Role of ICS in Asthma and COPD

Prof. Gamal Rabie Agmy, MD, FCCP
Professor of Chest diseases, Assiut University
Fairmont Nile City, Cairo 5/5/2016
Role of ICS in Asthma & COPD

 Asthma is a heterogeneous disease, usually
characterized by airflow inflammation.
 It is defined by the presence of respiratory
symptoms such as
• Wheezes.
• Shortness of breath.
• Cough .
• that vary overtime and in intensity, together with variable
airflow limitation.
What is Asthma? (GINA 2014)
Global strategy for Asthma management and prevention guidelines 2014.

Asthma: Burden
 Asthma is a problem worldwide, with an estimated
300 million affected individuals
 The global prevalence of asthma ranges from
1% to 18% of the population in different countries
 The World Health Organization has estimated that asthma
represents 1% of the total global disease burden
 Annual worldwide deaths from asthma have been
estimated at 250,000.

| Asthma Medical Training | Raed Darwish | Dec 2015 | Business Use Only
Severe allergic asthma
is a chronic condition,
which, when uncontrolled,
has a serious impact on
quality of life, morbidity,
mortality and health
expenditure
Asthma has serious consequences
~50,0000
hospitalisations each
year in Europe for people
with severe asthma2
40%
of patients with asthma have
moderate-severe disease1
Inflammation causing:
1. Wheezing
2. Breathlessness
3. Chest tightness
4. Coughing
15,000
people die each year from
asthma attacks in Europe2
• Of 195 UK asthma-related
deaths 2012-13:
• 17% = allergic asthma3
• 39% = severe asthma3
$6,022
mean cost over 12 months
for a patient with
asthma that is uncontrolled
despite ICS+LABA5Severe asthma accounts
for >50% of total costs
despite being 5-10% of total asthma patients 6,7
~300 million
people have
asthma worldwide4
22nd
in the ranking of
disease burden worldwide4
1| Asthma Medical Training | Raed Darwish | Dec 2015 | Business Use Only
5

GINA GUIDLINES 2014
Step 1 Step 2
Step 3
Step 4
Step 5
Consider
low dose
ICS
low dose ICS
Leukotrienereceptorantagonist(LTRA)
Low dose theophylline
As-neededshort-acting beta2-agonist
(SABA)
Low dose
ICS/LABA
Med/high
dose ICS
Low dose
ICS+LTRA
(or + theo.)
Med/high
ICS/LABA
High dose
ICS+LTRA
(or + theo.)
Refer for
add-on
treatment
e.g.
Anti-Ige
Add low
dose OCS
As neededSABAor low dose
ICS/Formoterol
Preferred
controller
choice
Other
controller
choice
Reliever
Before stepping up, always check inhaler technique,
adherence and key issues first
Stepwise Approach for
Optimal Asthma
management

ICS in Asthma
 ICS with or without LABA, continue to be the mainstay of
pharmacological treatment for mild to moderate asthma.
 Inhaled corticosteroids (ICS) are by far the most
effective controllers used in the treatment of asthma.
 The only drugs that can effectively suppress the
characteristic inflammation in asthmatic airways, even in
very low doses.
Pharmaceuticals 2010, 3, 514-540

ICS in Asthma (cont’d)
 ICS are the recommended first-line therapy for
persistent asthma of all severities and patients of all ages
and are the most effective asthma medications
currently available.

Role of ICS in Asthma
 ICS can reverse the specific chronic airway inflammation
present in asthma.
 ICS reduce the number of mast cells, macrophages,
T-lymphocytes and Eosinophils in the sputum, broncho-
alveolar lavage and bronchial wall.
 ICS reverse the shedding of epithelial cells, goblet-cell
hyperplasia and basement-membrane thickening
characteristic of the airway mucosa of patients with
asthma.
Eur J Clin Pharmacol (2009) 65:853–871

Source: Peter J. Barnes, MD
Asthma Inflammation: Cells and Mediators

ICS in Asthma
Cellular Effects

 When taken regularly, inhaled corticosteroids:
• Effectively control everyday asthma symptoms.
• Improve lung function.
• Decrease the risk for exacerbations.
Fernando D Martinez et al,Lancet 2013; 382: 1360–72

