longer Canadian Optimal Trial is a result of
properties unique to salmeterol, fluticasone, or the combination. A large trial
comparing salmeterol/fluticasone to formoterol/budesonide would be informative
but is unlikely to occur without funding from outside industry.
A recent Cochrane meta-analysis that included these studies showed that healthrelated quality of life and lung function were significantly different when
ICS/LABA combination therapy was added to tiotropium, although the size of
the average benefits of additional combination therapy was small; St Georges
Respiratory Questionnaire (mean difference, 2.49; 95 % CI 4.04 to 0.94)
and forced expiratory volume in 1 s (mean difference, 0.06 L; 95 % CI
0.040.08). There was no significant statistical difference in mortality, participants
with one or more hospitalizations, episodes of pneumonia, or adverse events [83].
Notably, no regulatory standard is established regarding the efficacy of combination treatment with triple therapy. It is not unexpected that incremental benefit on
measures of lung function (FEV1, IC, TDI) is small as agents are added, and the use
of composite endpoints combining measures of lung function with number of
exacerbations might enable a significant effect to be seen. Additionally, the regulatory approval of triple therapy may be aided by the development of new fixeddose combination inhalers and novel dual-ligand molecules combining beta-agonist
and muscarinic-antagonist effects (termed muscarinic-antagonist beta-agonist
[MABA]) [84].

5.3

PDE4i + LABA or LAMA

Roflumilast is a selective inhibitor of phosphodiesterase 4 (PDE4i) that was studied


in combination with salmeterol or tiotropium by Fabbri et al. in two separate trials,
with results published concomitantly [85]. After a 4-week run-in period where
subjects took daily placebo pills, 935 subjects were randomized to either roflumilast
or placebo plus salmeterol, and 744 subjects were randomized to either roflumilast
or placebo plus tiotropium for a duration of 24 weeks. These subjects all had GOLD
stage II or III COPD and were not permitted to use inhaled steroids or any other
bronchodilator during the study period except for the supplied SABA as needed.

16

J.F. Donohue et al.

For the primary endpoint, change in mean prebronchodilator FEV1 was 49 mL in


the salmeterol plus roflumilast group vs. salmeterol plus placebo and 80 mL in the
tiotropium plus roflumilast group vs. tiotropium plus placebo. A similar magnitude
of increase was noted in mean postbronchodilator FEV1 (60 mL and 81 mL), mean
prebronchodilator FVC (47 mL and 95 mL), and mean postbronchodilator FVC
(58 mL and 101 mL). Improvements in other secondary measures, including TDI,
shortness of breath questionnaire, and baseline use of rescue medications, were
variable, some reaching statistical significance but none greater than the MCID.
The presence of adverse reactions related to study medication was higher in the
groups receiving roflumilast; most of these were gastrointestinal in nature consistent with previous studies. The likelihood of study withdrawal was statistically
higher for roflumilast + salmeterol than placebo + salmeterol, but not for
roflumilast + tiotropium compared with placebo + tiotropium. A nonstatistically
significant decrease in mean bodyweight was also noted in the groups treated with
roflumilast (2.0 kg for roflumilast + salmeterol, 1.8 kg for
roflumilast + tiotropium).
Despite the relatively short duration of these trials, there were statistically
significant decreases in exacerbation rates and increases in time to first exacerbation
demonstrated in both. When added to salmeterol, roflumilast decreased the proportion of patients with any exacerbation by 6 % and increased the time to first
moderate or severe exacerbation by 12 days. When added to tiotropium, roflumilast
decreased the proportion of patients with any exacerbation by 8 % and increased the
time to any exacerbation by 13 days. On FDA Advisory panel review in April 2010,
these data, in addition to two earlier studies [63], were a major part of the
discussion. The advisory panel FDA presentation noted that effects on FEV1 and
SGRQ were modest (less than the MCID) and the clinical significance was uncertain. The reduction in exacerbations was considered a clinically relevant effect, but
it was noted that the use of concomitant standard therapies for COPD was heavily
restricted during these trials and the risk/benefit ratio may be better characterized
with additional study [86]. After reviewing the recommendations of the advisory
panel, the FDA granted approval to roflumilast on March 1, 2011 to decrease the
frequency of flare-ups (exacerbations) or worsening of symptoms from severe
chronic obstructive pulmonary disease (COPD) [87]. The magnitude of benefit
from roflumilast compared with that from ICS has not yet been rigorously studied.
At this time the best candidates for treatment with roflumilast appear to be those
patients already taking a bronchodilator who experience ongoing risk for
exacerbations and who cannot tolerate ICS.

5.4

Methylxanthine + ICS

There is a well-established decrease in histone deacetylase activity in asthma and


COPD [60, 62]. Theophylline has been shown to perform poorly as a bronchodilator
due to its narrow therapeutic window but at low doses can activate cellular histone

Current Pharmacotherapy for COPD

17

deacetylase and potentially restore responsiveness to corticosteroids [52]. Ford


et al. [88] recruited 30 patients with COPD (primarily stage II) and randomized
them to receive either inhaled fluticasone propionate or placebo for 4 weeks.
Subjects then underwent a 2-week washout period and were crossed over to
treatment with the alternate inhaler. During the first 4-week period, all subjects
took placebo capsules bid, and during the second 4-week period, all subjects took
active theophylline capsules. Apart from study medication, subjects who were
already taking a LABA or LAMA were permitted to continue the medication.
Use of oral corticosteroids was an exclusion criterion, and inhaled steroids were
discontinued during an initial 2-week washout period. Subsequently, seven subjects
were recruited into an open-label repeat of arm 2 for the purpose of determining
histone deacetylase activity using peripheral blood mononuclear cells (PBMCs).
Subjects tolerated theophylline well, with dose reduction required in four subjects
due to mild nausea and GI upset. The primary study endpoint was a reduction in
absolute sputum neutrophils, with secondary endpoints of sputum total and cellspecific counts, chemokine ligand 5 (CCL5), IL-8, and neutrophil elastase
(NE) levels in sputum, lung function, and quality-of-life data measured by selfadministered chronic respiratory questionnaire (SAS-CRQ). Significant differences
in lung function could only be demonstrated for FEV1 percent predicted in the
ICS + theophylline arm (from 52 to 58.6 % predicted, P 0.024) and FEF
2575 % (from 470 to 555 mL/s P 0.029). No significant change in sputum
neutrophils was noted, but sputum eosinophils were reduced in the ICS + theophylline arm compared with ICS alone (0.05  106/mL vs. 0.13  106/mL,
P 0.023). An analysis of sputum chemokines showed only a small reduction in
IL-8 in the combination group compared with ICS alone. Quality-of-life score did
not differ significantly between arms. Total HDAC activity increased from 95 to
875 U in the seven patients who repeated arm 2 of the study. In sum, this preliminary data was not designed to detect clinically significant differences in lung
function or disease natural history but does suggests some attenuation of inflammation in COPD as well as an increase in HDAC activity. Additional subjects and
additional time would be required to observe for any clinically significant effect of
low-dose theophylline on COPD.

6 Safety of Bronchodilator Therapy in COPD


It has been reported that the continued use of 2-AR agonists may be associated
with an increase in cardiovascular risk compared with placebo [89]. In general, the
short-acting 2-AR agonists are well tolerated, except for occasional episodes of
tachycardia and tremor. One out of a series of meta-analyses [90] which included
randomized controlled trials of at least 3 months duration that evaluated anticholinergic or 2-agonist use compared with placebo or each other in patients with
COPD documented that while inhaled anticholinergics significantly reduced severe
exacerbations and respiratory deaths in patients with COPD, 2-AR agonists were

18

J.F. Donohue et al.

associated with an increased risk for respiratory deaths. However, as highlighted by


the authors themselves, meta-analyses have several problems that limit their validity. Clearly, the use of LABAs as monotherapy in asthma can be considered unsafe
[91]; however, the use of these medications in COPD has generally been described
as safe. Data from the TORCH study suggests that chronic use of salmeterol as
monotherapy in patients with COPD for 3 years produced no increase in mortality
[68]. This is in conflict with a report in asthma which shows an increase in deaths in
the salmeterol monotherapy group [91]. Further, a meta-analysis (N 2,853) of
data from seven clinical trials examining the effects of salmeterol in patients with
COPD showed no clinically significant difference in the incidence of cardiovascular events between salmeterol and placebo [92]. This was confirmed by a more
recent meta-analysis of 27 COPD studies listed in the Cochrane Controlled Trials
Register [20]. This meta-analysis showed no difference in respiratory deaths
between LABA and placebo groups. Additionally the use of LABAs with ICS
reduced the risk of respiratory death compared with LABAs alone [20]. The safety
of nebulized formoterol has also been studied and found to be similar to that of the
dry powdered formulation [92]. Nevertheless, -agonists should be used with
caution in patients with underlying cardiac disorders including ischemic heart
disease [33, 89]. It has also been suggested that tolerance to the bronchodilator
effects of LABAs may occur with their prolonged use in COPD [1, 93]. However, a
recent study examining the bronchodilator effect of long-term use of salmeterol
demonstrated a sustained bronchodilator effect for salmeterol administered for
6 months [9].
Class effects of anticholinergics are dry mouth, an increased risk of glaucoma,
and urinary retention; however, the quaternary nitrogen atom prevents them from
being systemically absorbed. Therefore, currently available agents when used in
recommended doses are generally safe. These agents should also be used with
caution in patients with bladder neck obstruction due to prostatism and patients with
glaucoma. The safety of these agents (both long- and short-acting anticholinergics)
was questioned by a recent meta-analysis [94]. This study analyzed 13,645 subjects
enrolled into 17 trials and found that inhaled anticholinergics significantly
increased the risk of myocardial infarction (MI) (RR1.52 CI 1.042.22) and cardiovascular death (RR 1.92 CI 1.233.0). In direct conflict with the results of this metaanalysis is the UPLIFT study, a 4-year, prospective, head-to-head comparison
study of tiotropium and placebo [48]. Mortality at the end of the treatment phase
was significantly lower in this study in subjects receiving tiotropium compared with
placebo. The mortality benefit was lost at the end of the trial of 30 days after
cessation of therapy.
Theophylline is associated with tremors and nausea and less frequently with
cardiac arrhythmias and seizures [95]. The fact that serum toxicity levels overlap
therapeutic levels explains the high incidence of toxic side effects. The risk of such
adverse events can be reduced by monitoring the drugs plasma levels and reducing
the dose accordingly; however, the high frequency of drug interactions and clinical
conditions that interfere with hepatic metabolism of theophylline limits its extensive use in clinical practice [96].

Current Pharmacotherapy for COPD

19

7 Bronchodilators in COPD: Conclusions


The use of bronchodilators is central in the symptomatic management of COPD,
and currently available agents have been shown to have significant effects on the
long-term outcome and management of COPD. The use of the inhaled route is
currently preferred to minimize systemic effects. Quick-acting and short-acting
agents are best used for rescue of symptoms, while long-acting agents are best used
for maintenance therapy. The choice of agents may be based primarily on individual response, cost, side-effect profile, and availability.
Several new bronchodilators are currently being studied in ongoing clinical trials
that may improve the future treatment of COPD. 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. Specific future research should examine the long-term efficacy
and long-term safety of the different combination of bronchodilators  inhaled
corticosteroids, as well as their effects on the natural history of COPD when used
early in the disease progression. Furthermore, future studies should also identify
more sensitive methods to assess response to bronchodilators and identify through
responder analyses specific groups based on gender, age, race, or pharmacogenetic
makeup.

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Nephrology (Carlton) 8(5):239242

The Preclinical Pharmacology of Indacaterol


Alexandre Trifilieff, Steven J. Charlton, and Robin A. Fairhurst

Abstract The preclinical pharmacological profile of indacaterol, a novel, chirally


pure inhaled beta(2) adrenoceptor agonist, is described in this chapter. In various
in vitro systems, indacaterol is close to a full agonist at the human 2-adrenoceptor
with nanomolar potency. In isolated superfused human and guinea pig trachea,
indacaterol has a fast onset of and a long duration of action. In the conscious guinea
pig, when given intratracheally as a dry powder, indacaterol inhibits bronchoconstriction for at least 24 h and shows no tachyphylaxis when given for 5 consecutive
days. When given via nebulization to anesthetized rhesus monkeys, indacaterol
produces a prolonged bronchoprotective effect and induces a small increase in heart
rate. In in vitro systems as well as a large cohort of COPD patients, no association
could be demonstrated between 2-adrenoceptor polymorphisms and indacaterol
response. In conclusion, the preclinical profile of indacaterol suggests that this
compound has a duration of action compatible with once-daily dosing in human,
together with a fast onset of action.

1 Introduction
Indacaterol has been developed to meet the current needs for a long-acting bronchodilator for the maintenance therapy of chronic obstructive pulmonary disease
(COPD) [1]. Current bronchodilators for COPD include the 2-adrenoceptor agonist and the muscarinic receptor antagonist, both of them being delivered via the
inhaled route. The available 2-adrenoceptor agonists are either short acting
(salbutamol) and used as rescue medicine or compatible with twice-daily dosing

A. Trifilieff R.A. Fairhurst


Novartis Institutes for BioMedical Research, Basel, Switzerland
S.J. Charlton (*)
Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, RH12 5AB, UK
e-mail: steven.charlton@novartis.com
A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy,
DOI 10.1007/978-3-0348-0709-8_2, Springer Basel 2014

25

26

A. Trifilieff et al.

(formoterol and salmeterol) and used as maintenance therapy. The muscarinic


receptor antagonists consist of ipratropium, used as rescue medicine, and the
more recently available once-daily drug, tiotropium, used for maintenance therapy.
Up to recently, no once-daily 2-adrenoceptor agonists were available for the
treatment of COPD. The indacaterol research program started in 1998 with the
aim of delivering an inhaled 2-adrenoceptor agonist that combines high potency
and intrinsic efficacy together with a duration of action compatible with once-daily
dosing and a fast onset of action.

2 The 2-Adrenoceptor
-Adrenoceptors have been subclassified into three different receptor subtypes
called 1, 2, and 3. All three receptors belong to the seven transmembrane
receptor family of G protein-coupled receptor and are coupled to the Gs type of
G protein. Upon ligand receptor interaction, activation of the Gs protein leads to an
increase of intracellular cyclic adenosine monophosphate (cAMP) via activation of
adenylate cyclase [2]. In the case of the 2-adrenoceptor, one primary consequence
of this increase in intracellular cAMP levels is the activation of protein kinase A
(PKA), which causes airway smooth muscles to relax by a variety of complementary mechanisms, including activation of potassium channels leading to the efflux
of potassium and dephosphorylation of the 20-kDa regulatory light chain of myosin
II (MLC20) (Fig. 1). In addition to this classical mechanism, recent evidence
suggests that 2-adrenoceptor-induced airway smooth muscle relaxation could
also be mediated via PKA-independent pathways such as the activation of protein
kinase G, the tyrosine kinase Src, and the exchange protein activated by cAMP
(Epac) [3].

3 Potency and Intrinsic Efficacy


Potency is pharmacologically defined as the concentration of an agonist needed to
produce half of the maximal effect (efficacious concentration50, EC50). Intrinsic
efficacy is a measure of how powerfully an agonist can activate a receptor.
Compounds that bind to a receptor and are able to produce the maximum possible
response in a given system are called full agonist. On the other hand, agonists that
bind the receptor but are not able to fully activate the system are called partial
agonists. As an example for the 2-adrenoceptor system, isoprenaline is a full
agonist, whereas salbutamol is a partial agonist (Table 1). It is important to realize
that the efficacy of an agonist is highly dependent on the system used (i.e., in a
system where the receptors are highly expressed, a partial agonist can behave as a
full agonist). Using genetically engineering cells expressing medium level of the

The Preclinical Pharmacology of Indacaterol

27

Fig. 1 Mechanism of action of the 2-adrenoceptor agonists. AC adenylate cyclase, cAMP cyclic
adenosine monophosphate, Gs G stimulatory protein, MLC20 20-kDa regulatory light chain of
myosin II, P phosphate, PKA protein kinase A

2-adrenoceptor, we have shown that salmeterol and salbutamol behave as partial


agonists, inducing approximately 40 % of the maximal effect of isoprenaline,
whereas the maximum effect of indacaterol and formoterol were 73 and 90 % of
the maximal effect of isoprenaline, respectively (Table 1) [4]. Similar ranking of
the intrinsic activities for the compounds have been observed in other cells such as
human airway bronchial smooth muscle cells [57] and human lung mast cells [8].
Desensitization is a protective mechanism that prevents overstimulation of the
receptor in the presence of an excess of the agonist. This phenomenon, also known
as tachyphylaxis, reduces receptor activity and plays a role in signal duration,
intensity, and quality. Desensitization is initiated by phosphorylation of the receptor
that is followed by binding to -arrestin. -Arrestin serves to sterically inhibit G
protein coupling, thereby terminating the G protein activation, and may also target
the receptor for internalization [9].
Early studies investigating the desensitization of 2-adrenoceptor showed a
relationship between agonist efficacy and desensitization, with partial agonists
causing less phosphorylation and internalization than full agonists [10, 11]. This
suggests that formoterol and indacaterol should elicit a greater degree of
tachyphylaxis than salmeterol, but this has not been observed either in preclinical
models or in the clinic.
The potential for indacaterol tachyphylaxis, in comparison with salmeterol and
formoterol, was studied in the conscious guinea pig by comparing the
bronchoprotective effect of the compounds following a single treatment or fivedaily treatments. Results demonstrated that no tachyphylaxis was observed for
indacaterol, formoterol, and salmeterol administered as dry powder formulations.

28

A. Trifilieff et al.

Table 1 Functional properties for the marketed inhaled 2-adrenoceptor agonists at the human
adrenoceptors
Selectivity ratio
Isoprenaline

Potency (EC50, nM)


Intrinsic efficacy (% isoprenaline)
Indacaterol
Potency (EC50, nM)
Intrinsic efficacy (% isoprenaline)
Formoterol
Potency (EC50, nM)
Intrinsic efficacy (% isoprenaline)
Salmeterol
Potency (EC50, nM)
Intrinsic efficacy (% isoprenaline)
Salbutamol
Potency (EC50, nM)
Intrinsic efficacy (% isoprenaline)
Data are from [4]

1
35
99
251
16
110
29
67
11
1,175
3

2
60
98
8.7
73
2.6
90
0.7
38
251
47

3
12
99
190
113
27
103
933
59
1,820
99

1/2
0.6

29

42

96

3/2
0.2

22

10

1,333

A significant improvement in protection against serotonin-induced bronchoconstriction was demonstrated after 5 days dosing of indacaterol and formoterol
compared to a single treatment, but this was not demonstrated for salmeterol
[4]. A similar pattern is observed in the clinic. Despite an initial loss of
bronchoprotective efficacy with all ligands, their bronchodilator action is much
more resilient to tolerance, demonstrating efficacy that is normally stable after the
first few days (reviewed in [12]).
It therefore appears that the early in vitro studies did not accurately predict the
tendency for tachyphylaxis. This is likely because these studies were designed to
match receptor occupancy for each of the agonists, regardless of their efficacy. This
is important, because low-efficacy agonists must bind to a greater proportion of
receptors to elicit a given pharmacological response than higher-efficacy agonists,
which often have spare receptors [12]. It is therefore more appropriate to compare
concentrations based on their magnitude of pharmacological response, analogous to
the way clinical dose is chosen. When the tachyphylaxis induced by a series of 2adrenoceptor agonists was compared at equi-effective concentrations, it was found
that after 24 h exposure, all of the agonists desensitized the response to a subsequent
formoterol challenge to the same degree, irrespective of their intrinsic efficacies
[6]. In an effort to simulate the in vivo clearance of the drugs, the authors also
examined a pulse protocol where drugs were washed away after 1 h. Under these
conditions, it appeared that the lower-efficacy ligands caused more desensitization,
with indacaterol inducing much less tachyphylaxis than salmeterol. This is presumably because the higher-efficacy ligands have a greater receptor reserve than
lower-efficacy agonists, so they not only require a lower occupancy to generate an
equivalent response but also are less sensitive to loss of receptors than low-efficacy
ligands (discussed in [12]).
Importantly, these studies demonstrate that using in vitro systems to assess the
tendency for agonists to cause desensitization in the clinic is highly dependent on
the experimental design and of poor predictive value.

The Preclinical Pharmacology of Indacaterol

29

4 Receptor Selectivity
-Adrenoceptors were originally classically identified as the cardiac (1), airway
smooth muscle (2), and adipose tissue (3) receptors. However, it is now
recognized that they are widely distributed within the human body. Because the
targeted receptor for a 2-adrenoceptor bronchodilator is the airway smooth muscle
and to avoid side effects due to systemic activation of the receptor, the inhaled route
is preferred. However, despite the use of the inhaled route and probably because the
lung is one of the most vascularized organ, systemic exposure, albeit in low amount,
of the compound is inevitable. When entering the circulation, an inhaled 2adrenoceptor agonist would induce a number of undesired responses such as
tremor, a direct consequence of activation of the receptor on skeletal muscle [13];
metabolic responses such as hyperglycemia, hypokalemia, and hypomagnesemia
[14]; and cardiac effects [15]. Although tremor and the metabolic effects are
entirely mediated by the 2-adrenoceptor, the cardiac effects are mediated by
both the 1- and 2-adrenoceptors [16]. In addition, it has been reported that activity
at the 1-adrenoceptor might be responsible for some of the cardiovascular side
effects often observed with terbutaline, a 2-adrenoceptor agonist [17]. It is therefore thought that a highly selective 2-adrenoceptor would have a better cardiac side
effect profile when compared to an agonist that has activity at the 1-adrenoceptor.
At the human adrenoceptors, the marketed long-acting inhaled 2-adrenoceptor
agonists have different degree of functional selectivity at the 2-adrenoceptor
when compared with the 1-adrenoceptor. As such, salmeterol has no or very
weak functional activity on the 1-adrenoceptor, whereas formoterol is a weak
partial 1-adrenoceptor agonist with a selectivity ratio of 42. Indacaterol also
behaves as a weak partial 1-adrenoceptor agonist with a selectivity ratio of
29 (Table 1). However, despite this lower 1/2 selectivity ratio for indacaterol
when compared to salmeterol and formoterol, we have demonstrated in the rhesus
monkey that, for an equivalent degree of bronchoprotection, indacaterol has a better
cardiac safety profile than formoterol, salmeterol, and salbutamol [4]. This observation has been confirmed in a single-dose clinical study, where a supramaximal
dose of indacaterol (1,000 g) had a better safety profile when compared to a
supramaximal dose of salmeterol (250 g) [18]. All these data suggest that, at
least for the cardiac side effects observed with the inhaled 2-adrenoceptor, the 1/
2 degree of functional selectivity does not play a major role. Indeed, direct
activation of the 2-adrenoceptor in the human atrium and ventricle caused an
increase in contractile force [16]. In addition, tachycardia may result from dilatation
of peripheral vasculature, partially mediated by the 2-adrenoceptor, resulting in
reflex sympathetic nervous system stimulation, thereby increasing inotropic and
chronotropic effects [19]. Regarding the activity of the marketed 2-adrenoceptor
agonists at the 3-adrenoceptor, salmeterol is a partial agonist with a selectivity
ratio of more than 1,000, whereas formoterol and indacaterol are full agonists with
selectivity ratios of 10 and 22, respectively (Table 1). In contrast to the 1- and 2adrenoceptors, the 3-adrenoceptor has only been recently characterized [20], and

30

A. Trifilieff et al.

selective ligands have only been recently made available. As a consequence, its
physiological role is not entirely clear [21]; it is therefore difficult to assess whether
systemic activation of the 3-adrenoceptor can induce undesirable side effects.
However, the long-term clinical use of formoterol has not reveal potential 3adrenoceptor-mediated side effect.

5 Onset of Action
The onset of action of an inhaled bronchodilator is related to how rapidly, after
inhalation, the patient feels that the treatment is effective. As such, in the clinic,
salbutamol, formoterol, and indacaterol have been shown to have a fast onset, with
an effective bronchodilation that occurs within 23 min, whereas salmeterol is
slower [2224]. Although it can be argued that for an inhaled bronchodilator
designed for chronic treatment of COPD a fast onset is not relevant, one can see
at least two major advantages for a fast-acting bronchodilator when compared to a
slow-acting drug: increased treatment adherence and improvement in the ability to
perform morning activities. Very few data exist regarding adherence to inhaled
medication in COPD [25]. From the available data, on average, about 50 % of
patients do not adhere to their inhaled medication [26]. Although the reasons for
this lack of adherence are numerous, the patient feeling that the drug is not
beneficial for him and therefore doubt about personal need for medication is a
major reason [27]. Therefore it is reasonable to assume that with a fast-acting
inhaled bronchodilator, symptom relief will be experienced rapidly after inhalation,
and thereby patients will feel that the treatment is effective and will continue using
it. Impairment in performing early morning activities is particularly problematic for
COPD patients [28, 29], and it was recently shown that the fixed dose combination
of budesonide/formoterol (Symbicort, AstraZeneca), which has a more rapid onset
of action than the fixed dose combination of salmeterol/fluticasone (Seretide,
GlaxoSmithKline), had a greater improvement in the ability for COPD patients to
perform morning activities [30].
Indacaterol onset of action has been compared with the marketed inhaled 2adrenoceptor agonists in a number of experimental setups (Table 2). As such, in the
electrically stimulated guinea pig tracheal preparation, indacaterol has a fast onset
of action similar to that of salbutamol and formoterol. This is in contrast to the
much slower onset observed with salmeterol [4]. Similarly, in the isolated human
bronchus [31] or in the human small airways using the precision-cut lung slice
model [32], indacaterol was characterized as a fast-acting compound with an
equivalent onset as formoterol and salbutamol and faster than salmeterol.
Until recently, onset of action of inhaled 2-adrenoceptor agonists has been
considered to be dependent upon the physicochemical properties of the ligands,
in line with the plasmalemma diffusion microkinetic model [33]. In this model, a
hydrophobic molecule such as salbutamol is considered to diffuse rapidly to the site
of action and access the receptor directly from the aqueous environment, resulting

The Preclinical Pharmacology of Indacaterol

31

Table 2 Onset and duration of action for the marketed inhaled 2-adrenoceptor agonists in
isolated tissues
Guinea pig trachea
Onset (min)
Indacaterol 30
Formoterol 32
Salmeterol 169
Salbutamol 28
Data from [4, 31, 32]

Duration (h)
8.8
2.6
7.9
0.4

Human bronchus

Human small airways

Onset (min)
8
6
20
11

Onset (min)
3
2
7
2

Duration (h)
>12
0.6
>12
0.25

Duration (h)
>6
<2
>6
<1

in a fast onset of action. In contrast, lipophilic compounds such as salmeterol take


longer to diffuse into tissues and may even access the receptor via the membrane
compartment, resulting in a slower onset of action. This has been supported by
observations that the onset of relaxation of guinea pig trachea gets longer in a series
of homologous indacaterol analogous with increasing lipophilicity [34]. However,
although lipophilicity undoubtedly influences the onset, it does not explain the clear
differences in clinical onset of action between indacaterol and salmeterol, which
have very similar lipophilicity. It has been suggested that the unique structure of
salmeterol allows it to pack more effectively into lipid membranes, slowing onset of
action [35], but this is not supported by studies that show salmeterol and indacaterol
have very similar affinity for lipid bilayers, regardless of their structural differences
[36]. This suggests that other factors play an important role in governing the clinical
onset of action.
One factor that could influence the initial rate of receptor occupancy, and hence
the initiation of downstream signalling, is the binding kinetics of the 2adrenoceptor agonists. A recent study has measured the kinetics of a series of
inhaled 2-adrenoceptor agonists and examined the effect this has on observed
association rates [37]. It was found that the koff value for salmeterol was 4.5-fold
slower than that of indacaterol (Table 3), which at first appears to support this
notion. However, at equi-effective concentrations, the rate of association to the
receptor was equivalent, while at concentrations based on their relative clinical
doses, salmeterol occupied the receptors more rapidly than the other agonists
examined. This is likely due to the low efficacy of salmeterol, meaning it must be
used at higher relative concentrations to occupy sufficient receptors to give a
functional response. These higher relative concentrations of drug will speed the
observed association rate. Interestingly, these simulations also suggested that the
low efficacy of salmeterol means it needs to be dosed at higher relative levels in the
clinic when compared to other inhaled 2-adrenoceptor agonists. Importantly, this
study suggests that binding kinetics does not play a significant role in determining
clinical onset of action.
A potential explanation for the differences in onset of action is variations in
intrinsic efficacy between the molecules. A recent study compared the intrinsic
efficacy of a series of 2-adrenoceptor agonists with the rate at which they stimulate
cAMP production in primary human bronchial smooth muscle cells [7]. This study

32

A. Trifilieff et al.

Table 3 Affinity and kinetic binding parameters for agonists at the 2-adrenocepetor
koff min 1
Kd nM (pKd)
Ki nM (pKd)
Compound kon M min (k3) (k4)
Isoprenaline 2.47  1.39  107 3.06  1.53 132.9  24.2 (6.89)
218.3  81.7 (6.72)
Salmeterol 4.31  1.34  109 0.76  0.06
0.3  0.1 (9.70)
0.8  0.1 (9.18)
295.0  42.1 (6.54)
Salbutamol 2.05  1.03  107 4.06  1.19 249.1  85.8 (6.65)
15.9  3.6 (7.83)
56.3  14.6 (7.28)
Formoterol 2.15  0.45  108 3.29  0.79
Indacaterol 8.74  2.12  107 3.48  0.42
48.7  13.4 (7.37)
96.2  13.0 (7.04)
Adrenaline 3.15  0.61  106 5.12  1.39 1513.3  303.6 (5.85) 1547.4  182.8 (5.82)
2.6  1.6 (8.79)
1.7  0.3 (8.80)
GSK444
3.25  1.7  108 0.41  0.04
5.4  1.2 (8.32)
7.9  1.6 (8.16)
Carmoterol 8.66  0.46  107 0.46  0.09
Data are expressed as mean  S.E.M. (n  3) and are taken from [37]
1

showed a direct correlation of intrinsic efficacy with onset of cAMP signalling, with
the highest-efficacy ligands having the faster onset of action. This supports the
notion that strength of receptor activation determines the rate of second messenger
signalling and suggests that the slower onset of action of salmeterol compared to
indacaterol could be a result of its lower intrinsic efficacy.

