dual bronchodilation in copd

Prof. Gamal Rabie Agmy , MD, FCCPDual Bronchodilation in COPD

Patients with COPD have the symptoms of chronic bronchitis and emphysema. Which of the following morphologic patterns of emphysema is typically most severe in the upper lobes?

1-Centriacinar emphysema2-Panacinar emphysema3-Distal acinar emphysema4-Paraseptal emphysema

Which of the following is independently associated with an increased risk for all-cause mortality in patients with COPD?

1-Asthma2-Bronchiectasis3-Underweight status

4-Depression

Which of the following is generally recognized as the most significant symptom of COPD?

1-Productive cough2-Pulmonary hypertension3-Cor pulmonale4-Breathlessness

Which of the following studies provides the best clues to the acuteness and severity of disease exacerbation?

1-Serum chemistry evaluation2-Alpha1-antitrypsin measurement3-Arterial blood gas (ABG) analysis

4-Sputum evaluation

Which of the following is accurate regarding the treatment of patients with COPD?

1-Pneumococcal vaccines are contraindicated in patients with COPD2-Intravenous alpha1-antitrypsin levels should be kept at 8-10 mmol/L3-Long-term oxygen therapy is recommended for patients with a partial pressure of oxygen in arterial blood <55 mm Hg or oxygen saturation <86%4-Because cardiovascular disease is common in patients with COPD, beta-blockers are indicated in all patients

COPD is caused by inhaled noxious agents, with lung damage leading to airflow limitation

Inhaled noxious agents(e.g. cigarette smoking, pollutants)

Obstruction and airflow limitation

Lung damage

Small airway disease: Airway narrowing

and fibrosis

Mucus hyper secretion

(chronic bronchitis)

Parenchymal destruction:

Loss of alveolar attachments, decrease

in elastic recoil (emphysema)

GOLD 2014

Tissue Repair

InflammationOxidative stress

Impaired Quality of Life

InactivityDeconditioning

Hyperinflation

Death

Dyspnea

DecreasedExercise Capacity

Exacerbations

BRONCHODILATOR(pivotal)

THE PRIMARY PHYSIOLOGIC IMPAIRMENT IN COPD IS AIRFLOW LIMITATION

Rabe K et al. PATS 2006;3:270–5.

Expiratory airflow obstruction

Reduced recoil Reduced tethering Increased airways resistance

PL = translung pressure; V = ventilation

Airflow limitation includes irreversible and partially reversible components Irreversible components include1,2

Alveolar destruction - loss of elastic recoil Destruction of alveolar attachments - maintain patency of small airways Small airway fibrosis

Partially reversible components include1,2

- Accumulation of mucus - Smooth muscle bronchoconstriction2

- Inflammatory infiltrate in airway mucosa

1. GOLD 2009; 2. Brusasco Eur Respir Rev 2006

Airflow limitation in COPD reduced elastic recoil leads to hyperinflation

Normal COPD

Reduced IC

Impaired chest wall and diaphragm mechanics

Relationship between static lung volumes and disease severity.

Air trapping and lung hyperinflation were shown to occur even in the earliest stages of COPD and increased exponentially with severity of airway obstruction

Expert Rev. Respir. Med. 6(6), 651–662 (2012)

RV: Residual volume

Breathlessness exists in all GOLD stages Pr

opor

tion

of s

ubje

cts

(%)

Agusti et al Respir Res 2010

GOLD II

GOLD III

GOLD IV

mMRC Score

Decreased exercise tolerance in all GOLD stages

Spruit et al Respir Med 2010

Perc

ent

Distance walked (meters)

GOLD II

GOLD III

GOLD IV

Patients avoid dyspnoea by becoming less active, leading to a dyspnea/inactivity downward spiral

Adapted from Reardon et al. Am J Med 2006 ZuWallack R. COPD 2007

Becomes more sedentary to avoid

dyspnoea-producing activity

(decreases activity)

Dyspnoea with activities

Deconditioning aggravates dyspnoea;

patients adjust by reducing activity further

The dyspnea inactivity downward spiral

V

BD

Air flow Deflation

Improvement in flow – FEV1

Improvement in volumes – FVC and IC

Bronchodilator therapy deflates the lung

BD = bronchodilator; V = ventilation; FEV1= forced expiratory volume in 1 second;FVC= forced vital capacity; IC = inspiratory capacity

Rationale for combination

LAMA + LABA

• Further benefits expected in—Lung function—Symptoms—Exercise tolerance

• Similar safety profile as individual therapies anticipated• Increased convenience: patient only needs 1 inhaler

LAMA monotherapy LABA monotherapy

Proskocil BJ et al. Proc Am Thorac Soc. 2005;2(4):305-310.

SMC relaxationSMC contraction

M3- muscarinicreceptors

Beta Agonists(LABA)Antocholinergics

(LAMA)β2-adrenergic

receptors

Mechanisms of action of bronchodilators onairway smooth muscle

Serching for Maximal Bronchodilation

1.5

1.4

1.3

1.2

1.1

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24

09:00 h 15:00 h 21:00 h 03:00 h 09:00 h

FEV 1

(L)

Time (hours)

-2

*

*

**

**

***

**

*

**

AUC

FEV1 Peak

FEV1 trough

¿ceilling effect?

Ipratropium + Albuterol

Combination of short-actingBD’s

40

50

60

70

80

90

100

0 15 30 45 60 75 90 105 120

%R

espo

ndin

g

Albuterol Ipratropium

Minutes post-drug administrationDorinsky PM, et al. Chest. 1999;115:966–971.

The present and future

LAMAs• Tiotropium

• Glycopyrronium (NVA237)

• Umeclidinium bromide

• Aclidinium bromide

LABAs• Olodaterol

• Indacaterol

• Vilanterol

• Carmoterol

• Formoterol

• Salmeterol

Fixed - Combinations- Olodaterol/tiotropium

- Indacaterol/ glycopyrronium- Umeclidinium/ vilanterol- Formoterol/aclidinium- Formoterol/glycopyrrolate

Glycopyrronium + Indecaterol fixed combination

-

-

COPD:Therapeutic Approach

LABA + LAMA

ICS

COPD

Escalating Therapy

Long Active BronchodilatorsLAMA or LABA

+

++ Reflumilast, Theo.

Antibiotics

De-Escalating Therapy

Can we

withdraw ICS ?