 Controlled trials have consistently shown that
inhaled corticosteroids are better than leukotriene
receptor antagonists, such as montelukast, at :
• Controlling symptoms
• Improving lung function
• Reducing exacerbations
Fernando D Martinez et al, Lancet 2013; 382: 1360–72

 Several clinical trials have shown that patients who are
still symptomatic after treatment with inhaled
corticosteroids benefit from the addition of a LABA.
 A larger proportion of such patients respond better to
adding LABAs than to doubling the dose of inhaled
corticosteroids or adding a leukotriene receptor
antagonist.
Adding LABA is better than increasing ICS dose
Fernando D Martinez et al,Lancet 2013; 382: 1360–72

LABA with ICS for Asthma Management
 ICS therapy in combination with long acting inhaled beta
agonists (LABA) represents the most important treatment
for asthma.
 ICS therapy forms the basis for treatment of asthma of all
severities, improving asthma control, lung function and
preventing exacerbations of disease.
Eur J Clin Pharmacol (2009) 65:853–871

Anti-inflammatory Effects of β2-agonists in Asthma
 β2-agonists not only cause bronchodilation, but also exert anti-
inflammatory effects as has been shown in many in vitro studies.
 These effects include:
• Inhibition of the oxidative burst and release of thromboxane and leukotriene
C4 from Eosinophils.
• Inhibition of mediator release from circulating neutrophils.
M van den Berge at al ,Clinical Medicine:Therapeutics 2009:1 77–93

LABA / ICS for Asthma Management
 Adding a LABA is more effective than increasing the dose
of ICS in terms of improving asthma control and
reducing exacerbations.1
 Use of inhaled corticosteroids plus Formoterol, a fast-
onset LABA, has proven to be effective in preventing
exacerbations.2
1- Pharmaceuticals 2010, 3, 514-540
2-Fernando D Martinez et al,Lancet 2013; 382: 1360–72

Interaction between β2-agonists and ICS
 Corticosteroids can interact with β2-agonists in a
beneficial way, since they prevent desensitization.
Effects of β2-receptors on Corticosteroids
 β2-agonists are capable of potentiating the anti-
inflammatory actions of corticosteroids.
Effects of corticosteroids on β2-receptors
M van den Berge at al ,Clinical Medicine:Therapeutics 2009:1 77–93

April 2015_GMCC_NP4_GLRESP/COPD/0012o
ICS role in COPD

Recommendations for ICS are largely based on preventative
effect on exacerbations
 Use of ICS is associated with an 18% relative risk reduction in occurrence of
exacerbations1
• The commonly cited MCID for change in exacerbation frequency is a 20% reduction2
CI = confidence interval; ICS = inhaled corticosteroid
MCID = minimal clinically important difference 1. Agarwal et al. Chest 2010; 2. Calverley. COPD 2005
1 20.5
Study 1: 1.00
Study 2: 1.00
Study 3: 0.63
Study 4: 0.75
Study 5: 0.66
Study 6: 0.93
Study 7: 0.66
Study 8: 0.51
Study 9: 0.82
Study 10: 1.11
Study 11:0.91
Fixed:0.84
Random: 0.82
ICS Placebo
Rateratio

COPD exacerbation phenotypes and responsiveness
to steroids
 This observational, 1-year study of 182 exacerbations in 86 patients identified
four distinct biologic COPD exacerbation phenotypes
• Eosinophil-predominant phenotype is most responsive to
corticosteroid treatment
COPD = chronic obstructive pulmonary disease Bafadhel et al. Am J Respir Crit Care 2011
Th 2
Th 1
Proinflammatory
Bacteria predominant
(sputum IL-1β)
Eosinophilpredominant
(% peripheral eosinophils)
Viral predominant
(CXCL10)
Pauci-inflammatory
Biologic phenotype
(clinical biomarker)

