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Expert Opinion on Pharmacotherapy
ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
Next generation beta adrenoreceptor agonists for
the treatment of asthma
Ernesto Crisafulli, Annalisa Frizzelli, Alberto Fantin, Alessandra Manco,
Angelo Mangia, Giovanna Pisi, Valentina Fainardi, Veronica Alfieri, Marina
Aiello, Giuseppina Bertorelli & Alfredo Chetta
To cite this article: Ernesto Crisafulli, Annalisa Frizzelli, Alberto Fantin, Alessandra Manco, Angelo
Mangia, Giovanna Pisi, Valentina Fainardi, Veronica Alfieri, Marina Aiello, Giuseppina Bertorelli &
Alfredo Chetta (2017) Next generation beta adrenoreceptor agonists for the treatment of asthma,
Expert Opinion on Pharmacotherapy, 18:14, 1499-1505, DOI: 10.1080/14656566.2017.1378348
To link to this article: http://dx.doi.org/10.1080/14656566.2017.1378348
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Published online: 14 Sep 2017.
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REVIEW
Next generation beta adrenoreceptor agonists for the treatment of asthma
Ernesto Crisafulli
a
, Annalisa Frizzelli
a
, Alberto Fantin
a
, Alessandra Manco
a
, Angelo Mangia
a
, Giovanna Pisi
b
,
Valentina Fainardi
c
, Veronica Alfieri
a
, Marina Aiello
a
, Giuseppina Bertorelli
a
and Alfredo Chetta
a
a
Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy;
b
Cystic Fibrotic Centre,
University Hospital, Parma, Italy;
c
Paediatrics Unit, University Hospital, Parma, Italy
ABSTRACT
Introduction: A fixed-dose inhalation of a long-acting β-agonist (LABA) and inhaled corticosteroids
(ICS) is commonly recommended for moderate to severe asthmatic patients not adequately controlled
by an ICS only. In order to improve the patients’adherence and the control of disease there is a
noteworthy interest for the next generation inhaled βadrenoreceptor agonists maintaining an over
24 hours bronchodilatation and used once-daily (ultra-LABAs).
This review focuses on the currently available evidences on the clinical role of any single ultra-LABAs
in the treatment of asthmatic patients.
Areas covered: New ultra-LABAs have been developed in recent years for the treatment of asthma. In
particular, several evidences in asthmatic patients include indacaterol, vilanterol, olodaterol, and
abediterol.
Expert opinion: Pharmacologically, all new ultra-LABAs considered have demonstrated a good ability
to maintain a true bronchodilatation for over 24 hours and a good safety profile. This aspect could be a
key point to improve the patient’s perspective, the adherence to the treatment regimens and therefore
the control of disease. At this time, however, limited data are available and no ultra-LABA+ICS may be
recommended as preferred.
ARTICLE HISTORY
Received 10 June 2017
Accepted 7 September 2017
KEYWORDS
Asthma; long-acting
β-agonist; once-daily;
bronchodilatation; control of
disease
1. Introduction
Asthma is a problem of public health affecting approximately
300 million people worldwide, with a prevalence between 1%
and 18% of population [1,2]. Although a history of typical
recurrent respiratory symptoms such as wheeze, shortness of
breath, chest tightness and dry irritating cough may represent
the clinical key-points manifestations of asthma [1], airway
hyper-responsiveness and chronic inflammation may persist
even when symptoms are absent or without airflow limitation
at spirometry.
Exacerbations of asthma or asthma attacks are worsening
of symptoms and are associated with significant morbidity,
mortality and healthcare costs [3]. Current strategies in asthma
identify the control of disease as a primary objective of treat-
ment, which is achieved by long-term symptoms manage-
ment, preservation of physical level activity, prevention of
risk of asthma attacks, reduction of mortality, maintenance of
lung function, and avoidance of adverse effects from medica-
tions [1,2]. Based on the number and intensity of asthma
manifestations after treatment, asthmatic patients may be
classified as controlled, partly controlled or uncontrolled [1].