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


Run-in/screeningSFC 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

01 2 3 4 5

Time to first exacerbation (months)

Pat

ient

s ex

acer

batio

n-fre

e (%

)

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

Magnussen et al NEJM 2014

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/screeningTiotropium 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 groupReduced to 500 µg

Reduced to 200 µg

Reduced to 0 µg (placebo)

ICS continuation

ICS withdrawal

0

–20

–40

–60

–800 6 12 18 52

p<0.001

p=0.001

Adj

uste

d m

ean

chan

gein

FE

V1 (

mL)

WeekNumber at risk:ICS continuation 1,223 1,135 1,114 1,077 970ICS 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 patientswith 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

00

Est

imat

ed p

roba

bilit

y

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.

COPD = chronic obstructive pulmonary disease

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 ICSn=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 secondICS = inhaled corticosteroid; LABA = long-acting β2-agonistLAMA = long-acting muscarinic antagonist Rossi et al. Respir Res 2014

p=0.752100

0No ICS

FEV

1 % p

redi

cted

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 theophyllineICS = 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=0.347100

0No ICS

Pat

ient

s ex

acer

batio

n-fre

e af

ter

6 m

onth

s (%

)

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


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


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.

When I will be using fixed LAMA + LABA combination ?

First-line therapy for patients that are symptomatic with preserve lung function (GOLD B – Stage II)

Patients with worsening lung function relative few symptoms (GOLD C – Stage III)

Adjunctive therapy in Patients with more severe disease (GOLD D)

.1Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011.Accessed at http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf

http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf

LAMA or LABA or

SABA+SAMA

ICS+LABA+LAMA orICS+LABA+PDE4l or

LAMA+LABA orLAMA+PDE4l

LAMA+LABA

LAMA+LABA orLAMA+PDE4I or

LABA+PDE4l

CAT, COPD Assessment Test; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting 2-agonist; LAMA, long-

acting muscarinic antagonist; mMRC, modified Medical Research Council; PDE4, phosphodiesterase-4 inhibitor; SABA, short-acting 2-agonist; SAMA, short-acting

muscarinic antagonist

Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease

(GOLD) 2013. Available from: http://www.goldcopd.org./

A B

DC

Exac

erba

tions

per

ye

ar

<2

1

0

mMRC 0-1 CAT <10

GOLD 4

mMRC ≥2 CAT ≥10

GOLD 3

GOLD 2

GOLD 1

Pharmacological management of stable COPD: FUTURE

IND/GLY BREEZHALERStart a new chapter in COPD

• IND/GLY Breezhaler is the first 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 recommended dose is the inhalation of the content of one capsule once daily using the IND/GLY Breezhaler inhaler.

• IND/GLY Breezhaler is recommended to be administered at the same time of the day each day.

• If a dose is missed, it should be taken as soon aspossible on the same day.

IND/GLYBREEZHALER

54IND/GLY insert leaflet. Approved on 22/6/2015

55IND/GLY insert leaflet. Approved on 22/6/2015

IND/GLYBREEZHALERMECHANISM OF ACTION

• When indacaterol and glycopyrronium are administered together in IND/GLY Breezhaler, they provide additive efficacy due to their different mode of action targeting different receptors and pathways to achieve smooth muscle relaxation.

• The combination of indacaterol and glycopyrronium in IND/GLY Breezhaler showed a rapid onset of action within 5 minutes after dosing.

• The effect remains constant over the whole 24-h dosing interval.

3 .Tarsin et al. J Aerosol Med 2004 4 .Chodosh et al. J Aersol Med 2001

BREEZHALER: A LOW AIRFLOW RESISTANCE DEVICEThe Breezhaler device has low airflow resistance suitable for use by patients with chronic obstructive pulmonary disease, even those with severe disease.1

The majority of patients were able to achieve flow rates of >60 L/min1

In separate studies, airflow resistance has been determined for the following devices:

Breezhaler*1 2.2 10‒2 kPa½L/min

Diskus*2 2.7 10‒2

kPa½L/minTurbohaler*3 3.4 10‒2 kPa½L/min

HandiHaler*45.1 10‒2 kPa½L/min

DPI = dry powder inhaler

1. Pavkov et al. Curr Med Res Opin 2010

2 .Janssens et al. Eur Respir J 2008

Modified from Hodder, Price. Int J Chron Obstruct Pulmon Dis 2011

DEVICE CHARACTERISTICS: IMPORTANCE TO PATIENTSDevice factors*

Perceived efficacy

Ease of use

Convenience

Feelings of stigmatization due to need for device use in public

Physician device preference

Availability of drug/device preparations

Brand loyalty

Cost

Time to learn; clear instructions

Device appearance and characteristics

Cleaning issues

Disposability/environmental issues

*listed in no particular order of preferenceSeveral factors affect patients’ attitudes to devices used for COPD therapy

THE BREEZHALER DEVICE ALLOWS PATIENTS TOHEAR, FEEL AND SEE THAT THEY HAVE TAKEN THE DOSE CORRECTLY

The Breezhaler device was designed to providedose delivery feedback mechanisms1

The Breezhaler device is also a low-resistance inhaler, which delivers a consistent dose across a wide range of COPD severities2

The click when thecapsule is pierced and

the whirring sound during inhalation

The product upon inhalation due to thepresence of lactose in

the formulation

The clear and empty orangetransparent capsule after inhalation to confirm that

the full dose was taken

Adapted from QVA149 Breezhaler Summary of product characteristics, 2013

.1QVA149 Breezhaler Summary of product characteristics, 2013.2Colthorpe. J Drug Assess 2013

.1Chapman et al. Int J Chron Obstruct Pulmon Dis 2011.2Pavkov R, et al. Curr Med Res Opin 2010 ; 3. Indacaterol Breezhaler SmPC 2014

4 .Glycopyrronium Breezhaler SmPC 2014 ; 5. QVA149 Breezhaler SmPC 2014

BREEZHALER: CLARITY FOR COPD PATIENTS, CONFIDENCE FOR PHYSICIANS

Correct use Comfortable inhalation & consistent performance

Confirmed dose

Correct use from Day 1,even with minimal

instruction1

Low internal resistance1,2

Sufficient peak inspiratory flowacross all COPD severities2

Transparent capsule for dose confirmation3–5

IND/GLYBREEZHALERIGNITE PROGRAM

• IGNITE is a large program studying the efficacy and safety of QVA149– Includes 11 studies in total (n=11,198*), of which nine were

completed by 2014

• Studies in the IGNITE program examine a range of clinically relevant endpoints, comparing QVA149 with:– monocomponents

• indacaterol 150 µg• glycopyrronium 50 µg

– established current standards of care• tiotropium 18 µg (open label and blinded)• Tiotropium + Formoterol.• SFC 50/500 µg.

