Raising Standard of Care for

COPD patients

Y1-0348
Exp. Date. 15th Mar 2025
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The Burden of COPD

► Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating respiratory

condition that leads to significant burden, both medically and financially.

► Despite being a major cause of morbidity and mortality, chronic obstructive pulmonary disease
(COPD) is frequently undiagnosed.

► Studies have shown that about 60–86% of people with chronic obstructive pulmonary disease
(COPD) have not been diagnosed.1

► Overdiagnosed COPD is also common, with prevalence estimates ranging from 4% to 64% in the
general population and primary care settings2.

1-Soriano JB, Zielinski J, Price D. Screening for and early detection of chronic obstructive pulmonary disease. Lancet 2009; 374: 721–732
2-Walters JA, Walters EH, Nelson M, et al. Factors associated with misdiagnosis of COPD in primary care. Prim Care Respir J 2011; 20:
The Burden of COPD Varies Considerably,1-3 and Low Socioeconomic
Status May Drive Health Inequality and Disease Risk2,4-6

Considerable variation in COPD prevalence and COPD-related mortality rates between and within some countries 1–3

Significance level compared

with England
Deaths from Significantly higher than
COPD in 2017 per England – 99.8% level (63)
Significantly higher than
100,000 persons2 England – 95% level (14)
Age-standardized Not significantly different
from England (49)
mortality rate Significantly lower than
England – 95% level (13)
>30–230 Significantly lower than
>25–30 England – 99.8% level (56)
>20–25
>15–20
4–15 4.5x
Not reported difference in COPD-related mortality
rates between areas with the highest
and lowest numbers of deaths3

Contains Ordnance Survey data © Crown copyright and database right 2019. Contains National Statistics data © Crown copyright and database right 2019
1. Ho T et al. Breathe. 2019;15:24–35; 2. Li X et al. BMJ. 2020;368:m234; 3. Public Health England. The 2nd Atlas of variation in risk factors and healthcare for respiratory disease in England, 2019. http://tools.england.nhs.uk/images/RespiratoryAtlas/atlas.html. Accessed April 1,
2022; 4. Steenland K et al. Am J Public Health. 2004;94:1037–1042; 5. Pleasants RA et al. Int J COPD. 2016;11:2475–2496; 6. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2022 report. 4
https://goldcopd.org/2022-gold-reports/. Accessed April 1, 2022.
COPD is a Major Healthcare Burden and Cause of Mortality Worldwide

~384 million people globally

have COPD, equivalent ~50% of patients with COPD may be
to ~12% of adults1,a undiagnosed2,b

COPD is the second most ~40% of patients

common cause of emergency were readmitted or died within
admission in some countries3,4 90 days after an exacerbation5
Ischemic
1 heart disease
2 Stroke

3 COPD

COPD is the third leading cause of death worldwide,

accounting for ~3 million deaths annually6
a
Data from 2015; bStudies in 2008-2018; cIn 2019.
1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD 2022 report. https://goldcopd.org/2022-gold-reports/. Accessed April 1, 2022; 2. Diab N et al. Am J Respir Crit Care Med.
2018;198:1130–1139; 3. Lane ND et al. BMJ Open Respir Res. 2018;5:e000334; 4. Nardini S et al. Multidiscip Respir Med. 2014;9:46; 5. Echevarria C et al. Thorax. 2017;72:686–693; 6. World Health Organization. The top 10 causes of death. 5
https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death. Accessed April 1, 2022.
COPD definitions for exacerbations updated1

The GOLD report defines a COPD exacerbation as an acute worsening of respiratory

symptoms that require additional therapy

Worsening Symptoms Exacerbation Classification

Symptoms can last between 7 and 10 days,
Severity is defined by the treatment needed
but some events may last longer

Mild:
Dyspnea SABA or SAMA only

Cough Sputum
volume Moderate:
Wheeze SABA or SAMA and antibiotics and/or OCS

Sputum Severe:
purulence Hospitalization or ER visit
May be associated with acute respiratory failure

1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 report available at : 6
https://goldcopd.org/wp-content/uploads/2022/12/GOLD-2023-ver-1.1-2Dec2022_WMV.pdf
The Majority of Patients with COPD will Experience an Exacerbation.

Patients with COPD exacerbations

over the study period
Up to77% of patients will have
at least 1 moderate or severe
exacerbation within a 3-year period1

77% 68% 0.49

ECLIPSE 1 UPLIFT 2 SPIROMICS 3
(3 years) (up to 4 years) (3 years)
N=1679 N=5992 N=1105

Study

1. Hurst JR et al. N Engl J Med. 2010;363:1128-1138; 2. Tashkin DP et al. N Engl J Med.

2008;359:1543-1554; 3. Han MK et al. Lancet Respir Med. 2017;5:619-626. 7
Exacerbations are Frequently Unreported by Patients

A substantial number of COPD exacerbations are not reported despite meeting the criteria
exacerbations (%) of a symptom-based definition1-4,a
Unreported

78% 68% 66% 53% 50% 40%

Leidy et al1,b (1)
Europe Langsetmo
Canada2et al Leidy et al (2)
Multinational1,c
Xu et al
China 3
LeidyUS
et1al (3) Wilkinson
UK4
N=597 N=421 N=749 N=491 N=235 N=128

