Beruflich Dokumente
Kultur Dokumente
AlexandreTrifilieff Editor
Indacaterol
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
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
Library of Congress Control Number: 2013954835
Springer Basel 2014
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Preface
Alexandre Trifilieff
Contents
25
39
67
77
93
vii
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
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
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
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
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
2.5
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
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
3.3
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
4.2
Clinical Benefits
4.3
4.4
Roflumilast
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
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
11
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
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
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
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
(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.
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
16
5.4
Methylxanthine + ICS
17
18
19
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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
25
26
A. Trifilieff et al.
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].
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
28
A. Trifilieff et al.
Table 1 Functional properties for the marketed inhaled 2-adrenoceptor agonists at the human
adrenoceptors
Selectivity ratio
Isoprenaline
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.
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
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
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
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
33
34
A. Trifilieff et al.
35
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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25. Charles MS, Blanchette CM, Silver H, Lavallee D, Dalal AA, Mapel D (2010) Adherence to
controller therapy for chronic obstructive pulmonary disease: a review. Curr Med Res Opin
26:24219
26. Han MK (2009) Medication adherence in COPD: what have we learned? Thorax 64:9223
27. Horne R (2006) Compliance, adherence, and concordance: implications for asthma treatment.
Chest 130:65S72
28. Partridge MR, Miravitlles M, Stahl E, Karlsson N, Svensson K, Welte T (2010) Development
and validation of the capacity of daily living during the morning and global chest symptoms
questionnaires in COPD. Eur Respir J 36(1):96104
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29. Partridge MR, Karlsson N, Small IR (2009) Patient insight into the impact of chronic obstructive pulmonary disease in the morning: an internet survey. Curr Med Res Opin 25:20438
30. Partridge MR, Schuermann W, Beckman O, Persson T, Polanowski T (2009) Effect on lung
function and morning activities of budesonide/formoterol versus salmeterol/fluticasone in
patients with COPD. Ther Adv Respir Dis 3:111
31. Naline E, Trifilieff A, Fairhurst RA, Advenier C, Molimard M (2007) Effect of indacaterol, a
novel long-acting 2-agonist, on isolated human bronchi. Eur Respir J 29:57581
32. Sturton RG, Trifilieff A, Nicholson AG, Barnes PJ (2008) Pharmacological characterization of
indacaterol, a novel once daily inhaled 2 adrenoceptor agonist, on small airways in human and
rat precision-cut lung slices. J Pharmacol Exp Ther 324:2705
33. Anderson GP, Linden A, Rabe KF (1994) Why are long-lasting 2-adrenoceptor agonists longlasting? Eur Respir J 7:56978
34. 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 (2010) The
identification of indacaterol as an ultra-long-acting inhaled 2-adrenoceptor agonist. J Med
Chem 53:367584
35. Rhodes DG, Newton R, Butler R, Herbette L (1992) Equilibrium and kinetic studies of the
interactions of salmeterol with membrane bilayers. Mol Pharmacol 4:596602
36. Lombardi D, Cuenoud B, Kramer SD (2009) Lipid membrane interactions of indacaterol and
salmeterol: do they influence their pharmacological properties? Eur J Pharm Sci 38:53347
37. Sykes DA, Charlton SJ (2012) Slow dissociation from receptors is not a key factor in the
duration of action of inhaled long acting 2-adrenoceptor agonists. Br J Pharmacol 165
(8):267283
38. Sin DD (2004) Therapeutic options for chronic obstructive pulmonary disease: present and
future. Eur Rev Med Pharmacol Sci 8:24758
39. Sutherland ER (2004) Outpatient treatment of chronic obstructive pulmonary disease:
comparisons with asthma. J Allergy Clin Immunol 114:71524
40. Koumis T, Samuel S (2005) Tiotropium bromide: a new long-acting bronchodilator for the
treatment of chronic obstructive pulmonary disease. Clin Ther 27:37792
41. Summerhill S, Stroud T, Nagendra R, Perros-Huguet C, Trevethick M (2008) A cell-based
assay to assess the persistence of action of agonists acting at recombinant human beta
(2) adrenoceptors. J Pharmacol Toxicol Methods 58:18997
42. McNamara A, Pulido-Rios MT, Hegde SS, Martin WJ (2011) Application of the classical
Einthoven model of bronchoconstriction to the study of inhaled bronchodilators in rodents.