*target enrolmentSFC =salmeterol/fluticasone propionate

Long-term safety (vs placebo)

Exercise tolerance (vs tiotropium and

placebo)

)vs glycopyrronium and tiotropium(

FEV1, TDI, SGRQ)vs fluticasone/salmeterol(

FEV1, TDI, SGRQ)vs glycopyrronium, indacaterol,

tiotropium and placebo(

BDI, TDI)vs tiotropium(

Long-term exacerbations)vs fluticasone/salmeterol(

China safety and efficacy)vs fluticasone/salmeterol(

Long-term safety)vs tiotropium and placebo(

Japan pivotal safety (vs tiotropium)

Non-inferiority vs free

combination

Exacerbations

IND/GLYBREEZHALERIGNITE PROGRAM MORE THAN 6,500 PATIENTS

New

A NEW CHAPTER FOR SYMPTOMATIC COPD PATIENTS

62

SIGNIFICANT IMPROVEMENT IN LUNG FUNCTION

SIGNIFICANT IMPROVEMENT IN SYMPTOMS

SIGNIFICANT IMPROVEMENT IN QUALITY OF LIFE

SIGNIFICANT REDUCTION IN RESCUE MEDICATION

SIGNIFICANT REDUCTION IN EXACERBATIONS


63

SIGNIFICANT IMPROVEMENT IN

LUNG FUNCTIONSIGNIFICANT IMPROVEMENT IN SYMPTOMS




Trough FEV1* over the entire 26-week treatment period SIGNIFICANT

400 mLIMPROVEMENT

over placebo at week 26 peak FEV1

# (P<0.001)

*Forced expiratory volume in 1 s

#2 hrs. post dose

IND/GLYBREEZHALER SIGNIFICANTLY IMPROVEDLUNG FUNCTION VS. PLACEBO OVER 26 WEEK TREATMENT

A multicenter, randomized, double-blind, placebo- and active-controlled, 26-week trial. Patients with moderate-to- severe stable COPD (n=2144) were randomized (2:2:2:2:1) to receive once-daily IND/GLYBreezhaler (Indacaterol 110 mg/Glycopyrronium 50 mg), Indacaterol 150 mg, Glycopyrronium 50 mg, open-label tiotropium 18 mg or placebo. The primary end-point was trough forced expiratory volume in 1 s (FEV1) at week 26 for IND/GLYBreezhaler versus its mono components.

Bateman E et al, Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study; Eur Respir J 2013; 42: 1484–1494

Pre-dose FEV1* at week 12 (LSM)

tiotropium 18 µg + formoterol 12 µg

(n=421)

IND/GLYBREEZHALER

)n=432(

SIGNIFICANT

72mLIMPROVEMENT

vs. tiotropium + formoterol0 1.2FEV1 (L) 1.4 1.6

P<0.001

IND/GLYBREEZHALERSIGNIFICANTLY IMPROVEDLUNG FUNCTION VS. TIOTROPIUM + FORMOTEROL

Least square mean (LSM)

* Forced expiratory volume in 1 s

A 26-week multicenter, randomized, blinded, triple-dummy, parallel-group, non-inferiority trial 934 patients aged ≥40 years with moderate-to-severe COPD were randomized to IND/GLYBREEZHALER 110/50 mg o.d. or TIO 18 mg o.d.+ FOR 12 mg twice daily (1:1) for 26 weeks.The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George’s Respiratory Questionnaire-COPD (SGRQ-C).

Buhl R et al. Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily

tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a

randomized, non-inferiority study. Thorax. 2015:70(4):311-319.

Onset of action in terms of FEV1(L)* at 5 minutes post dose at week 26 (LSM)

randomized, double-blind, parallel-group study. Lancet Respir Med. 2013; 1:51-60.

1.52

1.67

P<0.0001

FEV1 (L) 1.60 1.5 1.7

SIGNIFICANT

150mLIMPROVEMENT

in FEV1 5 min post- dose

vs. fluticasone/salmeterol

IND/GLYBREEZHALER PROVIDED RAPID BRONCHODILATION WITHIN 5 MINUTES

* Forced expiratory volume in 1 s

A multicenter, randomized, double-blind, double dummy, parallel-group, 26-week study in patients with moderate-to- severe COPD. 523 patients were randomly assigned to once-daily IND/GLYBreezhaler 110/50 μg or twice-daily salmeterol–fluticasone 50/500 μg for 26 weeks.The primary endpoint was to demonstrate the superiority of IND/GLYBreezhaler compared with SFC for the standardized area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0–12h) after 26 weeks of treatment

Vogelmeier CF, et al. Efficacy and safety of once-daily QVA149 compared with twice-dailysalmeterol/fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a

fluticasone/

salmeterol (n=264)

IND/GLY

BREEZHALER)n=258(

2.11 2.421.8

2

2.2

2.4

2.6

Tiotropium

∆=140mL, p=0.002∆=320mL, p<0.001

Beeh, et al. Respir Med 2014

IND/GLYBREEZHALER IMPROVES DYNAMIC HYPERINFLATION VS. TIOTROPIUM

Dynamic IC is measured while patient is pedaling at isotime; values are LS mean ± SE

Dyna

mic

insp

irato

ry c

apac

ity (L

)

Placebo IND/GLY BREEZHALER

2.29

Day 21


16



SYMPTOMSSIGNIFICANT IMPROVEMENT IN QUALITY OF LIFE



Improvement in TDI* focal score after 26 weeks of treatment (LSM)5

A multicenter, randomized, double-blind, double dummy, parallel-group, 26-week study in patients with moderate-to-severe COPD. 523 patients were randomly assigned to once-daily IND/GLYBreezhaler 110/50 μg or twice-daily salmeterol–fluticasone 50/500 μg for 26 weeks.The primary endpoint was to demonstrate the superiority of IND/GLYBreezhaler compared with SFC for the standardized area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0–12h) after 26 weeks of treatment



SIGNIFICANT

47%IMPROVEMENT

vs. fluticasone/salmeterol

fluticasone/

salmeterol (n=213)

IND/GLYBREEZHALER

)n=212(

1.60

2.36

P=0.003 1

TDI focalscore

2.00 0.5 1.0 1.5 2.5

*Transition Dyspnea index

IND/GLYBREEZHALER SIGNIFICANTLY IMPROVES BREATHLESSNESS VS. FLUTICASONE/SALMETEROL

10 20 30 40 50 60 70

Patients achieving clinical important increase ≥1 in TDI score at week 26 SIGNIFICANT