Long-acting β-agonists (LABAs) play an important pharma-
cological role in reducing symptoms and induce bronchodila-
tion [4]. However, in asthmatics there are many doubts in their
prescription as monotherapy alone [5]. There are in fact solid
evidences suggesting that treatment with regular daily low
dose of inhaled corticosteroids (ICS) is highly effective in
improving the control of disease [6].
A fixed-dose inhaler of a LABA plus an ICS is a common
medication for chronic respiratory disorders [7], as well in
asthma [8]. However, in asthmatic patients there are discor-
dant conclusions about the real clinical efficacy of a LABA +
ICS in comparison to ICSs alone [9,10]. For this reason, the US
Food and Drug Administration (FDA) recommends reserving
LABAs for patients not adequately controlled by an ICS, with a
long-term use of LABAs limited to asthmatic patients only in
association with ICS and in patients who require prolonged
use of ICS (moderate to severe patients) [11].
Despite the availability of effective management therapies,
many patients continue to have suboptimal control [12], in
part due to failure to adhere to treatment regimens [13]. In
order to improve the patients’adherence and the control of
disease there is a noteworthy interest for the next generation
βadrenoreceptor agonists, that based on a powerful func-
tional antagonism of airways smooth muscle contraction and
a longer half-live guarantee a very long pharmacological effect
(over 24 h) and for this reason may be used once-daily (ultra-
LABAs). At present, several ultra-LABAs are in different stages
of clinical development [4,14].
This review focuses on the currently available evidences on
the clinical role of any single next generation inhaled ultra-
LABAs in the treatment of asthmatic patients.
CONTACT Ernesto Crisafulli ernesto.crisafulli@unipr.it Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of
Parma, Via Rasori 10, 43126 Parma, Italy.
EXPERT OPINION ON PHARMACOTHERAPY, 2017
VOL. 18, NO. 14, 1499–1505
https://doi.org/10.1080/14656566.2017.1378348
© 2017 Informa UK Limited, trading as Taylor & Francis Group
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2. Historical background
The history of bronchodilators in asthma formally starts in the
year 1860 by the identification of Sir Henry Hyde Salter of
smooth muscle contraction as the primary cause of the airway
obstruction [15]: the pathophysiological role of bronchospasm
had open the way for a treatment with bronchodilators medi-
cations and relief of symptoms. Before of Sir Salter, however, in
China the traditional medicine had identified the plant Ephedra
equisetina (The Chinese name for Ephedra species is Ma huang)
from which the alkaloid ephedrine was extracted and used for
the short-term relief of respiratory symptoms [16]. In the year
1901 with the adrenaline, a non-selected alfa (α) and beta (β)
adrenoreceptor agonist, the treatment of asthma patients has
made a step ahead [17]; adrenaline in fact was able to induce a
potent bronchodilation even if associated with cardiovascular
side effects, when systemically administered [17]. The inducted
hypertension and tachycardia (now we known to be related to
the α
1
and β
1
adrenoreceptors in the cardiovascular system), in
fact, had limit the use of this drug in asthmatic patients. In the
following century, the powerful bronchodilator effect of the
adrenaline was separated from cardiovascular action: the iso-
prenaline, maintaining the β
1
with the lost of αactivity had a
more selective βaction. However, the induced tachycardia and
the possible heart arrhythmias still limit the common use in
asthmatic patients. The modern era of a selective β
2
adrenor-
eceptor activity comes with the discovery of the salbutamol by
Sir David Jack and colleagues [18]; thanks to their structural
modifications, more resistant to metabolism from the catecol-
O-metiltrasferasi, the β
2
adrenoreceptor agonists, such as feno-
terol, salbutamol, and terbutaline, obtained a longer half-life
and lost their potency for β
1
agonists. In this context, however,
the short duration of action of these medications (4–6 h) was a
limit in the daily management of asthma. Short-acting β
2
-ago-
nists (SABA), in fact, are highly effective for the quick relief of
asthma symptoms but they should be reserved for patients
with occasional daytime symptoms of short duration and with
normal lung function [1]. With the discovery of molecules able
to have a functional antagonist effect of airway smooth muscle
contraction irrespective of the constricting stimulus, a longer
bronchodilation efficacy is achieved [19] thanks to salmeterol
and formoterol that have open the way for the LABAs.