Post-hoc analysis suggests that blood eosinophils are a
potential biomarker of ICS effectiveness in reducing
exacerbation rates
 Further research is required to help establish blood eosinophilia as a
biomarker for treatment response
COPD = chronic obstructive pulmonary disease
EOS = eosinophil; FF/VI = fluticasone furoate/vilanterol
ICS = inhaled corticosteroid; VI = vilanterol Pascoe et al. Lancet Respir Med 2015
0.7
0.9
1.1
1.3
1.5
EOS <2% EOS ≥2%
Annualexacerbationrate
(patient/year)
FF/VI all doses
VI 25 μg
0.79
n=795
0.89
n=299
0.91
n=1,583
1.28
n=500
29% difference
p<0.0001
10% difference
p=0.283
0

Sputum eosinophilia and response to budesonide in COPD
 Changes in post-bronchodilator FEV1 in patients with or without sputum
eosinophilia
Leigh et al. Eur Respir J 2006
Δpost-BDFEV1(L)
‒0.05
0.05
0.10
* †
0
0.15
* †
PrednisoneBudesonidePlacebo
Withoutsputum eosinophiliaWith sputum eosinophilia
*p<0.05 within group (sputum eosinophilia) vs placebo;
†p<0.05 between groups (with vs without sputum eosinophilia). Data are mean (SE)
BD = bronchodilator; COPD = chronic obstructive pulmonary disease
FEV1 = forced expiratory volume in 1 second; SE = standard error

Sputum eosinophilia and response to mometasone in COPD
 Response to treatment with mometasone compared with placebo for each
tertile of eosinophils in induced sputum
*p<0.05 vs placebo. Data are mean (SE). BD =
bronchodilator
COPD = chronic obstructive pulmonary disease;
CRQ = chronic respiratory disease questionnaire;
FEV1 = forced expiratory volume in 1 second Brightling et al. Thorax 2005
*
-0.10
-0.05
0.00
0.05
0.10
0.15
0.20
Leastto most eosinophilic tertile
Leastto most eosinophilic tertile
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
1
0
‒0.05
‒0.10
‒0.1
ΔtotalCRQ
‒0.2
‒0.3
Δpost-BDFEV1(L)
0.05
0.10
0.15
0.20
0
0.1
0.2
0.3

Risks associated with ICS use in COPD

Risks associated with ICS use in COPD
 Previous data have indicated an increased risk of pneumonia among patients
with COPD receiving ICS1
 Evidence for an association between ICS use and pneumonia in patients with
COPD has grown in recent years:2,3
CI = confidence interval; ICS = inhaled corticosteroid
1. Crim et al. Eur Respir J 2009; 2. Yawn et al. Int J
Chron Obstruct Pulmon Dis 2013; 3. Suissa et al. Thorax
2013
Evidence for sustained elevatedrisk
with long-term use3
2.0
1.8
1.6
1.4
1.2
1.0
0 10 20 30 40 50 60
Rateratio
Duration of ICS use in months
Rate ratio for ICS use vs non-ICS use represented
by solid line; dashed lines represent 95% CI
Evidence for a dose-response relationship2
Hazard ratio (95% CI)
Increased risk (compared with no ICS)Decreased risk
High ICS dose
Moderate ICS dose
No ICS (reference)
1.38 (1.27, 1.49)
p<0.001
1.69 (1.52, 1.88)
p<0.001
2.57 (1.98, 3.33)
p<0.001
(vs no ICS use)
Low ICS dose
0 1 2 3 4

25Probabilityofpneumonia(%)
0 24 48 72 96 120 156
1,544 1,117 947 587
1,552 1,189 992 574
1,542 1,214 1,024 645
1,546 1,231 1,034 631
Numberat risk
Placebo
Fluticasone
Salmeterol
SFC
Time to pneumonia (weeks)
HR (SFC vs placebo)1.64
(95% CI 1.33, 2.02)
20
15
10
5
0
TORCH study: SFC combination and risk of pneumonia
b.i.d. = twice daily; CI = confidence interval; SFC = salmeterol/fluticasone propionate
HR = hazard ratio TORCH = Towards a Revolution in COPD Health Crim et al. Eur Respir J 2009
Salmeterol 50 μg b.i.d.
Fluticasone500 μg b.i.d.
Placebo
SFC 50/500 μg b.i.d.

