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Mundipharma Research Ltd, Cambridge Science Park, Milton Road, Cambridge, Cambs CB4 0GW, UK
SkyePharma AG, Eptingerstrasse 61, 4132 Muttenz, Switzerland
KEYWORDS
Asthma management
Clinical trial data
Combination therapy
Fluticasone propionate
Formoterol fumarate
Single-aerosol inhaler
Summary
International asthma management guidelines recommend a long-acting b2 -agonist (LABA) as
add-on therapy in patients whose asthma is not controlled by low-dose inhaled corticosteroid
(ICS) monotherapy. Treatment with a single inhaler containing an ICS/LABA combination is
advocated because it may facilitate adherence to a regimen. When prescribing ICS/LABA
combination therapy, the potency of the ICS and the speed of onset of the LABA are
considered important factors; therefore, an inhaled therapy containing components with
these properties may be valued by physicians. The ICS uticasone propionate (uticasone)
has potent and sustained anti-inammatory effects, and the LABA formoterol fumarate
(formoterol) provides rapid bronchodilation; the efcacy and safety proles of these agents
have been well established in clinical practice. Fluticasone and formoterol have been
combined, for the rst time, in a single hydrouoroalkane-based aerosol (utiform ;
uticasone propionate/formoterol fumarate). Here, we review data from the published
randomized, controlled, clinical trials that demonstrate the efcacy and tolerability of this
product. It has been shown that uticasone/formoterol is more efcacious than uticasone
or formoterol given alone, and provides similar improvements in lung function to uticasone
and formoterol administered concurrently via separate inhalers. Fluticasone/formoterol
has similar efcacy and tolerability proles to budesonide/formoterol and uticasone/
salmeterol, but with the additional benet of more rapid bronchodilation than uticasone/
salmeterol.
2012 Elsevier Ltd. All rights reserved.
Introduction
International asthma management guidelines recommend
that a long-acting b2 -agonist (LABA) is prescribed as an
add-on therapy for patients whose asthma is not controlled
by low-dose inhaled corticosteroid (ICS) monotherapy.1
A substantial evidence base shows that co-administration
of a LABA and an ICS results in better clinical effectiveness
than that achieved with an ICS alone.2 4 It has also been
shown that the addition of a LABA to existing low-dose
ICS therapy is more effective at reducing the risk of a
* Corresponding author.
Tel.: +44 1223 424 900; fax: +44 1223 425 794.
E-mail address: Sanjeeva.Dissanayake@
mundipharma-rd.eu (S. Dissanayake).
0954-6111/$
S21
with a LABA.27 This review provides an overview of
the published data from a comprehensive clinical trial
programme that demonstrates the efcacy and tolerability
proles of uticasone/formoterol.
S22
the uticasone/formoterol treatment group discontinued
therapy due to lack of efcacy (6.1%) compared with
the uticasone, formoterol or placebo groups (7.7%, 11.2%
and 16.2%, respectively).43
Fluticasone/formoterol provided a signicant reduction
in rescue medication use compared with uticasone alone
(p = 0.008). Fluticasone/formoterol also provided greater
improvement than uticasone alone in several clinically
meaningful secondary endpoints, such as decrease in
symptom-free days (p = 0.027) and asthma control days
(p = 0.017). Although these endpoints had a p value of
0.05 versus uticasone alone, they were not considered
statistically signicant per the sequential gatekeeper
approach used in the study.43
In the second study, which assessed medium-dose
uticasone/formoterol versus its individual components
administered alone, 557 adolescent and adult patients
with asthma (40 80% predicted FEV1 at baseline) were
randomly assigned to treatment with uticasone/formoterol
(medium dose, 250/10 mg b.i.d. for the co-primary endpoints), uticasone alone (250 mg b.i.d.), formoterol alone
(10 mg b.i.d.) or placebo; patients were also assigned
to a uticasone/formoterol exploratory group (low dose,
100/10 mg b.i.d.); all treatments were administered via an
HFA-based pMDI (EudraCT number: 2006-005989-39; US NCT
number: NCT00393952).42
Medium-dose uticasone/formoterol was superior to
formoterol administered alone for change in mean FEV1
from pre-dose at baseline to pre-dose at week 12
(LS mean between-treatment difference: 0.189 L; 95% CI:
0.079, 0.298; p < 0.001). Similarly, uticasone/formoterol
was superior to uticasone monotherapy for change in
mean FEV1 from pre-dose at baseline to 2 hours post-dose at
week 12 (LS mean between-treatment difference: 0.146 L;
95% CI: 0.042, 0.250; p = 0.006). As described previously,
these data are indicative of the relative contributions of the
uticasone and formoterol components to the improvements
in lung function observed with uticasone/formoterol.