J Pharmacol Toxicol Methods 63(1):8995
43. Disse B, Speck GA, Rominger KL, Witek TJ Jr, Hammer R (1999) Tiotropium (Spiriva):
mechanistical considerations and clinical profile in obstructive lung disease. Life Sci 64:45764
44. Voss HP, Donnell D, Bast A (1992) Atypical molecular pharmacology of a new long-acting
beta 2-adrenoceptor agonist, TA 2005. Eur J Pharmacol 227:4039
45. Szczuka A, Wennerberg M, Packeu A, Vauquelin G (2009) Molecular mechanisms for the
persistent bronchodilatory effect of the beta 2-adrenoceptor agonist salmeterol. Br J Pharmacol
158(1):18394
46. Vauquelin G, Charlton SJ (2010) Long-lasting target binding and rebinding as mechanisms to
prolong in vivo drug action. Br J Pharmacol 161(3):488508
47. Battram C, Li J, Coulthard A, Hardaker L, Poll C, Askey-Sarvar A, Trifilieff A (2009)
Indacaterol does not blunt the effect of salbutamol in vivo. Am J Respir Crit Care Med 179:
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48. Hawkins GA, Weiss ST, Bleecker ER (2008) Clinical consequences of ADRbeta2
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49. Yelenski R, Li Y, Lewitzky S, Leroy E, Hurwitz C, Rodman D, Trifilieff A, Paulding CA
(2012) A pharmacogenetic study of ADRB2 polymorphisms and indacaterol response in
COPD Patients. Pharmacogenomics J 12:4848
HN
HO
indacaterol
5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one
N
H
OH
39
40
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
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
42
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
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
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
46
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.
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
48
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
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
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
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
52
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
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
53
54
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
12
0.5
0
H
Me
Et
n-Pr
n-Bu
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
55
56
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
58
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
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
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.
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
62
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.
63
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67
68
1.1
69
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].
2.1
70
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.
2.2
71
2.3
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
72
2.4
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
73
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
74
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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obstructive pulmonary disease. Am J Respir Crit Care Med 180:74150
13. Nelson HS (2006) The salmeterol multicentre asthma research trial: a comparison of usual
pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 129:1526
14. Battram C, Charlton SJ, Cuenoud B, Dowling MR, Fairhurst RA, Farr D et al (2006)
In vitro and in vivo pharmacological characterization of 5-[(R)-2-(5,6-diethyl-indan-2-
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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
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41. 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 23:16571
42. Donohue JF, Fogarty C, Lotvall J, Mahler DA, Worth H, Yorgancioglu A et al (2010) Oncedaily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus
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43. Chapman KR, Rennard SI, Dogra A, Owen R, Lassen C, Kramer B (2011) Long-term Safety
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44. Kerwin EM, Gotfried MH, Lawrence D, Lassen C, Kramer B (2011) Efficacy and tolerability
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45. Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D et al (2010) Efficacy of a new
once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in
COPD. Thorax 65:4739
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.
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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.
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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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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85
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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D. Lawrence et al.
threshold
MCID
(1h-4h)
For
Ind 75
Ind 150
Ind 300
Ind 600
(Y)
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
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
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
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
Active Control
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
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.
89
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.
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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
p-value
0.900
0.009
0.493
0.662
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.
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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
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
94
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
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.
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
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
a
1.6
99
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
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
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
103
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
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)
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])
105
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
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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
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
109
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)
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
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
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
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.
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5. Celli BR, MacNee W (2004) ATS/ERS Task Force. Standards for the diagnosis and treatment
of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 23:932946
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7. Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D, Bleasdale P, Owen R,
Higgins M, Kramer B, INVOLVE (INdacaterol: Value in COPD: Longer Term Validation
of Efficacy and Safety) Study Investigators (2010) Efficacy of a new once-daily long-acting
inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax 65:473479
8. 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 182:155162
9. Kornmann O, Dahl R, Centanni S, Dogra A, Owen R, Lassen C, Kramer B (2011) Once-daily
indacaterol vs twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir
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lung hyperinflation in patients with COPD. Eur Respir J 34:E4357
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pulmonary disease. Eur Respir J 27:822832
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
117
118
D. Young et al.
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
119
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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D. Young et al.
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
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].
121
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].
122
D. Young et al.
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
4.1
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).
124
D. Young et al.
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]
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
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.
126
D. Young et al.
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.
127
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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
130
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].
131
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.
5.1
133
Lipid Antagonists
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.
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].
7.1
Phosphodiesterase-4 Inhibitors
136
P.J. Barnes
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.
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
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
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
7.5
PPAR Activators
8.1
139
Theophylline-Like Drugs
8.2
Antioxidants
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
140
P.J. Barnes
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
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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P.J. Barnes
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