Increased risk (compared with no ICS)Decreased risk
High ICS dose
Moderate ICS dose
No ICS (reference)
1.38 (1.27, 1.49)
p<0.001
1.69 (1.52, 1.88)
p<0.001
2.57 (1.98, 3.33)
p<0.001
(vs no ICS use)
Use of ICS and risk of pneumonia: dose-response relationship
CI = confidence interval; ICS = inhaled corticosteroid Yawn et al. Int J Chron Obstruct Pulmon Dis 2013
Low ICS dose
0 1 2 3 4

ICS use and risk of bone fractures in COPD patients
Meta-analysis of inhaled corticosteroids versus controls for fractures in observational
studies; Odds ratio (OR) represented by solid line; dashed lines represent 95%
confidence intervals; COPD = chronic obstructive pulmonary disease; ICS = inhaled
corticosteroid Loke et al. Thorax 2011
0 500 1000 1500 2000 2500
Beclomethasone equivalentdose (µg)
0.4
0.2
0
–0.2
Log(adjustedOR)
0.6
Log (adjusted OR)
95% upperbound:log OR
95% lower bound:log OR
Prediction

Diabetes risk may be increased with ICS use in patients with
COPD
 In an observational cohort study (n=388,584), the risk of
diabetes associated with ICS use was investigated
 In total, 30,167 patients had diabetes onset during the
5.5-year follow-up
 The onset and progression of diabetes increased in
patients with COPD receiving ICS1
• Increased risk of diabetes: RR 1.34 (95% CI 1.29,1.39)
• Rate of diabetes progression: RR 1.34 (95% CI 1.17,1.53)
• Risk of diabetes increasedwith highestdoses of ICS
CI = confidence interval; COPD = chronic obstructive pulmonary disease
ICS = inhaled corticosteroid; RR = rate ratio Suissa et al. Am J Med 2010

ICS use and diabetes risk in patients with COPD:
effect of dose
Suissa et al. Am J Med 2010
3.0
2.5
2.0
1.5
1.0
0.5
0 250 500 750 1000 1250 1500 1750 2000
Daily dose in fluticasone equivalents(µg)
Rateratio
3.5
Adjusted rate ratio of diabetes incidence associated with ICS use; Rate ratio
represented by solid line; dashed lines represent 95% confidence intervals.
COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid

Correct diagnosis is key
to deciding the treatment strategy,
which differs between asthma and COPD.

There are now good scientific reasons why even high doses
of ICS fail to reduce inflammation in COPD patients.
 This corticosteroid-resistance has been demonstrated by
the failure of high doses of ICS to reduce
inflammatory markers in sputum or bronchial biopsies of
COPD patients.
Peter J. Barnes Respiration 2010;80:89–95

Possible reasons for corticosteroid resistance
 The reason for the extreme corticosteroid resistance in
COPD may be due to a marked reduction in the nuclear
enzyme histone deacetylase-2 (HDAC2), which is
required for corticosteroids to switch off activated
inflammatory genes that are associated with histone
acetylation
Peter J. Barnes Respiration 2010;80:89–95

Possible mechanisms for decreased HDAC-2 activity in
smokers with asthma and COPD.
Respiratory Medicine (2012) 106, 319-328
Inactivation of HDAC-2 results in increasedinflammatorygene
expressionand reduced response to anti-inflammatoryactions of
corticosteroids.

Glucocorticoids have been reported not to reduce, but even to
increase, neutrophils numbers in induced sputum
 Corticosteroids inhibit neutrophils apoptosis at
clinically relevant drug concentrations and the effect
seems to be mediated through glucocorticoid receptors.
 Accordingly, oral and inhaled corticosteroids have
been reported to increase neutrophils numbers in the
lung tissue.
European Journal of Pharmacology 431(2001)365–371
Journal of Chronic Obstructive Pulmonary Disease, 5:163–169

Can ICS be withdrawn safely?