6 Duration of Action
The available inhaled 2-adrenoceptor agonists are either used as a rescue medication (salbutamol) or as maintenance therapy (formoterol and salmeterol).
Salbutamol provides rapid bronchodilation; however, its major drawback is its
short duration of action (46 h). In contrast, the longer-acting inhaled 2adrenoceptor agonists, formoterol and salmeterol, are given twice a day [38,
39]. Despite the decrease in dosing frequency with the twice-daily inhaled 2adrenoceptor agonists, patient compliance is still an issue [25]. In addition, the
availability of tiotropium bromide, a once-daily inhaled muscarinic antagonist for
the treatment of COPD [40], would suggest that a new inhaled 2-adrenoceptor
agonist with a duration of action compatible with once-daily administration is likely
to become the future bronchodilator of choice, either on its own or when used with a
once-daily muscarinic antagonist in COPD.
Indacaterol has been shown to have duration of action compatible with a oncedaily dosing regimen in various in vitro preclinical models (Table 2). In the
electrically stimulated human bronchus [31], the duration of action for both
indacaterol and salmeterol was greater than 12 h compared to half an hour for
formoterol and 15 min for salbutamol. A similar ranking for the duration of action
was observed in the isolated electrically stimulated guinea pig trachea [4]. In
isolated human small airways contracted with carbachol, indacaterol had a comparable duration of action to salmeterol (greater than 6 h), whereas salbutamol (less
than 1 h) and formoterol (less than 2 h) had a shorter duration of action [32]. More
recently, using a cell-based assay, it was demonstrated that indacaterol had a longer

The Preclinical Pharmacology of Indacaterol

33

persistence of action at the 2-adrenoceptor, when compared with salbutamol or


formoterol [41].
The long duration of action for indacaterol was also demonstrated in vivo. In the
conscious guinea pig using lactose-blended dry powder formulations and serotonin
as a constrictor agent, the duration of action of indacaterol has been compared to
that of formoterol, salmeterol, and salbutamol. Using equi-effective doses, the
duration of action can be ranked in the following order: indacaterol (24 h) >
salmeterol (12 h) > formoterol (4 h) > salbutamol (2 h) [4]. This long duration
of action for indacaterol when compared to salbutamol and salmeterol has been
recently confirmed using an unconscious guinea pig Einthoven model and histamine as a constrictor agent [42].
The mechanism of prolonged duration of action of inhaled 2-adrenoceptor
agonists has been widely debated. One possible explanation is that the drugs exhibit
slow dissociation from the receptor, a feature exhibited by the once-daily inhaled
muscarinic receptor antagonist tiotropium [43]. Indeed, it has been suggested that
long duration of the exploratory 2-adrenoceptor agonist carmoterol can be
attributed to its slow dissociation from the receptor [44]. However, in a recent
study examining the binding kinetics of a series of inhaled 2-adrenoceptor agonists
in physiological buffers at 37  C, it was discovered that although there were some
small difference in off rate for the different agonists, even the agonist with the
highest residency time would be fully dissociated from the receptor within 10 min
([37], Table 3). This suggests that prolonged receptor residency time alone is not
sufficient to explain the duration of action of long-acting 2-adrenoceptor agonists.
A more widely accepted mechanism for the long duration of inhaled 2adrenoceptor agonists action is the plasmalemma diffusion microkinetic model
[33] that suggests the lipid membrane provides a depot for lipophilic ligands,
maintaining high concentrations of drug in the local vicinity of the receptor even
when the bulk of the compound has washed out of the lung. Hydrophilic ligands, in
contrast, remain in the aqueous phase and are rapidly washed away once they have
dissociated from the receptor. This hypothesis has been modeled for salmeterol and
found to adequately describe both the long action and the ability of salmeterol to
reassert its effect once an antagonist has been washed away [45]. An extension of
the diffusion microkinetic model is that in addition to the drug moving between
receptor and lipid membrane depot, ligands that have freshly dissociated from one
receptor can immediately bind another receptor in the local vicinity. This has been
termed rebinding and can provide even larger gains in pharmacodynamic duration, particularly when diffusion barriers are considered in an unstirred
model [46].
These studies suggest that the duration of action of 2-adrenoceptor agonists
should be directly related to their affinity for lipid membranes. The physicochemical properties governing this interaction with lipid membranes is described in detail
elsewhere (see chapter The Design of the Indacaterol Molecule).

34

A. Trifilieff et al.

7 Interaction with Short-Acting 2-Adrenoceptor Agonists


Apart from their duration and onset of action, an interesting difference between the
marketed long-acting 2-adrenoceptor agonists is their intrinsic efficacy. As
discussed above, salmeterol is a partial agonist, formoterol an almost full agonist
and indacaterol has intermediate efficacy (Table 1). Although when used as maintenance therapy, the clinical efficacy of these drugs is similar, the difference in their
intrinsic efficacy may translate into meaningful clinical differences in condition of
increased bronchial tone or overuse of short-acting 2-adrenoceptor relief medication. Indeed, in isolated human bronchi, we have shown that indacaterol,
formoterol, and salmeterol have the same efficacy on preparations at resting tone.
However, in bronchi precontracted with histamine or acetylcholine, the maximal
effect induced by formoterol or indacaterol was not significantly modified, whereas
the effect of salmeterol was moderately to considerably reduce [31]. In the same
study, it was shown that preincubation of salmeterol but not indacaterol or
formoterol decreased the potency of isoprenaline. These results are in agreement
with the receptor theory suggesting that a partial agonist can behave as an antagonist in the presence of an agonist with higher efficacy acting on the same receptor.
The lack of antagonism of isoprenaline-induced relaxation and the nearly full
agonist behavior of indacaterol could be of particular interest when considering
the use of rescue medication, where short-acting 2-adrenoceptor agonist are used
on top of maintenance treatment with long-acting 2-adrenoceptor agonist. These
results were confirmed in vivo using the conscious guinea pig model. In this
experimental setup, pretreatment with indacaterol or formoterol did not blunt the
effectiveness of the short-acting 2-adrenoceptor agonist salbutamol [47].

8 2-Adrenoceptor Polymorphism and Agonist Efficacy


Several polymorphisms of the human 2-adrenoceptor have been described that can
potentially modify the pharmacological properties of 2-adrenoceptor agonists. Of
these, the two most frequent single-nucleotide polymorphisms result in the presence
of either an arginine or a glycine at codon 16 and a glutamine or a glutamate at
codon 27. In addition, there is a rare but potentially important single-nucleotide
polymorphism that results in either a threonine or an isoleucine at codon
164 [48]. Although a number of clinical studies have been designed to assess the
potential detrimental effects of these different polymorphisms, no consensus has
been reached on the relationship between 2-adrenoceptor genetic variations and
2-adrenoceptor agonist response [48]. Nevertheless, since in vitro studies have
reported significant effect of the genetic variations on the response to various 2adrenoceptor agonists, it was important to assess the effect of indacaterol on the
most common of these polymorphisms. In a study comparing the functional efficacy of indacaterol with formoterol and salmeterol on the most common

The Preclinical Pharmacology of Indacaterol

35

haplotypes, no marked genotype-dependent effects were observed for all


compounds. Only for the rare single-nucleotide polymorphisms at codon 164, a
reduced efficacy for all compounds was observed [5]. Recently, a large
pharmacogenetic analysis testing for an association between common 2adrenoceptor polymorphisms and indacaterol response in COPD patients was
performed. A total of 648 indacaterol-treated patients were genotyped for the
most commonly studied polymorphisms in the 2-adrenoceptor gene. Results
showed little evidence for the association between 2-adrenoceptor variants and
indacaterol response, suggesting that 2-adrenoceptor genetic variation is unlikely
to have a major role in differential response to indacaterol treatment in COPD
patients [49].

9 Conclusion
The preclinical profile of indacaterol shows that it is the first inhaled 2adrenoceptor agonist that combines a fast onset of action together with a dosing
regimen compatible with once-daily dosing. It has good potency and intermediate
intrinsic efficacy at the 2-adrenoceptor. In addition, studies in animals or isolated
tissues have shown that it has reduced potential for cardiovascular side effects and
interaction with short-acting 2-adrenoceptor rescue medicine. All together, this
favorable preclinical profile has led us to select this compound for further development in the treatment of COPD.

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COPD Patients. Pharmacogenomics J 12:4848

The Design of the Indacaterol Molecule


Robin A. Fairhurst, Steven J. Charlton, and Alexandre Trifilieff

Abstract 2-Adrenoceptor agonists have been used as bronchodilators for the


treatment of asthma and COPD for over a century. Throughout this period, 2adrenoceptor agonists have continued to evolve to best meet the needs of the
patient, with improvements having been made to the selectivity, route of administration and duration of effect. As the next step in the progression of this class of
compound, ultra-long-acting inhaled 2-adrenoceptor agonists, suitable for oncedaily dosing, have been targeted to provide a new gold standard in patient compliance. Indacaterol is the first of these agents to be approved for the treatment
of COPD, having been designed by a rationale approach to deliver the optimal

HN
HO

indacaterol
5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one
N
H

CASRN: [312753-06-3] (maleate salt CASRN: [753498-25-8])

OH

R.A. Fairhurst (*)


Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland
Novartis Pharma AG, Werk Klybeck, Klybeckstrasse 141, CH-4057 Basel, Switzerland
e-mail: robin.fairhurst@novartis.com
S.J. Charlton
Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, UK
A. Trifilieff
Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland
A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy,
DOI 10.1007/978-3-0348-0709-8_3, Springer Basel 2014

39

40

R.A. Fairhurst et al.

ultra-long-acting inhaled 2-adrenoceptor agonist profile. Indacaterol was designed


following a lipophilicity-based hypothesis to maximise the retention of the compound in the airways, so as to be able to deliver the primary goal of 24 h
bronchodilation following a single inhaled dose. Further evaluation then ensured
the long duration of effect could be combined with the best overall profile with
respect to potency, selectivity, onset of action and side-effect profile. Following the
synthesis of a series of close analogues, in which all three regions of the
pharmacophore were modified, indacaterol could be confirmed as the optimal
compound from the series. Studies to better understand the mechanisms by which
indacaterol achieves the observed pharmacological profile are discussed.

1 Introduction
Dating back for over a century, reports can be found describing the use of 2adrenoceptor agonists for the treatment of asthma [1]. Starting from these earliest
reports of the isolation, synthesis and subsequent use of adrenaline as a treatment
for asthma, chemists have sought to identify improved agents with increased
potency and selectivity for the 2-adrenoceptor. In addition, these early reports
relied upon subcutaneous injection as the route of administration, and ways to
facilitate more efficient delivery options for the treatment of airway diseases also
became a focus from an early stage [2]. Throughout this progression, medicinal
chemistry research has centred upon chemical series which, in the majority of cases,
can be traced back to the endogenous ligand for this receptor family, adrenaline.
The three key structural elements of adrenaline can still be seen embedded in the
agonists that continue to be developed up to the current time, including the one most
recently approved for the treatment of respiratory disease, indacaterol [3]. These
three key structural elements are highlighted in Fig. 1 for indacaterol and a selection
of important 2-adrenoceptor agonists of historical significance as for adrenaline:
the catechol moiety in green, the ethanolamine linker in red and the N-methyl
amino substituent in blue.
The major steps in the progression of this class of compounds starting from
adrenaline and leading to the latest generation of ultra-long-acting inhaled 2adrenoceptor agonists are summarised briefly below [1]. As the first significant
step, improvements in the selectivity for - over -adrenoceptors were made with
the N-isopropyl analogue of adrenaline, isoprenaline. This compound still remains a
key reference compound to the present time, in particular for the assignment of
intrinsic efficacy. Next, replacements were identified for the labile catechol moiety,
which is susceptible to both metabolism and oxidation. These early catechol
mimetics brought further improvements in selectivity for the 2-adrenoceptor, in
the form of resorcinol and saligenin derivatives. In terms of clinical applications,
these two series are best exemplified by terbutaline and salbutamol as resorcinol

The Design of the Indacaterol Molecule

41

First Generation
HN

Me

HN

HO

HN
HN

HO

HO

HO

OH

OH

HO

OH

OH

isoprenalineb

adrenalinea

OH

OH

OH

salbutamolb

terbutalineb

OMe

Second Generation
O

HN

HN
HO

HO

OH

OH

OH

salmeterolb

N
H

formoterolc

Third Generation

HN
HO

N
H

OH

indacaterola

Fig. 1 Structural relationship between indacaterol, adrenaline and a selection of 2-adrenoceptor


agonists of historical significance. The three structural regions are highlighted: catechol mimetic in
green, ethanolamine linker in red and amino substituent in blue. aSingle enantiomer of the (R)configuration; bracemic mixture; cracemic mixture of the (l )-diastereoisomer

and saligenin derivatives, respectively. In particular, salbutamol has become


established as the rescue medication of choice, for the acute relief of bronchoconstriction, and remains so up to the current time. This is due to salbutamol possessing

42

R.A. Fairhurst et al.

a rapid onset of action of less than 5 min, but with only a relatively short 34 h
duration of action. To more effectively address the needs of nocturnal asthma,
agents with longer durations of action were subsequently sought to offer continuous
relief from bronchoconstriction throughout the night. This effort, to alleviate
nocturnal asthma symptoms, led to the discovery of the second-generation longacting bronchodilators formoterol and salmeterol, each compound possessing a 12 h
duration of action when administered by inhalation [4]. Although both formoterol
and salmeterol are suitable for twice-daily dosing, a number of differences exist
between these two compounds: formoterol is a high-intrinsic-efficacy agonist, with
a rapid onset of action, used both for maintenance and also in Europe as a rescue
medication; in contrast, salmeterol is a lower intrinsic efficacy agonist, with a slow
onset of action, which is used only as a maintenance therapy.
As part of the life-cycle management of both formoterol and salmeterol, fixeddose combination products have been introduced in which a corticosteroid is
co-formulated within the same inhalation device as the long-acting 2-adrenoceptor
agonist [5]. These combination products have proved to be extremely effective
treatments for both asthma and chronic obstructive pulmonary disease (COPD) and
highlighted the opportunity to improve patient compliance through a simplified
dosing regimen. In the context of chronic indications, the gold standard for achieving optimal patient compliance is considered to be once-daily dosing. Therefore,
inhaled 2-adrenoceptor agonists have subsequently been pursued with the ability to
deliver sustained 24 h bronchodilation. Such agents, when dosed once-daily, are
anticipated to offer the opportunity to achieve the maximum level of patient
compliance. Further, this increase in compliance is anticipated to lead to an
improvement in disease control to be attained, when compared to the established
twice-daily agents. This new family of once-daily agents has been termed both
ultra-long-acting 2-adrenoceptor agonists and third-generation 2-adrenoceptor
agonists [6, 7]. Additionally, in parallel, the co-development of an increasing
number of similarly once-daily dosed potential combination partners, which
include corticosteroids and muscarinic antagonists, has further driven the desire
to identify the next generation of ultra-long-acting 2-adrenoceptor agonists [8,
9]. Indacaterol was the first member of this family of ultra-long-acting 2adrenoceptor agonists to be developed and gained approval in Europe as a oncedaily bronchodilator single agent for the treatment of COPD in October 2008. As of
today, indacaterol is approved in more than 70 countries including the United States
of America.
This chapter describes the drug discovery approach taken to identify indacaterol
as an inhaled once-daily bronchodilator, the structureactivity relationships
surrounding the molecule which led to it being selected as a candidate for further
development, and the investigations into the mechanism of how indacaterol
achieves the sustained duration of effect. Currently other ultra-long-acting 2adrenoceptor agonists are reported to have entered into the advanced stages of

The Design of the Indacaterol Molecule

43
OH
H
N

OMe

HN

HN

HN

HO

HO

HO

O
N
H

N
H

OH

N
H

indacaterol

OH

OH

carmoterol

milveterol
Cl

HN

OMe

O
HN

HO

Cl

HO
O

N
H

HO

OH

OH

olodaterol

vilanterol
OH

F
N
H

HN
HO

HN
HO

O
N
H
OH

PF-610355

S
O

N
H

OH

abediterol

Fig. 2 Structural relationships between indacaterol and a selection of third-generation 2adrenoceptor agonists which have recently undergone, or are currently undergoing, clinical
evaluation. The three structural regions are highlighted: catechol mimetic in green, ethanolamine
linker in red and amino substituent in blue. All compounds are single enantiomers of the (R)configuration or (R,R)-configuration in the case of milveterol. The structure of AZD-3199 had not
been disclosed at the time of writing, but the structure of the compound has been speculated upon
from the patent literature [16]

clinical development, but none have yet gained approval at the time of writing
(January 2012); these include carmoterol (Chiesi) [10], olodaterol (Boehringer
Ingelheim) [11], milveterol and vilanterol (GlaxoSmithKline) [12, 13], abediterol
(Almirall) [14], PF-610355 (Pfizer) [15] and AZD-3199 (AstraZeneca) [16]
(Fig. 2).

44

R.A. Fairhurst et al.

2 Product Profile Targeted at the Beginning of the Project


As outlined in the above introduction, the key focus of the targeted product profile
at the onset of the project was to identify an inhaled 2-adrenoceptor agonist which
could provide sustained 24 h bronchodilation from a single dose to support oncedaily administration. Although delivering effective 24 h bronchodilation remained
the primary objective throughout, additional opportunities were also targeted to
further improve upon the two established twice-daily long-acting 2-adrenoceptor
agonists in clinical use: formoterol and salmeterol. These opportunities and the
anticipated associated benefits foreseen at the time are discussed below.
The established 2-adrenoceptor agonists in clinical use are employed as racemic
mixtures, and a single stereoisomer was targeted to reflect the current state of the art
and to avoid possible complications due to potential off-target activities from
eutomeric stereoisomers [17, 18]. In addition to delivering a sustained duration of
effect, an agent providing a rapid onset of action was also targeted. Such a profile
was anticipated to provide rapid feedback to the patient, that the dose has been
successfully administered, and therefore reduce the risk of overdosing. In addition,
a rapid onset of action also has the potential to increase compliance by reinforcing
the association of taking the dose with the perception of an improvement in lung
function [19]; this is discussed further in pharmacology (see chapter The Early
Clinical Development of Indacaterol). The inhaled route of administration is
employed for this class of compound to achieve the targeted efficacy in the lung
whilst minimising unwanted side effects arising from the activation of systemic 2adrenoceptors, such as tremor, hypokalemia and tachycardia. In particular for
certain groups of patients, these systemic side effects have been shown to be
responsible for a negative impact on compliance [20]. Therefore, our goal was to
identify a compound delivering the desired efficacy, but with as wide a therapeutic
index as possible with respect to systemic side effects when compared to marketed
inhaled 2-adrenoceptor agonists. Finally, a viable inhalation product requires a
formulation with good long-term stability and a high degree of reproducibility with
respect to the delivered dose. From previous Novartis in-house experience, the
technical challenge to satisfy both of these properties had been found to be
increased for low-dose highly potent compounds, such as formoterol. Hence, a
compound with an intermediate potency was targeted to minimise the risk of a
technical delay/failure in producing a formulation that would be suitable as a robust
drug product. This technical requirement being of increased importance, because
the ultimate goal for a candidate from the project would be to co-formulate as part
of fixed-dose combination products with other classes of inhaled drug molecules
(i.e. steroid and/or anti-muscarinic). In summary, the target product profile at the
start of the project was as highlighted below:
To deliver sustained 24 h bronchodilation consistent with being suitable for
once-daily administration
To be a single stereoisomer
To exhibit a rapid onset of action

The Design of the Indacaterol Molecule

45

To have as wide a therapeutic window as possible with respect to systemic 2adrenoceptor agonist-mediated side effects
To be of medium potency, with a projected human dose in the 50500 g range
to facilitate formulation for inhalation

3 Approaches Taken to Achieve the Targeted Profile


At the start of the project, a review was made of the mechanistic studies that had
been put forward to rationalise the sustained durations of effect for agents applied
topically to the lung. In particular, the basis of this review focused upon hypotheses
relating to the identification and rationalisation of the twice-daily bronchodilators
formoterol and salmeterol. In practice, these hypotheses are commonly used to
account for differences in the duration of activity observed in both in vitro and
in vivo preclinical models across a series of compounds with similar properties.
Attempts to rationalise the data from these studies have resulted in the development
of several models to account for the duration of action differences observed
between inhaled 2-adrenoceptor agonists. These include the following: the plasmalemma diffusion microkinetic theory, in which the high partitioning of lipophilic
bases into phospholipids that compose the cell membrane has been used to account
for the long duration of action of formoterol and salmeterol through the uptake of
the compound into airway smooth muscle cells following local administration [21];
the exosite binding hypothesis, in which the 4-phenylbutoxyhexyl amino substituent of salmeterol has been hypothesised to interact with a region of the 2adrenoceptor, remote from the catechol binding site, resulting in retention of the
compound in close proximity to the receptor [22]; extended receptor kinetics, in
which slow receptor off-rates have been proposed to account for differences
observed within a series of 8-hydroxyquinolinone-derived 2-adrenoceptor agonists
[23]; and tight ligand binding, in which the formation of a stable binary drugreceptor complex, which can repeatedly stimulate G proteins, has been proposed to
account for the duration of action of carmoterol [24]. Additionally, at the start of the
project, other factors were also considered to be possible contributors for achieving
a sustained duration of action: intrinsic efficacy, where the level of agonist receptor
occupancy required for delivering efficacy has the potential to influence the ease of
attaining and maintaining the pharmacological effect [25], and limiting solubility
and permeability, where a delayed passage from airway lumen to blood, due to
slowed dissolution and permeation, has the potential to further extend lung
residency [26].
Of these models, previous Novartis in-house experience with formoterol had
highlighted the importance of lipophilicity in regulating the duration of action of 2adrenoceptor agonists when applied topically to the lung [27]. Thus, the plasmalemma diffusion microkinetic theory formed the basis of the initial design hypothesis, with medicinal chemistry beginning by regulating the lipophilicity of the
compounds targeted for synthesis and relating this parameter to the associated
biological profiles. However, one question that caused particular concern at the

46

R.A. Fairhurst et al.

start of the project was: could a profile consistent with a rapid onset of action be
retained, when the intrinsic duration of action was extended by increasing
lipophilicity? This was based upon the observation that salmeterol, as the most
lipophilic of the clinically well-characterised 2-adrenoceptor agonists, exhibits a
slower onset of action in preclinical models, as well as in man. As an alternative
rationale, the lower intrinsic efficacy of salmeterol, and the subsequent requirement
for a higher level of receptor occupancy to deliver a satisfactory level of
bronchodilation, was also considered as a potential contributing factor to the
delayed onset of action observed with this compound. If the latter is the primary
factor, then a higher intrinsic efficacy analogue, of similar lipophilicity, would have
the potential to deliver the targeted profile of combining a rapid onset with a long
duration of action. Data supporting this rationale for intrinsic efficacy making a
significant contribution to regulating the onset of action has since been obtained and
shown this starting hypothesis to be valid [25]. In addition, compounds with higher
intrinsic efficacies were also favoured so as to avoid any potential complications
due to the antagonism of the pro re nata response to salbutamol, as previously
reported preclinically for salmeterol [28].
Thus, from a medicinal chemistry perspective, the project was initiated with the
goal to prepare prototype compounds with the desired 2-adrenoceptor agonist
properties (potency and intrinsic efficacy), and which could also support homologation
to sequentially increase lipophilicity [3]. To assess these compounds, a flow chart with
an early focus on assessing lipophilicity and understanding how this regulated the
in vitro measurements of potency, efficacy, duration and onset of action was
implemented. Interesting compounds were then further evaluated to characterise
their in vivo duration of action and also the separation of bronchodilator activity
from systemic 2-adrenoceptor-mediated side effects. The goal of this evaluation
being to ultimately select candidates with intermediate potency, a greater intrinsic
efficacy compared to salbutamol, a long intrinsic duration of action, a rapid onset of
action and as wide a therapeutic margin as possible. Such a preclinical profile was
anticipated to have the greatest chance to satisfy out targeted product profile in man.

4 Selection of the Starting Point for Medicinal Chemistry


Several starting points were evaluated at the onset of the project, and one series
which provided an interesting opportunity was the combination of an 8hydroxyquinolinone catechol mimetic with a 2-indanyl amino substituent, as
exemplified by the prototype structure 1, shown in Fig. 3 [3].
The reason for selecting the highly efficacious 8-hydroxyquinolinone catechol
mimetic was that a wide range of amino substituents were anticipated to provide
derivatives within the desired 2-adrenoceptor agonist potency and intrinsic efficacy range [29]. Additionally, the 8-hydroxyquinolinone containing 2adrenoceptor agonist carmoterol had already been reported to deliver greater than
24 h bronchodilation, albeit with a narrow therapeutic margin with respect to

The Design of the Indacaterol Molecule

47
7

6
5
4

HN
HO

N
H

OH
1

Fig. 3 Prototype structure 1 highlighting the key structural elements of the 8-hydroxyquinolinone
catechol mimetic in green, combined with the 2-indanyl amino substituent in blue. The ethanolamine linker is shown in red. The positions 4 through to 7 of the 2-indanyl moiety are also
indicated

systemic 2-adrenoceptor-mediated side effects, when dosed in asthma patients as a


nebulised solution [30]. In contrast, compounds containing the less efficacious
saligenin catechol mimetic, as exemplified by salbutamol and salmeterol (Fig. 1),
were anticipated to be more limited in the type of modifications that could yield the
targeted potency and efficacy range.
The selection of the 2-indanyl amino moiety in compound 1 was based upon the
ability to readily introduce substituents into the four unsubstituted positions within
the phenyl portion of this structural element. Such an approach was anticipated to
allow the regulation of lipophilicity, in a region remote from the key adrenalinemimicking pharmacophore, so as to have minimal impact on the 2-adrenoceptor
activation profile. Moreover, by employing a symmetrical substitution pattern, the
generation of additional chiral centres could be avoided. From an alternative
perspective, these substituted indan derivatives can also be considered as
stereochemically simpler cyclised versions of the -methyl--phenethyl amino
group present in a number of other 2-adrenoceptor agonists, e.g. formoterol and
carmoterol. With respect to the type of substituents to introduce into the indan
moiety, alkyl residues were seen as an attractive option, because incremental
homologations could be used to maintain the groups symmetry. Alkyl groups
were also anticipated to enable a wide range of lipophilicities to be rapidly explored
in a systematic fashion. Each double homologation, adding a pair of methylene
groups, was calculated to add approximately one log unit to the partition constant
between water and n-octanol (calculated logP or clogP). This parameter, clogP,
was shown to be a useful approximation for the strength of the interaction of the
compounds with phospholipid. The strength of this phospholipid interaction being
the key property for predicting duration of action based upon the plasmalemma
diffusion microkinetic theory, and clogP values are shown for all the subsequently
described compounds [21]. Strengthening the validity of this approach was that,
where measured, clogP was found to correlate well with measure logP values for
the investigated 2-adrenoceptor series [31].

48

R.A. Fairhurst et al.

5 Optimisation of the 8-Hydroxyquinolinone Aminoindan


Lead Series
Exploration of the combination of an 8-hydroxyquinolinone catechol mimetic with
the 2-indanyl amino substituent began with the synthesis of the prototype compound 1. Encouragingly, in vitro activity at the human 2-adrenoceptor for compound 1 was found to satisfy the targeted criteria of intermediate potency and a high
intrinsic efficacy. The intrinsic efficacy for compound 1 was found to be slightly
lower than for formoterol and significantly greater than for salmeterol and
salbutamol. Table 1 shows the pharmacological and physical chemistry data for
the 2-adrenoceptor agonists described in the following text, including key reference compounds. An analysis of compound 1 in the context of the plasmalemma
diffusion microkinetic theory suggested it would not be sufficiently lipophilic to
elicit an extended duration of effect (clogP 0.96).
Thus, to further increase the overall lipophilicity, homologation of the indan
moiety of compound 1 was carried out in a symmetrical manner (Fig. 4): dimethyl
substitution was predicted to slightly exceed the lipophilicity of formoterol and
carmoterol (clogP 1.91); and diethyl substitution was anticipated to achieve a level
comparable to salmeterol (clogP 3.20). To maintain the symmetrical indan substitution, the 4,7- and 5,6-dialkyl-substituted 2-aminoindan analogues became the
next targets for synthesis. Of these, the diethyl 5,6-disubstituted 2-aminoindan
analogue, indacaterol, was found to retain the targeted intermediate potency and
intrinsic efficacy levels of compound 1. In contrast, the dimethyl analogue
2 maintained a similar level of intrinsic efficacy but showed a drop-off in potency.
The impact of the 4,7-diethyl substitution pattern in 3 was even more marked and
resulted in a decrease in both potency and intrinsic efficacy. The above account
highlights that following this approach, indacaterol was prepared and identified as
an interesting compound at a very early stage of the project. A consequence of this
was that indacaterol became the first compound to be extensively profiled through
the flow chart and was quickly found to satisfy all the in vitro target product-profile
criteria. Hence, indacaterol became the benchmark compound from an early stage
of the project, and the focus of the project turned to looking at understanding the
key elements behind the profile of indacaterol and to see if an improved analogue
could be identified. These data are discussed in the following sections.
Following the identification of the favourable profile of indacaterol, attention
turned to close analogues retaining the active 5,6-disubstitution pattern within the
indanyl moiety. To understand the impact of further increasing lipophilicity, the npropyl and n-butyl 5,6-disubstituted analogues 4 and 5 were prepared (clogP 4.02
and 5.08, respectively). Each two-carbon double homologation results in an approximately 1 log unit increase in clogP, that is, a tenfold increase in the preference for
1-octanol partitioning, as a surrogate for phospholipid, versus the aqueous phase.
This translates into compound 1 starting out with a tenfold preference for the 1octanol phase over the water phase, rising to a 100,000-fold preference for the di-nbutyl analogue 5. Within this range indacaterol was determined to have an

The Design of the Indacaterol Molecule

49

Table 1 Summary of the clogP and in vitro human 2-adrenoceptor agonist activities of the
8-hydroxyquinolinone/2-aminoindanyl analogues and reference compounds
Bindinga

Functional activityb

Ki (nM)
EC50 (nM)
Intrinsic efficacy (% of isoprenaline)
Compound
clogP
1
0.96
218
5.0
88
2
1.91
522
39
74
Indacaterol
2.97
76
11
75
3
3.02
692
115
51
4
4.02
119
14
74
5
5.08
112
25
79
6
3.05
19

7
2.81
175

8
2.53
42

9
0.62
342
18
72
10
3.47
382

11
3.42
515

12
3.05
45

13
3.82
261

14
3.49
0.6
0.3
116c
15
3.01
77

16
2.92
464

17
2.81
1,397

18
2.71
133

19
3.53
132

Salbutamol
0.06
1,828
68
45
Salmeterol
3.06
0.4
0.3
30
Formoterol
1.26
23
1.3
100
Carmoterol
1.31
3.2
0.8
95
Zinterol
1.53
12

All methods for biological measurements are as previously reported [32].


a
clogP values were calculated using Biobyte CLOGP version 4.71
b
Human 2-adrenoceptor binding (n 34)
c
Human 2-adrenoceptor functional activity (n 3), intrinsic efficacy relative to formoterol
d
2-adrenoceptor functional activity measured in human bronchial smooth muscle cells (n 3),
intrinsic efficacy relative to formoterol [33]

approximately 1,000-fold preference for the 1-octanol phase. In terms of their 2adrenoceptor activities, analogues 4 and 5 retained the same level of potency and
intrinsic efficacy when compared to the prototype compound 1 and thus were also
of interest for further evaluation.
To explore alternative substitution patterns, two further isomers of indacaterol
were prepared: the mono-5-n-butyl- and 4,5,6,7-tetramethyl-indanyl analogues
6 and 7 with equivalent lipophilicity to indacaterol (clogP 3.05 and 2.81, respectively) [33]. The mono-5-n-butyl-indanyl analogue 6, prepared as a mixture of
diastereoisomers epimeric at the 2-indanyl centre, was found to be equipotent
with indacaterol. However, the additional stereochemical complexity, associated
with breaking the plane of symmetry in the indan moiety, made this analogue of

50

R.A. Fairhurst et al.