3. Methods
We performed a systematic search using published articles in
MEDLINE database from inception to 30 April 2017. The fol-
lowing search terms were used: ‘asthma’,‘control’,‘treatment’,
‘medication’,‘adherence’,‘preference’,‘adrenoreceptor ago-
nists’,‘β
2
adrenoreceptors’,‘long-acting β-agonists’,‘LABA’,
‘bronchodilation’,‘bronchodilators’,‘inhaled corticosteroids’,
‘ICS’,‘fixed-dose inhaler’,‘ultra-LABA’,‘indacaterol’,‘vilanterol’,
‘olodaterol’,‘abediterol’,‘once-daily’. The literature search was
limited to the English language.
4. Next generation beta adrenoreceptor agonists
Table 1 reports the characteristics that bronchodilator of a
next generation need to have. These molecules ultra-LABAs
under development include indacaterol, vilanterol, olodaterol,
and abediterol. The chemical structures and specific qualities
of these medications are illustrated in Figure 1 and Table 2,
respectively.
4.1. Indacaterol
Pharmacologically reported as QAB149, indacaterol has been
the first inhaled bronchodilator introducing the ultra-LABA
category. In-vitro and in-vivo preclinical studies on indacaterol
documents a rapid onset of action and a long-term broncho-
dilating effect (true 24 h) [20]. The lipophilicity, potency and
intrinsic efficacy have also been shown to be contributing
factors in regulating in vitro time course profile of this drug
[30]. Indacaterol appears to have a high intrinsic activity at
human β
2
adrenoreceptors in vitro; in fact, the mean maxi-
mum effect (E
max
) for indacaterol has been estimated 73% of
the maximum effect of isoprenaline, compared to 90%, 38%,
and 47% for formoterol, salmeterol and salbutamol, respec-
tively [21]. Similar to formoterol, indacaterol was a very weak
agonist versus the β
1
adrenoreceptors (mean E
max
16% of the
maximal effect of isoprenaline) and a full agonist at the β
3
adrenoreceptors (mean E
max
113%) [21]. Studies with isolated
human bronchi and small airway lung slices showed that
indacaterol behaves as a high efficacy β
2
adrenoreceptors
agonist, with an onset of action that is not significantly differ-
ent from formoterol and salbutamol but significantly faster
than that of salmeterol, and a significantly longer duration of
action than both formoterol and salmeterol [31,32].
In asthmatic patients, the efficacy and safety of indacaterol
has been explored in two large dose trials [33,34]. The first
study enrolling 115 persistent moderate to severe asthmatic
patients [33] had a randomized, double-blind, incomplete-
block, cross-over design to sequences of four 7-days treatment
periods with indacaterol 100, 200, 300, 400, or 600 μgor
Article highlights
●A long-acting β-agonist (LABA) is added to an inhaled corticosteroids
(ICS) in moderate to severe asthmatic patients not adequately con-
trolled by an ICS only;
●The next generation βadrenoreceptor agonists maintain an over 24
hours bronchodilatation and for this reason can be used once-daily
(ultra-LABAs);
●Ultra-LABAs proposed for the treatment of asthma are indacaterol,
vilanterol, olodaterol, and abediterol;
●All the new ultra-LABAs considered maintain a true bronchodilatation
for over 24 hours and have a good safety profile;
●How the long bronchodilatation may improve the patient’s perspec-
tive, the adherence to the treatment regimens and therefore the
control of disease is still not clear.