19%RELATIVE RISK REDUCTION IN PATIENTS WHO ACHIEVED

A CLINICALLY RELEVANT IMPROVEMENTvs.

fluticasone/salmeterol

fluticasone/

salmeterol (n=213)

IND/GLY

BREEZHALER)n=212(

56·8%

67·5%

p=0·046

Patients %0

IND/GLYBREEZHALERSIGNIFICANTLY IMPROVED DYSPNEA VS. FLUTICASONE/SALMETEROL

A multicenter, randomized, double-blind, double dummy, parallel-group, 26-week study in patients with moderate-to-severe COPD. 523 patients were randomly assigned to once-daily IND/GLYBreezhaler 110/50 μg or twice-daily salmeterol–fluticasone 50/500 μg for 26 weeks.The primary endpoint was to demonstrate the superiority of IND/GLYBreezhaler compared with SFC for the standardized area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0–12h) after 26 weeks of treatment



0 0.2 0.4 0.6 0.8 1 1.2

IND/GLYBREEZHALERSIGNIFICANTLY IMPROVED DYSPNEA VS. TIOTROPIUM

Improvement in TDI* focal score at week 26

P=0.0071.09

TDI focal score above placebo

open-label

tiotropium 18 µg vs placebo

(n=480)IND/GLYBREEZHALERvs placebo

)n=474(

SIGNIFICANT

88%RELATIVE

IMPROVEMENTVs.

TiotropiumWHEN BOTH COMPARED TO

PLACEBO

*TDI: Transition dyspnea index

P=0.0170.58



Percentage of patients achieving MCID* ≥1 in TDI** at week 26

tiotropium 18 µg + formoterol 12

µg)n=158(

IND/GLY

BREEZHALER)

n=195(

SIGNIFICANT

22.7%RELATIVE RISK REDUCTION

IN PATIENTS WHO ACHIEVED A CLINICALLY

RELEVANTIMPROVEMENT

VS.tiotropium + formoterol

0 42 60Patients (%)

44 46

P<0.01

48

*Minimum clinically important difference (≥1 unit). **TDI: Transition dyspnea index #In per protocol set analysis

IND/GLYBREEZHALER SIGNIFICANTLY IMPROVED DYSPNEA VS. TIOTROPIUM + FORMOTEROL





IND/GLYBREEZHALER SIGNIFICANTLY IMPROVES DYSPNEA VS. TIOTROPIUM

SIGNIFICANT

126%IMPROVEMENT

vs. tiotropium

-0.49

0.88

0.39

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

Placebo

SAC# TDI* total score

Ultibro Breezhaler110/50 µg

(N=223)

Tiotropium 18 µg (N=220)

)N=218(

*p<0.001 **p=0.021

Data are presented as least squares mean¡SE. TDI: Transition Dyspnea Index

Patient-reported dyspnea scores after 6 weeks of treatment (LSM)*p<0.001

COPD: the BLAZE study Eur Respir J 2014; 43: 1599–1609

#SAC: Self-administered computerized

A multicenter, blinded, double-dummy, three-period crossover study, 247 patients were randomized to once-daily IND/GLYBreezhaler 110/50 mg, placebo or tiotropium 18 mg. Superiority of IND/GLYBreezhaler versus placebo (primary objective) and tiotropium (secondary objective) was assessed for improvement in dyspnea via the self- administered computerized (SAC) version of the Baseline and Transition Dyspnea Index after 6 weeks.

Mahler DA et al, Dual bronchodilation with QVA149 reduces patient-reported dyspnea in


22




QUALITY OF LIFESIGNIFICANT REDUCTION IN RESCUE MEDICATION


Improvement from baseline in health status SGRQ* total score

open-labeltiotropium 18 µg

)n=737(

IND/GLYBREEZHALER

)n=729(

SIGNIFICANT

60%IMPROVEMENT

vs.tiotropiumChange in SGRQ

scorefrom baseline

8

double-blind, parallel-group study. Lancet Respir Med. 2013 May;1(3):199-209

5

-1 1 3 5 7 9

IND/GLYBREEZHALER SIGNIFICANTLY IMPROVED HEALTH STATUS VS. TIOTROPIUM

p<0.05

Wedzicha JA et al, Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomized,

*St. George respiratory questionnaire

A multicenter parallel-group study, 2224 patients were randomly assigned to once-daily IND/GLYBreezhaler (fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg), glycopyrronium 50 μg, or tiotropium 18 μg for 64 weeks. Assignment to IND/GLYBreezhaler and glycopyrronium was double-blind; tiotropium was open-label. The primary objective was to show superiority of IND/GLYBreezhaler versus glycopyrronium for rate of moderate to severe COPD exacerbations (defined by worsening symptoms and categorized by treatment requirements) during treatment.

IND/GLYBREEZHALER SIGNIFICANTLY IMPROVED HEALTH STATUS VS. TIOTROPIUM + FORMOTEROL

Percentage of patients achieving MCID* ≥4 in SGRQ-C** after 26 weeks

tiotropium 18 µg + formoterol 12

µg)n=374(

IND/GLY

BREEZHALER)

n=373

SIGNIFICANT

18%RELATIVE RISK REDUCTION

IN PATIENTS WHO ACHIEVED A CLINICALLY

RELEVANT IMPROVEMENT IN SGRQ

VS.tiotropium + formoterol

0 42 50Patients (%)

44 46

P<0.05 RR=1.18

48

*Minimum clinically important difference (≥4 unit).**SGRQ-C: St George’s Respiratory Questionnaire-COPD #In per protocol set analysis

52





0 2 4 6 8 10 12 14

Improvement in percentage of days patients able to perform daily activities at week 26

3.03

11.48

p<0.001

%of days

open-label

tiotropium 18 µg vs placebo (n=480)

IND/GLY

BREEZHALERvs placebo

)n=474(

SIGNIFICANT

279%RELATIVE

INCREASE IN PERCENTAGE OF DAYS PATIENTS

ABLE TO PERFORM DAILY ACTIVITIES

Vs. tiotropium

IND/GLYBREEZHALER SIGNIFICANTLY IMPROVES DAILY ACTIVITIES VS. TIOTROPIUM




26




SIGNIFICANT REDUCTION IN

RESCUE MEDICATIONSIGNIFICANT REDUCTION IN EXACERBATIONS

The use of rescue salbutamol over weeks SIGNIFICANT

53%Relative risk reduction

vs. tiotropium

Use of rescue salbutamol puffs/day

-1.5

-2.3

0

p<0.0001

QVA149−tiotropium least squares mean treatment difference−0.76, p<0.0001

IND/GLYBREEZHALER SIGNIFICANTLY REDUCES RESCUE MEDICATION vs. TIOTROPIUM

open-label tiotropium

18µg

(n=737)IND/GLY

BREEZHALER)n=729(

- 0.5- 1- 1.5-2 - 2.5





28





SIGNIFICANT REDUCTION IN

EXACERBATIONS

SIGNIFICANT

Zhong N et al: LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combinationin patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015;10(1):1015-1026

