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+LABA5 Severe 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

Leukotriene receptor antagonist (LTRA)

Low dose theophylline

As-needed short-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 needed SABA or 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 2 0.5

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

Ra

te ra

tio

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)

Eosinophil predominant

(% 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%

An

nu

al e

xa

ce

rba

tion

ra

te

(pa

tie

nt/ye

ar)

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

Δ p

ost-

BD

FE

V1 (L

)

‒0.05

0.05

0.10

* †

0

0.15 * †

Prednisone Budesonide Placebo

Without sputum eosinophilia With 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

Least to most eosinophilic tertile

Least to most eosinophilic tertile -0.3

-0.2

-0.1

0

0.1

0.2

0.3

10

‒0.05

‒0.10

‒0.1 Δ to

tal C

RQ

‒0.2

‒0.3

Δ p

ost-

BD

FE

V1 (

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 elevated risk

with long-term use3

2.0

1.8

1.6

1.4

1.2

1.0

0 10 20 30 40 50 60

Rate

ratio

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

25 P

rob

ab

ility

of p

ne

um

onia

(%

)

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

Number at 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.

Fluticasone 500 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 equivalent dose (µg)

0.4

0.2

0

–0.2

Lo

g (a

dju

ste

d O

R)

0.6

Log (adjusted OR)

95% upper bound: 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 increased with highest doses 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)

Ra

te ra

tio

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 increased inflammatory gene

expression and reduced response to anti-inflammatory actions 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 50/500 µg b.i.d. treatment difference (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)

Pa

tie

nts

exa

cerb

atio

n-f

ree (%

)

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 dose in ICS withdrawal group

0‒6 6–12 12–52 weeks

Daily fluticasone dose in ICS withdrawal group

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

Ad

juste

d m

ea

n c

ha

nge

in F

EV

1 (m

L)

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-square test ICS continuation

ICS withdrawal

1.0

0

0

Estim

ate

d p

rob

ab

ility

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%)

Treatment decision at

initial visit

Treatment received

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

FE

V1 %

pre

dic

ted

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

Pa

tie

nts

exa

cerb

atio

n-f

ree a

fte

r

6 m

on

ths (%

)

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.

Inhaled corticosteroids in COPD: the clinical evidence:Pierre Ernst, Nathalie Saad, Samy Suissa ERS J Published 1 February 2015

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.

Inhaled corticosteroids in COPD: the clinical evidence: Pierre Ernst, Nathalie Saad, Samy Suissa ERS J Published 1 February 2015

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 LABA indacaterol for at least 7 days and all

other LABAs and LABA/inhaled corticosteroid 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. Nanshan Zhong, Changzheng Wang, Xiangdong Zhou. LANTERN: a randomized study of ULTIBRO versus salmeterol/fluticasone combination in patients with

COPD. International Journal of COPD 2015:10 1015–1026

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. Nanshan Zhong, Changzheng Wang, Xiangdong Zhou. LANTERN: a randomized study of ULTIBRO versus salmeterol/fluticasone combination in patients with

COPD. International Journal of COPD 2015:10 1015–1026

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

Nanshan Zhong, Changzheng Wang, Xiangdong Zhou. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD.

International Journal of COPD 2015:10 1015–1026

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 exacerbation history at 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)

Without COPD exacerbation history at 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.

Nanshan Zhong, Changzheng Wang, Xiangdong Zhou. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD.

International Journal of COPD 2015:10 1015–1026

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/salmeterol 6

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-hoc analysis

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 patients will 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

COPD = chronic obstructive pulmonary disease 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

-THANK YOU-

64

role of ics in asthma and copd

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