This box summarizes key points contained in the article
Table 1. Five-points criteria to define a bronchodilator for a next generation.
1. Longer duration of action (>24 h bronchodilator efficacy)
2. Fast onset of action
3. Superior efficacy compared with existing LABAs
4. Favorable safety and tolerability profile
5. Efficient and convenient device
Reproduced with permission from [14].
1500 E. CRISAFULLI ET AL.
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placebo, once daily, via single-dose dry-powder inhaler. Mean
forced expiratory volume in the 1st second (FEV
1
) was mea-
sured for 24 h post-dose at day-1 and at day-7 of the study.
The findings document that once-daily dose 200 μg or more
of indacaterol after a week was more effective than placebo
pre-dose and at all post-dose time points measured trough
FEV
1
[33]; the bronchodilatation was guaranteed for more
than 24 h with a safe profile. In the second trial 436 patients
receiving inhaled corticosteroids for persistent asthma [34]
were randomized to 7 days treatment with once-daily indaca-
terol 50, 100, 200, or 400 μg via multiple-dose dry powder
inhaler and 400 μg via single-dose dry powder inhaler once
daily or placebo. On day-1 and day-7 serial 24 h spirometry
was performed. Although indacaterol 200 μg proved to be the
optimum dose, offering the best efficacy/safety balance, all
doses of drug demonstrated rapid-onset bronchodilatation
over 24 h on once-daily dosing from the first day up to
7 days [34]. In conclusion, once-daily dose of indacaterol
provided sustained 24 h bronchodilation in patients with
moderate to severe asthma, with a satisfactory overall safety
profile.
In clinical practice, indacaterol has been recently pro-
posed for asthmatic patients in a new inhaled once-daily
fixed-dose combination together to an ICS as mometasone
(indacaterol/mometasone or QMF-149) [35,36], demonstrat-
ing 24 h duration of action as monotherapy. A very recent
randomized, double-blind, multicenter, parallel-group study
[37] investigating the efficacy of inhaled indacaterol/mome-
tasone in term of serious asthma exacerbations (hospitalisa-
tions, intubations or deaths for asthma events) have
enrolled adolescents and adults with persistent asthma.
More then 1500 patients were randomized to indacaterol
maleate 500 μg/mometasone 400 μgormometasone
400 μg in a study period until 21 months. Although, the
risk for serious exacerbations was numerically in favor of
indacaterol/mometasone, this reduction was not statistically
significant (hazard risk [HR] 0.31; 95% confidence interval
[CI] 0.06–1.54; p= 0.151); no significant difference was
found in time to first serious exacerbation compared to
mometasone (two events versus six events; difference
−0.52 percentage point; 95% CI −1.25 to 0.21; p=0.160).
A significant effect using indacaterol/mometasone was
found on the annual rate of exacerbations requiring sys-
temic corticosteroids (rate ratio = 0.71; 95% CI 0.55–0.90;
p= 0.005). Similar safety profiles between formulations were
found [37].
4.2. Vilanterol
Also known as GSK-622444, vilanterol is an ultra-LABA with
daily activity developed by the incorporation of an oxygen
atom in the structure of salmeterol; this gives to the vilanterol
a feature of to be a potent, selective β
2
adrenoreceptors
agonist in human functional cellular assays. Moreover, vilan-
terol has greater intrinsic efficacy than salmeterol, greater
potency than indacaterol and salbutamol, and greater β
2
adrenoreceptors selectivity than formoterol, indacaterol, and
salbutamol [22]. In addition, it has been shown using human
recombinant β
1
/β
2
/β
3
adrenoreceptors cAMP assays that vilan-
terol has significantly greater β
2
adrenoreceptors selectivity
than formoterol, indacaterol and salbutamol [22,23].