RISK REDUCTION OF

IND/GLYBREEZHALER SIGNIFICANTLY REDUCED THE RATE OF MODERATE OR SEVERE EXACERBATIONS

Annualized rate of moderate or severe exacerbations

IND/GLY BREEZHALER (n=372) vs.fluticasone/salmeterol (n=369)

31%MODERATE OR SEVERE

EXACERBATIONSvs.

fluticasone/salmeterol

P=0.048

A double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were randomized (1:1) to IND/GLYBREEZHALER 110/50 μg once daily or salmeterol- fluticasone 50/500 μg twice daily for 26 weeks. The primary endpoint was non-inferiority of IND/GLYBREEZHALER versus salmeterol-fluticasone for trough forced expiratory volume in 1 second (FEV1) at week 26.6

SIGNIFICANTREDUCTION OF

Zhong N et al: LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combinationin patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015;10(1):1015-1026

69%IND/GLY BREEZHALER (n=372) vs

fluticasone/salmeterol (n=369)

*In a post-hoc analysis

SEVEREEXACERBATIONS

vs.fluticasone/salmeterol

P=0.023

IND/GLYBREEZHALER SIGNIFICANTLY REDUCED THE RATE OF MODERATE OR SEVERE EXACERBATIONS

Annualized rate of severe exacerbations

A double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were randomized (1:1) to IND/GLYBREEZHALER 110/50 μg once daily or salmeterol- fluticasone 50/500 μg twice daily for 26 weeks. The primary endpoint was non-inferiority of IND/GLYBREEZHALER versus salmeterol-fluticasone for trough forced expiratory volume in 1 second (FEV1) at week 26.6

SIGNIFICANTREDUCTION OF

14%

IND/GLYBREEZHALER SIGNIFICANTLY REDUCED RATE OF ALL EXACERBATIONS VS. TIOTROPIUM

Annualized rate of all exacerbations

in allEXACERBATIONS

vs.tiotropium

P=0.0017




FLAME STUDYEFFECT OF INDACATEROL GLYCOPYRRONIUM VS. FLUTICASONE SALMETEROL ON COPD EXACERBATIONS

EVALUATING EFFICACY OF IND/GLYBREEZHALER IN TERMS OF EXACERBATIONS IN MODERATE-TO-VERY SEVERE PATIENTS*

Double-blind treatment period (52 weeks)

Day –35 toDay –29

Day 1 to Day 365

30-day safety follow-up

Screening period

IND/GLY 110/50 μg q.d.


Day –28 toDay –1

Visit 1

Day 366 toDay 395

Visit 101

• Patients had history of ≥1 exacerbation in the previous 12 months that required treatment with systemic corticosteroids and/or antibiotics

52-week, multicenter, randomized, double-blind, parallel-group, double-dummy study

Prerandomization

Visit 20112 clinic visits

*FEV1 ≥25 and <60% predicted. IND = indacaterol; GLY = glycopyrronium FEV1 = forced expiratory volume in 1 second; OL = open label

Randomization

Run-in periodOL tiotropium

18 μg q.d.

Wedzicha JA, et al. N Engl J Med 2016

KEY INCLUSION CRITERIA INCLUDED A HISTORY OF≥1 EXACERBATION IN THE PREVIOUS YEAR

Inclusion• Male or female adults aged ≥40 years

• Stable COPD according to the current GOLD strategy (GOLD 2011)

• Current or ex-smokers who have a smoking history of ≥10 pack years

• Post-bronchodilator FEV1 ≥25 and <60% of the predicted normal value, and post-bronchodilator FEV1/FVC <0.70

• Documented history of ≥1 COPD exacerbation in the previous 12 months that required treatment with systemic glucocorticosteroids and/or antibiotics

• Patients taking stable COPD medication for at least 60 days prior to study entry• Patients with an mMRC grade of ≥2

FVC = forced vital capacity; mMRC = modified Medical Research Council


Patients targeted by inclusion criteria

CD

A B

PATIENT POPULATION APPROXIMATED TO GOLD D

Inclusion criteria

• Post-bronchodilator FEV1 ≥25 and <60%of predicted normal

• Symptomatic as defined by mMRC ≥2

• ≥1 documented COPD exacerbation requiring treatment with antibiotics and/or systemic corticosteroidswithin 1 year of randomization

Primary outcome

Rate of all COPD exacerbations (mild/moderate/severe) during 52 weeks of treatment

• Primary objective

To demonstrate thatIND/GLY was at least non-inferior toSFC

• Secondary objective

If non-inferiority could be established, the secondary objective was to demonstrate that IND/GLY is superior to SFC


PRIMARY OBJECTIVE OF FLAME WAS TO DEMONSTRATE THAT IND/GLY IS NON-INFERIOR TO SFC IN TERMS OF RATE OF COPD EXACERBATIONS

Primary

• Rate of all COPD exacerbations (mild/moderate/severe) during 52 weeks of treatment

Secondary

• Time to first COPD exacerbation (mild/moderate/severe)

Rate and time to first moderate/severe COPD exacerbation


FURTHER STUDY OBJECTIVES INCLUDED THEASSESSMENT OF LUNG FUNCTION AND HEALTH STATUSSecondary (continued)• Lung function:

– Trough FEV1

– Standardized FEV1 AUC0–12h in a subset of patients

• St George’s Respiratory Questionnaire (SGRQ-C)• Use of rescue therapy• 24-hour urinary cortisol in a subset of patients

• Safety and tolerability of IND/GLY versus SFC

Subgroup analyses• Subgroup analyses (e.g. by baseline blood eosinophil count) were pre-specified in the

Statistical Analysis Plan prior to unblinding but not in the protocol


PATIENT DEMOGRAPHICS WERE WELLBALANCED BETWEEN TREATMENT GROUPS (1/2)

IND/GLY110/50 μg q.d.

(n=1,680)

SFC50/500 μg b.i.d.