INSTEAD study design
b.i.d. = twice daily; FEV1 = forced expiratory volume in 1 second
TDI = transition dyspnea index; SGRQ = St George’s Respiratory
Questionnaire; q.d. = once daily; SFC = salmeterol/fluticasone
propionate Rossi et al. Eur Respir J 2014
SFC 50/500 µg b.i.d.
Indacaterol 150 µg q.d.
Randomization (1:1)
Continue on SFC or
switch to indacaterol
SFC 50/500 µg
b.i.d.
Run-in/screening
SFC 50/500 µg
b.i.d.
2 weeks≥3 months
Visits: Weeks 4, 8
Primary endpoint
• Trough FEV1 at Week 12 (non-inferiority)
Secondary endpoints include:
• Lung function
• Breathlessness (TDI)
• Health status (SGRQ)
26-week blinded treatment

INSTEAD: switch from SFC 50/500 µg b.i.d. to indacaterol
150 µg q.d. had no clinically relevant effect on lung function
PPS (all patients in FAS without major protocol deviations) was used for primary efficacy analysis.
FAS included all randomised patients who received at least one dose of study drug, and was used
for all secondary analyses. Non-inferiority demonstrated if 95% CI for difference between
indacaterol and SFC was above –0.06 (i.e. to right of dashed rule)
b.i.d. = twice daily; CI = confidence interval; FAS = full analysis set; LSM = least-squares mean
q.d. = once daily; FEV1 = forced expiratory; volume in 1 second; PPS = per-protocol set (primary
analysis); SFC = salmeterol/fluticasone propionate Rossi et al. Eur Respir J 2014
LSM treatment difference in trough FEV1 after 12 weeks
Indacaterol 150 µg q.d. versus SFC 50/500µg b.i.d. treatmentdifference(L)
Trough FEV1
Primary analysis
(PPS)
Secondary analysis
(FAS)
Difference (95% Cl)
–0.009
(–0.045,0.026)
–0.014
(–0.046,0.019)
–0.09 –0.06 –0.03 0.00 0.03

Time to first moderate or severe COPD exacerbation to Week 26
Hazard ratio: 0.80, p=0.258
Indacaterol 150 µg q.d.
SFC 50/500 µg b.i.d.
100
80
60
40
20
0
1 2 3 4 5
Time to first exacerbation(months)
Patientsexacerbation-free(%)
6
INSTEAD: switch from SFC to indacaterol did not increase
risk of moderate-to-severe exacerbations
b.i.d. = twice daily; q.d. = once daily
SFC = salmeterol/fluticasone propionate Rossi et al. Eur Respir J 2014
0

WISDOM study design
b.i.d. = twice daily; ICS = inhaled corticosteroid
q.d. = once daily Magnussen et al. N Engl J Med 2014
Salmeterol 50 µg b.i.d.
+ fluticasone 500 µg b.i.d.
Tiotropium 18 µg q.d. +
salmeterol 50 µg b.i.d.
Randomization (1:1)
Continue on triple or
withdraw ICS in a stepwise manner
Run-in/screening
Tiotropium 18 ug q.d.
+ salmeterol 50 ug b.i.d.
+ fluticasone 500 µg b.i.d.
6 weeks
52-week blinded treatment
Reduced
to 500 µg
Reduced
to 200 µg
Reduced
to 0 µg (placebo)
Daily fluticasone dosein ICS withdrawalgroup
0‒6 6–12 12–52 weeks

Daily fluticasone dosein ICS withdrawalgroup
Reduced
to 500 µg
Reduced
to 200 µg
Reduced
to 0 µg (placebo)
ICS continuation
ICS withdrawal
0
–20
–40
–60
–80
0 6 12 18 52
p<0.001
p=0.001
Adjustedmeanchange
inFEV1(mL)
Week
Number at risk:
ICS continuation 1,223 1,135 1,114 1,077 970
ICS withdrawal 1,218 1,135 1,092 1,058 935
WISDOM: ICS withdrawal led to a small but significant
reduction in FEV1 versus ICS continuation in patients
with severe COPD
b.i.d. = twice daily; COPD = chronic obstructive pulmonary disease
FEV1 = forced expiratory volume in 1 second
ICS = inhaled corticosteroid; q.d. = once daily Magnussen et al. N Engl J Med 2014

Number at risk:
ICS continuation 1,243 1,059 927 827 763 694 646 615 581 14
ICS withdrawal 1,242 1,090 965 825 740 688 646 607 570 19
WISDOM: withdrawal of ICS did not increase the risk of
moderate or severe exacerbations in patients with severe
COPD
b.i.d. = twice daily; CI = confidence interval; COPD = chronic obstructive pulmonary
disease; FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid Magnussen et al. N Engl J Med 2014
Moderate or severe COPD exacerbation
Hazard ratio, 1.06 (95% CI 0.94, 1.19)
p=0.35 by Wald’s chi-squaretest
ICS continuation
ICS withdrawal
1.0
0
0
Estimatedprobability
Weeks to event
0.2
0.4
0.6
0.8
6 12 18 24 30 36 42 48 54