In clinical practice, vilanterol has been used in persistent
asthmatic patients associated to fluticasone furoate, a novel
inhaled ICS. About vilanterol/fluticase furoate comparable
improvements were produced whether the association was
used in the morning or in the evening [38] and across specific
ethnic patients (Asian ancestry) [39], with a demonstrated very
longer bronchodilator duration of action (until 72 h) [24].
In patients with asthma, who remained symptomatic
despite ICS therapy, vilanterol trifenatate (with different
dosage of 3, 6.25, 12.5, 25, and 50 μg) has been used in a
Figure 1. The chemical structures of the new inhaled ultra-LABAs.
Table 2. New ultra-LABAs and their specific qualities.
Indacaterol Rapid onset of action [20]
Long-term bronchodilatation (>24 h) [20]
High intrinsic activity at human β
2
adrenoreceptors in vitro [21]
Vilanterol β
2
adrenoreceptors selectivity [22,23]
Very longer bronchodilatation (> 72 h) [24]
Olodaterol High selectivity for β
1
and β
2
adrenoreceptors [25,26]
Valuable 24 h bronchodilatation effect [27]
Abediterol High potency of bronchodilation [28,29]
β
1
β
2
adrenoreceptors selectivity [28,29]
Rapid onset and long duration of action [28,29]
EXPERT OPINION ON PHARMACOTHERAPY 1501
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randomized, double-blind, placebo-controlled trial, adminis-
tered once daily by dry powder inhaler for 28 days in combi-
nation with fluticasone furoate [40]. A significant improvement
in mean trough FEV
1
was observed for vilanterol at the doses
between 12.5 and 50 μg; at these dosage the drug was well
tolerated and had a prolonged duration of action of at least
24 h. Based on the overall efficacy and adverse event profile,
this study found the optimum dose of vilanterol to be
25 μg[40].
About the effect of the addition of vilanterol (25 μg), to a
once-daily fluticasone furoate (100 μg) on the risk of severe
asthma exacerbations, a study has been performed in more
than two thousand patients with uncontrolled asthma with a
design of a randomized double-blind comparative study of
variable duration (between 24 and 78 weeks) [41]. Compared
to fluticasone furoate alone, the association between vilan-
terol and fluticasone furoate delayed the time to first severe
exacerbation (HR 0.79, 95% CI 0.64–0.98) and produce an
effect on the annualized rate of severe exacerbations (rate
reduction 25%; 95% CI 5–40%). Significantly greater improve-
ments in trough FEV
1
(p< 0.001) were observed with vilanterol
and fluticasone furoate in comparison to fluticasone at weeks
12, 36, 52, and at endpoint [41].
A 24 weeks, randomized, double-blind, double-dummy,
parallel group study, aimed to compare the efficacy of once
daily vilanterol/fluticasone furoato (25/100 μg) with bid salme-
terol/fluticasone propionate (50/250 μg) has been evaluated in
more than 800 patients with persistent asthma uncontrolled
with a medium dose of ICS [42]. However, the study demon-
strated an improvement from baseline to 24 h of weighted
mean FEV
1
with both formulation of LABA/ICS (in vilanterol/
fluticasone furoate and salmeterol/fluticasone propionate the
improvement was +341 and +377 mL, respectively). The
adjusted mean treatment difference was therefore not statis-
tically significant (−37 mL; 95% CI −88 to 15; p= 0.162).
Moreover, there were no differences between treatment
groups in the asthma control and in the quality-of-life ques-
tionnaire scores [42].
To compare the efficacy and safety of once-daily vilanterol/
fluticasone furoate (25/200 μg) with fluticasone furoate alone
(200 μg) or twice-daily fluticasone propionate (500 μg) in a
period of 24 weeks, 586 patients with moderate-to-severe
persistent asthma have been studied in the year 2014 [43].