HN

HN

HO

HN

HO

N
H

N
H

OH

OH

HO

N
H

OH

O
5

HO

N
H

O
6a

OH

HN

HO

N
H

N
H

HN

HN
HO

OH

HN

HO

OH

O
7

N
H
OH

O
8

Fig. 4 Structures of the analogues combining the 8-hydroxyquinolinone catechol mimetic with
the 2-indanyl amino substituent. The three structural regions are highlighted: catechol mimetic in
green, ethanolamine linker in red and amino substituent in blue. aDiastereoisomeric mixture or the
(R,R)- and (R,S)-configuration, epimeric at the 2-indanyl centre. All other compounds are single
enantiomers of the (R)-configuration

lower interest for further follow-up studies. The 4,5,6,7-tetramethyl-indanyl analogue 7 proved to be less potent and was not pursued further due to falling outside
the targeted potency range. These data reinforced the negative impact of substitution at the indan 4- and 7-positions and further focused our attention on the
5,6-indanyl disubstitution pattern. In addition to the acyclic-substituted analogues
17, the 5,6-fused cyclic analogue 8 was also prepared with a lipophilicity similar
to indacaterol (clogP 2.81) [34]. This ringed-indacaterol analogue 8 had a similar
in vitro profile to indacaterol and was also selected for further profiling.
To further explore the structureactivity relationship surrounding indacaterol, a
series of close analogues were synthesised in which modifications were made in all
three structural regions of the molecule, and these compounds are shown in Fig. 5.
The 5,6-dimethoxyindanyl analogue 9, in which methoxy substituents are
introduced into the indan moiety in place of alkyl groups, retained the 2adrenoceptor potency and intrinsic efficacy of indacaterol. However, from the
plasmalemma diffusion microkinetic theory, a shorter duration of action was
anticipated due to the lower level of lipophilicity of analogue 9 (clogP 0.62)
[21]. Methylation of the 8-hydroxyquinolinone catechol mimetic at either the 3or the 6-position produced the analogues 10 and 11, respectively [33]. Both of these
methylated compounds resulted in a marked decrease in the affinity for the 2adrenoceptor, and as a result, these analogues were not pursued further. The closely

The Design of the Indacaterol Molecule

51

O
HN

HN

N
H

N
H

N
H

10a

OH

HN

HN

N
H

OH

O
12

HN
HO

O
13b

N
H

O
11a

OH

HO

OH

HO

HO

O
9

OH

HN

HN

HO

HO

N
H
OH

O
14

N
H
OH

O
15

Fig. 5 Exploring the SAR surrounding indacaterol with modifications to all three structural
regions. The three structural regions are highlighted: catechol mimetic in green, ethanolamine
linker in red and amino substituent in blue. aRacemic mixture; bachiral; all other compounds are
single enantiomers of the (R)-configuration

related 3,4-dihydro-8-hydroxyquinolinone analogue 12 was only slightly less


potent when compared to indacaterol in a ligand binding assay and therefore was
of interest for further follow-up studies [33]. Deoxygenation of the ethanolamine
linker generated the analogue 13 which exhibited a marked drop in 2-adrenoceptor
activity, and this compound was not pursued further [33]. The introduction of the
methyl group at the 2-position of the indanyl moiety of indacaterol resulted in the
analogue 14, which was shown to exhibit a marked increase in 2-adrenoceptor
activity. Similar increases in activity have been reported previously for a number of
2-adrenoceptor agonists with amino substituents bearing a methylated quaternary
-carbon centre [23, 35]. Such compounds include terbutaline and salbutamol and,
more recently, the third-generation long-acting 2-adrenoceptor agonists olodaterol
and PF-610355 [11, 15]. However, as discussed in the target product profile, such a
large increase in potency for analogue 14 was considered to be restrictive for the
targeted application. Such a high level of activity with 14 would be anticipated to
lead to a very low human dose. Previous in-house experience with formoterol had
highlighted the high technical challenge for producing an inhaled formulation to
deliver such low dose levels, and this prevented any further interest in progressing
analogue 14 [36]. Partial saturation of the 5,6-diethylindanyl moiety of indacaterol
gave the 4,7-dihydroindanyl analogue 15 in which a double bond is replaced by a
single bond. Interestingly, this structurally very close analogue of indacaterol

52

R.A. Fairhurst et al.

HN

HN

HO

HN

HN

HO

HO

HO

O
N
H
OH

H
16a

N
H
OH

OH

17b

OH

N
H

S
O

18a

OH

19b

Fig. 6 Combination of the 5,6-diethylaminoindan amino substituent with a series of established


2-adrenoceptor agonist catechol mimetics. The three structural regions are highlighted: catechol
mimetic in green, ethanolamine linker in red and amino substituent in blue. aSingle enantiomer of
the (R)-configuration; bracemic mixture

resulted in a marked loss of affinity for the 2-adrenoceptor to a level which made
this compound of no further interest [33].
Having identified the 5,6-diethylindan amino substituent to be capable of fully
satisfying the targeted product profile when matched with the 8hydroxyquinolinone catechol mimetic in indacaterol, the combination of this
amino substituent with a range of other well-established 2-adrenoceptor catechol
mimetics was also investigated [34]. This approach was designed to make use of the
lipophilicity of the 5,6-diethylindanyl to produce analogues calculated to be in a
very similar lipophilicity range to indacaterol the analogues prepared falling within
the clogP range 2.713.53. These analogues are shown in Fig. 6 with the in vitro
data described in Table 1 and include the combination with the following: the 3-Nformyl-4-hydroxyphenyl catechol mimetic found in formoterol to give analogue
16; the saligen catechol mimetic found in salbutamol and salmeterol to give
analogue 17; the 3-N-methanesulphonylamino-4-hydroxyphenyl catechol mimetic
found in zinterol and PF-610355 to give analogue 18; and the 4hydroxybenzothiazolone catechol mimetic found in the marine natural product
S1319, which Novartis have recently reported to have formed the basis for a backup
series of 2-adrenoceptor agonists to indacaterol 19 [37].
Upon profiling, analogues 16 and 17 exhibited reduced affinities for the 2adrenoceptor, when compared to indacaterol (>fivefold), and also to the parent 2adrenoceptor agonists from which they were derived. For analogues 18 and 19, Ki
values within twofold of indacaterol were determined, especially when the racemic
nature of 19 was taken into account. However, for 18 with the sulphonamide
containing catechol mimetic, a significant reduction in affinity was observed
when compared to the parent 2-adrenoceptor agonist zinterol. The structurally
closer analogue 19, like indacaterol, being derived from a bicyclic catechol
mimetic, also exhibited a similar affinity for the 2-adrenoceptor. However, this
level of activity was much lower than anticipated based upon the combination of the
4-hydroxybenzothiazolone catechol mimetic with several other well-established
amino substituents [37]. These data highlighted the unique outcome from combining the 8-hydroxyquinolinone and 5,6-diethylamino structural elements to generate

The Design of the Indacaterol Molecule

53

indacaterol possessing the targeted once-daily 2-adrenoceptor agonist profile.


Based upon the 2-adrenoceptor affinities for the above analogues with catechol
mimetic variations, only 18 and 19 were selected for further follow-up studies.

6 Further In Vitro Evaluation of the 8-Hydroxyquinolinone


Aminoindan Lead Series
To follow up on the interesting analogues from the above binding and functional
studies at the human 2-adrenoceptor, an electrically stimulated superfused guineapig tracheal-strip assay was used to measure the onset of action and intrinsic
duration of action profiles [32]. Data from this assay are shown in Table 2. For
the homologous series of 5,6-dialkyl-substituted indan examples 1, 2, 4, 5 and
indacaterol, a good correlation between lipophilicity and increasing onset and
intrinsic duration of action was observed, as shown by the representation in
Fig. 7. The plots show that with increasing lipophilicity, between the dimethyl
analogue 2 and indacaterol (the diethyl analogue), there is a transition from a short
duration of action (<2 h) to a long duration of action (>12 h). In contrast, a further
increase in lipophilicity to the di-n-propyl analogue 4 resulted in a trend for an
increasing onset of action, which became even further protracted for the dibutyl
analogue 5. The di-n-butyl analogue 5 also was determined to be of much lower
potency in the tissue preparation, when compared to the radioligand binding assays.
Suggesting such high levels of affinity for biological matrices (high serum binding
in addition to the high affinity for phospholipids was also determined for compound
5) may be sufficient to significantly limit the free drug concentration available for
receptor activation in intact tissue as compared to measurements in simpler assay
systems.
Also in line with the plasmalemma diffusion microkinetic theory are analogue 8,
with a similar lipophilicity to indacaterol, which exhibited a rapid onset of action
and a long duration of action, and analogue 9, with the lowest level of lipophilicity
from the series, which exhibited a rapid onset of action and a short duration of
action. Interestingly not fitting quite so well with the hypothesis are analogue 12
with a similar lipophilicity to indacaterol which exhibited a rapid onset of action,
but with a relatively short duration of action, and analogues 18 and 19, with
lipophilicities similar to indacaterol, but both showed a trend for an extended
onset of action in combination with a moderately long duration of action. The
common feature to these not so well-fitting analogues 12, 18 and 19 being that they
all contain an alternative catechol mimetic when compared to indacaterol.
Overall, the guinea-pig tracheal-strip data showed a good correlation between
lipophilicity and intrinsic duration of action for the series of 5,6-dialkyl-substituted
indan analogues. Expanding to other series, comparison with the reference
compounds showed the correlation to remain strong: salbutamol as the least
lipophilic example exhibited the shortest intrinsic duration of action; formoterol

54

R.A. Fairhurst et al.

Table 2 Potency and time


course data from the
electrically stimulated
guinea-pig tracheal-strip
assay

Guinea-pig tracheal stripb


Compound

clogPa

IC50 (nM)

Onset (min)

Duration (h)

1
0.96
0.8  0.3
28  2
1.2  0.5
2
1.91
48  1
42  9
1.4  0.3
Indacaterol 2.97
7.9  0.1
35  2
>12
3
3.02
75  1
51  6
2.1  0.5
4
4.02
20  1
55  10
>12
5
5.08
>1,000
>180
>12
8
2.53
50
35
9.0
9
0.62
2.3  0.9
28  3
1.2  0.3
12
3.05
3.9
32.5
2.3
13
3.82
240
131
9.3
18
2.71
3.2
60.7
10.1
19
3.53
15
50
3.9
Salbutamol 0.06
17  0.8
28  3
0.9  0.1
Salmeterol 3.06
3.5  0.9
120  34
>12
Formoterol 1.26
0.4  0.1
28  1
1.2  0.2
Carmoterol 1.31
0.30  0.01 28  2
1.6  0.1
All methods for biological measurements are as previously
reported [32]
a
clogP were calculated using Biobyte CLOGP version 4.71
b
Mean IC50  s.e.m. (n 35); onset of action and duration of
action were measured at compound concentrations nearest to
their IC50 values
3
R

2.5
R

10

HN

HO

1.5

6
N
H

OH

onset of action (hrs)

intrinsic duration of action (hrs)

12

0.5

0
H

Me

Et

n-Pr

n-Bu

Analogues arranged by increasing order of lipophilicity (R)

Fig. 7 Relationship between lipophilicity and onset (linear plot) and intrinsic duration of action
(bar graph) for the 5,6-substituted indan analogues: 1, 2, indacaterol, 4 and 5. Adapted with
permission from J Med Chem, Volume 53, The identification of indacaterol as an ultralong-acting
inhaled 2-adrenoceptor agonist, pages 36753684, Baur F, Beattie D, Beer D, Bentley D,
Bradley M, Bruce I, Charlton SJ, Cuenoud B, Ernst R, Fairhurst RA, Faller B, Farr D, Keller T,
Fozard JR, Fullerton J, Garman S, Hatto J, Hayden C, He H, Howes C, Janus D, Jiang Z, Lewis C,
Loeuillet-Ritzler F, Moser H, Reilly J, Steward A, Sykes D, Tedaldi L, Trifilieff A, Tweed M,
Watson S, Wissler E, Wyss D. Copyright 2010 American Chemical Society

The Design of the Indacaterol Molecule

55

and carmoterol with similar levels of lipophilicity, falling between that of


analogues 1 and 2, gave rise in all four cases to relatively short intrinsic durations
of action in the range of 1.2 and 1.6 h; salmeterol, as the most lipophilic reference
2-adrenoceptor agonist, with a comparable lipophilicity to indacaterol and analogue 8, gave rise to a long intrinsic duration of action of >12 h. Interestingly, an
example failing to fit this correlation well was the 4,7-diethyl regioisomer 3, with
comparable lipophilicity to salmeterol, indacaterol and analogue 8, which showed a
much shorter intrinsic duration of action and slower onset of action than predicted
based upon lipophilicity alone. As discussed earlier in this chapter, the longer onset
of action and shorter duration of effect determined for 3 in the guinea-pig preparation are presumably due to the 10- to 20-fold lower potency and lower intrinsic
efficacy compared to indacaterol. This reduced activity is thought to lead to the
requirement for a much higher local concentration to be attained for activation of
the 2-adrenoceptor. Additionally, this higher lung concentration would need to be
maintained to continue the bronchodilating effect, and sustaining such high local
concentrations for long periods appears not to be feasible. These data further
support the hypothesis that potency and intrinsic efficacy are also significant
contributors, in addition to lipophilicity, to determining not only the onset of action
but also the duration of action of inhaled 2-adrenoceptor agonists [25].
In conclusion, an overall assessment of the guinea-pig tracheal-strip data for the
analogues in Table 1 indicated that lipophilicity, in combination with a satisfactory
level of potency and intrinsic efficacy, proved to be a good predictor of a molecule
duration and onset of action characteristics. Through the regulation of these
properties, in vitro profiles consistent with a long duration of action and a rapid
onset of action could be achieved. From the analogues described above, indacaterol,
the ringed-indacaterol analogue 8, and the 3,4-dihyro-8-hydroxyquinolinone
analogue 12 were selected as interesting with respect to the projects targeted
in vitro profile and were progressed into further in vivo profiling as described
below.

7 In Vivo Evaluation of the 8-Hydroxyquinolinone


Aminoindan Lead Series
For the analogues 8 and 12, which had demonstrated interesting in vitro profiles,
follow-up in vivo studies were conducted in comparison with indacaterol to, at the
time, select the optimal compound. The aim of these studies was to establish the
duration of action and therapeutic index with respect to systemic 2-adrenoceptormediated side effects following topical application to the lung. These investigations
were conducted using a serotonin-induced bronchoconstriction model in the guinea
pig and a methacholine-induced bronchoconstriction model in the rhesus monkey
[32]. The latter model in particular proved to be useful for discriminating between
compounds in terms of their therapeutic index with respect to the associated

56

R.A. Fairhurst et al.

Table 3 Summary of the anti-bronchoconstrictor and cardiovascular activities of the


8-hydroxyquinolinone/2-aminoindanyl analogues and reference compounds in the rhesus monkey
Maximum increase in heart rate (% from baseline)
Compound
ED80 (g/kg)
Indacaterol
12.5
13  1
8
21
51
12
53
22  2
Salbutamol
27
21  2
Formoterol
1.2
25  2
Salmeterola
5.5a
20  4
Data are expressed as mean  standard error of the mean and taken from [32] for indacaterol,
salmeterol, salbutamol and formoterol
a
Salmeterol was found to be a partial agonist, and the 5.5 g/kg dose represents an ED50 antibronchoconstrictor dose

2-adrenoceptor-mediated tachycardia. These data are described below, and the


rhesus monkey model is discussed in more detail in [32].
Comparative studies in the rhesus monkey were performed with the compounds
dosed at an ED80 anti-bronchoconstrictor dose level. The ED80 for each compound
was determined from a doseresponse study to a methacholine challenge 5 min post
dosing. All the compounds were able to achieve an 80 % inhibition of the
methacholine-induced bronchoconstriction with the exception of salmeterol,
which was found to be a partial agonist in this model. The inability of salmeterol
to achieve an 80 % anti-bronchoconstrictor effect was consistent with the lower
intrinsic efficacy of the compound. For the following duration of action and
therapeutic index studies with salmeterol, an ED50 dose level of 5.5 g/kg was
selected. The rhesus monkey data are summarised in Table 3.
From these studies, indacaterol was found to deliver the greatest intrinsic
duration of action when compared to the reference compounds. Indacaterol
maintained a significant anti-bronchoconstrictor effect at all the time points studied
(out to 275 min) compared to salbutamol, formoterol and salmeterol, where significance was lost after 5, 155 and 155 min, respectively. In contrast, the associated
systemic side effects, as assessed by changes in heart rate, were significantly lower
for indacaterol and of a shorter duration of action compared to the clinical reference
compounds. In particular, salmeterol produced the greatest, and most sustained,
increase in heart rate when dosed at the less effective ED50 anti-bronchoconstrictor
level [32]. These data provided confidence that indacaterol possessed the targeted
profile of a long duration of action and a greater therapeutic index, when compared
to the key reference compounds.
From the in vitro structureactivity relationship studies, the ringed analogue
8 and the 3,4-dihydroquinolinone analogue 12 possessed the closest profiles to
indacaterol and were also studied in the rhesus monkey. Interestingly, both
analogues only differing slightly in structure by the minor change of a single
bond compared to indacaterol resulted in a marked difference in their overall
profiles. The ringed analogue 8 was twofold less potent and exhibited a much
shorter intrinsic duration of action compared to indacaterol, with significant

The Design of the Indacaterol Molecule

57

Fig. 8 Time course for the inhibition of methacholine-induced bronchoconstriction and heart-rate
changes in the rhesus monkey for analogues 8 and 12 compared to indacaterol at the ED80 dose
level. Data are expressed as mean  standard error of the mean and taken from [32] for
indacaterol

inhibition of bronchoconstriction lost between 95 and 155 min after dosing.


Although the associated 2-adrenoceptor-mediated side effects for analogue
8 were lower than for indacaterol, the twofold shorter intrinsic duration, shorter
than formoterol and salmeterol, ended the interest in this compound. The saturated
analogue 12 was found to exhibit a fourfold reduction in potency and a slightly
reduced intrinsic duration of action compared to indacaterol. At the ED80 dose
level, compound 12 was shown to maintain a significant anti-bronchoconstrictor
level out to the 210 min time point. However, a greater maximal increase in heart
rate was observed for 12, which remained significantly higher than the vehicletreated control throughout the duration of the experiment, as shown in Fig. 8. This
slightly reduced duration of action for 12, and greater level of associated side
effects, ended the interest in this analogue.
In conclusion, these data showed marked differences in the in vivo profiles for
analogues with minimal structural differences and with very similar in vitro pharmacological profiles. However, these data clearly showed indacaterol to be the
compound with the optimal profile from the series and enabled it to be promoted as
the first development candidate from the project.

8 Rationalisation of the Profile of Indacaterol


Having selected indacaterol as the first development candidate from the project, a
number of studies were conducted to explore which properties of the compound are
important for achieving the observed profile, and these studies are discussed below.
In terms of understanding what drives the long duration of action of indacaterol,
the correlation between intrinsic duration of effect and lipophilicity, as a surrogate
for phospholipid binding, was found to be valid throughout the discovery phase of
the project, as discussed in Sect. 6 of this chapter. This observation is in line with

58

R.A. Fairhurst et al.

the plasmalemma diffusion microkinetic theory and highlights that the lipophilicity
of indacaterol is at the optimal level for achieving a long duration of action in
combination with a rapid onset of action. These studies, which eventually covered
several structurally different 2-adrenoceptor agonist series, strongly reinforced the
role of lipophilicity in regulating the duration of action profiles of inhaled agents.
Equally important to this observation is the contribution of the ionisation state of
the compound for supporting the amphiphilic interaction with phospholipids, and
this is considered in more detail below.
Phospholipid affinity alone could not explain all the observations leading to the
selection of indacaterol, and it remained clear that other factors also contributed to
the onset and duration of action time courses. In particular, a decent level of
potency and a relatively high level of intrinsic efficacy were also required for a
compound to achieve the full onset and duration of action potential that would be
predicted by the level of lipophilicity [3]. Such an observation is not unreasonable,
as both parameters define the absolute concentration that needs to be achieved at the
level of the airway smooth muscle to establish, and to maintain, the pharmacological effect. As potency and intrinsic efficacy decrease, the concentration required for
delivering maximal bronchodilation increases, to the point where the rate of uptake
into smooth muscle begins to plateau. At this point, the time to reach the maximum
response, and the ability to sustain the effect at that level, will start to be impeded.
This observation is well exemplified when comparing the 4,7-diethyl analogue
3 with indacaterol: both compounds have the same lipophilicity, but the lower
potency and lower efficacy of 3 lead to the slower onset of action and shorter
duration of action. A further example supporting this hypothesis is the comparison
of indacaterol with salmeterol, where both compounds posses essentially the same
level of lipophilicity, but the higher intrinsic efficacy of indacaterol potentially
contributes to the faster onset of action, as discussed in the pharmacology chapter 2.
Analysing the plasmalemma diffusion microkinetic theory in more detail, the
contribution of lipophilicity is proposed to increase the interaction with cell membrane phospholipids. This phospholipid-bound fraction of the administered dose
then provides a reservoir of drug, proximal to the airway smooth muscle 2adrenoceptor, to maintain the pharmacological effect over time. The reservoir is
then depleted as the drug slowly redistributes from the lung and into the whole
body, before finally being cleared. Although logP values, as an easily determined
parameter, proved to be a good measure of lipophilicity in the discovery phase of
the project, this parameter only considers a single component of the potentially
amphiphilic interaction with phospholipid. Additionally, a key part of the 2adrenoceptor agonist pharmacophore is the basic amine which provides an additional ionic contribution to increase the interaction with phospholipid. The importance of the amphiphilic nature of the phospholipid interaction has been shown for a
series of 2-adrenoceptor agonists in which modifications, which significantly
reduced the basicity of the amine function, were found to negatively impact upon
the duration of effect, even when lipophilicity remained high [38]. In addition to the
basic amine, the majority of 2-adrenoceptor agonists also retain one of the phenol
groups within the catechol mimetic which adds a further acidic functionality. The

The Design of the Indacaterol Molecule

59

Table 4 Ionisation constants, CHIIAM values and human serum albumin affinities for indacaterol
and representative 2-adrenoceptor agonists
Binding to human
Compound
pKa phenol
pKa amine
CHIIAM at pH 7.4
serum albumin (%)
Indacaterol
6.7
8.3
59.7
95.7
Salmeterol
10.2
8.5
56.7
91.1
Salbutamol
Not measured
Not measured
21.0
29.9
Formoterol
8.8
8.2
40.4
31.7
Carmoterol
7.3
8.6
37.7
57.1
All methods are as previously reported [3]. pKa values were determined by potentiometric titration

presence of this second ionisable group leads to a more complex situation in terms
of the charged species which can be adopted. In particular the nature of the
intermediate neutral species can either be predominantly uncharged or zwitterionic,
depending on the extent to which the amine and phenol pKa values overlap. To
better understand the amphiphilic nature of the interaction with phospholipids, the
pKa values for indacaterol, salmeterol and formoterol were measured as representative members of three well-established catechol mimetics: 8-hydroxyquinolinone,
saligenin and 4-hydroxyphenylformamide, respectively [3]. These pKa data, as
determined by two independent methods, and affinity for phospholipid, as
measured by CHIIAM, are shown in Table 4.
Analysis of these pKa data indicates an increased acidity for the 8hydroxyquinolinone phenol moiety of indacaterol relative to the equivalent functionality present in salmeterol and formoterol. A consequence of this difference is
that, at physiological pH, indacaterol and other 8-hydroxyquinolinones containing
2-adrenoceptor agonists such as carmoterol are anticipated to exist in solution
predominantly as the zwitterionic species (protonated amine/phenoxide). In contrast, in the case of formoterol and salmeterol, the uncharged species will be the
predominate neutral species in solution. However, these differences resulted in no
substantial deviation in the bulk amphiphilic interaction, as measured by CHIIAM
(HPLC method measuring the affinity for a phospholipid stationary phase) [39],
from that which would be predicted by extrapolation from the clogP values for the
8-hydroxyquinolinone containing examples when compared to the other 2adrenoceptor agonist series.
In contrast, a more detailed study of the membrane interaction with indacaterol
and salmeterol has revealed some differences between the two molecules which
potentially arise as a consequence of their ionisation states [40]. From surface
plasmon resonances studies, indacaterol was found to permeate membranes twofold
faster than salmeterol. This increased diffusion rate has been attributed to
indacaterol existing primarily as a zwitterionic species at physiological pH and
has the potential to make a contribution to the faster onset of action of seen with
indacaterol. Additionally, equilibrium dialysis experiments with membrane-raft
extract as the partition phase showed a twofold greater membrane partitioning for
indacaterol relative to salmeterol. These highly ordered lipid-raft micro-domains

60

R.A. Fairhurst et al.

have been proposed as the membrane regions in which the functional 2adrenoceptor agonist signalling complexes are localised [41]. From these
observations, an expanded plasmalemma diffusion microkinetic theory has been
proposed in which the compound is asymmetrically distributed in the lipid bilayers
of airway smooth muscle cells, as depicted in Fig. 9. For compounds with greater
partitioning into lipid-raft regions, a greater proximal concentration, surrounding
the microenvironment of the 2-adrenoceptor, can be maintained. This proximally
distributed compound then has the potential to gain direct access to the 2adrenoceptor, without interacting with the bulk extracellular aqueous phase
and/or setting up a favourable rebinding concentration gradient focused on the 2adrenoceptor containing membrane region [42]. Therefore, following either scenario, a higher local concentration interacting directly with the 2-adrenoceptor can
be hypothesised. Such a higher concentration, proximal to the receptor, would be
anticipated to facilitate both a more rapid onset of action and to sustain a longer
duration of action.
To assess the potential contribution of receptor kinetics, an assessment of the 2adrenoceptor association and dissociation rates for indacaterol and the key reference compounds were made, as described in more detail in chapter 2. These studies
revealed similar rapid receptor association and dissociation rates, suggesting that
these parameters make no substantial contribution to the observed clinical onset and
duration of action profiles [43].
In terms of understanding the origin of the excellent therapeutic index observed
with indacaterol, a number of factors can be considered as potential contributors.
The inhaled route of administration is the preferred option in the vast majority of
cases for 2-adrenoceptor agonists to maximise bronchodilator activity whilst
minimising the compound exposure to the systemic circulation. In the clinical
setting, the ability to deliver efficacy with an acceptable separation from doses
that are associated with significant 2-adrenoceptor-mediated systemic side effects
is one of the key factors in defining the human dose [44]. Additionally for inhaled
compounds, increasing the delivered dose typically leads to increases in the duration of effect. Combining the above observations indicates that the separation of
bronchodilating doses from doses that produce an unacceptable level of systemic
2-adrenoceptor activation also provides a further opportunity to extend the duration of action for an inhaled compound. Agents with a larger separation offer the
potential to increase the duration of action, beyond the intrinsic duration of action,
with relatively higher doses, if required. Alternatively, such agents offer the
potential to deliver a greater safety margin, in addition to a long duration of effect,
when they also possess a particularly long intrinsic duration of action. Applying this
rationale potentially allows an understanding of the large preclinical differences
seen in the intrinsic duration of action measurements observed between the clinically similar 2-adrenoceptor agonists salmeterol and formoterol [45]. In the case of
indacaterol, it is both the long intrinsic duration of action in combination with the
large separation between the doses delivering bronchodilation from those producing systemic 2-adrenoceptor-mediated side effects that leads to the excellent
clinical duration of action and favourable safety profile.