OPTIMO study design
 Prospective, real-life study: physicians prescribed treatment as they saw fit
• Aim: to investigate whether withdrawal of ICS in COPD patients at low risk of
exacerbation is linked to a deterioration in lung function and symptoms and to a
higher frequency of exacerbations.
ICS = inhaled corticosteroid; LABA = long-acting β2-
agonist Rossi et al. Respir Res 2014
914 patients on
LABA+ ICS
Remained on ICS:
n=482 (59.1%)
No ICS
n=334 (40.9%)
Remained on ICS:
n=546 (59.7%)
Changed to no ICS
n=368 (40.3%)
Treatmentdecision at
initial visit
Treatmentreceived
at Month 6 visit
Tiotropium (27%)
Indacaterol (29%)
Formoterol or salmeterol (15%)
Tiotropium/indacaterol (20%)
Other (9%)

OPTIMO: lung function was similar for a bronchodilator-only
regimen versus remaining on LABA/ICS therapy at
6 months
 914 patients at low risk of an exacerbation treated with a LABA/ICS
• Of these, 59.7% of patients continued with LABA/ICS; the remaining 40.3% had their
ICS withdrawn and treatment with bronchodilator monotherapy or dual therapy was
instituted*
*LABA; LAMA; LABA/LAMA; short-acting bronchodilators and/or theophylline
FEV1 = forced expiratory volume in 1 second
ICS = inhaled corticosteroid; LABA = long-acting β2-agonist
LAMA = long-acting muscarinic antagonist Rossi et al. Respir Res 2014
p=0.752
100
0
No ICS
FEV1%predicted
80
60
40
20
ICS
72.5 72.1

OPTIMO: withdrawal of ICS in COPD did not increase risk of
exacerbations versus a bronchodilator-only regimen
*Patients with moderate airflow limitation (forced expiratory volume in 1 second >50%
predicted); †LABA; LAMA; LABA/LAMA; short-acting bronchodilators and/or theophylline
ICS = inhaled corticosteroid; LABA = long-acting β2-agonist
LAMA = long-acting muscarinic antagonist Rossi et al. Respir Res 2014
Withdrawal of ICS can be safe in COPD patients at low risk of exacerbation*,
provided maintenance treatment with bronchodilators† is continued
p=0.347
100
0
No ICS
Patientsexacerbation-freeafter
6months(%)
80
60
40
20
ICS
74.0 71.0

Inhaled corticosteroids in COPD: the clinical
evidence:Pierre Ernst, Nathalie Saad, Samy Suissa
ERS J Published 1 February 2015
In this article, we focus on the scientific evidence from
randomised trials supporting treatment with inhaled
corticosteroids (ICS) in chronic obstructive pulmonary
disease (COPD), including treatment with combinations of
long-acting β-agonist (LABA) bronchodilators and ICS. Our
emphasis is on the methodological strengths and limitations
that guide the conclusions that may be drawn.

evidence:Pierre Ernst, Nathalie Saad, Samy Suissa
The evidence of benefit of ICS and, therefore, of the
LABA/ICS combinations in COPD is limited by major
methodological problems. From the data reviewed herein,
we conclude that there is no survival benefit independent of
the effect of long-acting bronchodilation and no effect on
FEV1 decline, and that the possible benefit on reducing
severe exacerbations is unclear. Our interpretation of the
data is that there are substantial adverse effects from the
use of ICS in patients with COPD, most notably severe
pneumonia resulting in excess deaths.

evidence: Pierre Ernst, Nathalie Saad, Samy Suissa
Currently, the most reliable predictor of response to ICS in
COPD is the presence of eosinophilic inflammation in the
sputum. There is an urgent need for better markers of
benefit and risk that can be tested in randomised trials for
use in routine specialist practice. Given the overall safety
and effectiveness of long-acting bronchodilators in subjects
without an asthma component to their COPD, we believe
use of such agents without an associated ICS should be
favoured.