In comparison to both groups with fluticasone alone, vilan-
terol/fluticasone furoate demonstrated a significant improve-
ment of trough FEV
1
and weighted mean FEV
1
[43]. These
findings however were not confirmed in another 12 weeks
randomized double-blind trial, published in the same year
[44]. This study found in asthmatic patients significant
improvements in lung function in both groups of vilanterol/
fluticasone furoate (25/100 μg) and fluticasone furoate alone
(100 μg) versus placebo, but not significant improvement of
FEV
1
was found when vilanterol was added to fluticasone
furoate [44]. Similar results demonstrated a failure of efficacy
for the primary endpoint (change from baseline in 24 h of
weighted mean FEV
1
) between vilanterol (change of +359 mL),
salmeterol (change of +283 mL) and placebo (change of
+289 mL) after 12 weeks of treatment in asthmatic patients
who were maintained on a stable background dose of ICS [45].
The safety and tolerability of vilanterol/fluticasone furoate
has been evaluated in a longer period of treatment (52 weeks)
in a randomized study with a ratio of 2:2:1 with once daily
vilanterol/fluticasone furoate (at the dosage of 25/100 μgor
25/200 μg) or twice daily fluticasone propionate 500 μg[46].
In both dosage of 25/100 μg or 25/200 μg, vilanterol/flutica-
sone furoate was well tolerated with an acceptable safety
profile and there were no findings of significant clinical con-
cern [46].
4.3. Olodaterol
Defined as BI 1744 CL, olodaterol is a novel enantiopure
inhaled βagonist characterized by a high selectivity for β
1
and β
2
adrenoreceptors [25,26], able to induce a valuable 24 h
bronchodilatation effect and a demonstrated high intrinsic
efficacy profile for asthma [27]; moreover, related to limited
side effects, olodaterol may be defined as a drug with a very
good safety profile [27]. In vivo, in anesthetized guinea pigs
and dogs for up to 24 h using the Respimat®Soft Mist™
inhaler (Boehringer Ingelheim, Ingelheim, Germany) antago-
nist effects of single doses of olodaterol was measured against
acetylcholine challenges, providing bronchoprotection more
longer antagonistic effects (over 24 h) in comparison to for-
moterol [47]; moreover, in both models olodaterol showed a
rapid onset of action comparable with formoterol [47].
Interestingly, olodaterol has a biphasic dissociation profile
from the human β
2
adrenoreceptors, with the slow compo-
nent (30–40% of the total β
2
adrenoreceptors pool) showing a
half life of dissociation of more than 12 h, providing a ratio-
nale for its long duration of action in human therapy [47]. In
patients with intermittent asthma, olodaterol was evaluated in
a single-dose study that showed significant protection against
methacholine bronchoconstriction compared to placebo for
less than 32 h [48].
In more than 200 patients with moderate to severe asthma,
a phase II, multicenter, randomised, double-blind, placebo-
controlled, crossover trial [49] compared the 24 h time profile
of FEV
1
for 3 weeks with different olodaterol doses (2.5 μg
twice-daily, 5 μg once-daily, 5 μg twice-daily, 10 μg once-
daily). There was a 2-week washout period between treat-
ments. Therefore, in the two sequences of 2.5 μg twice-daily
and 5 μg once-daily a total daily dose of 5 μg of olodaterol
was explored, while in the other two sequences of 5 μg twice-
daily, 10 μg once-daily a total daily dose of 10 μg of olodaterol
was explored. All dosage of olodaterol demonstrated a statis-
tically significant improvement in the FEV
1
of the area under
the curve from 0 to 24 h (AUC 0–24) versus placebo
(p< 0.0001). Olodaterol 5 μg once-daily provided numerically
lower mean values for 24 h bronchodilation than olodaterol
2.5 μg twice-daily (p= 0.0465), with no statistically significant
difference between treatment with olodaterol 10 μg once-
daily and 5 μg twice-daily. The adverse events were generally
of mild to moderate seevrity and comparable between treat-
ment groups [49].