The Design of the Indacaterol Molecule

61

Fig. 9 The expanded plasmalemma diffusion microkinetic theory highlighting the potential for
increased indacaterol levels in the raft caveola proximal to the 2-adrenoceptor. Adapted from Eur J
Pharm Sci, Vol 38, Lipid membrane interaction of indacaterol and salmeterol: do they influence their
pharmacological properties?, pages 533547, Lombardi D, Cuenoud B, Kramer SD. Copyright
2009, with permission from Elsevier

Several pharmacokinetic factors can be anticipated to contribute to a more


favourable separation of the bronchodilating properties from the systemic 2adrenoceptor-mediated side effects, and these are outlined below. Protein binding
is one such factor where higher levels will lead to a reduced circulating free fraction
of the compound being available for receptor activation. The effect of this is to
buffer the pharmacological activity of the 2-adrenoceptor agonist redistributing
from the lung [46, 47]. Additionally, rapid clearance from the systemic circulation
can also be considered as a way to help minimise systemic 2-adrenoceptormediated side effects. The rapid elimination of the parent drug, or rapid metabolism
to produce metabolites of reduced 2-adrenoceptor activity, would also help to
minimise the impact of the compound redistributing from the lung [15]. A further
example of this is the formation of the phenolic glucuronides of formoterol and
indacaterol, which have been shown to be devoid of 2-adrenoceptor activity [3,
48]. However, a high level of plasma protein binding is antagonistic towards a high
clearance rate, because clearance mechanisms are typically thought to act only on
the unbound drug that is free from protein binding. The consequence of this is that
high levels of plasma protein binding will also protect a compound from metabolism and elimination, so as to reduce the rate of in vivo clearance. Therefore, the
overall impact of the drug redistributing from the lung into the systemic circulation
will be impacted upon by opposing pharmacokinetic parameters, and it is the
balance between these parameters that will dictate how they impact upon the
therapeutic index. As shown in Table 4, the plasma protein binding predicted for

62

R.A. Fairhurst et al.

indacaterol, from the human serum albumin binding data, is at the higher end of the
range for the established 2-adrenoceptors agonists and is in good agreement with
the value determined using an ultracentrifugation method [3, 49].
Distribution effects are another possibility for influencing the side-effect profile
of inhaled 2-adrenoceptor agonists, on both the macro- and microscopic scales. On
the macroscopic scale, there is interorgan distribution, where preferential distribution into lung tissue would lead to sustained concentrations of compound at the
targeted site of action, and reduced/delayed systemic redistribution. Such preferential lung distribution, as assessed by whole lung levels, has been observed for a
number of lipophilic bases in lower species [50]. Indacaterol, and other long-acting
2-adrenoceptor agonists, as lipophilic bases, should also benefit to varying degrees
from this preferential lung distribution effect. On the microscopic scale are intraorgan and intracellular distribution, where increased distribution into specific
organelles, or intracellular regions, favouring lung retention and/or bronchodilation
could assist in increasing the separation from doses at which undesired systemic
side effects are observed [51]. Such an effect has already been described above in
the context of onset and duration of action, where indacaterol exhibits a greater
preference for distribution into the lipid-raft regions, proximal to the 2adrenoceptor, when compared to salmeterol. Each of the above factors is not
anticipated to be exclusive to impacting only the therapeutic index of agents applied
topically to the lung. In particular, the latter two were also considered as positive
attributes for increasing the intrinsic duration of action of a molecule, which as
discussed above is also linked to the safety profile.

9 Conclusion
Following a hypothesis that lipophilicity is a key factor in regulating the duration
and onset of action, profiles of inhaled 2-adrenoceptor agonists enabled the rapid
identification of indacaterol from a novel 8-hydroxyquinolinone and indan-derived
chemical series. The 5,6-diethyl analogue indacaterol was first synthesised in
September 1998, and preclinical profiling revealed a high probability for the
compound to satisfy the targeted product profile of intermediate potency, an
intrinsic efficacy greater than salbutamol, a rapid onset of action, a long duration
of action and a favourable therapeutic index compared to the key reference
compounds. Additionally, the uniqueness of the preclinical profile of indacaterol
was established by comparison with close structural analogues and also with
analogues derived from the combination of the 5,6-diethylindan amino substituent
of indacaterol with the most commonly employed catechol mimetics. Following the
establishment of a good preclinical safety profile, indacaterol was promoted as the
first development candidate from the Novartis ultra-long-acting 2-adrenoceptor
agonist project in March 2000.

The Design of the Indacaterol Molecule

63

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The Early Clinical Development


of Indacaterol
Jutta Beier and Kai M. Beeh

Abstract Indacaterol is a novel once-daily 2-adrenoceptor agonist developed for


the treatment of obstructive airway diseases. While indacaterol is now approved for
the maintenance treatment of chronic obstructive pulmonary disease (COPD) in
several countries worldwide, the early clinical development of indacaterol was
conducted in both asthma and COPD patients. During these early clinical studies,
the bronchodilator profile of action on patients with established airflow obstruction
was investigated, including duration and onset of action, optimal dosage and
delivery, and safety. The early clinical development of indacaterol confirmed
preclinical data characterizing indacaterol as a long-acting 2-agonist with a
sustained 24 h duration of bronchodilation, thus suitable for once-daily dosing, a
rapid onset of action and a favourable safety profile over a range of dosages and
delivery modes, both in asthma and COPD patients of various severities.

1 Introduction: Rationale for Long-Acting -Agonists


in the Treatment of Asthma and Chronic Obstructive
Pulmonary Disease
Inhaled 2-adrenoceptor agonists are the most effective bronchodilators for the
management of moderate to severe asthma, and their importance for achieving
asthma control in these patients in combination with inhaled corticosteroids (ICS) is
supported by current Global Initiative for Asthma (GINA) guidelines [1]. Currently
available inhaled long-acting -agonists (LABAs) effect bronchodilation for
approximately 12 h at recommended doses, necessitating twice-daily dosing to
provide optimal clinical efficacy [2]. The availability of a once-daily 2-agonist
therefore represents a potential improvement in the treatment of asthma, providing
J. Beier K.M. Beeh (*)
Insaf Respiratory Research Institute GmbH, Biebricher Allee 34, 65187 Wiesbaden, Germany
e-mail: k.beeh@insaf-wi.de
A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy,
DOI 10.1007/978-3-0348-0709-8_4, Springer Basel 2014

67

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J. Beier and K.M. Beeh

patients with sustained bronchodilation, greater convenience and, possibly,


improved adherence and clinical outcomes.
In contrast to asthma, current chronic obstructive pulmonary disease (COPD)
guidelines emphasize the role of long-acting bronchodilators, which are
recommended to be used early on, whereas anti-inflammatory treatment with,
e.g. ICS is reserved for specific subgroups in more advanced stages [3]. While in
moderate COPD, monotherapy with a long-acting bronchodilator is preferable,
different classes of bronchodilators can be combined in severe or very severe
COPD. Until the introduction of indacaterol, these agents included the twicedaily 2-agonists, formoterol and salmeterol, and the once-daily anticholinergic,
tiotropium. There is now ample evidence that long-acting bronchodilators improve
lung function, symptomatology, quality of life, exercise tolerance, frequency and
severity of exacerbations and potentially mortality in COPD [46], mainly as a
result of prolonged bronchodilation and reduction of both static and dynamic
hyperinflation. Once-daily anticholinergics have also been shown to produce clinically superior effects when compared to short-acting agents with multiple daily
doses [7] and appear superior to a twice-daily -agonist in regard to reducing the
risk for COPD exacerbations [8], therefore supporting the validity of the concept of
once-daily, sustained bronchodilation to further improve clinical outcomes
in COPD.
A reduction of dosing frequency for inhaled therapies to a required minimum is
an important goal to eventually simplify the management of chronic airway
diseases like COPD or asthma. Once-daily dosing of inhaled therapies has in the
more recent past been proven to represent a useful strategy in improving compliance, e.g. with the introduction of once-daily inhaled corticosteroids in asthma or
the once-daily bronchodilator tiotropium in COPD [9]. A once-daily regimen is also
preferred by most affected chronically ill patients [10].
Finally, there is evidence that the onset of bronchodilation plays an important
role in the relief of symptoms in both asthma and COPD [11, 12]. Therefore, the
clinical pharmacological profile of a new once-daily bronchodilator should ideally
include a fast onset of action, providing immediate relief of airflow obstruction and
related symptoms following inhalation.
With this background, it appears that the development of indacaterol as a novel,
rapid-acting once-daily 2-adrenoceptor agonist developed for the treatment of
asthma and COPD follows a sound scientific and clinical rationale. However,
while bronchodilator monotherapy is approved and recommended in COPD, such
a strategy must not be applied to asthmatics due to a potential increased risk of
asthma-related hospitalizations and deaths with LABA monotherapy [13]. Therefore, despite some of the early clinical data generated with indacaterol in the asthma
population, the current development of indacaterol in this disease is being
progressed using indacaterol in a fixed-dose combination with an inhaled
corticosteroid.

The Early Clinical Development of Indacaterol

1.1

69

Relevant Preclinical Data and Pharmacologic Profile

Indacaterol is an almost full 2-agonist with high intrinsic efficacy at the receptor
level [14]. In preclinical studies, a fast onset of action and longer duration of action
versus formoterol and salmeterol was also demonstrated [1416]. Pharmacokinetic
data taken during multiple-dose studies of indacaterol 400 or 800 g once daily for
14 days demonstrated rapid absorption and a mean elimination half-life of >30 h,
while in a single-dose study, doses between 600 and 2,000 g were rapidly absorbed
with maximum serum concentrations reached within 15 min [17, 18]. Steady state
after inhalation was reached within 12 days of once-daily dosing [19].

2 Early Clinical Development of Indacaterol


The early clinical development of indacaterol mainly faced the challenge to establish an optimal dose that could be carried forward to the phase III studies and to
identify the optimal formulation and inhaler device. During the early clinical
development programme of indacaterol in asthma and COPD, several hundreds
of patients therefore received indacaterol in various dosages and devices.

2.1

Bronchodilator Efficacy in Asthma

In studies with asthmatics, single doses of indacaterol produced significant and


sustained 24 h bronchodilation, with regard to trough forced expiratory volume in
1 s (FEV1) and forced vital capacity (FVC). The first clinical proof-of-mechanism
and dose-ranging study in asthma was performed using a metered dose inhaler
(MDI) at doses of 50, 100, 200 and 400 g. In this study published by Beeh
et al. [20], the mean percentage increases in FEV1 versus placebo with indacaterol
200 and 400 g delivered from an MDI were 7.6 and 14.9 % at 30 min and 7.5 and
10.4 % at 21 h postdose, respectively. Both doses were significantly superior to
placebo in improving FEV1 from as early as 5 min to 25 h postdose, inclusive,
whereas the lower doses were superior to placebo at most timepoints during the
26-h observation period.
The 24-h bronchodilator efficacy of indacaterol delivered via MDI was also
confirmed in persistent asthmatics, where indacaterol demonstrated a rapid onset of
action, with 200 and 400 g increasing FEV1 by 0.17 L at 5 min (400 g) and 0.21 L
at 10 min (200 g) compared with placebo [21]. LaForce et al. compared the singledose bronchodilator efficacy of indacaterol 150, 300 and 600 g delivered via
single-dose dry powder inhaler (SDDPI) to placebo and twice-daily formoterol
(12 g) in persistent asthmatics [22]. The 24-h trough FEV1 (primary endpoint) was
significantly higher than placebo following all doses of indacaterol (0.11, 0.21,

70

J. Beier and K.M. Beeh

0.22 L for 150, 300 and 600 g, respectively) and higher than formoterol for
indacaterol 300 and 600 g (0.08 and 0.09 L, respectively).
Finally, in a single-dose study by Sugihara et al. conducted in Japanese
asthmatics, all indacaterol doses (150, 300 and 600 g via SDDPI) showed significantly higher FEV1 area under the curve (2224 h) than placebo (treatment-placebo
differences of 180, 220 and 260 mL for indacaterol 150, 300 and 600 g, respectively). Compared with salmeterol, all indacaterol doses were superior from 5 to
30 min postdose, confirming the rapid onset of bronchodilation with
indacaterol [23].
Hence, these early studies in asthma indicated that indacaterol not only had a
long duration of action but also a rapid onset comparable to that of salbutamol or
formoterol, confirming preclinical pharmacological data.
During the multiple-dose, dose-ranging studies indacaterol was inhaled not only
in multiple doses but also different devices, i.e. a multiple-dose dry powder inhaler
(MDDPI) or a SDDPI. In a 7-day dose-ranging study by LaForce et al., all doses of
indacaterol (50, 100, 200, 400 g) produced significant bronchodilation over
placebo at 2224 h post-inhalation on days 1 and 7, respectively [24]. Significant
effects for all doses were already demonstrable at 5 min postdose on day 1. Of the
doses evaluated, 200 g once daily appeared to be optimum as shown by trough
FEV1 24-h postdose on days 1 and 7. This was further supported by a multiple-dose,
dose-ranging study by Kanniess et al. [25] and a 28-day safety study by Chuchalin
et al. [26]. Finally, indacaterol 200 g was also superior to salbutamol 200 g and
salmeterol 50 g in a single-dose study in persistent asthmatics [27]. Peak
bronchodilation in these studies was observed between 2 and 4 h postdose.
While indacaterol at different doses produces effective bronchodilation in
asthmatics, the further development of this drug in asthma was significantly
affected by the ongoing safety debate questioning the long-term safety of LABAs
as a general drug class in asthma, since some published studies suggested an excess
incidence of asthma-related mortality associated with the use of available twicedaily LABAs [13, 28], in particular when used as monotherapy. Although certain
aspects of these data have been criticized and debated [29], it is clear that LABA
monotherapy without concomitant anti-inflammatory therapy with inhaled
corticosteroids is discouraged in current asthma guidelines. Regulatory agencies
therefore have questioned whether these drugs should be approved as single-agent
inhalers in asthma at all due to the fear of incorrect use in this population without
appropriate anti-inflammatory treatment. Therefore, the further clinical development of indacaterol in asthma was taken forward in a fixed-dose single inhaler
combination with the once-daily inhaled corticosteroid mometasone [30]. Given the
large body of evidence supporting the clinical benefit of LABA/ICS fixed
combinations in asthma, such a novel combination product could considerably
improve the current treatment options for asthma.

The Early Clinical Development of Indacaterol

2.2

71

Bronchodilator Efficacy in COPD

Unlike in asthma, there is a clear role for bronchodilator monotherapy in COPD,


with guidelines recommend long-acting bronchodilators as first-line agents for
patients with moderate, severe and very severe disease stage. Thus, it is reasonable
that already the early clinical development of indacaterol had a strong focus
on COPD.
Similar to lung function data in asthmatics, single doses of indacaterol produced
rapid and sustained bronchodilation in patients with moderate to severe COPD.
Bauwens et al. compared the effect of single-dose indacaterol at three different
doses (150, 300 and 600 g via SDDPI) and formoterol 12 g bid on 24-h trough
FEV1. In their study, all doses of indacaterol resulted in larger trough FEV1 over
formoterol and placebo, with once-daily indacaterol at 600 g and 300 g also
being statistically significantly superior to twice-daily formoterol in terms of trough
FEV1 improvement [31].
Rennard et al. conducted a dose-ranging study of once-daily indacaterol 50, 100,
200 and 400 g via MDDPI for 7 days in COPD patients (prebronchodilator
FEV1  40 % of predicted) [32]. While on day 1 both indacaterol 200 and
400 g improved FEV1 by more than 120 mL (suggested as the minimal clinically
important difference), all doses of indacaterol were superior to placebo on day
7, with trough FEV1 values of 160230 mL versus placebo. There was also a clear
dose response in this study. Moreover, the study incorporated an open-label comparison with tiotropium 18 g once daily for 7 days. Although not truly a direct,
blinded comparison, the results of Rennard et al. [32] suggested superior peak (area
under the curve at 04 h postdose) and trough (area under the curve 2224 h
postdose) FEV1 values for indacaterol 200 and 400 g on days 1 and 7. Similar
observations were made in a study by Beier et al., although the primary endpoint of
this study was safety [33]. Nevertheless, using indacaterol 400 or 800 g versus
placebo over 28 days treatment duration, Beier et al. observed trough FEV1
improvements of 230 and 210 mL for 400 and 800 g, respectively, on day
14, and 220 and 210 mL for 400 and 800 g, respectively, on day 28 [33]. Similar
to observations in multiple-dose studies in asthmatics [26, 34], there was no
evidence of bronchodilator tolerance over the time period studied (up to 28 days).

2.3

Additional Clinical Outcomes in Early Phase Studies


in COPD

In COPD, outcomes beyond pure measures of airway calibre have become increasingly important during recent years, including symptoms like dyspnoea, hyperinflation and exercise tolerance [35]. The early clinical development of indacaterol
covered some of these outcomes, providing more exploratory data that lay the
foundation for large-scale phase III clinical trials. A study by Beier

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J. Beier and K.M. Beeh

et al. investigated the effect of single-dose indacaterol 300 g versus formoterol


12 g twice daily and placebo on airflow obstruction and resting hyperinflation
(inspiratory capacity) in patients with COPD [36]. In this study, indacaterol was
superior to formoterol twice daily in improving FEV1 at 8 and 24 h postdose and
also had marked superiority in improving resting inspiratory capacity at all
timepoints between 4 and 24 h postdose. In another placebo-controlled trial, the
effect of 14 days treatment with indacaterol 300 g once daily on resting hyperinflation, dynamic hyperinflation and exercise tolerance was studied by Beeh
et al. [37]. Using a constant-workload cycling ergometry protocol, indacaterol
reduced static hyperinflation, dynamic hyperinflation during peak and isotime,
exercise endurance time and exercise-induced dyspnoea at days 1 and 14 of treatment. While this small study generated important exploratory data, these results
were at later stages confirmed in a larger study over 3 weeks of treatment in COPD
patients [38]. Overall, these data clearly supported the concept of prolonged airway
patency through sustained bronchodilation as an important factor reinforcing lung
emptying and reduction of hyperinflation in COPD.

2.4

Safety and Tolerability

Safety studies with indacaterol addressed the occurrence of adverse events and
serious adverse events, cardiovascular safety and known class effects from betaagonists due to systemic absorption of drug, potentially leading to tachycardia,
palpitations, changes in ECG parameters (e.g. QT prolongation), hypokalaemia,
increase in blood glucose levels and adverse events like tremor or headache.
An initial single-dose study using supratherapeutic doses of indacaterol,
salbutamol and salmeterol in asthmatic subjects indicated a good overall safety
profile of indacaterol in regard to the most relevant clinically anticipated classrelated adverse effects [27]. Further, the effect of indacaterol at doses up to 600 g
once daily over 14 days on QTc values has been studied in a thorough QT study in
healthy subjects. All doses of indacaterol had no effect on mean QTc values and
changes were within the regulatory safety margin [39]. Finally, inhalation of
supratherapeutic single doses of indacaterol up to 3,000 g in COPD patients
revealed only minor systemic effects on vital signs, potassium levels or QTc
changes, thus confirming the wide therapeutic safety margin of single doses of
indacaterol [40].
Longer-term safety studies during the early clinical development of indacaterol
included three multiple-dose phase II trials primarily evaluating safety and tolerability of indacaterol, two in asthma [26, 34] and one in COPD [33]. All trials
incorporated a treatment duration of 28 days. However, the dosages of indacaterol
used and the multi-dose dry powder inhaler used to deliver the drug differ from the
currently marketed doses and single-dose dry powder inhaler device. In the study by
Yang et al. [34] and Beier et al. [33], indacaterol at once-daily doses of 400 and

The Early Clinical Development of Indacaterol

73

800 g SDDPI was investigated, whereas Chuchalin et al. [26] evaluated


indacaterol at doses of 200, 400 or 600 g daily.
In all studies, the overall incidence of adverse events was similar for active
treatment and placebo groups, and there was no dose-related increase in the
incidence of adverse events. The most common adverse event associated with
indacaterol use was cough, which was reported in 16.9 and 15.3 % of patients in
the indacaterol 400 and 800 g groups, respectively, in the study by Yang
et al. [34]; in 8.1, 17.1 and 10.3 % of patients in the indacaterol 600, 400 and
200 g groups, respectively, in the study by Chuchalin et al. [26]; and finally in 14.7
and 28.4 % of patients in the 400 and 800 g groups, respectively, in the study by
Beier et al. [33]. For typical class-related effects of -agonists, only modest effects
were observed. While Yang et al. reported small changes in postdose serum
potassium and glucose levels of asthmatic patients exposed to indacaterol 400 or
800 g [34], no effect on these parameters was observed in the study by Beier
et al. using the same doses in COPD patients [33]. In the study by Chuchalin et al. in
asthmatics, no effect of once-daily indacaterol 200, 400 and 600 g on potassium
and glucose levels was observed [26]. In this study, there were also no changes in
pulse rate, blood pressure or mean QTc interval after 28 days exposure to
indacaterol. However, there was a small, statistically significant increase of the
QTc interval (8.9 ms) and pulse rate (4.9 beats per minute) with the 800 g dose
(n 59) on day 28 in the study by Yang et al., but these changes were numerically
small and not clinically significant [34]. Again, none of these effects were observed
by Beier et al. in the study using indacaterol 400 and 800 g once daily in COPD
patients [33].
In light of the currently approved doses for indacaterol once daily (150 and
300 g in the European Union, 150 g in Japan, 75 g for the United States and
Canada), the overall safety data generated during the early clinical development of
indacaterol suggested a favourable tolerability profile and a wide therapeutic
window of indacaterol.

3 Summary
Indacaterol is a novel, fast-acting once-daily inhaled LABA approved for the
treatment of COPD and under clinical development (as fixed combination with a
once-daily inhaled corticosteroid) in asthma. Early clinical studies demonstrated
that indacaterol once daily produced rapid (within 5 min) and sustained (at least
24 h) bronchodilation in patients with COPD and asthma of various severities.
Multiple-dose exposure over several weeks treatment with different doses of
indacaterol confirmed the suitability of the drug for once-daily dosing, with a
favourable overall safety profile and lasting efficacy without evidence of development of tolerance. Indacaterol was effective over a wide range of dosages, delivered
through various inhaler devices. In addition to improvements in airway calibre,
early clinical studies in COPD also demonstrated that indacaterol improved static

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J. Beier and K.M. Beeh

and dynamic hyperinflation, and these changes were associated with improvements
in exercise tolerance and exercise-induced dyspnoea. Studies involving active
comparator drugs confirmed equal or superior clinical efficacy of indacaterol over
available drugs. These early data finally provided important evidence to support the
selection of device and dosages for the large-scale phase III clinical trial
programme in COPD [41], where doses of 75, 150 and 300 g delivered via
SDDPI were investigated for long-term efficacy [4244], with an additional dose
of 600 g studied for long-term safety [45].

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24. LaForce C, Alexander M, Deckelmann R, Fabbri LM, Aisanov Z, Cameron R et al (2008)
Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: a 7-day
dose-ranging study. Eur J Allergy Clin Immunol 63:10311
25. Kanniess F, Cameron R, Owen R, Higgins M (2008) Indacaterol, a novel 24-hour 2-agonist,
demonstrates 24-hour efficacy and is well tolerated in patients with asthma. A multiple-dose,
dose-ranging study. J Asthma 45:88792
26. Chuchalin A, Tsoi AN, Richter K, Krug N, Dahl R, Luursema PB et al (2007) Safety and
tolerability of indacaterol in asthma: a randomized, placebo-controlled 28-day study. Respir
Med 101:206575
27. Brookman L, Knowles LJ, Barbier M, Elharrar B, Fuhr R, Pascoe S (2007) Efficacy and safety
of single therapeutic and supratherapeutic doses of indacaterol versus salmeterol and
salbutamol in patients with asthma. Curr Med Res Opin 23:311322
28. Castle W, Fuller R, Hall J, Palmer J (1993) Serevent nationwide surveillance study comparison
of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. Br Med J 306:10347
29. Nelson HS (2006) Is there a problem with inhaled long-acting beta-adrenergic agonists? J
Allergy Clin Immunol 117:316
30. Bousquet J (2009) Mometasone furoate: an effective anti-inflammatory with a well-defined
safety and tolerability profile in the treatment of asthma. Int J Clin Pract 63:80619
31. Bauwens O, Ninane V, van de Maele B, Firth R, Dong F, Owen R et al (2009) 24-hour
bronchodilator efficacy of single doses of indacaterol in subjects with COPD: comparison with
placebo and formoterol. Curr Med Res Opin 25:46370
32. Rennard S, Bantje T, Centanni S, Chanez P, Chuchalin A, DUrzo A et al (2008) A doseranging study of indacaterol in obstructive airways disease, with a tiotropium comparison.
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33. Beier J, Chanez P, Martinot JB, Schreurs AJM, Tkacova R, Bao W et al (2007) Safety,
tolerability and efficacy of indacaterol, a novel once-daily2-agonist, in patients with COPD:
a 28-day randomised, placebo-controlled clinical trial. Pulm Pharmacol Ther 20:7409
34. Yang WH, Martinot JB, Pohunek P, Beier J, Magula D, Cameron R et al (2007) Tolerability of
indacaterol, a novel once-daily 2-agonist, in patients with asthma: a randomized, placebocontrolled, 28-day safety study. Ann Allergy Asthma Immunol 99:55561
35. Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ et al (2008) Outcomes
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of indacaterol and formoterol in patients with COPD. Pulm Pharmacol Ther 22:4926
37. Beeh KM, Wagner F, Khindri S, Drollmann AF (2011) Effect of indacaterol on dynamic lung
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Effect of indacaterol on exercise endurance and lung hyperinflation in COPD. Respir Med
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bronchodilator, in subjects with COPD. Int J Clin Pharmacol 49:15361
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Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless
design. Pulm Pharmacol Ther 23:16571
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and Efficacy of indacaterol, a novel long-acting beta 2-agonist, in subjects with COPD: a
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disease: results from 2 double-blind, placebo-controlled 12-week studies. Clin Ther
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once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in
COPD. Thorax 65:4739

INHANCE: An Adaptive Confirmatory


Study with Dose Selection at Interim
David Lawrence, Frank Bretz, and Stuart Pocock

Abstract Adaptive designs use accumulating data to modify aspects of the study
without undermining its validity and integrity. There are key practical and statistical issues that must be considered when planning an adaptive design, for example,
controlling the Type I error rate, prespecifying the adaptation criteria, and setting
up well-organised procedures to maintain data confidentiality at interim analyses.
The number of adaptations should be limited, preferably to just one in the confirmatory setting. There are several possible types of adaptation; this chapter focuses
on a pivotal confirmatory two-stage adaptive design with dose selection at interim,
illustrated by the INHANCE study. This comprised a dose-finding stage with dose
selection after 14 days of treatment, and a second stage evaluating efficacy and
safety during 26 weeks of treatment. An independent data monitoring committee
(DMC) selected two indacaterol doses (out of four) based on predefined decision
rules and review of unblinded results from an interim analysis. The decision rules
were based on trough (24 h post-dose) and early (14 h post-dose) bronchodilator
effect after 14 days, and safety data. Selected doses were continued into the second,
26 weeks, stage. The INHANCE study provides a successful example of the use of
an adaptive design in the confirmatory setting.

D. Lawrence (*)
Novartis Pharmaceuticals Corporation, New Jersey, USA
e-mail: David-1.Lawrence@novartis.com
F. Bretz
Novartis Pharma AG, Basel, Switzerland
S. Pocock
London School of Hygiene and Tropical Medicine, London, UK
A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy,
DOI 10.1007/978-3-0348-0709-8_5, Springer Basel 2014

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1 Introduction
By 2006 the safety, tolerability, pharmacokinetics, and efficacy of inhaled
indacaterol following single and multiple doses (once a day [o.d.] for up to
28 days) had been investigated in an extensive phase I and II programme involving
patients with asthma or chronic obstructive pulmonary disease (COPD). At that
time approximately 1,850 patients with asthma or COPD had been exposed to at
least one dose of indacaterol, with approximately 850 COPD patients having
received at least one dose of indacaterol at single doses up to 3,000 g and repeated
doses of 50800 g o.d. for treatment periods of 728 days. These studies had
demonstrated that indacaterol was an effective bronchodilator, with rapid onset of
action and with bronchodilator efficacy still apparent 24 h post-dose. Indacaterol
was generally well tolerated and demonstrated a good overall safety profile. Doses
of 200 and 400 g o.d. had been selected at the end of phase II for full development
in COPD in phase III. However, on scaling production up from small-scale phase II
supplies to larger-scale phase III supplies, the characteristics of the indacaterol
powder changed. As a consequence, the results of the phase II dose-ranging studies
could no longer be directly applied to the selection of doses for the phase III
programme. Therefore the decision was made to repeat dose-ranging using the
new formulation of indacaterol. As conducting a traditional dose-ranging study
would result in a significant delay to the start of the phase III programme, instead a
pivotal trial was conducted in two stages with an adaptive design that included this
dose-ranging work. To our knowledge this was the first time that such an adaptive
design was included as part of the registration of a new molecular entity.

2 Adaptive Trial Designs


Adaptive designs use accumulating data to modify aspects of the study without
undermining the validity and integrity of the trial [1]. Validity involves the statistical properties of the trial related to inference and estimation, i.e. providing correct
statistical inference (by ensuring strong control of the Type 1 error rate and the
calculation of adjusted p-values, estimates, and confidence intervals, assuring
consistency between different stages of the study and minimising statistical bias).
Trial integrity is primarily about transparency and trial conduct acceptable to the
intended external audience, i.e. providing convincing results to a broader scientific
community; pre-planning, as much as possible; basing any study changes on
intended adaptations and maintaining confidentiality of data while the study is
ongoing.
Not all drug development programmes are candidates for inclusion of an adaptive design. Feasibility considerations for use of these designs include the length of
follow-up time for the endpoint used for selection compared with duration of
enrolment. A shorter follow-up will be more conducive to an adaptive design as

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79

it allows early decision-making, whereas using such a design may not be appropriate for a relatively long endpoint follow-up period. Indacaterol is known to reach
pharmacodynamic steady state after 2 weeks of treatment (with respect to forced
expiratory volume in 1 s, FEV1); this time point is early in comparison with typical
recruitment times in COPD studies thus making the compound suitable for use in an
adaptive design.
There are a number of other key factors to be considered when contemplating an
adaptive design for a confirmatory phase III study. Adaptive designs may only be of
benefit if sufficient evidence is expected as compared to a non-adaptive strategy
(e.g. with a phase II dose-ranging trial that is followed by a separate phase III trial).
Thus, before embarking on an adaptive trial design, it needs to be ensured that the
totality of information is sufficient to support a submission at the end of phase III.
That is, necessary information on safety, regimen, mode of application, endpoint of
interest, etc., which is needed for a successful phase III programme, must be
collected either before or in parallel with the adaptive design trial.
There are many kinds of adaptation possible but in this chapter we focus on a
pivotal confirmatory two-stage adaptive design with dose selection at interim. This
design aims at addressing two objectives by a single, uninterrupted study conducted
in two stages, which otherwise would have been addressed by two separate studies.
Under the adaptive design, one (or more) dose level(s) are selected using data from
the first stage reviewed at an interim analysis. These dose(s) are then carried
forward to the second stage. The final analysis of the selected dose(s) includes
data from both stages, and is performed in such a way that the validity of the
conclusions is maintained [2].
As this type of study is used for pivotal confirmation of efficacy and safety, it
will be submitted to regulatory agencies. Regulatory agencies are more cautious
about adaptive designs for confirmatory trials than for exploratory trials [3]. This
arises from their concerns over trial validity and integrity, for example, due to
potential information leak (i.e. unblinding of patients or investigators to study
results before final database lock) and due to the ensuing adaptations, introducing
operational bias and therefore compromising trial integrity [4]. This caution is
understandable, since confirmatory trials assume a considerable body of
pre-existing information and limit sponsor options in dealing with uncertainties.
The adverse impact of moving forward (i.e. approval) with an ineffective or unsafe
product is much greater at this stage than at earlier stages of drug development. As a
result, regulators want scientific assurance that the proposed adaptive design has the
desirable property of a confirmatory trial and is not proposed purely to save trial
cost and time at the possible expense of scientific rigour. It is, therefore, not
surprising that both the European Medicines Agency (EMA) and the US Food
and Drug Administration (FDA) have produced guidances on adaptive designs [5,
6]. EMA and FDA guidances are aligned with clear common areas for attention:
Type I error rate control, rigorous planning, data confidentiality at interim analyses
as well as a limited number and frequency of adaptations (preferably limited to only
one type of adaptation in a confirmatory, i.e. phase III trial).