Clinical efficacy of IND/GLY in COPD

What is QVA 149 ?
 ULTIBRO is an inhaled once-daily fixed-dose combination
of a LABA (indacaterol) and a LAMA (glycopyrronium
bromide) in a single inhaler, developed for use in COPD.
 The dry-powder formulation of ULTIBRO is suitable for
once-daily dosing via the Breezhaler® device.
 ULTIBRO has been approved for the management of
COPD in the EU and in a number of countries worldwide,
including Australia, Japan, Canada and Singapore.

Effect of IND/GLY on COPD Exacerbations

IND/GLY significantly improved important patient outcomes
vs monotherapies and LABA/ICS
1. Wedzicha et al. Lancet Respir Med 2013
2. Bateman et al. Eur Respir J 2012
3. Vogelmeier et al. Lancet Respir Med 2013
4. Mahler et al. ATS 2013 Abstract
Dyspnea
Quality of
Life(SGRQ)
Rescue
medication
Exacerbations
Lung Function

LANTERN Study design
Before the run-in period,patients discontinued LAMAs and the LABAindacaterolforat least7 days and all
otherLABAs and LABA/inhaledcorticosteroid combinations for 48 hours.o.d., once-daily
26-week,multicenter,randomized,double-blind,double-dummy,parallel-group,active controlled study
Pre-randomization period
Pre-screening Run-in period
Day -21 to
Day -15
Day -14 to
Day -1
Treatment Period
IND/GLY110/50 μg o.d.
via the Breezhaler® Device
Day 1 to Day 184
Randomization (1:1)
Salmeterol/Futicasone 50/500 μg b.i.d.
via the Accuhaler® Device
30 Days
Post-treatment
follow-up
1. NanshanZhong,ChangzhengWang,XiangdongZhou.LANTERN:a randomizedstudyof ULTIBRO versus salmeterol/fluticasone combinationin patients with
COPD.InternationalJournalof COPD 2015:101015–1026

IND/GLY significantly lowered moderate or severe COPD
exacerbations versus SFC, with a risk reduction of 31%
Moderate or severe COPD exacerbations
IND/GLY
(n=372)
SFC
(n=369)
Number of exacerbations per patient ( n [%])
0 328 (88.2) 301 (81.6)
1 35 (9.4) 55 (14.9)
2 9 (2.4) 13 (3.5)
3 0 0
≥4 0 0
Total number of exacerbations 53 81
Total number of treatment years 179.2 174.9
Rate of exacerbations per year 0.30 0.46
Treatment comparison vs. SFC
Ratio of rate (95 % CI) 0.69 (0.48, 1.00)*
*p<0.05
1. NanshanZhong,ChangzhengWang,XiangdongZhou.LANTERN:a randomizedstudyof ULTIBRO versus salmeterol/fluticasone combinationin patients with
COPD.InternationalJournalof COPD 2015:101015–1026

IND/GLY significantly prolonged the time to first moderate or
severe exacerbation by 35% compared with SFC
 Kaplan-Meier plots of the time to first moderate or severe COPD exacerbation
over 26 weeks of treatment (full analysis set)
IND/GLY
IND/GLY
NanshanZhong,Changzheng Wang,Xiangdong Zhou.LANTERN:a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD.
InternationalJournalof COPD 2015:101015–1026

IND/GLY reduced rate of moderate or severe exacerbation,
irrespective of baseline exacerbation history
Treatment Annualized rate (95% CI) Comparison Rate ratio 95% CI p-value
With COPD exacerbationhistoryat baseline
IND/GLY (n=61) 0.49 (0.29, 0.82) IND/GLY - SFC 0.60 (0.33, 1.08) 0.086
SFC (n=93) 0.81 (0.56, 1.19)
WithoutCOPD exacerbationhistoryat baseline
IND/GLY (n=311) 0.23 (0.16, 0.33) IND/GLY - SFC 0.76 (0.46, 1.24) 0.266
SFC (n=276) 0.30 (0.21, 0.43)
Rate ratio, its 95% CI, and p-value are from a negative binomial regression model: log (exacerbation
rate)=treatment+baseline ICS use (yes/no)+baseline total symptom score+FEV1 reversibility components. Log (length of
time in the study) is included in the model as an offset term. CI, confidence interval.
NanshanZhong,Changzheng Wang,Xiangdong Zhou.LANTERN:a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD.
InternationalJournalof COPD 2015:101015–1026