In patients with asthma in ongoing ICS, the efficacy and
safety of once-daily olodaterol (2, 5, 10, and 20 μg) for 4 weeks
was evaluated in two recent multicenter studies both
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published in the year 2015 [50]. The first was a randomized,
double-blind, parallel-group study including 296 asthmatic
patients in which olodaterol was administered in the morning;
a statistically significant increase in the response of the trough
FEV
1
with olodaterol 20 μg versus placebo (+147 mL; 95% CI
59–234 mL; p= 0.001) was found with more limited efficacy
and no evidence of dose response compared to placebo
across the other olodaterol doses (2, 5, and 10 μg) [50]. In
the second randomized, double-blind, placebo- and active-
controlled (formoterol 12 μg twice daily) crossover study
including 198 asthmatic patients, olodaterol was administered
in the evening. In 4 weeks of treatment, olodaterol demon-
strated an increasing FEV
1
AUC 0–24 responses with all active
treatments (p< 0.0001) with an increasing adjusted mean
difference from placebo for increasing doses of drug
(+140 mL [95% CI, 97–182 mL], +182 mL [140–224 mL],
+205 mL [163–248 mL], and +229 mL [186–272 mL] for olo-
daterol at the dosage of 2, 5, 10, and 20 μg, respectively, and
+169 mL [126–211 mL] for formoterol. Olodaterol was gener-
ally well tolerated with few events mainly associated to dose
of 20 μg[50].
4.4. Abediterol
Also known as LAS100977, abediterol is a novel, once-daily,
selective ultra-LABA and its pharmacological properties have
recently been reported [28,29]. These consist in the high
potency of bronchodilation (is 10 times more potent than
salmeterol and similar to formoterol and indacaterol) and in
aβ
1
β
2
adrenoreceptors selectivity, with rapid onset and long
duration of action [28,29]. The onset of action of abediterol
was 10 min, faster than salmeterol and indacaterol (19 and
14 min, respectively) but slower than formoterol (6 min). In
anaesthetized guinea pigs, abediterol was also the most
potent compound, with 5–20 times higher bronchoprotective
potency than other once-daily LABAs against acetylcholine.
The bronchoprotective half-life of abediterol in guinea pigs
was 36 h compared with 51 h for indacaterol, 47 h for oloda-
terol, and 18 h for vilanterol. Moreover, abediterol showed
greater safety index than olodaterol and vilanterol [28,29].
For the first time in the year 2014, in a randomized, parallel,
single-blind, placebo controlled study conducted in Germany,
has been evaluated the safety, tolerability, pharmacokinetics,
and pharmacodynamics of a single, escalating doses of abedi-
terol (5, 10, 25, and 50 μg) in 48 healthy male subjects [51]. For
all doses tested and for all time-points up to 36 h, in compar-
ison to placebo, abediterol showed an increase of airways
conductance and a decrease in airways resistance. An overall
good safety and tolerability profile in the dose range tested
was found; however, a dose-dependent increase of systemic
treatment-emergent adverse events was observed (palpita-
tions, tremor, nausea, and asthenia), although mild in intensity
and resolved without the need for intervention [51].
In patients with persistent mild to moderate asthma, a
phase IIa, randomized, double-blind, placebo- and active-con-
trolled (salmeterol), crossover study has been designed to
investigate the single doses of abediterol (5, 10, and 25 μg)
added to ongoing maintenance therapy with ICS [52]. All three
abediterol doses induced statistically significant increases in
trough FEV
1
versus placebo and salmeterol (primary end-
point); moreover, improvements in other lung function para-
meters were also found in all abediterol doses versus both
placebo (p< 0.0001) and salmeterol (p< 0.05) than the first
assessment at 5-min post-dose and were sustained to 36 h
post-dose. The adverse events occurred exclusively in patients
who received abediterol 10 or 25 μg[52].