(n=1,682)Total

(N=3,362)Age, years 64.6 (7.9) 64.5 (7.7) 64.6 (7.8)

Male, n (%) 1,299 (77.3) 1,258 (74.8) 2,557 (76.1)

Duration of COPD, years 7.2 (5.3) 7.3 (5.5) 7.3 (5.4)ICS use at baseline, n (%) 954 (56.8) 939 (55.8) 1,893 (56.3)

LAMA use at baseline, n (%) 1,008 (60.0) 1,029 (61.2) 2,037 (60.6)LABA use at baseline, n (%) 1,129 (67.2) 1,128 (67.1) 2,257 (67.1)

Current smoker, n (%) 664 (39.5) 669 (39.8) 1,333 (39.6)

Severity of COPD (GOLD 2015), n (%)

Low risk and less symptoms (Group A) 2 (0.1) 0 2 (0.1)

Low risk and more symptoms (Group B) 400 (23.8) 422 (25.1) 822 (24.4)

High risk and less symptoms (Group C) 1 (0.1) 2 (0.1) 3 (0.1)High risk and more symptoms (Group D) 1,265 (75.3) 1,249 (74.3) 2,514 (74.8)

Severity of airflow limitation (GOLD 2011–2014), n (%)

Mild (GOLD 1) 0 0 0

Moderate (GOLD 2) 560 (33.3) 563 (33.5) 1,123 (33.4)

Severe (GOLD 3) 973 (57.9) 981 (58.3) 1,954 (58.1)

Very severe (GOLD 4) 133 (7.9) 124 (7.4) 257 (7.6)

Data are mean (SD) unless otherwise stated


PATIENT DEMOGRAPHICS WERE WELLBALANCED BETWEEN TREATMENT GROUPS (2/2)


(n=1,680)


(n=1,682)Total

(N=3,362)

Pre-bronchodilator FEV1, L 1.0 (0.3) 1.0 (0.3) 1.0 (0.3)

Post-bronchodilator FEV1, L 1.2 (0.3) 1.2 (0.4) 1.2 (0.3)

Post-bronchodilator FEV1, % predicted 44.0 (9.5) 44.1 (9.4) 44.1 (9.5)

Post-bronchodilator FEV1 reversibility, % of baseline value 22.2 (16.0) 22.5 (16.0) 22.4 (16.0)

Post-bronchodilator FEV1/FVC, % 41.7 (9.8) 41.5 (9.9) 41.6 (9.9)

Number of COPD exacerbations in previous year, n (%)

1 1,355 (80.7) 1,355 (80.6) 2,710 (80.6)

≥2 324 (19.3) 325 (19.3) 649 (19.3)

SGRQ-C total score 47.3 (15.8) 47.2 (15.9) 47.3 (15.8)CAT score 16.9 (7.1) 16.6 (7.0) 16.7 (7.0)

mMRC dyspnea scale, n (%)

Grade 2 1,202 (71.5) 1,210 (71.9) 2,412 (71.7)

Grade 3 439 (26.1) 432 (25.7) 871 (25.9)

Grade 4 36 (2.1) 38 (2.3) 74 (2.2)

Rescue medication use, puffs/day 3.95 (3.8) 4.12 (4.0) 4.0 (3.9)

Urine cortisol*, ng/mL 16.3 (20.7) 15.8 (24.0) 16.0 (22.4)

*24-hour urine cortisol measured in a total of 535 patients (266 on IND/GLYand 269 on SFC). Data are mean (SD) unless otherwise stated


IND/GLYBREEZHALER WAS NON-INFERIOR (PRIMARY ENDPOINT) AND SUPERIOR TO SFC FOR THE RATE OF ALL (MILD/MODERATE/SEVERE) EXACERBATIONS OVER 52 WEEKS

0.8 1.0 1.15

Rate ratio (95% Cl)

Per-protocol set)Primary analysis(

Modified intention-to-treat set (Supportive analysis)

Superiority margin

Non-inferiority margin

0.9

Favors IND/GLY Favors SFC

p=0.003

0.89 0.960.83

p<0.001

0.88 0.940.82

FLAME is the first study to demonstrate superiority of IND/GLYBreezhaler in exacerbation prevention versus SFC in COPD patients with ≥1 exacerbation in the preceding year


IND/GLYBREEZHALER SIGNIFICANTLY REDUCED THE RATE OF ALL (MILD/MODERATE/SEVERE) EXACERBATIONS VERSUS SFC OVER 52 WEEKS

4.03 3.59

All e

xace

rbati

ons (

annu

alize

d ra

te)

3.0

4.0

2.0

RR (95% CI)0.89 )0.83 ,0.96,( p=0.003

1.0

0

11% reduction

SFC 50/500 μg b.i.d. (n=1,544) IND/GLY 110/50 μg q.d. (n=1,518)

5.0


CONSISTENT RESULTS OBSERVED FOR THE RATE OF ALL (MILD/MODERATE/SEVERE) EXACERBATIONS ACROSS ALL DEMOGRAPHIC SUBPOPULATIONS

1.0 2.0

IND/GLY SFC R ate ratio of IND/GLY vs SFC *Rate ratio (95% CI)Age group <55 years 148 155 0.80 (0.63, 1.01)

55<65 years 655 666 0.80 (0.71, 0.90)65<75 years 661 678 0.94 (0.84, 1.05)

≥75 years 187 157 0.98 (0.78, 1.23)

Gender Male 1,271 1,238 0.88 (0.81, 0.96)

Female 380 418 0.88 (0.76, 1.02)

Race Caucasian 1,286 1,283 0.89 (0.82, 0.96)

Asian 301 308 0.88 (0.74, 1.05)

Other 64 65 0.90 (0.62, 1.29)

Region Africa 49 47 0.86 (0.57, 1.30)

Asia 297 307 0.89 (0.75, 1.06)

Eastern Europe 537 565 0.80 (0.71, 0.91)Latin and South America 146 153 0.83 (0.66, 1.05)

North America 24 25 0.93 (0.50, 1.75)

Western Europe 598 559 0.97 (0.86, 1.10)

0.5Favors IND/GLY

1.5Favors SFC


CONSISTENT RESULTS OBSERVED FOR THE RATE OF ALL (MILD/MODERATE/SEVERE) EXACERBATIONS ACROSS ALL BASELINE DISEASE CHARACTERISTICS SUBPOPULATIONS

1.0 1.5 2.0

IND/GLY SFC Rate ratio of IND/GLY vs SFC *Rate ratio (95% CI)Severity of airflow limitation Moderate (GOLD 2) 557 557 0.93 (0.82, 1.06)

Severe (GOLD 3) 962 975 0.84 (0.76, 0.92)Very Severe (GOLD 4) 132 124 0.94 (0.72, 1.22)