IND/GLY SIGNIFICANTLY REDUCED THE RATE OF
MODERATE OR SEVERE EXACERBATIONS
SIGNIFICANT
RISK REDUCTION OF
31%
Annualized rate of moderate or severe exacerbations
IND/GLY (n=372) vs.
fluticasone/salmeterol (n=369)
MODERATE OR SEVERE
EXACERBATIONS
vs.fluticasone/salmeterol6
BENEFITS vs.
fluticasone/salmeterol
IND/GLY significantly prolonged the time to first moderate or severe exacerbation and
reduced the hazard of having such exacerbations by 35% vs. fluticasone/salmeterol
(P=0.028) 6
P=0.048

IND/GLY SIGNIFICANTLY REDUCED THE RATE OF
MODERATE OR SEVERE EXACERBATIONS
SIGNIFICANT
REDUCTION OF
69%SEVERE
EXACERBATIONS
vs.fluticasone/salmeterol 6
P=0.023
Annualized rate of severe exacerbations
BENEFITS vs.
fluticasone/salmeterol
IND/GLY (n=372)vs
fluticasone/salmeterol(n=369)
IND/GLY reduces the rate of severe exacerbations vs. fluticasone/salmeterol6
* In a post-hocanalysis

Where does dual bronchodilation fit?
 For patients in GOLD Groups B, C, and D, a LABA/LAMA combination is
included as an alternative choice option1
Which patientswill benefit from dual bronchodilation?
 The IGNITE Phase III clinical program showed superior efficacy on a variety of
outcomes (including lung function, dyspnea, health status) to placebo and
active comparators in patients in Groups A, B, and D2–7
• In particular, ILLUMINATE highlighted the potential of LAMA/LABA therapy to replace
and provide superior efficacy to ICS/LABA in GOLD Group B patients2
1. GOLD 2013; 2. Vogelmeier et al. Lancet Respir Med 2013
3. Bateman et al. Eur Respir J 2013; 4. Wedzicha et al. Lancet Respir Med
2013
5. Beeh et al. BTS 2012 Abstract; 6. Mahler et al. ATS 2013 Abstract;
7. Dahl et al. Respir Med 2013; 8. Adelphi DSP 2011
Importance of Dual Bronchodilation
In Conclusion.....

When should physicians consider stepping up or
switching to dual bronchodilation?
 Physicians recognize symptomatic patients who require treatment
change and also for ‘not well controlled’ and ‘symptomatic’ patients8
 The GOLD 2013 strategy advocates more focus on symptoms that
may improve patient outcomes, if adhered to1
Importance of Dual Bronchodilation
In Conclusion.....

Summary
 ICS use is associated with benefits in lung function, HRQoL and exacerbation
risk
 However, ICS use was found to be associated with increased risk pneumonia,
bone fracture and diabetes
 Real-world prescription data indicate that ICS are prescribed to patients with all
severities of COPD, contrary to GOLD recommendations
 Withdrawal of ICS may be warranted and appropriate in some patients
• Studies have shown no increased risk of moderate-to-severe exacerbations following
ICS withdrawal in patients with moderate COPD and no exacerbation history if
appropriate bronchodilator therapy is in place
GOLD = Global initiative for chronic Obstructive Lung Disease
HRQoL = health-related quality of life
ICS = inhaled corticosteroid

Dual bronchodilation : summary
 The GOLD 2015 strategy document recommends combining
bronchodilators in Groups B−D in order to optimize symptom benefits
 β2-agonists and muscarinic antagonists target different sites and modes
of action
 Several studies have shown that LAMA/LABA free combinations
provide greater bronchodilation than LAMA or LABA monotherapy,
which translated in greater improvements in important clinical outcomes
 QVA149 is an inhaled fixed-dose combination indacaterol and
glycopyrronium approved for the treatment of COPD
LABA= long-acting β2-agonist; LAMA = long-acting muscarinic antagonist

Role of ICS in Asthma and COPD

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