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In the confirmatory setting, hypotheses about the potential beneficial effect for a
new therapy have to be prespecified in the study protocol and need to be confirmed
at the study end using proper statistical analysis methods [2].
As mentioned above all adaptive clinical trials should ensure the integrity of the
experiment and the validity of the conclusions. This requires rigorous planning that
needs enough lead time to allow careful discussion and extensive simulations of
different scenarios. Thus, the assumption that the use of an adaptive design requires
less upfront planning is totally false. In fact, the opposite is true, as researchers will
need time to conduct extensive simulations to ensure that the proposed adaptations
will lead to a design with the desired operating characteristics (e.g. with stage
1 providing the kind of, and quality of, data to facilitate a clear selection of doses for
stage 2) and for discussions between the sponsor and external advisors as well as
regulators and the DMC themselves. An illustration of the timeline and potential
interactions required to plan a two-stage adaptive design are shown in Fig. 1.
As the indacaterol adaptive design was to be used for registration purposes, it
was designed very carefully with input from sponsor and external advisors as well
as from regulatory agencies.
The additional time spent in upfront planning can often lead to major savings, if
not in the specific study time, to the overall development time. This was the
rationale that led to the use of the adaptive design in the indacaterol development
programme: it was calculated that its use would cut 6 months from the time to
submission as compared to a traditional development programme with separate
phase II dose-ranging and phase III pivotal studies.

3 INHANCE: A Two-Stage Confirmatory Adaptive Design


INHANCE was a multinational, multicenter, double-blind, double-dummy, adaptive, parallel group study design with blinded formoterol and open-label tiotropium
as active controls in patients with COPD. The study was split into 2 stages. The
study was adaptive in that it consisted of a first period of treatment which allowed
selection of two from four indacaterol doses at an interim analysis (based on data
from the first 14 days of treatment) to continue into a second stage where efficacy,
safety and tolerability of the two selected doses could be confirmed in comparison
to active and placebo comparators over a total of 26 weeks. It was one of the pivotal
confirmatory trials used to support registration of indacaterol. The overall aim of
the trial was to provide confirmation of efficacy, safety and tolerability of the
selected doses of indacaterol. The study design is shown in Fig. 2, where the two
selected indacaterol doses in stage 2 (which could be any two of the four indacaterol
doses from stage 1) are denoted as A and B.
The study had three main objectives, classified as primary, key secondary and
important secondary objectives. Additional secondary and exploratory efficacy and
safety objectives were also prespecified in the protocol. The primary objective of
the study as whole (i.e. over stages 1 and 2) was to demonstrate superiority of at

INHANCE: An Adaptive Confirmatory Study with Dose Selection at Interim

FPFV
Protocol
Development

DMC Charter
Development

Internal
discussion
Informal
expert input
RA interaction

Internal
discussion
Informal
expert input
RA interaction
DMC
interaction

IA DBL &
DMC dose
selection
Stage 1
Recruitment
Detailed IA
plan written

81

Final
DBL
Stage 2

Recruitment
Reporting

Fig. 1 Study activity timeline for a two-stage adaptive design. RA regulatory agency, IA interim
analysis, FPFV first patient first visit, DBL database lock

Fig. 2 Study design of the confirmatory adaptive trial. b.i.d bis in die (twice a day)

least one dose of indacaterol selected in stage 1 versus placebo with respect to 24-h
post-dose (trough) FEV1 after 12 weeks of treatment in patients with COPD. The
key secondary objective was to demonstrate non-inferiority of at least one of the
selected doses of indacaterol versus tiotropium with respect to 24-h post-dose
(trough) FEV1 following 12 weeks of treatment. The important secondary objective
was to evaluate the effect of the two selected doses of indacaterol on the percentage
of days of poor control reported over the 26-week randomised treatment period, as
compared to placebo.
The study population consisted of a representative group of male and female
patients aged 40 years or above, with a smoking history of at least 20 pack years and
a diagnosis of moderate-to-severe COPD [7]. Patients were not enrolled if they had
been hospitalised for a COPD exacerbation within 6 weeks prior to screening, had
received oral corticosteroids in the month prior to screening or had a history of
asthma. Patients with co-morbid conditions could be included, but not if that
condition might compromise patient safety, interfere with evaluation or preclude
completion of the study.

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During stage 1 patients were randomly assigned in a 1:1:1:1:1:1:1 allocation


ratio using an automated interactive system to receive either open-label tiotropium
18 g o.d. or one of the following six double-blind, double-dummy treatments:
indacaterol 75, 150, 300 and 600 g o.d.; placebo and formoterol 12 g b.i.d.
The primary aim of stage 1 of the trial was to determine the risk-benefit of the
four indacaterol doses (based on efficacy and safety results in a pre-planned interim
analysis) in order to select two doses to carry forward into the second stage of the
trial.
The interim analysis was planned to be performed when 770 patients (approximately 110 evaluable patients from each of the seven treatment groups) from stage
1 had each completed at least 2 weeks of treatment. This required approximately
805 patients to have been randomised (allowing a dropout rate of 5 %). This sample
size was calculated to ensure that at least one of the two doses selected for stage
2 would be efficacious with probability of at least 75 % (see Sect. 4 in this chapter
for details on the interim selection rules).
From the date of the 805th patient completing 2 weeks of treatment until the dose
selection had been made at interim analysis, enrolment and randomisation was
suspended but patients already on treatment continued until dose selection was
complete.
Spirometry for the interim analysis (FEV1 and forced vital capacity, FVC) was
performed 50 and 15 min before dosing of trial treatment and at 5 and 30 min and
1, 2, 4 and 23 h 10 min and 23 h 45 min post-dose (based on the time of morning
study drug administration) on days 1 and 14. Electrocardiogram [ECG for heart rate
and corrected QT (QTc) interval] was monitored and blood samples (to measure
serum potassium and blood glucose) were taken at 25 min pre-dose and at 30 min
and 1 h post-dose on days 1 and 14. All reported adverse events (AE) were noted.
A DMC independent of study conduct reviewed efficacy and safety data. Dose
selection was primarily based on predefined criteria comparing the efficacy of
indacaterol with placebo and the active controls (see Sect. 4), as well as safety
data. Based on the results of this analysis, two of the four indacaterol doses were
continued into stage 2 together with the tiotropium and placebo arms.
The DMC was an autonomous group of recognised experts in the respiratory and
statistical field. The DMC was appointed by the study sponsor but functioned
independently of all other persons involved with the study. The responsibilities of
the DMC were predefined as follows (1) to review and approve the DMC charter,
which set out responsibilities, functions, rules of conduct and the basis for
evaluating the interim analysis results; (2) to review the results of the interim
analysis; (3) to recommend two indacaterol doses to be evaluated in the second
stage and (4) to make recommendations on safety if warranted by the safety results.
An independent statistician (external to the sponsor) was appointed to produce
the interim analysis report and interact with the DMC. The independent statistician
had access to the clinical data and the treatment codes (labelled from A to G) but
not the actual treatment descriptions.
Following dose selection, patients randomised in stage 1 to the discontinued
indacaterol dose arms or formoterol continued treatment until a completion visit

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83

could be scheduled (no further scheduled study visits were carried out), where study
medication was stopped and collected and patients were prescribed therapy deemed
necessary to treat their COPD. Those patients randomised in stage 1 to the two
selected indacaterol doses, placebo or tiotropium continued on their assigned study
treatments into stage 2 of the study for a total of 26 weeks treatment.
The clinical trial team and the investigators were informed of the two chosen
doses of indacaterol following the interim analysis but remained blinded to any
other information including efficacy results arising from that analysis. Moreover,
patients, investigators and the clinical trial team remained blinded to the specific
treatments for any individual patient until the final database lock after completion
of stage 2.
In stage 2, sites recommenced recruitment, randomising patients to the two
chosen indacaterol doses, placebo and tiotropium in a 1:1:1:1 ratio. An additional
285 patients per treatment group were randomised until the total required number of
patients (400 per group) had been included. This number of patients was calculated
based on the requirement to have at least 85 % power for the key secondary
endpoint of non-inferiority of indacaterol versus tiotropium.
In the confirmatory setting control of the Type I error is fundamental to the
acceptability of an adaptive design. Indeed, Wang et al. [8] have suggested that a
strong control of the studywise Type I error rate should be the minimum criterion
for a trial to be considered adequate and well controlled, following common US
legal requirements [9]. In the INHANCE study, the final analysis consisted of
comparing the two selected dose groups with placebo and tiotropium on a
prespecified sequence of the primary, key and important secondary endpoints.
Evidence from both stages was combined in a rigid statistical hypothesis-testing
framework. In this study, a Bonferroni adjustment with a significance level /4 was
used for comparing each of the two dose groups against placebo, since the study
started with four indacaterol doses. Here, denotes the usual studywise significance
level acceptable for confirmatory trials (i.e. 0.05 for two-sided or 0.025
for one-sided hypotheses testing). The primary, key and important study objectives
were tested sequentially at level /4 in the prespecified hierarchy for each of the two
selected doses separately [10]. Because no other adaptation than dose selection was
performed at the interim analysis (in particular, no sample size reassessment was
foreseen), the combination of Bonferroni adjustment and hierarchical testing
guarantees a strong control of the studywise Type I error rate at level . The
Type I error rate is controlled regardless of how the two doses were selected,
allowing for the decision-making committee to weigh in both efficacy and safety
information [2]. Note that more powerful approaches could have been applied, but
were not chosen because of the complexity of the trial design.

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4 Dose Selection Guidelines


One of the most important issues in adaptive designs for confirmatory clinical trials
is an adequate separation of the decision-making committee (in this case, the DMC)
from the project team, i.e. there should be no sponsor involvement in the decisions
made at the end of stage 1 of a confirmatory adaptive design. Therefore there is a
need to prespecify the process by which any decision will be made by this external,
independent DMC, with an algorithm for determining the adaptation specified and
agreed in advance. This is usually accomplished by creating a DMC charter [11].
For the INHANCE study, a set of dose selection guidelines for a variety of
possible interim analysis scenarios was compiled and included in the DMC charter.
These are discussed in detail in this section. As mentioned at the end of Sect. 3, the
use of appropriate statistical methods allowed the DMC to deviate from these
guidelines if necessary (mainly in case of unexpected results, such as unforeseen
safety signals or lack of dose response) and select the doses on its own.
The DMC was asked to select two adjacent doses (i.e. either 75 and 150 g,
150 and 300 g or 300 and 600 g) based on numerical comparison of the adjusted
(least squares) means from the seven treatment groups, obtained by a predefined
mixed-effects model. This model contained treatment as a fixed effect with the
baseline FEV1 measurement and components of short-acting 2 adrenoceptor agonist and anticholinergic reversibility. Additionally, to reflect the randomisation
scheme, the model also included smoking status (current/ex-smoker) and country
as fixed effects with centre nested within country as a random effect. No inferential
methods were formally used to select the two doses of indacaterol.
The differences in adjusted means of each indacaterol dose versus placebo were
compared with two thresholds. The first dose selected should be the lowest dose that
met the criteria based on both thresholds and the next higher dose (unless the 600 g
dose was selected, in which case the 300 g dose had to be chosen as the second
dose). The thresholds were defined as:
Xbased on trough FEV1 after 2 weeks of treatment and defined as the
maximum of:
Minimum clinically important difference (MCID), prespecified as 120 ml
Adjusted mean effect of formoterol versus placebo
Adjusted mean effect of tiotropium versus placebo
Ybased on FEV1 area under curve (AUC)(14 h) after 2 weeks of treatment and
defined as the maximum of:
Adjusted mean effect of formoterol versus placebo
Adjusted mean effect of tiotropium versus placebo
These criteria reflected the overall profile of bronchodilation over time by
including indicators of peak/early (14 h) and trough (24 h post-dose) effect.
Trough FEV1 was defined as the average of two FEV1 measurements taken 23 h

INHANCE: An Adaptive Confirmatory Study with Dose Selection at Interim

85

Table 1 Possible interim analysis outcomes and decisions


Possible outcome
More than one dose beats X and Y
One dose beats X and Y
More than one dose beats X but not Y
One dose beats X but not Y
More than one dose beats Y but not X
One dose beats Y but not X
One dose beats X but not Y and one dose
beats Y but not X
No dose beats X or Y

Decision
Select lowest dose that beats X and Y and the next
higher dose
Select this dose and the next higher dose
Select the dose that beats X and is closest to Y, and
the next higher dose
Select this dose and the next higher dose
Select the dose that beats Y and is closest to X, and
the next higher dose
Select this dose and the next higher dose
Select the dose that beats X and the next higher dose
Select the dose that is closest to X and the next
higher dose

10 min and 23 h 45 min post-dose after 2 weeks of treatment. AUC for FEV1 was
calculated between 1 and 4 h post-morning dose and standardised with respect to
time. To remove any possible impact or bias due to fast onset (since indacaterol is
known to have a faster onset of action than tiotropium), the FEV1 AUC was
measured over 14 h to exclude the first hour of bronchodilator effect, rather than
using the more common starting point of 0 h. The preset efficacy criteria for trough
FEV1 started at the level of 120 ml versus placebo. This level has been routinely
prespecified in clinical studies with indacaterol as representing a clinically relevant
level of bronchodilation that would ideally be demonstrated 24 h following dosing.
The preference was for the selected lowest dose to exceed both thresholds.
Depending on the results at the interim analysis, a number of dose selections
were possible. These were outlined in the DMC charter and are shown in Table 1.
As can be seen from the last row of Table 1, a futility stop was not foreseen,
although the DMC were empowered to recommend this if the data pointed this way.
We illustrate Table 1 with a hypothetical example in Fig. 3. In this example the
threshold for trough FEV1 is driven by the comparison of tiotropium versus
placebo, and the threshold for AUC 14 h is driven by the comparison of formoterol
to placebo. The lowest dose that exceeds both thresholds is the 300 g dose and
therefore the expectation would be that this dose and the 600 g dose (the next
higher) would be selected to continue into stage 2.
As well as results from efficacy analyses (primarily based on trough FEV1 and
AUC 14 h but also including FVC and peak FEV1), safety data was also presented
to the DMC to include in its deliberations. Safety analyses were based on AE and
serious AE incidences, serum potassium and blood glucose at each post-baseline
time point (including minimum serum potassium and maximum blood glucose),
pulse rate at each post-baseline time point (including maximum pulse rate), QTc
interval (according to Bazetts and Fridericias formulae) at each post-baseline time
point (including maximum QTc interval), ventricular rate at each post-baseline time
point, investigators overall ECG interpretation and the overall number of COPD
exacerbations.

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Difference from placebo (mL)

Trough FEV1 (X)

threshold

MCID

(1h-4h)

For

Ind 75

Ind 150

Ind 300

Ind 600

(Y)

Difference from placebo (mL)

FEV1 AUC

Tio

threshold

MCID

Tio

For

Ind 75

Ind 150

Ind 300

Ind 600

Fig. 3 Example (hypothetical) of interim analysis results and doses selected. MCID minimum
clinically important difference, Tio tiotropium, For formoterol, Ind indacaterol. In both panels the
circles are the mean treatment effect with the upper and lower boundaries of the 95% confidence
interval are represented by the arrows

The presentation of efficacy and safety data was agreed with the DMC prior to
the interim analysis to ensure as much as possible the DMC had all the information
they needed to make an expedited decision. At the time of the interim analysis, the
DMC received semi-blinded results from an independent statistician with treatment
group labelled from A to G and an envelope with decodes.
As well as the dose selection guidelines, a communication plan between the
DMC and the sponsor was included in the DMC charter. According to this plan, if
there were no complexities in the data and the DMC did not see any reason to
deviate from the predefined dose selection guidelines, the DMC chair was to inform
the sponsor of the recommended doses only, i.e. no comparative information was to
be given, with a statement that the dose selection guidelines had been followed.
Current regulatory guidance in more traditional monitoring settings, such as
group sequential designs, holds that sponsors should not have access to interim data
while trials are ongoing. One concern in the context of adaptive designs is that
unanticipated complexities might not fit a prespecified algorithm, such as unexpected safety signals, lack of monotone dose response or potential stop for futility.
Additionally, in some cases, such as in the INHANCE trial, the interim decision
could have major impacts on the sponsors business, and it is therefore in the
sponsors interest to have some limited role pre-planned in the DMC charter. For
the INHANCE study, the proposed interim decision rules in Table 1 were included

INHANCE: An Adaptive Confirmatory Study with Dose Selection at Interim

87

in the DMC charter with the understanding that the DMC had the discretion to
deviate from them as necessary. Any involvement of the sponsor should be based
on the following principles: a clear rationale for a sponsor involvement, sponsor
representatives properly distanced from trial operations, clear understanding by all
parties involved of the issues and potential risks and documentation of the processes
followed with restrictive firewalls put in place. The general aim should be a
minimal sponsor exposure sufficient to make decisions, meaning that the smallest
possible number of sponsor representatives should only get involved at the adaptation point with the minimally relevant information. Such an approach would
minimise the sponsors involvement and associated information leakage but still
guarantee the sponsors interest in case of unexpected emerging results [12, 13].
For the INHANCE study if the DMC were confronted with data that would result
in a deviation from the dose selection guidelines, the DMC were able to confidentially discuss the unblinded results with two senior members of the sponsor (who
were identified by role in the company in the charter and were not otherwise
involved in the study) to reach consensus on the doses chosen. If the consensus
deviated from the guidelines, the DMC would document an explanation of the
decision-making for possible future reference by regulatory agencies, but that was
to remain confidential while the trial was ongoing.

5 INHANCE Results
The results of the interim analysis have been published in full [14] as have those of
the final analysis [15]. Therefore they will only be briefly discussed here.
A total of 2,059 patients were randomised in 334 centres from 11 countries
during the study. Of these, 801 were included in the interim analysis, with 1,683
patients randomised (either in stage 1 or stage 2) to treatment in the four treatment
arms selected at interim.
Patient characteristics were similar across treatment arms, and there were no
differences between the patients randomised in the different stages in terms of
demographic and disease characteristics, as well as reversibility testing and baseline FEV1.

5.1

Key Interim Analysis Results Leading to Dose Selection

The primary variables for the interim analysis were trough FEV1 and FEV1
AUC(14 h) after 2 weeks of treatment. Treatment group comparisons for these
two primary variables are shown in Fig. 4.
The reference value for trough FEV1 was 140 ml (tiotropium versus placebo
difference) and for FEV1 AUC(14 h) was 220 ml (formoterol versus placebo). The
lowest dose to surpass both of these reference values was the indacaterol 150 g

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D. Lawrence et al.
Day 15 Trough FEV1

Day 14 FEV1 1-4h AUC

Difference from placebo (mL)

300

300

180

250
200


210

200

250

150

140
110

150


280

230

220

200

190

200
150

100

100

50

50
75


230

150

300

600

For

Tio

75

150

300

600

For

Tio

Indacaterol doses (g)

Active Control

Fig. 4 Interim analysis (stage 1) results. Tio tiotropium, For formoterol

dose, with the next higher dose being the 300 g. These are shown with ticks in
Fig. 4.
As mentioned in Sect. 4, the DMC was also provided with interim safety data
from the study as well as blinded interim safety data from another indacaterol
pivotal study that was ongoing at the same time. The DMC did not have any safety
concerns and so the indacaterol 150 g and 300 g doses were selected to continue
into stage 2 of the study, based on the guidelines specified in the DMC charter and
did not need any discussion with the sponsor. Therefore, no one from the sponsor
was aware of the interim results before final database lock.
On the same day as the DMC made the decision, the automated randomisation
system, which had been switched off during the preparation of the interim analysis
and the DMC review, was switched back on and randomisations could begin for
stage 2. This was made possible by the preparation of the possible randomisation
lists (i.e. lists containing (1) indacaterol 75 g, 150 g, tiotropium, placebo or
(2) indacaterol 150 g, 300 g, tiotropium, placebo or (3) indacaterol 300 g,
600 g, tiotropium, placebo) ahead of time. Again, this allowed the maximum
benefit to accrue to the study in terms of time to conclusion.

5.2

Final Analysis: Primary Endpoint

A comparison of the 24 h post-dose trough FEV1 after 12 weeks of treatment for the
four treatment arms continued into stage 2 is presented by treatment in Fig. 5.

INHANCE: An Adaptive Confirmatory Study with Dose Selection at Interim

89

Week 12 Trough FEV1


220
Difference from placebo (mL)

200

180

180

180

140

160
140

120
100
80

60
40
20

150

300

Tio

0
Indacaterol doses (g)

Tiotropium

Fig. 5 Trough FEV1 (ml) at Week 12: treatment comparisons versus placebo (stage 1 and
2 combined)

Reassuringly the results of the selected doses at interim were similar to those
seen for the same doses at the final analysis. The results of a supportive analysis to
assess the heterogeneity of the results of the primary endpoint (trough FEV1 at
12 weeks) for the four treatment arms (indacaterol 150 g, indacaterol 300 g,
tiotropium and placebo) are shown in Table 2.
These analyses suggest that the performance of three of the treatment arms
(indacaterol 150 g, placebo and tiotropium) was similar in both stages, while the
efficacy of indacaterol 300 g differed significantly between the two stages. However, the p-value of the treatment-by-stage interaction term (across all treatments)
approached, but did not reach, statistical significance ( p 0.068) suggesting that
this heterogeneity was a spurious result, occurring by chance rather than indicating
a systematic difference across the stages. This is further supported by the fact that
the characteristics of the patients in stage 1 and 2 in each treatment group were
relatively uniform.

6 Discussion
The use of an adaptive design in the indacaterol development programme provided
an opportunity for dose selection and pivotal confirmation of safety and efficacy in
the same clinical trial. Integrating the dose selection and confirmatory phases of
drug development in this way has a number of advantages, most obviously in the
lack of delay between the two phases and a faster overall drug development process.

90

D. Lawrence et al.

Table 2 Trough FEV1 (ml) at week 12: mean effect stage 1 versus stage 2
Treatment comparison
Ind 150 g
Ind 300 g
Tiotropium
Placebo

Stage 1 mean (l)


1.4677
1.5058
1.4070
1.2751

Stage 2 mean (l)


1.4646
1.4405
1.4241
1.2861

Difference (ml) (95 % CI)


3 (46, 52)
65 (16, 114)
17 (66, 32)
11 (61, 39)

p-value
0.900
0.009
0.493
0.662

The design makes efficient use of resources by reducing patients exposure to


potentially less effective or unnecessarily high doses. For the selected doses, the
data from both study stages contribute to the confirmatory analysis of the overall
study.
However, any adaptive design requires careful pre-planning and involves additional resources. In the confirmatory setting a DMC that is independent of the
sponsor is mandatory in order to avoid bias and ensure scientific integrity, while an
independent statistician dedicated to providing interim data analysis to the DMC
(with no other involvement in the study) was needed to avoid any risk of unintentional unblinding.
The adequacy of the interim dose selection procedure is critical to the success of
any such adaptive trial. Ideally, the endpoint(s) used at the interim analysis should
be the same as or shown to be strongly correlated with the final study primary
endpoint and should be recognised and accepted [16]. Here, trough FEV1 was both
a preset efficacy criterion for dose selection, measured after 14 days of treatment,
and the primary efficacy endpoint of stage 2 of the study, measured after 12 weeks
of the 26-week treatment period. FEV1 is widely used in COPD studies and is a
required endpoint for drug registration studies in COPD. Additionally the size of
stage 1 (100 patients per treatment arm) in this study meant confidence could be
placed in the decision-making and enabled a robust safety assessment as part of the
risk-benefit evaluation and had the consequence of reducing the time spent in
recruitment when randomisation was reopened after the interim analysis.
The use of an adaptive design is not without potential risk. The initial dosefinding period needs to be long enough for a thorough evaluation of effects. Two
weeks was considered a fully adequate period for indacaterol in which to attain
pharmacodynamic steady state. In the event, the differences in trough FEV1
between active and placebo treatments were maintained at the same or very similar
level at Week 2 and Week 26 for all the continuing treatment arms (Week 2 150
versus placebo 170 ml, 300 versus placebo 180 ml; Week 26 150 versus placebo
160 ml, 300 versus placebo 180 ml) [15].
In 2008 indacaterol was submitted to the European Union and the FDA with
approval requested for the two doses selected in the INHANCE study. In 2009,
indacaterol, at doses of 150 and 300 g once daily, was approved in the European
Union (EU). Since then these doses have been approved in more than 50 countries
worldwide for the treatment of COPD.

INHANCE: An Adaptive Confirmatory Study with Dose Selection at Interim

91

7 Conclusions
Adaptive designs have the potential to improve the efficiency of clinical drug
development [1719]. The goal of these designs is to increase the information
value generated per resource unit invested and thus ultimately to enable earlier
and better decision-making in the context of the overall clinical development plan.
However, the potential for improved efficiency comes at a price: compared with
more traditional trial designs, adaptive approaches require more work and additional effort during planning, implementation, execution and reporting.
In studies like INHANCE additional early planning is required compared with
the traditional separation of dose-finding and confirmatory stages, with careful
attention to the critical points of the decision process, the maintenance of blinding
and the independent personnel involved (DMC and statisticians) [12].
The unblinded interim results of an adaptive trial design need to inform the
future conduct of the remainder of the trial, without compromising its validity and
integrity. The INHANCE study provides a successful example of how this may be
achieved, by using stringent preset efficacy criteria to make a confident selection of
the most appropriate doses of indacaterol for long-term evaluation of efficacy.

References
1. Dragalin V (2006) Adaptive designs: terminology and classification. Drug Inf J 40:42535
2. Bretz F, Koenig F, Brannath W, Glimm E, Posch M (2009) Adaptive designs for confirmatory
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3. Wang SJ, Bretz F (2010) From adaptive design to modern protocol design for drug development: part I. Editorial and summary of Adaptive Designs session at the Third FDA/DIA
Statistics Forum. Drug Inf J 44:32531
4. Gallo P (2006) Confidentiality and trial integrity issues for adaptive designs. Drug Inf J
40:44550
5. CHMP (2007) Reflection paper on methodological issues in confirmatory clinical trials with an
adaptive design (CHMP/EWP/2459/02)
6. FDA (2010) Guidance for industry: adaptive design clinical trials for drugs and biologics (draft
Feb 2010). http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/
guidances/UCM201790.pdf
7. Global Initiative for Chronic Obstructive Lung Disease (2005). Global strategy for the
diagnosis, management and prevention of chronic obstructive pulmonary disease. NHLBI/
WHO workshop report. National Heart, Lung, and Blood Institute, Bethesda. http://www.
goldcopd.com/
8. Wang SJ, Hung HMJ, ONeil RT (2010) Impacts of type I error rate with inappropriate use of
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9. FDA (2002) Code of federal regulation, 21CFR314.126. Food and Drug Administration,
Health Human Services
10. Maurer W, Hothorn L, Lehmacher W (1995) Multiple comparisons in drug clinical trials and
preclinical assays: a-priori ordered hypotheses. In: Vollmar J (ed) Biometrie in der chemischpharmazeutischen Industrie. Fischer Verlag, Stuttgart, pp 318

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11. Orloff J, Douglas F, Pinheiro J et al (2009) The future of drug development: advancing clinical
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5:11924
13. Benda N, Brannath W, Bretz F, Burger HU, Friede T, Maurer W, Wang SJ (2010) Perspectives
on the use of adaptive designs in clinical trials. Part II. Panel discussion. J Biopharm Stat
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14. Barnes PJ, Pocock SJ, Magnussen H et al (2010) Integrating indacaterol dose selection in a
clinical study in COPD using an adaptive seamless design. Pulm Pharmacol Ther 23:16571
15. Donohue JF, Fogarty C, Lotvall J (2010) Once-daily bronchodilators for chronic obstructive
pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med 182:15562
16. Chow S-C, Chang M (2008) Adaptive design methods in clinical trialsa review. Orphanet J
Rare Dis 3:11
17. Bretz F, Branson M, Burman CF et al (2009) Adaptivity in drug discovery and development.
Drug Dev Rev 70:16990
18. Quinlan J, Gaydos B, Maca J, Krams M (2010) Barriers and opportunities for implementation
of adaptive designs in pharmaceutical product development. Clin Trials 7:16773
19. Krams M, Sharma M, Dragalin V et al (2009) Adaptive approaches in clinical drug development. Opportunities and challenges in design and implementation. Pharm Med 23:13948

Phase 3 Clinical Efficacy Studies: Lung


Function
Ronald Dahl

Abstract Indacaterol has a 24 h bronchodilatory effect, which allows the drug to


be effective with once-daily administration. The speed of onset of bronchodilation
after inhalation of indacaterol is as fast as that seen for salbutamol and formoterol.
Compared to placebo, significant improvements are seen 5 min after dosing.
Patients with COPD who received indacaterol 150 g or 300 g once daily in
large (n > 400), randomized, double-blind, placebo-controlled, multicenter phase
3 trials had a significantly higher mean trough FEV1 compared to placebo after
12 weeks treatment. The absolute differences in trough FEV1 between indacaterol
and placebo were 130180 ml and exceeded the predetermined clinically relevant
threshold of 120 ml in all trials.