Severity of COPD 2015 (GOLD 2015) Group B 398 417 0.98 (0.85, 1.14)

Group D 1,252 1,243 0.86 (0.78, 0.92)COPD exacerbation history 1 exacerbation 1,329 1,335 0.87 (0.81, 0.95)

≥2 exacerbations 321 320 0.89 (0.76, 1.05)

Reversibility Not reversible 900 904 0.88 (0.80, 0.97)

Reversible 735 741 0.88 (0.79, 0.98)

ICS use at screening No ICS use 710 729 0.88 (0.79, 0.98)

ICS use 941 927 0.88 (0.80, 0.97)

LABA use at screening No LABA use 540 542 0.91 (0.81, 1.04)

LABA use 1,111 1,114 0.86 (0.79, 0.94)

ICS/LABA use at screening No ICS/LABA use 879 889 0.88 (0.80, 0.97)ICS/LABA use 772 767 0.88 (0.79, 0.97)

LAMA use at screening No LAMA use 662 643 0.91 (0.81, 1.02)

LAMA use 989 1,013 0.86 (0.78, 0.94)

Smoking status at screening Ex-smoker 1,004 998 0.92 (0.83, 1.01)

Current smoker 647 658 0.83 (0.74. 0.92)

Overall 1,651 1,656 0.88 (0.82, 0.94)

0.5Favors IND/GLY Favors SFC


IND/GLYBREEZHALER SIGNIFICANTLY PROLONGED THE TIME TO FIRST MILD, MODERATE OR SEVERE EXACERBATION VERSUS SFC OVER 52 WEEKS

0 6 12 38 5245

100

90

80

70

60

50

40

30

20

10

0

Perc

enta

ge o

f pati

ents

with

eve

nt )

(%

192632Time to events (weeks)

Patients at riskIND/GLY 1,675 763 535 409 281SFC 1,679 642 415 313 217

HR (95% CI):0.84 )0.78 ,0.91,( p<0.001

16% riskreduction

SFC 50/500 μg b.i.d. IND/GLY 110/50 μg q.d.


IND/GLYBREEZHALER SIGNIFICANTLY REDUCED THE RATE OF MODERATE OR SEVERE EXACERBATIONS VERSUS SFC OVER 52 WEEKS

1.19 0.98

RR (95% CI)0.83 )0.75 ,0.91,( p<0.001

1.5

Mod

erat

e or

seve

re e

xace

rbati

ons (

annu

alize

dra

te( 0.75

1.0

1.25

0.5

0.25

0


17% reduction


CONSISTENT RESULTS OBSERVED FOR THE RATE OF MODERATE OR SEVERE EXACERBATIONS ACROSS ALL DEMOGRAPHIC SUBPOPULATIONS

1.0 2.0

IND/GLY SFC Rate ratio of IND/GLY vs SFC Rate ratio (95% CI)Age group <55 years 148 155 1.00 (0.73, 1.37)

55<65 years 655 666 0.85 (0.72, 0.99)

65<75 years 661 678 0.83 (0.72, 0.97)

≥75 years 187 157 0.62 (0.46, 0.84)

Gender Male 1,271 1,238 0.81 (0.73, 0.91)

Female 380 418 0.89 (0.74, 1.07)

Race Caucasian 1,286 1,283 0.87 (0.78, 0.98)

Asian 301 308 0.71 (0.56, 0.89)Other 64 65 0.81 (0.51, 1.30)

Region Africa 49 47 0.89 (0.54, 1.48)Asia 297 307 0.71 (0.56, 0.88)

Eastern Europe 537 565 0.84 (0.70, 1.01)Latin and South America 146 153 0.88 (0.65, 1.19)

North America 24 25 0.97 (0.47, 2.01)

Western Europe 598 559 0.86 (0.73, 1.01)

0.0

0.5Favors IND/GLY

1.5Favors SFC


CONSISTENT RESULTS OBSERVED FOR THE RATE OF MODERATE OR SEVERE EXACERBATIONS ACROSS ALL BASELINE DISEASE CHARACTERISTICS SUBPOPULATIONS

1.0 2.00.00.5

Favors IND/GLY1.5

Favors SFC

IND/GLY SFC Rate Ratio of IND/GLY vs SFC Rate ratio (95% CI)Severity of airflow limitation Moderate (GOLD 2) 557 557 0.81 (0.68, 0.97)

Severe (GOLD 3) 962 975 0.81 (0.72, 0.92)Very Severe (GOLD 4) 132 124 1.04 (0.75, 1.44)

Severity of COPD 2015 (GOLD 2015) Group B 398 417 0.86 (0.69, 1.06)

Group D 1,252 1,243 0.83 (0.74, 0.92)

COPD exacerbation history 1 exacerbation 1,329 1,335 0.83 (0.75, 0.93)

≥2 exacerbations 321 320 0.85 (0.70, 1.03)

Reversibility Not reversible 900 904 0.81 (0.71, 0.93)

Reversible 735 741 0.85 (0.73, 0.98)

ICS use at screening No ICS use 710 729 0.78 (0.67, 0.91)

ICS use 941 927 0.86 (0.76, 0.97)

LABA use at screening No LABA use 540 542 0.81 (0.68, 0.96)

LABA use 1,111 1,114 0.84 (0.75, 0.94)

ICS/LABA use at screening No ICS/LABA use 879 889 0.86 (0.75, 0.98)

ICS/LABA use 772 767 0.80 (0.70, 0.92)

LAMA use at screening No LAMA use 662 643 0.83 (0.71, 0.97)

LAMA use 989 1,013 0.83 (0.74, 0.94)

Smoking status at screening Ex-smoker 1,004 998 0.84 (0.74, 0.95)

Current smoker 647 658 0.82 (0.70, 0.95)

Overall 1651 1656 0.83 (0.75, 0.91)


IND/GLYBREEZHALER SIGNIFICANTLY PROLONGED THE TIME TO FIRST MODERATE OR SEVERE EXACERBATION VERSUS SFC OVER

52 WEEKS

0 6 38 5245

100

90

80

70

60

50

40

30

20

10

0

Perc

enta

ge o

f pati

ents

with

eve

nt )

(%

12 192632

Time to events (weeks)

HR (95% CI):0.78 )0.70 ,0.86,( p<0.001

22% risk reduction



Patients at riskIND/GLY 1,675 1,299 1,091 948 711SFC 1,679 1,210 975 820 608

THE RATE OF SEVERE EXACERBATIONS WAS 13% LOWER WITH IND/GLYBREEZHALER COMPARED WITH SFC

)NOT SIGNIFICANT(

0.17 0.15

RR (95% CI)0.87) 0.69 ,1.09,( p=0.231

Sev

ere

exac

erba

tions

(ann

ualiz

ed

rate

)