In 62 patients with mild-to-moderate asthma who were
also receiving an ICS another phase II, randomized, double-
blind, double-dummy, crossover, placebo-controlled, dose-
ranging study to determine the abediterol doses with similar
peak bronchodilatory effect to salbutamol 400 μg, and dura-
tion of action compatible with once-daily dosing was per-
formed [53]. The study arms were related to patients
receiving single doses of abediterol (0.313, 0.625, 1.25, or
2.5 μg), salbutamol 400 μg, or placebo. A dose-dependent
improvement in peak FEV
1
from baseline compared with
placebo, from 274 mL (95% CI, 221–327mL)to405mL
(353–458 mL) for abediterol 0.313 to 2.5 μg was found,
respectively (p< 0.0001 all doses). Abediterol 0.625, 1.25,
and 2.5 μg had similar magnitude of peak FEV
1
effect to
salbutamol (primary endopoint). All abediterol doses
achieved significant improvements versus placebo in FEV
1
AUC 0–6, 0–12, and 0–24 h, and peak and trough FVC
(p< 0.05). Treatment-related adverse events were evident
in less than 10% of patients (most common were headache
and nasopharyngitis) [53].
5. Conclusion
In moderate to severe patients with asthma the inhaled corti-
costeroids (ICS) is the milestone of the treatment. In patients
not adequately controlled by an ICS only a fixed-dose inhala-
tion of a long-acting β-agonist (LABA) plus ICS is commonly
recommended, although there are discordant conclusions
about the real clinical efficacy of this association in compar-
ison to an ICS alone [9,10]. Recently, there is a noteworthy
interest for the next generation βadrenoreceptor agonists
maintaining an over 24 h bronchodilatation (ultra-LABAs)
and new molecules have been developed in the last years
for the treatment of asthma. In particular, evidences are
related to the use of indacaterol, vilanterol, olodaterol, and
abediterol.
6. Expert opinion
In moderate to severe asthmatics several different factors
reduce adherence to therapy and in particular factors related
to complex medical treatments requiring different drugs, the
complexity of dosage and the different devices used for inha-
lation therapy [6]. In patients using ICS several interventions
have been proposed to improve adherence, although the
clinical relevance of these improvements, highlighted by
inconsistent impact on clinical outcomes such as control of
disease, is less clear [54].
New ultra-LABAs considered, as well the LABAs, can be
prescribed in asthmatics only in association with ICS, although
further confirmations need to be clarified on what really these
new ultra-LABAs add if used in association to ICS and in what
EXPERT OPINION ON PHARMACOTHERAPY 1503
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asthmatic patients the association of an ultra-LABAs plus ICS
may have more efficacies. In general, several studies about
new ultra-LABAs have focalized as primary aim the ability to
maintain a true bronchodilatation for over 24 h, and this by to
the improvement of a ventilatory parameter (trough FEV
1
);
pharmacologically, at this time, for indacaterol, vilanterol, olo-
daterol, and abediterol this feature of long bronchodilaltion is
confirmed. And this without particular side effects.
Nevertheless, how the improvement of the trough FEV
1
by
the use of ultra-LABAs may improve the adherence to therapy
and to be crucial for the control of disease has not yet been
fully clarified or demonstrated. The feature of long broncho-
dilatation (>24 h), in fact, could be a key element to improve
the patient’s perspective, the adherence to the treatment regi-
mens and therefore the control of disease [6,54]. Simplify the
therapeutic plan by a possible reduction of the number of
daily doses could be a key point for uncontrolled asthmatics
[55]. Asthmatic patients may have a drug-specific preference
that should be considered in the therapeutic plan and the
better patient’s perspective include a once-daily dose. At this
time, however, limited data are available on the how much the
use of a new ultra-LABA may improve the adherence of
patients and how much this may improve the control of
disease; moreover, no ultra-LABA plus ICS may be recom-
mended as preferred [56]. We think that further confirmations
are needed to determine whether the features of an ultra-
LABA is able to translate the patient’s perspective in an
improvement of clinical outcomes.
Funding
This paper was not funded.
Declaration of Interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
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