1 Introduction
In clinical drug development, a compound may be selected for more definite
clarification of performance in phase 3 studies. These studies are performed when
smaller studies have given sufficient evidence for efficacy of a certain size and
shown a good safety profile. They are the most costly, time-consuming, and difficult
trials to design and perform especially for chronic conditions like COPD. Phase
3 trials are usually randomized, controlled, multicenter trials including large patient
number from 300 to 400 to several thousand patients. The studies are crucial
because they must give a definite result of efficacy preferably also compared to
reference recommended treatments. The pivotal phase 3 trials are those trials that
form the basis for the application to drug agencies for approval and label indication.
Between the time for application and approval additional studies are often done to
support and supplement the pivotal studies.

R. Dahl (*)
Allergy Centre, Odense University Hospital, Odense, Denmark
e-mail: Ronald.dahl2@rsyd.dk
A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy,
DOI 10.1007/978-3-0348-0709-8_6, Springer Basel 2014

93

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R. Dahl

The pivotal and supportive large clinical studies completed and published for
indacaterol have the acronyms INLIGHT 1 [1], INHANCE [2], INLIGHT 2 [3], and
INVOLVE [4] (pivotal studies) and INDORSE [5], INTENSITY [6], INTIME [7],
and INSIST [8] (supportive studies). All were randomized, parallel-group, placebocontrolled studies and had the same primary efficacy endpoint: 24 h post-dose
(trough) forced expiratory volume in first second (FEV1) after 12 weeks treatment,
except for INSIST, where this parameter was a secondary endpoint, and INTIME,
where the primary endpoint was trough FEV1 after 14 days.
The patient inclusion criteria were almost the same. Adults with an age of
40 years or more, with a clinical diagnosis of COPD (GOLD 2005) [9], and with
a smoking history of at least 20 pack years were recruited (for INTENSITY and
INSIST > 10 pack years). Patients should have post-bronchodilator FEV1 of
<80 % but 30 % of predicted normal value and a ratio FEV1/forced vital capacity
(FVC) of <0.70 within 30 min of inhalation of 400 g of salbutamol.
Patients could not participate if they had any recent respiratory tract infection,
were hospitalized for a COPD exacerbation within 6 weeks, or had a history of
asthma, any significant pulmonary disease, or cardiovascular abnormality.
Disallowed medications were the regular use of short- and long-acting 2-agonists,
short- and long-acting anticholinergic drugs alone or in any combination, xanthine
derivatives, and systemic corticosteroids. Patients were allowed regular
monotherapy with inhaled corticosteroid and inhaled salbutamol as a rescue
medication.
Randomization was stratified by smoking status to ensure the balance between
smokers and ex-smokers was the same in the treatment groups.
Presence or absence of reversibility to bronchodilators was not an entry
criterion.
In some studies, the % improvement in FEV1 was measured 30 min after
salbutamol and 60 min after ipratropium.
The inhaler device for indacaterol was the single-dose dry-powder inhaler
named Onbrez Breezhaler (see chapter The History and Performance of the
Breezhaler Device).
Across all of the studies, the mean age was 6364 years, and around 50 %
(3356 %) were present smokers. The use of ICS was around 50 % (3356 %).
Spirometry equipment was calibrated and spirometry was performed in accordance with American Thoracic Society/European Respiratory Society
standards [10].
In placebo-controlled studies, a difference of 120 ml in trough FEV1 between
indacaterol and placebo was prespecified as the minimal clinically important
difference for the improvement, based on present evidence from the literature
[1113].
In subsets of patients, serial FEV1 measurements were performed to look for
onset of action and magnitude and persistence of bronchodilation by expressing the
area under the FEV1 curve in different intervals.
Patients were given a diary to record morning and evening peak expiratory flow
(PEF; highest of three consecutive efforts), daily clinical symptoms, rescue

Phase 3 Clinical Efficacy Studies: Lung Function

95

salbutamol use, any change in concomitant medications, and adverse events (AEs).
Diaries were to be completed at the same time in the morning (before taking study
drug) and in the evening (approximately 12 h later). These data are discussed in
chapter Phase 3 Clinical Efficacy of Indacaterol: Patient-Centered Outcomes.

2 Pivotal and Supportive Studies to Document the


Bronchodilatory Efficacy of Indacaterol
The objective of the study INLIGHT 1 [1] was to confirm the efficacy and safety of
indacaterol 150 g o.d. for 12 weeks, in patients with moderate-to-severe COPD.
The study treatment was given in a double-blind fashion as indacaterol 150 g
once daily (o.d.) or matching placebo through a single-dose dry-powder inhaler for
12 weeks.
At clinic visits after 1 day and then 4, 8, and 12 weeks, FEV1 was assessed at
50 and 15 min pre-dose and 5 and 30 min after dose administration in the clinics. On
days 1 and week 12, FEV1 was also assessed at 1, 2, and 4 h post-dose.
In total 788 patients were screened and 416 were randomized to indacaterol
150 g (n 211) and placebo (n 205). Overall, 364 patients (87.5 %) completed
the study.
Trough FEV1 at week 12 was 1.48  0.018 l for indacaterol and 1.35  0.019 l
for placebo, a clinically relevant difference of 130  24 ml ( p < 0.001). Trough
FEV1 after one dose was significantly higher with indacaterol than placebo
( p < 0.001) (Fig. 1).
Indacaterol demonstrated significantly higher peak FEV1 than placebo, both on
day 1 and at week 12, with indacaterol-placebo differences of 190  28 ml
( p < 0.001) and 160  28 ml ( p < 0.001), respectively. Standardized areaunder-the-curve (AUC) measurements for FEV1 (between 5 min and 4 h, 5 min
and 1 h, and 1 and 4 h post-dose) at week 12 were all significantly greater with
indacaterol than placebo ( p < 0.001), with differences of 170  24, 180  24,
and 170  24 ml, respectively (Fig. 2).
The efficacy and safety of indacaterol compared with placebo and the twice-daily
beta2-agonist, salmeterol, was investigated in a 6 month double-blind randomized
study with treatments consisting of indacaterol 150 g once daily, salmeterol
50 g twice daily, or placebo [3]. 1,002 patients were randomized and 838 (84 %)
completed the study. Indacaterol increased trough FEV1 at week 12 by 170 ml over
placebo ( p < 0.001) and by 60 ml over salmeterol ( p < 0.001) (Fig. 3).
A further study was therefore designed to compare indacaterol 150 g once daily
with salmeterol 50 g twice daily over 12 weeks [8]. The study was a randomized,
parallel-group study in patients with moderate-to-severe COPD. Of 1,123 patients,
randomized 92.1 % completed the study. The primary efficacy parameter was AUC
measured 5 min to 11 h and 45 min after dosing at week 12. Indacaterol was
statistically superior ( p < 0.001) to salmeterol with a mean difference of 57 ml

96

R. Dahl

Fig. 1 Twenth-four hour post-dose trough FEV1 after 1 day and at week 12 of treatment with
indacaterol 150 g or placebo (from [1])

Fig. 2 Change from baseline at individual time point in FEV1 on day 1 and at week 12. (a) was
measurements on day 1 (baseline to 4 h) and (b) at week 12 (50 min to 4 h) (from [1])

(95 % CI, 3579 ml) and also superiority over salmeterol 50 g bid at week 12 for
trough FEV1 (60 ml [CI, 3783 ml] p < 0.001) and FVC (Fig. 4).
Serial FEV1 and FVC measurements over 24 h at week 12 are depicted in
Fig. 5a. FEV1 measurements for indacaterol were statistically superior
( p < 0.001) over salmeterol at all time points including 50 and 15 min pre-dose.
Similarly as depicted in Fig. 5b, at week 12 the FVC measurements for indacaterol
were statistically superior to salmeterol at all time points.
The INHANCE study involved three stages. The first stage used preset criteria to
select two indacaterol doses after 14 days treatment [14] to be selected for use into
the second 6-month stage, which included an open-label tiotropium arm [2]. The
two doses selected in this study were 150 g and 300 g. These are the licensed

Phase 3 Clinical Efficacy Studies: Lung Function

97

Fig. 3 Differences between salmeterol (triangles) and indacaterol (squares) over placebo for
trough FEV1. Data are presented as least squares means and 95 % confidence interval (CI). The
broken line marks the threshold of 120 ml for a clinically relevant effect (from [3])

Fig. 4 Absolute difference between indacaterol and salmeterol for trough FEV1 after 4 and
12 weeks (from [8])

doses for indacaterol in Europe. The third phase was a further 6 months extension to
obtain efficacy and safety data for a prolonged period of 52 weeks treatment [5]. A
total of 1,683 patients with a mean age of 63.3 years were randomized. Their postbronchodilator FEV1 was 56 % predicted and the FEV1/FVC ratio 0.53. Patients
were randomized to once-daily treatment in the morning with one of the four
treatment arms which were placebo, indacaterol 150 g, indacaterol 300 g, and
open-label tiotropium HandiHaler 18 g.
On day 1 in the whole population, FEV1 at 5 min post-dose was increased
relative to placebo by 120 ml (95 % CI, 100140 ml) with both indacaterol doses

98

R. Dahl

a
0.3

Indacaterol 150 g od

Salmeterol 50 g bid

FEV1(L)

0.2

0.1
Second salmeterol dose

0
-2

8
10
12
14
Time post - dose (h)

16

18

20

22

24

b
0.4

Indacaterol 150 g od

Salmeterol 50 g bid

FVC (L)

0.3

0.2

0.1
Second salmeterol dose
0
-2

10

12

14

16

18

20

22

24

Time post-dose(h)

Fig. 5 Serial measurement of FEV1 (a) and FVC (b) on week 12 over 24 h post-dose (from [8])

and by 60 ml (95 % CI, 3080 ml) with tiotropium (all p < 0.001 versus placebo
and for indacaterol versus tiotropium).
Trough FEV1 at week 12 increased versus placebo by 180 ml with both
indacaterol doses and by 140 ml with tiotropium (all p < 0.001 versus placebo).
All these improvements for active drugs exceeded the minimum clinically important difference of 120 ml. The 40- to 50-ml differences between indacaterol and
tiotropium were significant when tested for superiority ( p < 0.01) and
non-inferiority ( p < 0.001). The effects of indacaterol and tiotropium on trough

Phase 3 Clinical Efficacy Studies: Lung Function

a
1.6

99

Indacaterol 150 g q.d. (n = 82)

Indacaterol 300 g q.d. (n = 90)

Tiotropium (n = 90)

Placebo (n = 69)

1.5

FEV1 (L)

1.4
1.3
1.2
1.1
1.0

Treatment
0 1 2 3 4 5 6 7 8 9 10 11 12
Time post-dose (hours)

b
3.0

23 24

Indacaterol 150 g q.d. (n = 82)

Indacaterol 300 g q.d. (n = 91)

Tiotropium (n = 87)

Placebo (n = 70)

2.9
2.8

FVC (L)

2.7
2.6
2.5
2.4
2.3
2.2
2.1
2.0

Treatment
0 1 2 3 4 5 6 7 8 9 10 11 12
Time post-dose (hours)

23 24

Fig. 6 Serial measurements of FEV1 (a) and FVC (b) from 250 min to 23 h and 45 min post-dose
measured in subset with 12 h serial spirometry at week 26 (from [2])

FEV1 were maintained over the course of the study, in terms of both difference from
placebo and change from baseline.
Twelve hour serial spirometry measurements of FEV1 and FVC were performed
at week 26 in a subset of patients (Fig. 6). The result showed that peak FEV1 was

100

R. Dahl

increased by indacaterol 150 g and 300 g compared to placebo by 210 ml (95 %


CI, 130280 ml) and 240 ml (95 % CI, 170320 ml) and by 180 ml (95 % CI,
100250 ml) with tiotropium (all p < 0.001 versus placebo). These values
corresponded to increases from baseline of 290 ml (22 %), 330 ml (25 %), and
250 ml (22 %), respectively; the increase on placebo was 70 ml (5 %).
Patients that completing the 26-week core part of the INHANCE study [2] were
invited to continue in a double-blind treatment with indacaterol, 150 or 300 g, or
placebo once daily for a further 26 weeks. Four hundred and fifteen patients
participated in the extension study [5]. The primary objective was to evaluate the
52-week safety of indacaterol, and bronchodilator efficacy was one of the secondary evaluations. Trough FEV1 at week 52 was significantly higher in the indacaterol
groups relative to the placebo group, with differences of 170 ml (95 % CI, 110230)
and 180 ml (95 % CI, 120240) (both p < 0.001) for the 150 and 300 g doses,
respectively (Fig. 8). The changes from baseline in trough FEV1 at week 52 were
120 ml (10 %), 130 ml (10 %), and 40 ml (3 %) with indacaterol, 150 g;
indacaterol, 300 g; and placebo, respectively. The differences between indacaterol
and placebo in trough FEV1 were maintained at a similar level from week 2 to the
end of the study, with differences of >160 ml compared with placebo for both doses
at each time point (all p < 0.001) (Fig. 7).
The results of INHANCE are supported by two third-party blinded studies. The
INTIME study investigated the bronchodilator efficacy of 150 and 300 microgram
once daily doses of indacaterol compared with placebo and tiotropium HandiHaler
18 microgram once daily over 14 days [7].
The INTENSITY trial compared indacaterol 150 g with tiotropium over
12 weeks in a multicenter, randomized, parallel-group, blinded, double-dummy
study [6] in 1,598 patients with moderate-to-severe COPD as described earlier.
They were randomized to treatment with indacaterol 150 g o.d. (number 797)
or tiotropium 18 g o.d. (number 801) for 12 weeks. After 12 weeks, the two
treatments had similar overall effects on trough 24 h post-dose FEV1.
The INVOLVE trial was of 52 weeks duration. It was a double-blind doubledummy parallel-group study [4]. It provides further data for the efficacy and safety
300 g o.d. dose. The study also support long-term usage and give additional safety
data from the 600 g o.d. group. In addition, it included a comparison with
formoterol.
Following screening 1,732 patients were randomized to 52 weeks of treatment
with indacaterol 300 g or 600 g o.d., placebo, or formoterol 12 g twice daily.
Formoterol was delivered via the proprietary single-dose dry-powder inhaler. The
primary efficacy parameter was based on trough FEV1 at week 12 measured 24 h
after dosing. Indacaterol 150 g and 300 g o.d. increased FEV1 by 170 ml versus
placebo and by 100 ml versus formoterol (all p < 0.001). These significant
differences were maintained at 52 weeks (Fig. 8).

Phase 3 Clinical Efficacy Studies: Lung Function

101

Fig. 7 Differences between active treatments and placebo for trough FEV1 after 1 day and at
weeks 2, 12, 26, and 52 (all p < 0.001 compared with placebo). The broken line marks the
threshold of 120 ml for a clinically relevant effect (from [5])

Fig. 8 Trough FEV1 after 1 day and at weeks 12 and 52 of treatment (from [4])

102

R. Dahl

3 Subgroup Analysis to Explore Efficacy in Subgroups with


Common Characteristics
Further analysis on subgroups of patients with characteristics that may interfere on
the bronchodilator response were done by analysis of data pooled from three
randomized, double-blind, placebo-controlled studies [24]. Baseline data and
spirometry and reversibility data were similar across the treatment groups.
A post hoc analysis of these pooled clinical study data was conducted to
investigate the efficacy and safety of indacaterol compared with placebo and the
long-acting bronchodilators tiotropium, salmeterol and formoterol. The influence if
ICS use at baseline (N 4,088) was analyzed for an influence on the bronchodilator response [15]. In addition, the influence if age above or below 65 years was
tested [16] and If the degree of reversibility after short-acting beta agonist (SABA)
and after short-acting muscarinic antagonist (SAMA) at baseline (>12 % or 12 %
or 5 %) would influence the response during regular treatment [17].
At screening 43 % patients used ICS. At week 12, both indacaterol doses in each
subgroup improved trough FEV1 compared to placebo by >120 ml (minimal
clinically important difference). Both indacaterol doses were statistically superior
to formoterol and tiotropium in each subgroup ( p < 0.05) (Table 1).
At baseline 53 % were <65 years of age. Indacaterol improved trough FEV1
compared to placebo >120 ml (minimal clinically important difference) at week
12 ( p < 0.001) (Table 2). Indacaterol was statistically more effective than
formoterol in both subgroups, statistically more effective than tiotropium in the
65 years group, and numerically more effective than tiotropium in the <65 years
group.
The bronchodilator efficacy of indacaterol was maintained at a similar level in
both patients <65 and 65 years of age and with similar rate of adverse events in
both age groups. These data support the use of o.d. long-acting bronchodilators as
first-line maintenance treatment for COPD regardless of age.
Mean FEV1 reversibility was at baseline 15.5 % for SABA and 15.5 % for
SAMA, and similar for all groups. Median baseline reversibility within categories
(>12 %, 12 %, 5 %) was for SABA 260, 60, and 0 ml and for SAMA
260, 60, and 0 ml. Week 12 trough FEV1 values are shown in Table 3.
At week 12, indacaterol o.d. provided significant bronchodilation in all
subgroups regardless of the degree or type of baseline reversibility, with bronchodilator efficacy at least as good as tiotropium.

4 Is Tachyphylaxis to Bronchodilation Observed with


Treatment with Indacaterol?
Tachyphylaxis to the bronchodilator effect was not seen in any of the studies.

Phase 3 Clinical Efficacy Studies: Lung Function


Table 1 Trough FEV1 at
week 12 according to
patients use of inhaled
corticosteroids during the
studies (from [15])

Table 2 Trough FEV1 at


week 12 according to
patients age above or below
65 years (from [16])

103

Week 12 trough FEV1 (ml) active-PBO treatment differences


ICS non-users

ICS users

IND 150 g
180 (150210)*, **
130 (90160)*
IND 300 g
170 (140200)*
160 (130190)*, **
FOR
100 (70140)
60 (30100)
TIO
140 (100170)
110 (60150)
Data are least squares means (95 % CIs)
All p < 0.001 versus PBO, *p < 0.05 versus FOR, **p < 0.05
versus TIO

Week 12 trough FEV1 (ml) active-PBO treatment differences


<65 years
65 years
IND 150 g
170 (140200)
160 (120190)*, **
IND 300 g
170 (140200)*
160 (130190)*, **
FOR
100 (60130)
70 (30110)
TIO
140 (100180)
110 (70150)
Data are least squares means (95 % CIs)
All p < 0.001 versus PBO, *p < 0.05 versus FOR, **p < 0.05
versus TIO

Table 3 Trough FEV1 at week 12 according to patients bronchodilator response to SAMA and
SABA at baseline (from [17])
Trough FEV1 (ml) at week 12, active-PBO treatment difference
Reversibility
>12 %
12 %
SABA (n)
831
716
IND 150 g
210 (170250)
150 (110200)
IND 300 g
210 (170250)
140 (90180)
TIO
130 (90180)
140 (90180)
SAMA (n)
857
690
IND 150 g
220 (180260)
130 (90180)
IND 300 g
220 (180260)
130 (80170)
TIO
160 (120200)
110 (60150)
Data are least squares means (95 % CIs). All p < 0.05 versus PBO
Both IND doses were non-inferior to TIO ( p < 0.05) in all subgroups

5 %
381
160 (100220)
150 (80210)
130 (70200)
366
100 (30170)
100 (30160)
80 (20140)

5 What Is the Optimum Dose for Indacaterol in COPD?


Determination of the optimal dose for bronchodilators in COPD is difficult in large
conventional studies because of inter-patient and inter-study variability.
An alternative approach was chosen to elucidate this question an analysis of
pooled summary statistics for each steady-state visit in 11 placebo-controlled
studies was performed [18]. These study-level summaries included data from
7,476 patients on indacaterol doses from 18.75 g to 600 g once daily.

104

R. Dahl

Fig. 9 Prediction of dose response for trough FEV1 at steady state in the study-level analysis with
comparators (from [18])

Fig. 10 Ranking of efficacy by dose in reaching the maximum effect on trough FEV1, the studylevel analysis (from [18])

Phase 3 Clinical Efficacy Studies: Lung Function

105

Doses of 75 g o.d. and above achieved clinically important improvements in


predicted trough FEV1 response. Indacaterol 75 g achieved 74 % of the maximum
effect on trough FEV1. Indacaterol 150 g achieved 85 % maximum effect on
trough FEV1 and was numerically superior to all comparators (99.9 % probability
of exceeding MCID). Indacaterol 300 g was the lowest dose that achieved the
model-predicted maximum trough response (Figs. 9 and 10).
These comprehensive analyses of the dose response of indacaterol in COPD
showed that 75 g is the minimum effective dose and confirms that indacaterol
150 g and 300 g are expected to provide optimal bronchodilation, particularly in
patients with severe disease.

References
1. Feldman G, Siler T, Prasad N, Jack D, Piggott S, Owen R, Higgins M, Kramer B (2010) The
INLIGHT 1 study group. Efficacy and safety of indacaterol 150 g once-daily in COPD: a
double-blind, randomised,12-week study. BMC Pulm Med 10:11. doi:10.1186/1471-2466-10-11
2. Donohue JF, Fogarty C, Lotvall J, Mahler DA, Worth H, Yorgancioglu A, Iqbal A, Swales J,
Owen R, Higgins M, Kramer B, INHANCE study investigators (2010) Once-daily
bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium.
Am J Respir Crit Care Med 182:15562
3. Kornmann O, Dahl R, Centanni S, Dogra A, Owen R, Lassen C, Kramer B, INLIGHT 2 study
investigators (2011) Once-daily indacaterol vs twice-daily salmeterol for COPD: a placebocontrolled comparison. Eur Respir J 37:273279
4. Dahl R, Chung K, Buhl R, Magnussen H, Nonikov V, Jack D, Bleasdale P, Owen R,
Higgins M, Kramer B, INVOLVE study investigators (2010) Efficacy of a new once-daily
LABA, indacaterol, versus the twice-daily LABA formoterol, in COPD. Thorax 65:473479
5. Chapman KR, Rennard SI, Dogra A, Owen R, Lassen C, Kramer B, INDORSE Study (2011)
COPD: a randomized, placebo-controlled a long-acting beta2-agonist, in subjects with longterm safety and efficacy of indacaterol. Chest 140:6875
6. Buhl R, Dunn LJ, Disdier C, Lassen C, Amos C, Henley M, Kramer B, INTENSITY study
investigators (2011) Blinded 12-week comparison of once-daily indacaterol and tiotropium in
COPD. Eur Respir J 38:797803
7. Vogelmeier K, Ramos-Barbon D, Jack D, Piggott S, Owen R, Higgins M, Kramer B, INTIME
study investigators (2010) Indacaterol provides 24-hour bronchodilation in COPD: a placebocontrolled blinded comparison with tiotropium. Respir Res 11:135
8. Korn S, Kerwin E, Atis S, Amos C, Owen R, Lassen C, INSIST study group (2011) Indacaterol
once-daily provides superior efficacy to salmeterol twice-daily in COPD: A 12-week study.
Respir Med 105:719726
9. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the
diagnosis, management, and prevention of chronic obstructive pulmonary disease:
revised 2011. Available from: http://www.goldcopd.org/uploads/users/files/GOLD_Report_
2011_Jan21.pdf
10. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van
der Grinten CP, Gustafsson P et al (2005) ATS/ERS task force. Standardisation of spirometry.
Eur Respir J 26:319338
11. Donohue JF (2005) Minimal clinically important differences in COPD lung function. COPD
2:111124

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12. Westwood M, Bourbeau J, Jones PW, Cerulli A, Capkun-Niggli G, Worthy G (2011) Relationship between FEV1 change and patient reported outcomes in randomised trials of inhaled
bronchodilators for stable COPD: a systematic review. Respir Res 12:40
13. Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS,
Calverley PM, Celli BR, Jones PW, Mahler DA, Make B, Miravitlles M, Page CP, Palange P,
Parr D, Pistolesi M, Rennard SI, Rutten-van Molken MP, Stockley R, Sullivan SD, Wedzicha
JA, Wouters EF (2008) Outcomes for COPD pharmacological trials: from lung function to
biomarkers. Eur Respir J 31:416469
14. Barnes PJ, Pocock SJ, Magnussen H, Iqbal A, Kramer B, Higgins M, Lawrence D (2010)
Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless
design. Pulm Pharmacol Ther 23:165171
15. Buhl R, Mahler DA, Owen R, Lassen C, Kramer B (2010) Indacaterol provides effective
bronchodilation in patients with COPD irrespective of age. Abstract 1190 ERS annual
congress
16. Decramer M, Donohue J, Owen R, Lassen C, Kramer B (2010) Indacaterol provides effective
bronchodilation in patients with COPD regardless of inhaled corticosteroid use. Abstract 5555
ERS annual congress
17. Kleerup EC, DUrzo A, Owen R, Lassen C, Kramer B (2010) Once-daily indacaterol provides
significant bronchodilation in chronic obstructive pulmonary disease patients irrespective of
baseline reversibility. Am J Respir Crit Care Med 181:A4439
18. Renard D, Looby M, Kramer B, Lawrence D, Morris D, Stanski DR (2011) Characterization of
the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model based approaches. Respir Res 12:54

Phase III Clinical Efficacy of Indacaterol:


Patient-Centered Outcomes
Donald A. Mahler

Abstract International guidelines for the treatment of patients with chronic


obstructive pulmonary disease (COPD) state that effective management should
relieve symptoms, improve health status, prevent exacerbations, and improve
exercise tolerance. In randomized placebo-controlled trials evaluating once-a-day
indacaterol over 2652 weeks, valid, reliable, and responsive instruments/methods
were used to quantify the impact of treatment on patient outcomes. Compared with
placebo treatment, both 150 and 300 g doses of indacaterol provided significant
and clinically meaningful improvements in dyspnea as measured by the Transition
Dyspnea Index. Analyses showed that as-needed use of salbutamol, an indirect
assessment of the efficacy of therapy on relief of dyspnea, was significantly lower
with 150 and 300 g doses of indacaterol than with placebo. With 150 and 300 g
doses of indacaterol, there were significant improvements in health status, as
measured by the St. Georges Respiratory Questionnaire, relative to placebo therapy. In two of three randomized trials, the differences in the St. Georges Respiratory Questionnaire between indacaterol and placebo achieved the minimal
important difference of 4 U. Time to first exacerbation was significantly
decreased with 150 and 300 g doses of indacaterol compared with placebo. In
two randomized trials published as abstracts, the 300 g dose of indacaterol
significantly improved exercise endurance times on the cycle ergometer (by 88
and 111 s; p < 0.05) and significantly increased inspiratory capacity at
end-exercise (by 280 and 317 ml; p < 0.05) compared with placebo. These overall
findings demonstrate the clinical efficacy of indacaterol on patient-centered
outcomes.

D.A. Mahler (*)


Geisel School of Medicine at Dartmouth, Hanover, NH 03755-1404, USA
Section of Pulmonary and Critical Medicine, Dartmouth-Hitchcock Medical Center,
One Medical Center Drive, Lebanon, NH 03756-0001, USA
e-mail: Donald.a.mahler@hitchcock.org
A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy,
DOI 10.1007/978-3-0348-0709-8_7, Springer Basel 2014

107

108

D.A. Mahler

1 Introduction
Chronic obstructive pulmonary disease (COPD) results in biological and physiological abnormalities that are manifest in patients by symptoms and physical
limitations. As the disease progresses, breathing difficulty (dyspnea) develops and
typically impacts the patients ability to perform daily activities (exercise tolerance)
and overall well-being (health status). These concerns often lead the patients to seek
medical care. The progressive course of COPD is often aggravated by episodes of
increased dyspnea, cough, and/or sputum production (exacerbation) that may
require prompt medical attention in the clinic or emergency department.
The forced expiratory volume in 1 s (FEV1) has been the traditional metric used
to evaluate the efficacy of a bronchodilator. However, over time, the objectives of
treating patients with COPD have shifted from improving lung function to focusing
on what is important to the patient. For example, Alifano and colleagues [1] have
stated that the most important outcomes in clinical trials evaluating treatment of
COPD are patient centered. Instruments with established reliability and
responsiveness are available to evaluate the benefits of pharmacotherapy on different patient-related outcomes [2]. International guidelines for COPD emphasize that
effective management includes the following goals: alleviate breathlessness and
relieve other symptoms, improve health status, reduce the frequency and severity of
exacerbations, and improve exercise tolerance [35].
Long-acting inhaled bronchodilators are recommended as initial maintenance
therapy for patients with COPD based on consistent evidence that these
medications are more effective than inhaled short-acting bronchodilators [3, 5,
6]. In this chapter, I review data on the clinical efficacy (i.e., beneficial changes)
of the once-a-day inhaled beta-agonist, indacaterol, compared with placebo. Additional comparisons are made for indacaterol with currently available twice-daily
beta-agonists, formoterol and salmeterol, and once-a-day inhaled anticholinergic
medication, tiotropium.
Table 1 lists the specific patient outcomes and the corresponding methods of
assessment that are reviewed in this chapter.