0.25

0


0.2013% numerical

reduction0.15

0.10

0.05


IND/GLYBREEZHALER SIGNIFICANTLY PROLONGED THETIME TO FIRST SEVERE EXACERBATION VERSUS SFC OVER 52 WEEKS

40

30

20

10

00 6 12 19 26 32 38

Patients at riskTime to event (weeks)

IND/GLY 1,675 1,530 1,434 1,368 1,138

SFC 1,679 1,507 1,389 1,303 1,071

Perc

enta

ge o

f pati

ents

with

eve

nt )

(%

HR (95% CI):0.81 )0.66 ,1.00,( p=0.046

4552

19% risk reduction



4.22 4.023.56 3.63

IND/GLYBREEZHALER REDUCED THE RATE OF ALL (MILD/MODERATE/SEVERE) EXACERBATIONS VERSUS SFC OVER 52 WEEKS IN PATIENTS WITH <2 AND ≥2% BLOOD EOSINOPHILS AT RANDOMIZATION

RR (95% CI)0.84 )0.75 ,0.95( p=0.004 RR (95% CI)

0.90 )0.82 ,0.99( p=0.030

>2Percentage blood eosinophils

(%)

≥2

SFC 50/500 µg b.i.d IND/GLY 110/50 µg q.d

4

3.5

3

2.5

2

1.5

1

0.5

4.5

All

exac

erba

tions

(ann

ualiz

ed

rate

)

5

0


1.24 1.150.99 0.98

IND/GLYBREEZHALER REDUCED THE RATE OFMODERATE OR SEVERE EXACERBATIONS VERSUS SFC OVER 52 WEEKS IN

RR (95% CI)0.80 )0.68 ,0.93,( p=0.004 RR (95% CI)

0.85 )0.75 ,0.96,( p=0.010

1.5

1.25

1

0.75

0.5

0.25

0

Mod

erat

e to

sev

ere

exac

erba

tions

)an

nual

ized

rate

(

PATIENTS WITH <2 AND ≥2% BLOOD EOSINOPHILS AT RANDOMIZATION

SFC 50/500 µg b.i.d IND/GLY 110/50 µg q.d

>2Percentage blood eosinophils

(%)

≥2


IND/GLYBREEZHALER SIGNIFICANTLY IMPROVED TROUGH FEV1 VERSUS SFC AT WEEK 52

–48

15


=∆62 mL, p<0.001

Adju

sted

mea

n ch

ange

from

bas

elin

e in

pre-

dose

trou

gh F

EV1

(mL)

50

–50

0

–25

25


LS = least square Time (days)

Adju

sted

mea

n SG

RQ-C

tota

l sco

re

48

41

47

46

45

Day 0 (baseline)

44

43

42

0Day 29 Day 85 Day 183 Day 267 Day 365

SFC 50/500 µg b.i.d (n=1,593)

IND/GLY 110/50 µg q.d. (n=1,602)

LS mean difference –1.3

P<0.001LS mean

difference –1.2 P=0.001


P=0.003


P<0.001LS mean

difference 0 P=NS

Improvem

ent

SGRQ-C responder rates: IND/GLY 49.2%; SFC 43.7% (OR 1.30; p<0.001)

IND/GLYBREEZHALER SIGNIFICANTLY IMPROVED HEALTH STATUS VERSUS SFC AT EACH MEASURED

TIMEPOINT BETWEEN WEEKS 12 AND 52


IND/GLYBREEZHALER SIGNIFICANTLY DECREASED RESCUEMEDICATION USE COMPARED WITH SFC AT WEEK 52

‒0.76 ‒1.01


–=∆0.25, p<0.001

Adju

sted

mea

n ch

ange

in re

scue

med

icati

on u

se fr

omba

selin

e (p

uffs

/day

)

0

–0.25

–0.50

–0.75

–1.0

–1.25

–1.5


THE INCIDENCE OF PNEUMONIA WAS SIGNIFICANTLY LOWER WITH IND/GLYBREEZHALER THAN WITH SFC

Radiographic imaging was required to confirm pneumonia AE = adverse event; SAE = serious adverse event

Preferred term, n (%)


(n=1,678)


(n=1,680)

Patients with at least one AE 1,459 (86.9) 1,498 (89.2)

Adverse events ≥3% in any treatment group

Chronic obstructive pulmonary disease 1,299 (77.4) 1,374 (81.8)

Nasopharyngitis 197 (11.7) 195 (11.6)

Viral upper respiratory tract infection 132 (7.9) 138 (8.2)

Upper respiratory tract infection bacterial 125 (7.4) 168 (10.0)

Lower respiratory tract infection 82 (4.9) 98 (5.8)

Upper respiratory tract infection 81 (4.8) 83 (4.9)Pneumonia 53 (3.2) 80 (4.8)

Cough 50 (3.0) 51 (3.0)

P=0.017Dyspnea 49 (2.9) 51 (3.0)

Influenza 35 (2.1) 56 (3.3)

Oral candidiasis 20 (1.2) 71 (4.2)

SAE(s) 308 (18.4) 334 (19.9)

Death 24 (1.4) 24 (1.4)

Discontinuation due to AE(s) 126 (7.5) 143 (8.5)

Discontinuation due to SAE(s) 85 (5.1) 87 (5.2)

Discontinuation due to non-SAE(s) 49 (2.9) 70 (4.2)Wedzicha JA, et al. N Engl J Med 2016

• IND/GLYBreezhaler significantly:– reduced the rate of all (mild, moderate and severe) and moderate or severe

exacerbations compared with SFC– delayed the time to first exacerbation (all, moderate or severe, and severe)

comparedwith SFC

• Results for demographic and baseline disease characteristics subpopulations were consistent with those for the overall population

• IND/GLYBreezhaler was superior to SFC in terms of all exacerbations and moderate or severe exacerbations in patients with <2 and ≥2% blood eosinophils at randomization

• IND/GLYBreezhaler was also superior to SFC with regards to improving lung function and health status and reducing rescue medication use

• IND/GLYBreezhaler had a comparable safety profile to SFC, while being associated with a lower incidence of pneumonia

FLAME summary: the first study to demonstrate superiority of IND/GLYBreezhaler in exacerbation prevention versus SFC in COPD patients with ≥1 exacerbation in the preceding year

dual bronchodilation in copd

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