Medium-dose uticasone/formoterol also demonstrated a
signicantly longer time to discontinuation due to lack of
efcacy (assessed as either an asthma exacerbation or a loss
of asthma control) than placebo (p < 0.001). Furthermore,
fewer patients in the uticasone/formoterol treatment
group discontinued therapy due to lack of efcacy (10.2%)
than in the uticasone, formoterol or placebo groups
(12.8%, 20.9% and 39.0%, respectively).42
Analysis of clinically meaningful secondary endpoints also
supported the greater efcacy of uticasone/formoterol
compared with uticasone monotherapy. Fewer patients
in the uticasone/formoterol group had an exacerbation
of any severity (p = 0.030) than in the uticasone-alone
group. In addition, uticasone/formoterol was associated
with more rescue-medication-free days (p = 0.042) and
more asthma control days (dened as days with an
asthma symptom score indicating no symptoms; p = 0.027)
than uticasone alone. Although these endpoints had a
p value of 0.05 versus uticasone alone, they were
not considered statistically signicant per the sequential
gatekeeper approach used in the study.42
S. Dissanayake et al.
In both studies described above, uticasone/formoterol
had a tolerability prole similar to that of its individual
components. Adverse events (AEs) were mostly mild-tomoderate in severity, with a numerically smaller proportion
of patients in the uticasone/formoterol group reporting
treatment-emergent AEs compared with those in the
uticasone, formoterol or placebo groups.42,43
S23
0.5
(a)
0.4
0.3
0.2
0.1
0
0
4
Treatment week
0.6
0.5
(b)
0.4
0.3
0.2
Fluticasone/formoterol 500/20 g b.i.d. (n = 132)
Fluticasone 500 g b.i.d. + formoterol 24 g b.i.d. (n = 138)
0.1
4
Treatment week
Figure 1. Fluticasone/formoterol administered as a combination therapy via a single inhaler has an efcacy prole similar to that
of its components administered concurrently (uticasone + formoterol). Data show (a) the mean change in morning predose forced expiratory volume in 1 second (FEV1 ) from baseline to week 8, and (b) change in morning pre-dose FEV1
from baseline to 2 hours post-dose at week 8, for the per-protocol population.46 b.i.d., twice daily. Figures adapted from
Bodzenta-Lukaszyk A, Pulka G, Dymek A, Bumbacea D, McIver T, Schwab B, Mansikka H, Efcacy and safety of uticasone
and formoterol in a single pressurized metered dose inhaler. Respiratory Medicine 2011;105(5):674 82. Copyright 2011,
with permission from Elsevier.
S24
S. Dissanayake et al.
LS mean difference: 4.70% (95% CI: 1.57, 7.83); p = 0.003
25
(a)
20
*
*
15
10
5
0
0
10
60
Time from dosing (minutes)
90
120
25
(b)
30
20
15
10
30
60
Time from dosing (minutes)
90
5
0
0
10
120
Figure 2. Fluticasone/formoterol provides more rapid bronchodilation than uticasone/salmeterol. Values are shown as percentage
change in least-squares (LS) mean forced expiratory volume in 1 second (FEV1 ) from morning pre-dose at baseline
standard error. *p 0.05. Data from a post hoc analysis are shown for the full analysis set. Improvement in lung function
was assessed by change in FEV1 from morning pre-dose at 5, 10, 30, 60, 90 and 120 minutes post-dose, on (a) day 0
and (b) day 84.48 Figure reproduced with kind permission from Springer Science+Business Media B.V. from Figure 2 of
Aalbers R, Brusselle G, Bodzenta-Lukaszyk A, Onset of bronchodilation with uticasone/formoterol combination versus
uticasone/salmeterol in an open-label, randomized study. Advances in Therapy 2012;29(11):958 69.
treatment (odds ratio [OR]: 4.0; 95% CI: 2.0, 8.0). Moreover,
the odds of achieving bronchodilation at 5 minutes after
dosing were almost tenfold greater with uticasone/
formoterol after 12 weeks treatment (OR: 9.6; 95% CI:
2.1, 42.9).48 Fluticasone/formoterol also provided greater
increases than uticasone/salmeterol in LS mean post-dose
FEV1 in the 2 hours following dosing, both on day 0 and
after 12 weeks (overall change on day 0: 17.3% versus 12.6%,
respectively, p = 0.003; day 84: 8.9% versus 6.2%, p = 0.011)
(Fig. 2).48
Fluticasone/formoterol and uticasone/salmeterol demonstrated similar efcacy for other lung function parameters, rescue medication use, asthma symptom scores, sleep
disturbance scores, asthma exacerbations and health status
scores. Fluticasone/formoterol had a similar tolerability
prole to that of uticasone/salmeterol.47
80
Deposition (%)
S25
60
40
20
0
0.5
Alveolar
Bronchial
Extra-thoracic
Total
10
20
Size (m)
S26
formoterol aerosol are indicative of the potential for
high drug deposition in the lung, an effective regional
lung deposition pattern and a favourable oropharyngeal to
pulmonary deposition ratio. The consistent delivery of a high
ne particle fraction with uticasone/formoterol may be a
useful characteristic in an inhaled therapy, because patients
often exhibit variability in inhalation ow rate in the dayto-day use of their inhaler.
S. Dissanayake et al.
Conict of interest statement
S.F., B.G. and S.D. are employees of Mundipharma
Research Limited. K.K. is an employee of SkyePharma AG.
Prescribing information
Prescribing information can be obtained from:
http://www.medicines.org.uk/emc/medicine/26954
Conclusions
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Acknowledgments
The authors thank Sarah Fletcher for her advice and
comments during the development of the paper. The
authors wish to thank Oxford PharmaGenesis Limited
(Oxford, UK) for providing medical writing and editorial
support. This work was arranged and funded by Mundipharma International Limited (Cambridge, UK).
Funding
This paper forms part of a supplement commissioned and
funded by Mundipharma International Limited entitled
A new combination therapy for asthma; bridging the gap
between effectiveness in trials and clinical practice? The
supplement contains papers based on presentations from
an advisory meeting of health-care professionals held on
22 June 2010, which was also arranged and sponsored
by Mundipharma International Limited. All participants
received travel expenses and an honorarium from
Mundipharma International Limited for their attendance
and participation in the advisory meeting.
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