2 Dyspnea
Dyspnea, or breathlessness, is the major reason that patients with COPD seek
medical attention. The baseline (BDI) and transition (TDI) dyspnea indexes were
used to quantify patient-reported breathlessness in the phase III randomized clinical
trials (RCTs) examining the efficacy and safety of indacaterol [79]. With each
instrument, an interviewer queries the patient about how his/her breathlessness is
affected by usual activities and occupation (functional impairment), the magnitude
of various tasks, and how much effort is required to perform activities of daily
living. The BDI is a discriminative instrument used to quantify the severity of

Phase III Clinical Efficacy of Indacaterol: Patient-Centered Outcomes

109

Table 1 Patient-centered outcomes and corresponding methods of assessment


Patient-centered outcomes
Dyspnea

Methods of assessment
Baseline and Transition Dyspnea Indexes [10]
Number of puffs of salbutamol used as needed
Health status
St. Georges Respiratory Questionnaire [21]
Exacerbations
Event-free rates
Time to first COPD exacerbation
Exercise tolerance
Exercise duration during cycle ergometry
Additional information on these outcomes is available in the American Thoracic Society/European
Respiratory Society Task Force statement on Outcomes for COPD Pharmacological Trials [2]

dyspnea at an initial or baseline state and has been shown to be valid and reliable
[10, 11]. The TDI is an evaluative instrument that measures any changes in dyspnea
from the baseline assessment and has been shown to be valid and responsive [10,
11]. The minimal clinically important difference (MCID) of the TDI is 1 U
[12]. Patients with COPD have exhibited clinically important improvements in
breathlessness, as demonstrated with the TDI, in response to various treatments
[1319].
The overall benefits of indacaterol on relief of dyspnea are shown in Table 2. The
mean improvements in the TDI with once-daily indacaterol at doses of 150 and
300 g compared with placebo were statistically significant and clinically meaningful over 2652 weeks [79]. For all comparisons between indacaterol (both
150 and 300 g doses) and placebo, the mean differences in the TDI total score
were equal to or exceeded 1 U.
In the 26 week study by Donohue and colleagues [8], the odds ratio (OR) for
achieving a clinically relevant improvement in the TDI total score (1 U) was
greatest with indacaterol 300 g versus placebo (OR 2.85) compared with
indacaterol 150 g versus placebo (OR 2.16) and open-label tiotropium versus
placebo (OR 1.69). At the end of the 26-week study by Kornmann and
colleagues [9], the OR for the TDI  1 U was 1.87 for indacaterol 150 g and
1.90 for salmeterol 50 g compared with placebo treatment.
As-needed use of salbutamol has been used as an indirect method to assess the
benefits of bronchodilator therapy on relief of breathlessness [19, 20]. The changes
from baseline in the number of puffs of salbutamol used as needed for the different
studies with indacaterol are reported in Table 3. As-needed use of salbutamol was
consistently lower with both 150 and 300 g doses of indacaterol than with placebo
[79]. Comparative analyses revealed that as-needed use of salbutamol was significantly lower with indacaterol (150 and 300 g doses) than with tiotropium
( p  0.0001) [8] and formoterol ( p < 0.05) [7], but not with salmeterol
( p > 0.05) [9].

110

D.A. Mahler

Table 2 Treatment differences versus placebo in the Transition Dyspnea Index (TDI) total score
at the end of the study period
Tiotropium Formoterol
Salmeterol
18 g
12 g
50 g
+0.9 (0.4,
1.3)*
(n 309)
Dahl
52 weeks
+0.7 (0.2, 1.2)
**
(n 434)
Kornmann 26 weeks
+1.0 (0.5,
+1.0
1.5)*
(0.5, 1.5)*
(n 297)
(n 292)
Values are least square means and 95 % confidence intervals which are rounded to the nearest
tenths
n number of subjects for each treatment group
*p < 0.001 compared with placebo; **p < 0.01 compared with placebo
Author
Donohue

Duration
26 weeks

Indacaterol
150 g
+1.0 (0.6,
1.5)*
(n 343)

Indacaterol
300 g
+1.2 (0.7,
1.6)*
(n 353)
+1.0 (0.5,
1.5)*
(n 437)

Table 3 Change from baseline in puffs of salbutamol used as needed


Indacaterol
Indacaterol
Tiotropium Formoterol Salmeterol
Author
Placebo
150 g
300 g
18 g
12 g
50 g
Donohue 0.4 (0.1) 1.5 (0.1)*
1.6 (0.1)*
1.0 (0.1)*
Dahl
0.0 (0.1)
1.7*
1.3*
Kornmann 0.3 (0.2) 1.3 (0.2)*
1.2 (0.2)*
Values are least square means (SE) in puffs/day averaged over the duration of the study
*p < 0.05 compared with placebo

3 Health Status
Health status refers to the impact of disease on the daily lives of patients including
activities and well-being [2, 21]. Measurement of health status provides a
standardized method to assess groups of patients and to compare results in different
populations. The St. Georges Respiratory Questionnaire (SGRQ) was used to
quantify health status in the phase III RCTs examining the efficacy and safety of
indacaterol [79]. This instrument considers three components: frequency and
severity of respiratory symptoms, activities that cause or are limited by breathlessness, and the impacts of the disease on social functioning and psychological
disturbances [21]. When compared with the baseline score, a negative value in
the SGRQ indicates an improvement in health status [21]. The MCID of the SGRQ
is 4 U [22]. The SGRQ has been used in previous RCTs involving patients with
COPD to assess improvements in health status with various treatments [14, 2326].
The overall benefits of indacaterol on health status are shown in Table 4. The
mean improvements in the SGRQ with once-daily indacaterol at doses of 150 and
300 g compared with placebo were statistically significant over 2652 weeks
[79]. In two of these studies, the differences with treatment versus placebo
achieved the MCID of the SGRQ for indacaterol 150 and 300 g as well as for

Phase III Clinical Efficacy of Indacaterol: Patient-Centered Outcomes

111

Table 4 Treatment differences versus placebo in the St. Georges Respiratory Questionnaire
(SGRQ) total score at the end of the study period
Tiotropium Formoterol Salmeterol
18 g
12 g
50 g
1.0 (2.8,
0.8)
(n 357)
Dahl
52 weeks
4.0 (6.0,
2.0)*
(n 302)
Kornmann 26 weeks
5.0 (7.2,
4.1 (6.2,
2.9)*
2.0)*
(n 299)
(n 292)
Values are least square means and 95 % confidence intervals which are rounded to the nearest
tenths
*p < 0.001 compared with placebo
**p < 0.01 versus tiotropium
Author
Donohue

Duration
26 weeks

Indacaterol
150 g
3.3 (5.1,
1.5)*, **
(n 346)

Indacaterol
300 g
2.4 (4.2,
0.6)*
(n 360)
4.7 (6.7,
2.7)*
(n 322)

formoterol 12 g and for salmeterol 50 g [7, 9]. Although the mean differences in
the SGRQ total score were statistically significant for indacaterol 150 and 300 g in
the 26-week study by Donohue and colleagues [8], the differences did not achieve
the 4 U MCID. However, the improvement in health status with indacaterol
150 g was significantly better compared with open-label tiotropium [8].
In the study by Donohue and colleagues [8], the OR for achieving a clinically
relevant improvement in the SGRQ total score (4 U) was greatest with indacaterol
150 g versus placebo (OR 1.75) compared with indacaterol 300 g versus
placebo (OR 1.38) and open-label tiotropium versus placebo (OR 1.15). At
the end of the 26-week study by Kornmann and colleagues [9], the OR for the
SGRQ  4 U was 1.96 for indacaterol 150 g ( p < 0.001) and 1.72 for
salmeterol 50 g ( p < 0.01) compared with placebo.

4 Exacerbations
The chronic and progressive course of COPD is often aggravated by episodes of
increasing symptoms that may require medical attention and treatment. In the two
RCTs involving indacaterol in which exacerbations were reported as an outcome,
an exacerbation was defined as the onset or worsening of one or more respiratory
symptoms (dyspnea, cough, sputum purulence/volume, or wheeze) for 3 or more
consecutive days, plus intensified treatment (e.g., systemic steroids, antibiotics,
oxygen) and/or hospitalization or emergency room visit [7, 8].
Event-free rates of exacerbations are presented in Table 5. Active treatments
were consistently superior compared with placebo. Donohue and colleagues [8]
reported that the time to first exacerbation was reduced for indacaterol 150 g
(hazard ratio 0.69; p 0.019), indacaterol 300 g (hazard ratio 0.74;

112

D.A. Mahler

Table 5 Event-free rates of exacerbations at the end of the study period


Formoterol
Placebo
Indacaterol 150 g Indacaterol 300 g Tiotropium 18 g 12 g
75 (70, 79) 81 (77, 85)
80 (76, 84)
79 (75, 83)
(n 418) (n 416)
(n 416)
(n 415)
Dahl
57 (52, 62)
63 (58, 68)
65 (60, 70)
(n 399)
(n 405)
(n 400)
Kornmann Exacerbations were not reported
Data were calculated by the Kaplan Meier method
Values are percentages and 95 % confidence intervals and rounded to the nearest tenths
n number of subjects evaluated
Author
Donohue

p 0.054), and tiotropium (hazard ratio 0.76; p 0.080) relative to placebo.


Dahl and colleagues [7] found that the time to first exacerbation was significantly
reduced for indacaterol 300 g (hazard ratio 0.77; p < 0.05) and formoterol
(hazard ratio 0.77; p < 0.05) compared with placebo.

5 Exercise Tolerance
Two double-blind, randomized, placebo-controlled RCTs have examined the
effects of indacaterol 300 g on exercise performance [27, 28]. In the study by
Beeh and colleagues [27], inspiratory capacity (IC) during exercise was the primary
outcome. This metric examines the magnitude of dynamic hyperinflation. On the
other hand, ODonnell and associates [28] considered exercise endurance time as
the primary outcome. The preliminary results of these studies have been presented
at international meetings, whereas data are only available as abstracts [27,
28]. Complete findings have not been published in peer-review journals.
In a 2-week, two-period crossover design, Beeh and colleagues [27] reported
that indacaterol 300 g increased mean values of IC by 268 ml ( p 0.0032) at
exercise isotime and by 317 ml ( p 0.0033) at end-exercise compared with
placebo during cycle ergometry performed at 80 % of maximal workload. In
addition, exercise endurance time, a secondary outcome, was significantly
increased by 88 s ( p 0.0032) with indacaterol, and there was a corresponding
decrease of 1.5 U in Borg ratings of breathlessness at exercise isotime
( p 0.005) [27].
In a 3-week, two-period crossover design, ODonnell and colleagues [28]
reported that indacaterol increased exercise endurance time by 111 s
( p 0.011), but there was no significant difference in Borg ratings of breathlessness or leg discomfort at exercise isotime. End-exercise IC increased by a mean

Phase III Clinical Efficacy of Indacaterol: Patient-Centered Outcomes

113

value of 280 ml ( p 0.002) with indacaterol compared with placebo during cycle
ergometry at 75 % of maximal workload [28].

6 Summary
Although spirometry is necessary to diagnose COPD, lung function values do not
provide an assessment of the daily life experienced by patients with COPD. Over
the past decade, there has been increased recognition that improvement in patientcentered outcomes is important objectives in the management of patients with
COPD [13, 29]. Development programs of new pharmacological treatments for
patients with COPD have included patient-centered outcomes as an integral part of
the overall assessment of efficacy [13, 14, 19, 23].
This review summarizes the effects of indacaterol, a once-a-day beta-agonist, on
patient-related outcomesdyspnea, health status, and exacerbations. These clinical
measures were examined in three RCTs used for the registration of indacaterol with
regulatory agencies. For comparison purposes, treatments arms in these studies
included with placebo, tiotropium, formoterol, and/or salmeterol. At doses of
150 and 300 g, indacaterol achieved consistent improvement for relief of dyspnea
compared with placebo that was clinically meaningful. The proportion of patients
with a TDI score  1 U (MCID) was consistently greater with indacaterol 300 g
compared with open-label tiotropium throughout 26 weeks. The improvements in
breathlessness are supported by significant reductions in the as-needed use of
salbutamol throughout the study periods. Doses of 150 and 300 g of indacaterol
also provided consistent benefit in the health status of patients compared with
placebo. The odds ratios were numerically higher for indacaterol versus placebo
to achieve the 4 U change (MCID) in the SGRQ than for open-label tiotropium
and for salmeterol. Event-free rates of exacerbations and the time to first exacerbation were reduced for indacaterol compared with placebo. Preliminary results
published as abstracts show that indacaterol 300 g increased exercise endurance
times and reduced dynamic hyperinflation during high-intensity cycle ergometry
relative to placebo.
These collective data demonstrate the efficacy of once-a-day inhaled indacaterol
for improving patient-centered outcomes in those with COPD.

References
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pulmonary disease. Eur Respir J 27:822832

The History and Performance of the


Breezhaler Device
David Young, Lee Wood, Dilraj Singh, and Juergen Dederichs

Abstract The device used for marketed indacaterol maleate is a single-dose dry
powder inhaler (SDDPI) known as the Onbrez Breezhaler. The device was
designed such that patients receive immediate feedback that the dose has been
taken correctly, as they can hear a distinctive whirring noise on correct inhalation,
can check that the clear capsule is empty, and most will feel the lactose excipient
against the back of their throats.
A series of in vivo and in vitro studies with the Breezhaler examined device
handling and preference, airflow through the device and dose delivery
characteristics. Compared with another SDDPI (HandiHaler, Boehringer
Ingelheim), two-thirds of patients who expressed a preference preferred the
Breezhaler device. The Breezhaler is a low airflow resistance device suitable
for use by patients with a range of COPD severities, with most able to generate a
peak flow through the device in excess of 60 L/min. Further, across the range of
flow rates relevant to COPD patients, there is consistent dose delivery, both of the
delivered dose and fine particle mass.
In conclusion, the Breezhaler device is suitable for patients with a full range of
COPD severities, with a design that means patients receive immediate feedback
that they have used it correctly.

D. Young (*)
Novartis Horsham Research Centre, West Sussex, UK
e-mail: david-1.young@novartis.com
L. Wood D. Singh J. Dederichs
Novartis Pharma AG, Basel, Switzerland
A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy,
DOI 10.1007/978-3-0348-0709-8_8, Springer Basel 2014

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1 Introduction
Indacaterol maleate has been developed using a range of inhalation devices
(inhalers). The first inhaler used to deliver indacaterol maleate was the Aerolizer,
which was the same single-dose dry powder inhaler (SDDPI) that is used for the
delivery of marketed product Foradil. Some of the following phase I and II studies
then used a pressurised metered-dose inhaler (pMDI), followed by later phase II
studies which either used an SDDPI or a multi-dose dry powder inhaler (MDDPI).
The device finally selected for the phase III development programme (and subsequently for the marketed product) was an SDDPI device based on the Aerolizer
technology, with design changes intended to improve device handling and the
appearance. This inhaler is now commercially available in the European Union as
the Breezhaler device (and is known as the Neohaler device in the United States
of America). This chapter will summarise the increasingly important role of human
factor engineering in inhalation devices, summarise known issues with commercially available inhalation devices and will present available data on the
Breezhaler device including technical performance, usability and patient
feedback.
Unlike most other methods of drug administration, the efficacy of the drug
delivered by an inhaler can be significantly affected by the usability of the device.
The usability of an inhaler is affected by ergonomic factors, which concern the
interactions between, and ultimately the relationship between the user and the
device. Therefore, an overview of the characteristics of the drug is incomplete
without due consideration for the importance of the inhaler. The importance of the
inhalers role in delivery of drug therapy was summarised in the European Respiratory Society/International Society for Aerosols in Medicine (ERS/ISAM) Task
Force Report (2011), which stated:
The use of an inhaler by a patient has a strong scientific basis that is related to the dose of
drug that is deposited into the lungs. Because the dose delivered to the lungs is so dependent
on the correct use of the delivery system, those who prescribe inhaler devices should ensure
that patients can and will use them correctly. This requires that prescribers: know the
devices that are currently available to deliver the prescribed drugs and the various
techniques that are appropriate for each device; are able to evaluate the patients inhalation
technique to be sure they are using the devices properly; and ensure that the inhalation
method is appropriate for each patient [1].

There are broadly two types of inhalation devices: dry powder inhalers (either
single-dose or multi-dose) and pressurised metered-dose inhalers. Within these two
broad categories, an increasingly wide variety of inhalation devices are commercially available, with a range of characteristics that determine the inhalers suitability for a particular patient. Some ideal characteristics of an inhalation device have
been suggested to be [27]:
Uniform dose delivery, that is, consistent over a wide range of inspiratory flow
rates
Optimal particle size for lung delivery

The History and Performance of the Breezhaler Device

119

Easy to learn and use correctly


Feedback of dose administration to the patient
Environmental protection (humidity, moisture)
Product stability
Cost effectiveness
Portability
Durability (physically robust)

Depending on the drug being delivered, and the indication being treated, some of
these characteristics may be more important than others. However, not all of the
inhalation devices are suitable for all patients; this is because differences exist in the
way that devices perform and there are different physical and cognitive demands on
a user to use a particular device. This is reinforced by the proceedings of the
International Pharmaceutical Aerosol Consortium on Regulation and Science
(IPAC-RS) conferenceBringing value to the patient in a changing world
(March 2011) where a key recommendation was for greater emphasis on matching
the inhaler to the patient, rather than the patient to the inhaler, implying that inhalers
should better fit patients actual needs [8]. For example, in the case of indacaterol
maleate as the drug is inhaled once daily, the portability of the inhaler is less
important than would be the case for a drug taken on demand (e.g. rescue medication) where a user would need to carry their inhaler with them, whereas ease of
correct use is of increased importance in a population that is elderly and with high
levels of comorbid conditions, as is the case in chronic obstructive pulmonary
disease (COPD).
Dry powder devices are breath actuated (the powder deagglomeration occurs
when a user breathes through the mouthpiece). The advantage of this is that there is
no need to synchronise device actuation and inhalation as is the case with most
pMDIs, which are the type of inhaler most frequently used incorrectly by patients
[9, 10]. However, for dry powder inhalers to be used effectively, patients must be
able to generate sufficient inspiratory flow (and reduced inspiratory flow is typical
in patients with COPD). Further, the low mass of powder typically delivered per
actuation can mean that patients do not know whether they have used such a device
correctlya particular concern with reservoir-type MDDPIs (even devices with
dose counters as these offer only indirect feedback to patients) or with SDDPIs that
have opaque capsules.
The usability problems and patient-related factors (human factors) with inhalers
have been investigated in several studies during recent years in asthma and COPD
patient populations. Errors in inhalation technique have been reported to range up to
85 % [9].
Patient-related factors leading to known use errors can be divided into two
categories [11]:
1. Device-independent usability issues, where a usability issue is not directly
associated with the inhaler user interface and is common with use of inhalers
in general

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2. Device-dependent usability issues, where a usability issue is associated with the


device user interface

1.1

Device-Independent Issues

Studies have shown that two of the most common device-independent use errors
include not exhaling fully prior to inhalation and failing to hold breath immediately
following inhalation. For example, Molimard et al. [11] reported an observational
study with a total of 3,811 asthma or COPD patients treated in primary care in
France with the Aerolizer, Autohaler, Diskus, pMDI or Turbuhaler. In this
study, the two most common device-independent errors in all subjects were failure
to breathe out before actuation (28.9 %) and not holding breath for a few seconds
after inhalation (28.3 %).

1.2

Device-Dependent Usability Issues

Usability problems with inhalers have been widely studied in recent years, and the
following list comprises of the most common device-dependent use errors recorded
between each type of device: user exhales into the device mouthpiece after loading
the dose, user stops inhaling prematurely, user does not seal lips properly around
mouthpiece during inhalation, user makes a slow and not forceful inhalation, user
exhales into the device mouthpiece after inhalation [12] and user does not tilt head
back during inhalation (hyperextending) [9].
Specific usability problems observed in studies with MDDPIs include errors in
opening the inhaler and errors in loading dose (by rotating or pressing a button
and orientation of the inhaler during loading, etc.) [912].
Specific usability problems observed in studies with SDDPIs include failure to
insert the capsule into the inhaler, failure to pierce a capsule by pressing and
releasing the buttons and failure to control capsule (capsule has been emptied)
following use [912].

2 The Breezhaler Device


The Breezhaler device is an SDDPI that is used to deliver capsules containing
indacaterol maleate powder (Onbrez Breezhaler, Novartis Pharma AG) (Fig. 1).
Novartis announced their intentions to commercialise additional inhaled drugs of
various drug classes, and combinations thereof, in conjunction with that inhalation
device over the next few years. The first of these, the long-acting muscarinic
antagonist glycopyrronium, is now approved in the EU as Seebri Breezhaler.

The History and Performance of the Breezhaler Device

121

Fig. 1 The Onbrez


Breezhaler

To use the device, patients insert a capsule into a chamber. After closing the lid,
the two buttons are depressed, piercing the capsule at both ends; the patient then
inhales through the device, which causes the capsule to rotate within the device
chamber, and this creates a distinctive whirring noise, as the capsule spins.
Furthermore, patients can see that they have inhaled all the powder as the capsule
is clear. As a consequence, patients receive immediate and direct feedback that the
dose has been taken correctly, as they can see that the capsule is emptied, can hear
the capsule rotate within the chamber, and most patients will feel the lactose
excipient of the indacaterol maleate powder against the back of the throat.
The operating principle of the Breezhaler device as an SDDPI incorporates
several potentially significant benefits in usability over the majority of MDDPIs:
Dosing affirmation: a user is both able to hear the capsule as it spins during
inhalation, may feel a slight vibration as the capsule rattles during spinning and
may experience a slight taste of lactose powder deposited in the mouth during
and immediately after use. Each of these characteristics is expected to enforce to
a user that they are inhaling correctly.
Dosing confirmation: following use, the user is able to visually check if the
transparent inhalation capsule has been correctly emptied. If the capsule is not
empty, the user can inhale again. The ability to check that the inhaler has been
used correctly is expected to reduce the risk of double dosing if users take
another dose because they arent confident that they have correctly dosed the
first timeand of underdosing if users do not inhale the entire contents of the
capsule. The ability to visually verify that the capsules are empty could also
provide a richer training experience whereby a healthcare professional can
verify a users technique by inspecting a used capsule.
Positive transfer of learning: a positive transfer is a key concept contributing to
the learnability of the inhaler. AAMI/ANSI-HE-75:2009 Human factors
engineeringDesign of medical devices defines transfer of training or transfer
of learning: As applied to medical devices, application of lessons learned from
using one device to another one. Positive transfer occurs when the lessons
learned using one device apply correctly to another one [13].

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As the Breezhaler device is based on the same operating principle as other


SDDPIs such as the Aerolizer, it is expected to be easy for a patient currently using
a single-dose dry powder inhaler to transition to the Breezhaler device.

3 Device Handling Characteristics and Preference


A study was conducted to assess the preference of patients to two different
SDDPIsthe Breezhaler and the HandiHaler (Spiriva HandiHaler,
Boehringer Ingelheim Pharma GmbH & Co. KG) [14].
This was a 2-period crossover study, with all patients using both devices (one in
each treatment period). On day 1 of each period, patients were asked to read the
instruction leaflet for one of the devices and were then assessed on their use of the
device (using a placebo capsule), using a checklist that listed each of the 21 steps
required for correct use of Breezhaler and 19 for the HandiHaler. They then
received training on the correct use of the device and were asked to use the device
once a day for another 5 days. On day 7 of each period, patients returned to the
study centre and were again assessed on their use of the device. On day 7 of the
second period, patients completed a questionnaire to indicate their preference for
each deviceboth overall and using a number of criteria, including ease of opening
and closing cap and mouthpiece, ease of holding, checking inhalation and confidence that medication was taken.
At day 7, most patients (78100 % for Breezhaler device; 81100 % for
HandiHaler) completed each handling step correctly. For most steps, there was
improvement from day 1 to day 7 (corresponding day 1 rates were 81100 % and
6999 %). For one key step (fully releasing button before inhalation), the
Breezhaler device score was high on both days (93 %, 96 %), while the
HandiHaler score changed 11 points from 88 % (day 1) to 99 % (day 7).
When asked which of the two devices they would prefer to use on a daily basis,
two thirds of the patients who expressed a preference chose the Breezhaler device
over the Handihaler.

4 Technical Characteristics of the Breezhaler Device


When comparing dry powder inhalers, the following are key considerations:
Airflow resistance
Flow rate
Dose deliveryin terms of both delivered dose and fine particle mass (the ideal
being consistent delivery across a range of flow rates)
In comparison with other available dry powder devices, the Breezhaler device
was designed to have a low airflow resistance, as shown in Fig. 2. COPD patients
can typically build up a peak inspiratory airflow of approximately 90 L/min in the

The History and Performance of the Breezhaler Device

123

Fig. 2 Comparison of airflow through a range of dry powder devices [15]. Onbrez and
Breezhaler are registered trademarks of Novartis AG. Diskus is a registered trademark of
Glaxo Group Limited. Turbuhaler is a registered trademark of AstraZeneca AB. HandiHaler
is a registered trademark of Boehringer Ingelheim Pharma GmbH & Co. KG

Breezhaler device, overcoming a pressure drop of approximately 3 kPa. Lower


peak inspiratory flow rates in other devices result from their higher inspiratory flow
resistance [15].
The flow rate and dose delivery characteristics of the Breezhaler device were
examined in two studiesan initial in vivo study determined the inspiratory flow
rate generated by patients with a range of severities of COPD; a subsequent in vitro
study used inhalation profiles from these patients to analyse dose delivery of
indacaterol maleate through this device.

4.1

In Vivo Airflow Study

An initial in vivo study was conducted to measure the airflow generated through the
Breezhaler device by patients with a range of severities of COPD [16]. The
characteristics of the 26 patients studied are shown in Table 1.
As can be seen from this table, the COPD severity of the patients studied varied
from mild to very severe, with a mixture of male and female patients, and a range of
ages from 49 to 84 years. Patients were trained on the correct use of the Breezhaler
device using both written and verbal instructions. Each patient then used the device
(attached to an inhalation profile recorder) three times, and the highest peak
inspiratory flow rate (PIFR) achieved by each patient was recorded (Fig. 3).

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D. Young et al.

Table 1 Patient characteristics [16]


Patient no.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26

Age
70
83
54
78
70
57
55
74
62
74
76
54
84
69
73
69
73
68
82
49
71
67
80
69
77
62

Gender
F
M
F
M
M
M
F
F
M
M
M
F
M
M
M
M
F
F
M
F
M
M
M
M
M
M

COPD severity
Moderate
Severe
Severe
Severe
Mild
Moderate
Severe
Very severe
Severe
Severe
Moderate
Moderate
Moderate
Moderate
Severe
Moderate
Moderate
Moderate
Severe
Moderate
Moderate
Severe
Severe
Severe
Severe
Very severe

PIFR (L)
77
86
113
82
104
133
102
61
106
121
114
109
111
97
83
110
82
94
52
83
76
101
65
110
82
108

Vinhale (L)
1.6
1.6
2.0
2.5
2.2
3.3
1.7
0.9
2.3
2.5
2.1
2.3
1.6
2.6
1.7
1.8
1.0
1.5
1.7
2.3
2.1
2.2
1.7
1.2
1.8
1.7

Fig. 3 PIFR generated through the Breezhaler device, according to disease severity [16]

The History and Performance of the Breezhaler Device

125

The overall mean PIFR generated through the Breezhaler was 94.8 L/min,
decreasing with increasing COPD severity (103, 99, 92 and 84 L/min in mild,
moderate, severe and very severe COPD, respectively). All but one of the patients
were able to generate a peak flow in excess of 60 L/minthe one exception was an
82-year-old patient with severe COPD, who was able to generate a PIFR of 52 L/min.
The overall mean inhaled volume by these 26 patients was 1.92 L, which also
decreased with increasing COPD severity (2.2, 2.0, 1.9 and 1.3 L in mild, moderate,
severe and very severe COPD, respectively).

4.2

In Vitro Dose Delivery Study

The subsequent in vitro study used data generated from patients in the in vivo study
to analyse dose delivery of indacaterol maleate for a range of constant inspiratory
flow rates from 30 L/min (i.e. below the minimum flow that was achieved by any of
the patients) to 100 L/min (the upper limit that could be generated through the test
equipment) [16]. A sintered glass funnel was used to determine the delivered dose,
with the mass analysed via high performance liquid chromatography. The aerodynamic particle size distribution was also determined at each flow rate using a Next
Generation Impactor; this was then used to calculate the fine particle mass (FPM;
i.e. the mass of drug particles <4.7 mm in diameter) of indacaterol maleate. This
parameter is of particular interest as particles of this size are generally considered to
be the optimum size to deposit in the bronchi and alveoli. Finally, inspiratory
airflow profiles from six of the patients in the in vivo study were used to analyse
the consistency of dose delivery, using the experiment setup shown in Fig. 4.
Across the range of constant flow rates from 50 to 100 L/min (i.e. the range
relevant to COPD patients), there was consistent dose delivery, both of the delivered dose and the fine particle mass [16]. For the 150 g capsule, the mean delivered
dose ranged from 120 to 134 g, and the fine particle mass ranged from 38 to 48 g
(Table 2), corresponding to a fine particle fraction range from 25 to 32 %.
The interpretation of data derived from constant airflow rates was extended by
data generated according to simulated patient inspiratory airflow profiles. In vitro
data generated according to airflow profiles are particularly powerful to simulate
the individual patient impact on dose delivery. The six inspiratory flow profiles
selected for the dose delivery consistency analysis are shown in Fig. 5 [15]. These
profiles were selected to cover a range of severities of COPD from mild to very
severe, ages from 49 to 82, and a balance of males and females.
The fine particle fraction (as a percentage of the delivered dose) is shown in
Fig. 6 [15]. These results suggest that the Breezhaler device will deliver a
consistent fine particle fraction of indacaterol maleate across a range of COPD
severities and inhalation profiles.

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D. Young et al.

Fig. 4 Experimental setup with flow-volume simulator [14]

Table 2 Flow rate dependency of indacaterol maleate 150 g capsule fine particle mass and
delivered dose [16]
Delivery dose Flow rate, L/min
Indacaterol
30a
40a
50
60
70
80
90
100
150 g
FPM, g (SD) 27 (2.1) 34 (1.7) 38 (1.3) 42 (0.9) 43 (0.7) 45 (0.7) 47 (1.7) 48 (1.0)
Mean deliv- 117
119
120
125
126
129
128
134
ered dose
(g)
Range of
111128 111125 107139 113137 118138 118139 120135 127141
delivered
doses (g)
FPM fine particle mass (<4.7 m)
a
Results at 30 L/min and 40 L/min are below the relevant air flow range of COPD patients and are
for information only

5 Conclusions
The Breezhaler device is a capsule based SDDPI that has been designed to have
low airflow resistance and so to be suitable for a wide range of patients, including
those with limited inspiratory capacity. All patients studied were able to generate a
peak inspiratory flow rate through the device in excess of 50 L/min, and the delivery
characteristics of the device (both in terms of delivered dose and fine particle mass)
remain consistent at flow rates from 50 to 100 L/min. The design of the Breezhaler
device means that patients receive immediate feedback that they have used the
device correctly, and, in a study that compared the Breezhaler device with the
HandiHaler (another marketed SDDPI), patients preferred the Breezhaler device
overall.

The History and Performance of the Breezhaler Device

127

Fig. 5 Inspiratory profiles


selected for dose delivery
consistency analysis [15]

Fig. 6 Fine particle


fraction results (error bars
denote standard deviation)
[15]

References
1. Laube BL, Janssens HM, de Jongh FH et al (2011) What the pulmonary specialist should know
about the new inhalation therapies. European Respiratory Society/International Society for
Aerosols in Medicine (ERS/ISAM) Task force report. Eur Respir J 37:130831
2. Ashurst I, Malton A, Prime D et al (2000) Latest advances in the development of dry powder
inhalers. Pharm Sci Technolo Today 3:24656
3. Newman SP (2004) Dry powder inhalers for optimal drug delivery. Expert Opin Biol Ther
4:2333
4. Chrystyn H (2006) Closer to an ideal inhaler with the Easyhaler: an innovative dry powder
inhaler. Clin Drug Investig 26:17583
5. Newman SP, Busse WW (2002) Evolution of dry powder inhaler design, formulation, and
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6. Byron PR (2004) Drug delivery devices: issues in drug development. Proc Am Thorac Soc
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7. Bisgaard H (1996) Drug delivery from inhaler devices. Lung deposition, clinical effect and
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8. Conference report from International Pharmaceutical Aerosol Consortium on Regulation and
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9. Rootmensen G, van Keimpema A, Jansen H, Haan R (2010) Predictors of incorrect inhalation
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10. Khassawneh BY, Al-Ali MK, Alzoubi KH et al (2008) Handling of inhaler devices in actual
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11. Molimard M, Raherison C, Lignot S et al (2003) Assessment of handling of inhaler devices in
real life: an observational study in 3811 patients in primary care. J Aerosol Med 16:24954
12. Melani AS, Bonavia M, Cilenti V et al (2011) Inhaler mishandling remains common in real life
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14. Chapman KR, Fogarty CM, Peckitt C et al (2011) Delivery characteristics and patients
handling of two single-dose dry-powder inhalers used in COPD. Int J Chron Obstruct Pulmon
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inhaler for the delivery of indacaterol. Curr Med Res Opin 26:252733

What Does the Future Hold for the Therapy


of COPD?
Peter J. Barnes

Abstract Current therapies for COPD fail to prevent disease progression or mortality. The mainstay of current drug therapy is long-acting bronchodilators; several
longer-acting inhaled 2-agonists and muscarinic antagonists (and combinations)
are now in development. No treatments have so far been shown to suppress chronic
inflammation in COPD lungs. With better understanding of the inflammatory and
destructive process in the pathophysiology of COPD, several new therapeutic
targets have been identified. Several mediator antagonists tested in COPD have
so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil
and monocyte recruitment may be more promising. Broad-spectrum antiinflammatory drugs may be more effective and include inhibitors of the enzymes
phosphodiesterase-4, p38 mitogen-activated protein kinase, NF-B kinase and PI3
kinase- and PI3 kinase-, but side effects will be a major limitation with systemic
administration, so that inhaled delivery may be necessary. Perhaps the most
promising approach is reversal of corticosteroid resistance through increasing
histone deacetylase-2 (HDAC2) activity. This might be achieved by theophyllinelike drugs, selective PI3 kinase- inhibitors, more effective antioxidants and nonantibiotic macrolides.

1 Introduction
Despite the enormous global impact of COPD, there are no drug therapies that have
been shown to significantly prevent disease progression or reduce mortality. However, there has recently been greatly increased interest in COPD by researchers and
the pharmaceutical industry, and this has been linked to a better understanding of its
cellular and molecular mechanisms [1] and in the identification of novel targets for
P.J. Barnes (*)
National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street,
London SW3 6LY, UK
e-mail: p.j.barnes@imperial.ac.uk
A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy,
DOI 10.1007/978-3-0348-0709-8_9, Springer Basel 2014

129

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P.J. Barnes

Fig. 1 Cigarette smoke (and other irritants) activates macrophages in the respiratory tract that
release multiple chemotactic factors that attract neutrophils, monocytes and T lymphocytes
(particularly CD8+ cells). Several cells also release proteases, such as neutrophil elastase
(NE) and matrix metalloproteinase-9 (MMP-9) which break down connective tissue in the lung
parenchyma (emphysema) and also stimulate mucus hypersecretion (chronic bronchitis). CD8+
may also be involved in alveolar wall destruction. Transforming growth factor (TGF)- and
connective tissue growth factor (CTGF) released from inflammatory cells may mediate small
airway fibrosis. The inflammatory process may be inhibited at several stages (shown in the boxes).
PDE phosphodiesterase, IKK inhibitor of nuclear factor-B kinase, MAPK mitogen-activated
protein kinase, PI3K phosphoinositide-3-kinase, PPAR peroxisome proliferator activated receptor,
NE neutrophil elastase, MMP matrix metalloproteinase, COB chronic obstructive bronchitis

the discovery of new treatments [2] (Fig. 1). Furthermore, it is now recognized that
COPD is associated with significant extrapulmonary effects and co-morbidities that
also require therapy [3, 4].

2 The Need for New Therapies


There have been few advances in the drug therapy of COPD, in contrast to the
enormous advances made in asthma management. Not only are there no drugs that
prevent disease progression and death, but prevention and treatment of acute
exacerbations is poor. The only significant advances in drug therapy have been in
the development of longer-acting bronchodilators, but there are currently no

What Does the Future Hold for the Therapy of COPD?

131

effective anti-inflammatory treatments, with the exception of theophylline that has


attracted little clinical interest [5]. Development of new therapies depends on better
understanding of the cellular and molecular mechanisms that are involved in
inflammation, structural changes and aberrant repair mechanisms that characterize
the pathophysiology of COPD. The inflammation of COPD is very different from
that seen in asthma, with different inflammatory cells and mediators, indicating that
different treatments are likely to be needed [6].

3 The Difficulty of Finding New Treatments


Development of new drugs for COPD has proved to be very difficult for the
pharmaceutical industry. The underlying cellular and molecular mechanisms are
less well understood than in asthma, and more research is needed. Animal models
of COPD for early drug testing are poor and focus on emphysema rather than the
small airway disease that appears to underlie the progressive loss of FEV1 and the
increasing symptoms over time that is characteristic of COPD patients [7]. Better
animal models that have predominantly small airway disease are needed [8, 9].
There are also uncertainties about how to test drugs for COPD, which may
require long-term studies (3 years or longer) in relatively large numbers of patients
at an enormous cost [10]. For example, a recent study looking at the effects of drug
intervention on mortality is believed to have cost several hundred million dollars
[11]. It is likely that there are several clinical phenotypes that comprise the
diagnosis of COPD and it may be necessary to differentiate these in clinical trials
[10]. Many patients with COPD may have co-morbidities, such as ischaemic heart
disease and diabetes, which may exclude them from clinical trials of new therapies
[4]. There is little information about surrogate markers, for example, biomarkers in
blood, sputum or breath, to monitor the short-term efficacy and predict the longterm potential of new treatments [10, 12]. Finally, it is difficult to accurately
measure small airway function in patients with COPD, so there is a need to develop
better tests of small airway function that are not affected by emphysema or
abnormalities of large airway function [8].

4 New Bronchodilators
Long-acting inhaled bronchodilators (long-acting 2-agonists and a long-acting
muscarinic antagonist) are now the mainstay of current management of COPD
[13], so there are considerable efforts extended to improving existing classes of
bronchodilators and to search for novel bronchodilator compounds. This volume
focuses on the first once-daily inhaled 2-agonist indacaterol, which is now in
clinical use. Several other once-daily inhaled 2-agonists, such as vilanterol,
olodaterol and carmoterol, are now in clinical development [14]. Indacaterol is a

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P.J. Barnes

very effective and long-lasting dilator of small human airways measured by video
microscopy in a precision-cut lung slice preparation in vitro [15] and has a
bronchodilator action of over 24 h in patients with COPD with a fast onset of
action and no evidence of tolerance or significant side effects [16, 17].
The once-daily inhaled anticholinergic tiotropium bromide has been an important advance in therapy, and several other long-acting inhaled muscarinic
antagonists (LAMA), such as aclidinium bromide and glycopyrrolate, are now in
clinical development [18, 19]. Combination inhalers with a long-acting 2-agonist
(LABA) with a LAMA are also in development as there is an additive effect
between these two bronchodilator classes [20]. Indeed, addition of glycopyrrolate
produces significant further bronchodilatation when added to the maximum effective dose of indacaterol as the combination QVA149. This is surprising as 2agonists reverse all-known bronchoconstrictors (including cholinergic tone), so the
additional benefit of the LAMA must be due to some undocumented
non-bronchodilator effect (such as on mucus secretion) or explained by the fact
that there are some patients who respond better to a LABA and others to a LAMA.
Single molecules that link a muscarinic antagonist to a 2-agonist (MABA), such as
GSK-961081, are now also in clinical development but lack the flexibility of a
combination inhaler as it is difficult to optimize both drug activities [21].
It has proved difficult to discover novel classes of bronchodilator drug. Potassium channel openers, while effective in relaxing human airways in vitro, were not
effective in asthma as they were more potent as vasodilators, and this limited the
dose that could be administered. There has been interest in developing drugs that
inhibit the contractile machinery in airway smooth muscle, including rho kinase
inhibitors, inhibitors of myosin light chain kinase and direct smooth muscle myosin
inhibitors. As these agents also cause vasodilatation, it will be necessary to administer them by inhalation.

5 Blocking Inflammatory Mediators


There is a pressing need for novel anti-inflammatory treatments as corticosteroids
are ineffective in most patients. The better understanding of the underlying inflammatory mechanisms in COPD has identified several new therapeutic approaches
(Fig. 1). The simplest anti-inflammatory strategy is to block specific mediators that
are involved in the inflammatory response. Many mediators have been implicated in
the pathophysiology of COPD [22, 23], but as in asthma it seems unlikely that these
will prove to be very effective therapies as there is considerable redundancy in the
effects of these mediators.

What Does the Future Hold for the Therapy of COPD?

5.1

133

Lipid Antagonists

Leukotriene(LT)B4 is increased in sputum and bronchoalveolar lavage fluid of


patients with COPD and is chemotactic for neutrophils and lymphocytes. Several
antagonists of the major receptor BLT1 have developed [24], but so far clinical
studies in COPD have been negative. 50 -Lipoxygenase inhibitors should also be
beneficial by blocking the production of endogenous LTB4, but it has been difficult
to discover 5-LO inhibitors without hepatic toxicity.

5.2

Cytokine Inhibitors

Tumour necrosis factor- (TNF-) concentrations are increased in sputum, particularly during exacerbations, and this cytokine amplifies inflammation and may
account not only for neutrophilic inflammation in the lungs but also some systemic
features such as skeletal muscle wasting. However, blockade of TNF- with a
blocking antibody (infliximab) has no beneficial clinical effects in patients with
COPD, using the same doses which are effective in rheumatoid arthritis [25]. Of
particular concern was the finding that more COPD patients treated with anti-TNF
developed respiratory cancers and severe lung infections [26]. Other cytokines that
are currently targeted for inhibition include IL-1, IL-6 and IL-17. IL-6 is increased
in sputum and in the systemic circulation of COPD patients and may account for the
increase in circulating C-reactive protein. A potent blocker of IL-6 is the receptor
antibody tocilizumab, which is effective in rheumatoid arthritis but has not yet been
tested in COPD patients [27].

5.3

Chemokine Antagonists

Several chemokines are implicated in COPD, and there has been a lot of interest in
small molecule chemokine receptor antagonists (Fig. 2) [28]. A blocking antibody
to CXCL8 (interleukin-8) had a small effect in reducing dyspnoea in COPD patients
[29], but other CXC chemokines, such as CXCL1 (GRO-) and CXCL5 (ENA-78),
are also increased in COPD and play a similar role to CXCL8. The chemotactic
effect of CXCL8, CXCL1 and CXCL5 on neutrophils and monocytes is mediated
by a common receptor CXCR2. A CXCR2 antagonist (ADZ8309) has been shown
in a pilot study to inhibit neutrophil inflammation in the lung following ozone
challenge in normal volunteers [30], and preliminary results suggest that it also
reduces sputum neutrophils in COPD patients. This is an oral medication so may
have a particular advantage in COPD patients as it can reach inflammation in
peripheral lungs. Another chemokine receptor target is CXCR3 as the CXCR3
ligands CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC) are increased in

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P.J. Barnes

Fig. 2 Several chemokines and chemokine receptors are involved in the inflammation of COPD.
Chemokines released from epithelial cells and macrophages in the lung recruit inflammatory cells
(Tc1 CD8+ T lymphocytes, neutrophils and monocytes) from the circulation. Small molecule
chemokine receptor antagonists are now in development (shown in boxes)

COPD, and there is an increase in CD4+ and CD8+ T-cells expressing CXCR3
[31]. CXCR3 antagonists have not yet been tested in COPD patients but are
currently in development. CCL5 (RANTES) is also increased in COPD, and
CCR5 antagonists, such as maraviroc, have now been developed for HIV/AIDS
so may be available for testing in COPD.

5.4

TGF- Inhibitors

Transforming growth factor- may play a key role in the fibrosis of small airways,
which is turning out to be a major mechanism for progressive loss FEV1 and
reduced exercise performance in COPD, and may be activated by oxidative stress
and cigarette smoke [32]. TGF--related genes show increased expression in small
airways of COPD patients [33]. Small molecule inhibitors of TGF- receptor
tyrosine kinase (activin receptor-like kinase 5), such as SD-280, have been developed and shown to inhibit airway fibrosis in a model of asthma [34]. However, there
may be long-term concerns about inhibiting TGF-, which plays an important role
in maintaining regulatory T lymphocytes. Many of the effects of TGF- are
mediated via connective tissue growth factor so that inhibiting this cytokine or its
receptor may be a more attractive approach in the future.

What Does the Future Hold for the Therapy of COPD?

135

6 Antiproteases
In COPD there is an imbalance between proteases that digest elastin (and other
structural proteins) and antiproteases that protect against this. This suggests that
either inhibiting these proteolytic enzymes or increasing endogenous antiproteases
may be beneficial and should prevent the progression of emphysema. However,
several proteases are implicated in COPD so that blocking a single enzyme may not
have a therapeutic major effect. Endogenous antiproteases (1-antitrypsin, secretory leukoprotease inhibitor, elafin, tissue inhibitors of MMP) may be given either
in recombinant form or by viral vector gene delivery, but these approaches are
unlikely to be cost-effective as large amounts of protein have to be delivered and
gene therapy is unlikely to provide sufficient protein. A more promising approach is
to develop small molecule inhibitors of proteases, particularly those that have
elastolytic activity. Neutrophil elastase inhibitors have been developed but have
so far all failed in clinical trials [35]. Matrix metalloproteinases (MMPs) with
elastolytic activity are also a target for drug development, and MMP-9 appears to
be the predominant enzyme, which is released from macrophages, neutrophils and
epithelial cells. Non-selective MMP inhibitors, such as marimastat, have major side
effects [36], suggesting that isoenzyme-selective inhibitors or inhaled delivery may
be needed. A dual MMP9/MMP12 inhibitor, AZ11557272, has been shown to
prevent emphysema, small airway thickening and inflammation in guinea pigs
exposed to cigarette smoke over 6 months [37]. MMP-12 has also been implicated
in animal models of COPD, and selective inhibitors have been developed [38].

7 New Anti-inflammatory Treatments


Inflammation in COPD lungs is corticosteroid-resistant so that alternative antiinflammatory approaches are needed (Table 1) [39, 40]. There are several broadspectrum anti-inflammatory treatments in development for COPD, but there are
concerns over the safety of these approaches, since these drugs hit targets that are
widely distributed. This suggests that inhaled delivery may be necessary to increase
the therapeutic ratio.

7.1

Phosphodiesterase-4 Inhibitors

PDE4 is the predominant phosphodiesterase expressed in neutrophils, T-cells and


macrophages, suggesting that PDE4 inhibitors would be effective in controlling
inflammation in COPD [41]. A selective PDE4 inhibitor, roflumilast, inhibits lung
inflammation and emphysema in a smoking model of COPD in mice
[42]. Roflumilast also inhibits T lymphocytes and monocytes as well as structural

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P.J. Barnes

Table 1 New anti-inflammatory treatments in development for COPD


Drug class
LTB4 antagonists
Anti-TNF
CXCR2 antagonists
MMP-9/12 inhibitors
Neutrophil elastase inhibitors
Phosphodiesterase-4 inhibitors
p38 MAP kinase inhibitors
NF-B (IKK2) inhibitors
PI3 kinase-/ inhibitors
PPAR- agonists

Clinical development
Development stopped
Development stopped
In early clinical development
In early clinical development
In early clinical development
Phase III trials but side effects a major limitation
Phase I studies but problems with side effects and toxicity
Preclinical but concerns about side effects
Early clinical development
Already developed for diabetes, clinical studies in progress

cells such as fibroblasts and airway epithelial cell mucus secretion [43]. In COPD
patients, oral roflumilast given over 4 weeks significantly reduces the numbers of
neutrophils (by 36 %) and CXCL8 concentrations in sputum [44]. In clinical trials,
roflumilast (500 mg once daily) given over 12 months improves lung function in
COPD patients to a small extent but has little effect in reducing exacerbations or
improving quality of life [45]. More recently roflumilast has been shown to
significantly improve FEV1 (approximately 50 ml) and reduce exacerbations
(by about 15 %) in patients with severe disease who have frequent exacerbations
and mucus hypersecretion, although disappointingly there was no reduction in
symptoms [46]. Roflumilast provides clinical benefit when added to salmeterol or
tiotropium [47], so may be used as an additional treatment in patients with severe
disease and was recently approved by the FDA to reduce exacerbations in patients
with severe COPD. These results reflect the fact that side effects, particularly
nausea, diarrhoea and headaches, limit the dose that can be tolerated. This problem
could be overcome by inhaled delivery, but to date two inhaled PDE4 inhibitors
have been found to be ineffective, although well tolerated. Another approach is to
develop isoenzyme-selective inhibitors. PDE4D inhibition appears to account for
nausea and vomiting, whereas PDE4B inhibition may account for the antiinflammatory effects, so that PDE4B-selective inhibitors may be better tolerated.
PDE7A is also expressed in the same inflammatory cells as PDE4 so inhibition of
PDE7 may be beneficial. However, a selective PDE7 inhibitor had only a small
anti-inflammatory effect alone but potentiated the anti-inflammatory effects of a
PDE4 inhibitor, suggesting that a combined inhibitor may be useful as it should not
increase side effects [48, 49]. PDE3 inhibitors may produce bronchodilatation so
that dual PDE3/4 inhibitors may combine bronchodilatation with anti-inflammatory
activity [50]. However, there are concerns about the potential cardiovascular
toxicity of PDE3 inhibits so these drugs may also have to be given by inhalation.

What Does the Future Hold for the Therapy of COPD?

7.2

137

NF-B Inhibitors

NF-B regulates the expression of CXCL8 and other chemokines, TNF- and other
inflammatory cytokines as well as MMP9. NF-B is activated in macrophages and
epithelial cells of COPD patients, particularly during exacerbations. Inhibitors of
inhibitor of NF-B kinase(IKK)2 are effective in some animal models of COPD
(LPS exposure) but not in others (neutrophil elastase instillation), indicating that the
effects may be complex [51]. Although several IKK2 inhibitors are now in development, so far none have been tested in COPD patients. A major concern about
long-term inhibition of NF-B is that effective inhibitors may result in immune
suppression and impair host defences, since mice which lack NF-B genes succumb
to septicaemia.

7.3

p38 MAP Kinase Inhibitors

Mitogen-activated protein kinases (MAPK) play a key role in chronic inflammation, and several complex enzyme cascades have now been defined. One of these,
the p38 MAPK pathway, is activated by cellular stress and regulates the expression
of inflammatory cytokines, including CXCL8, TNF- and MMPs. p38 MAPK
(measured by phosphorylated p38 MAPK) is activated in alveolar macrophages
of COPD lungs [52]. Several small molecule inhibitors of p38 MAPK have now
been developed. A potent inhibitor of p38- isoform, SD-282, is effective in
inhibiting TNF- release from human lung macrophages in vitro [53] and in
suppressing inflammation in a smoking model of COPD in mice in which
corticosteroids are ineffective [54]. Several p38 MAPK inhibitors have entered
clinical trials, but there have been major problems with side effects and toxicity,
indicating that it is probably necessary to deliver these drugs by inhalation to reduce
systemic exposure.
Recent studies indicate that other MAPK pathways, particularly extracellular
signal-regulated kinase (ERK1/2), may also play an important role in regulating the
expression of proinflammatory cytokines in alveolar macrophages, in contrast to its
lack of effect in blood monocytes [55].

7.4

Phosphoinositide 3-Kinase Inhibitors

PI3Ks are a family of enzymes that lead to the generation of lipid second
messengers that regulate a number of cellular events, including innate and adaptive
immune responses. A particular isoform, PI3K-, is involved in neutrophil recruitment and activation. Knock-out of the PI3K- gene results in inhibition of neutrophil migration and activation, as well as impaired T lymphocyte and macrophage

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P.J. Barnes

function, so PI3K- inhibitors may be potential anti-inflammatory therapy for


COPD [56]. PI3K- is also involved in expression of inflammatory genes, and
several PI3K- or mixed PI3K-/ inhibitors are now in development [57].
Pan-isoform inhibitors of PI3K are likely to be associated with side effects as
these enzymes appear to serve a number of key cell function, but the - and -
isoforms have a distribution more restricted to leukocytes and may therefore be
better tolerated, especially if delivered by inhalation. PI3K- inhibitors also have
the potential to reverse corticosteroid resistance in COPD patients [58, 59].

7.5

PPAR Activators

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear


hormone receptors belonging to the steroid receptor superfamily, and the three
recognized subtypes PPAR-, PPAR- and PPAR- are widely expressed. There is
evidence that activation of PPAR- and PPAR- may have anti-inflammatory and
immunomodulatory effects. For example, PPAR- agonists, such as troglitazone
and rosiglitazone, inhibit the release of inflammatory cytokines from monocytes
and induce apoptosis of T lymphocytes, suggesting that they may have antiinflammatory effects in COPD [60]. PPAR- agonists also inhibit lung fibrosis
and therefore have the potential to prevent progression of small airway fibrosis in
COPD [61]. There is a reduction in PPAR- expression in skeletal muscle of COPD
patients that correlates with muscular weakness, indicating that PPAR- agonists,
such as clofibrate, may be useful in treating muscle weakness in severe disease [62].

8 Reversal of Corticosteroid Resistance


Even high doses of corticosteroids have minimal effects on the progression of
COPD and no effects on mortality [63]. Even their effect in preventing
exacerbations has been questioned on the basis of flawed study design [40, 64,
65]. This may reflect the resistance of COPD inflammation to the anti-inflammatory
effects of corticosteroids. There is increasing evidence that this may be due to a
reduction in HDAC2 as a result of oxidative and nitrative stress [66]. This results in
increased acetylation of the glucocorticoid receptor which prevents it from
inhibiting NF-B-driven inflammation [67]. A novel therapeutic strategy is therefore reversal of this corticosteroid resistance by increasing the expression and
activity of HDAC2, and this may be achieved in several ways [39].

What Does the Future Hold for the Therapy of COPD?

8.1

139

Theophylline-Like Drugs

Low doses of oral theophylline increase HDAC2 expression in alveolar


macrophages from COPD patients and thereby restore steroid responsiveness [5,
68]. This has also been demonstrated in mice exposed to cigarette smoke, which
develop a steroid-resistant inflammation in the lungs with increased neutrophils and
macrophages. This inflammation is not reversed by high doses of corticosteroids or
by theophylline alone but is reversed by low dose oral or inhaled theophylline
combined with a corticosteroid via an increase in HDAC2 activity [69]. In a pilot
clinical study of COPD patients, a low dose of oral theophylline combined with an
inhaled corticosteroid was more effective in reducing inflammation in sputum than
either drug alone [70]. Understanding the molecular mechanisms of action of
theophylline, which appear to be independent of PDE inhibition, may lead to
novel therapeutic approaches to restoration of corticosteroid responsiveness
which avoid the side effects and drug interaction problems of theophylline itself.
Theophylline appears to reverse steroid resistance by inhibiting oxidant stressactivated PI3K-, so that PI3K- inhibitors may also be effective [58]. The tricyclic
antidepressant nortriptyline also increases HDAC2 and reverses corticosteroids
resistance by inhibiting PI3K-.

8.2

Antioxidants

Oxidative stress is increased in patients with COPD, particularly during


exacerbations, and reactive oxygen species contribute to its pathophysiology.
Oxidative stress reduces steroid responsiveness via a reduction in HDAC2 activity
and expression. This suggests that antioxidants may reverse corticosteroid resistance and also reduce inflammation. Unfortunately currently available antioxidants
based on glutathione are relatively weak and are inactivated by oxidative stress, so
new more potent and stable antioxidants are needed, such as superoxide dismutase
mimics and NADPH oxidase inhibitors [71]. The transcription factor Nrf2 (nuclear
factor erythroid 2-related factor-2) plays a key role in the regulation of endogenous
antioxidant genes and is defective in COPD patients. Several Nrf2 activators, such
as sulforaphane (which occurs naturally in broccoli) and the synthetic triterpenoid
1-[2-cyano-3-,12-dioxooleana-1,9-dien-28-oyl]imidazole-methyl ester, have now
been identified [72].

8.3

Macrolides

It has long been recognized that macrolides have anti-inflammatory effects that may
be independent of their antibiotic effects. Macrolides appear to inhibit inflammation

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P.J. Barnes

by inhibiting NF-B and other transcription factors. A nonantibiotic macrolide


(EM-703) reverses corticosteroid resistance due to oxidative stress by increasing
HDAC2 activity [73]. Several nonantibiotic macrolides are now in development as
anti-inflammatory therapies.

9 Lung Regeneration
Since a major mechanism of airway obstruction in COPD is due to loss of elastic
recoil due to proteolytic destruction of lung parenchyma, it seems unlikely that this
could be reversible by drug therapy, although it might be possible to reduce the rate
of progression by preventing the inflammatory and enzymatic disease process.

9.1

Retinoic Acid

Retinoic acid increases alveolar septation during lung development and in adult rats
and mice reverses the histological and physiological changes induced by elastase
treatment [74]. This has not been seen in several other species, and there are doubts
whether emphysema is reversible in humans as alveolar formation ceases about the
age of 6 years. A clinical trial of all-trans-retinoic and 13-cis-retinoic acid in
patients with emphysema failed to show any improvement in clinical parameters,
health status or CT density after 6 months of therapy [75].

9.2

Stem Cells

Another possible approach to repairing damaged lung in emphysema is the use of


stem cells to seed the lung combined with drugs that stimulate their homing and
proliferation in the lung. Human embryonic stem cells have been transformed into
alveolar type II pneumocytes which have the capacity to repair alveolar damage
[76]. Adult bone marrow-derived stem cells may also be suitable for populating the
lung, particularly if enhanced by retinoic acid or granulocyte-macrophage colony
stimulating factor. However, there are several concerns about the use of stem cells
for lung repair as there may be a problem engrafting these cells in the alveoli and
there is always a risk of cancer or teratoma development [77]. The lung is a
complex organ, and it would probably be necessary to grow both endothelial and
alveolar cells to repair emphysema. Remarkable progress has been made in
reconstructing lung using a lung scaffold that is seeded with endothelial and
epithelial cell precursor cells [78].

What Does the Future Hold for the Therapy of COPD?

10

141

Future Developments

New drugs for the treatment of COPD are greatly needed, and there has been an
enormous effort now invested by the pharmaceutical industry to find such
treatments. While preventing and quitting smoking is the obvious preferred
approach, this has proved to be very difficult in the majority of smokers. Furthermore, it is now recognized that not all COPD is due to cigarette smoking, particularly in developing countries [79]. It is important to identify the genetic factors that
determine why only a minority of heavy smokers develop COPD, and identification
of genes that predispose to the development of COPD may provide novel therapeutic targets in the future. However, it will be difficult to demonstrate the efficacy of
novel treatments on the rate of decline in lung function, since this requires large
studies over 3 years. Hence, there is a need to develop novel outcome measures and
surrogate biomarkers, such as analysis of sputum parameters (cells, mediators,
enzymes) or exhaled condensates (lipid mediators, reactive oxygen species)
[12]. The use of imaging techniques, such as high-resolution computerized tomography (CT), to measure disease progression is another promising approach as
scanning resolution increases [80]. It may also be important to more accurately
define the presence of emphysema versus small airway obstruction using CT scans,
as some drugs may be more useful for preventing emphysema, whereas others may
be more effective against the small airway inflammatory-fibrotic process. More
research on the basic cellular and molecular mechanisms of COPD and on more
useful animal models is urgently needed to aid the logical development of new
therapies for this common and important disease, for which no effective preventative drugs currently exist.
Of the drugs currently in development PDE4 inhibitors, p38 MAP kinase
inhibitors and IKK-2 inhibitors appear to be promising, but there are concerns
about side effects so that inhaled administration is likely to be needed. There are
also concerns about their long-term safety in increasing lung infection and cancer
through inhibition of TNF-. CXCR2 antagonists show promise as an antineutrophilic and anti-macrophage therapy and should be well tolerated by oral
administration. It is likely that effective anti-inflammatory therapies would not only
reduce exacerbations but would also improve symptoms and health status. In the
long-term, these drugs should slow the decline in lung function and prevent the
considerable morbidity imposed by this common disease. Perhaps the most
promising approach is reversal of corticosteroid resistance, which is the main
barrier to effective anti-inflammatory treatments in COPD. Drugs derived from
theophylline may be effective through increasing HDAC2 activity and expression
and should be relatively well tolerated. More potent antioxidants and nonantibiotic
macrolides also deserve further study. However, the mainstay of COPD drug
therapy is likely to remain inhaled long-acting bronchodilators, and fortunately,
this is where progress in drug development has been most successful to date.

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