Study duration 3 months 6 months 3 months 1 year 6 months 1-6 years

Unreported exacerbations 205 327 256 466 139 441

Reported exacerbations 59 159 132 410 137 658

a
Definitions differ slightly between studies; bEurope refers to Bulgaria, Czech Republic, Hungary, Poland, Romania, and Slovakia; cMultinational refers to Australia, Canada, Germany, Japan, Korea, Philippines, Poland, Russia, Slovakia, Taiwan, Ukraine, US.
1. Leidy NK et al. Ann Am Thorac Soc. 2014;11:316-325; 2. Langsetmo L et al. Am J Respir Crit Care Med. 2008;177:396-401; 3. Xu W et al. Eur Respir J. 2010;35:1022-1030; 8
4. Wilkinson TM et al. Am J Respir Crit Care Med. 2004;169:1298-1303.
COPD Exacerbations can Have a Long-term Impact on Patients’
Health and Wellbeing1

Worsening
symptoms

COPD Lung function

exacerbation

Cardiovascular
Events2-4

Physical activity
& de-conditioning Mental health

Quality of Life
Further COPD
exacerbations

Death/mortality

Note: Figure adapted from Hurst JR et al. Eur J Int Med. 2020;73:1.
1. Hurst JR et al. Eur J Int Med. 2020;73:1‒6; 2. Donaldson GC et al. Chest. 2010;137:1091–1097; 3. Kunisaki KM et al. Am J Respir Crit Care Med. 2018;198:51–57; 4. Goto T et al. J Gen Intern Med. 9
2018;33(9):1461-1468.
Lung function may not fully recover after an exacerbation

Lung function starts to decline prior to the first reported symptoms of an exacerbation*

20

0
In some patients,
Mean change (± SE) from

there was still a loss

Week −8 in FEV1 (mL)

of lung function
−20
8 weeks following
an exacerbation
−40

−60 Exacerbation

−80
−8 −7 −6 −5 −4 −3 −2 −1 1 2 3 4 5 6 7 8
Weeks from moderate exacerbation CC BY 4.0

Figure adapted from Watz H, et al. Respir Res 2018;19:251; image license available from: https://creativecommons.org/licenses/by/4.0 (accessed October 2022)
*A post-hoc analysis of the WISDOM study in 317 patients with severe to very severe COPD to characterise lung function before, during and after a moderate COPD exacerbation
FEV1, forced expiratory volume in 1 second; SE, standard error; WISDOM, Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management
Watz H, et al. Respir Res 2018;19:251
Lung function decline following an exacerbation is greatest in
patients with mild COPD1

3.0
COPD severity (defined Excess change per
by lung function) severe exacerbation
2.5
Mild

While each exacerbation can -23 mL

FEV1 (L)
2.0
lead to a decline in FEV1, the
Moderate
greatest decline was observed
1.5 -10 mL
in patients with mild COPDab
Severe
1.0 -8 mL

Very severe 0 mL
0.5
1
Visit 2
FEV1 decline in patients with one exacerbationa
No exacerbation Exacerbation

Figure adapted from Dransfield MT et al. Am J Respir Crit Care Med. 2017;195:324-330. aData on the first 2000 patients who returned for a second visit in the COPDGene study 5 years after enrolment were evaluated to determine the
association between acute COPD exacerbations and FEV1 decline in all GOLD stages. bExacerbations were defined as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for
hospitalisation. 11
1. Dransfield MT et al. Am J Respir Crit Care Med. 2017;195:324-330.
 The Impact of an Exacerbation Goes Beyond the Lungs

In patients with COPD and existing or risk factors for CVD,

MI and stroke risk increased in the
the risk of CV events persisted for up to
first 10 days following
a year after an exacerbation2,d
a moderate exacerbation1

MI Stroke
Risk of CV event in the days after an exacerbation
2.27 2x 40%
Incidence rate ratios1

increased increased risk

risk of MIa 1.74 of strokeb
Days Days Days
1.40
1-30 31-90 91-365

~4x risk ~2x risk ~2x risk

0.55

1–5 days 6–10 days

Risk of a CV event increased by ~10X within 30 days
Days following a moderate COPD exacerbation 1,c
following a hospitalization for a severe exacerbation 2

• a
risk of MI doubled within 5 days (P=0.03) and returned to baseline over time; bIncidence rate ratio for MI on days 6-10 and for stroke on days 1-10 were not statistically significant; ca case-series study conducted in 25,857 patients
with COPD to assess the magnitude and timing of the risk of MI and stroke following a COPD; dpost-hoc analysis of the SUMMIT trial (n=16,485) was performed to determine whether the risk for CV events increases after a 12
moderate/severe COPD exacerbation.
• 1. Donaldson GC et al. Chest. 2010;137:1091–1097; 2. Kunisaki KM et al. Am J Respir Crit Care Med. 2018;198:51–57.
An increased frequency and severity of baseline AECOPD was
associated with an increased risk of mortality1
Secondary UK EHR cohort study (N=340,515)

Even one moderate exacerbation at baseline* increased risk of COPD-related mortality by 17% and CV-related mortality by 23%2
Increased frequency and severity of exacerbations is associated with increased risk of all-cause and COPD-related mortality2
There is a relationship between CV-related mortality and an increased frequency and severity of COPD exacerbations2
N = 86,3062‡
Risk of Risk of Risk of Risk of
COPD-related death COPD-related death CV-related mortality CV-related mortality
was increased by:2 was increased by:2 was increased by:2 was increased by:2
N of deaths = 22,437 N of deaths = 22,437 N of deaths = 8,169 N of deaths = 8,169

17% 26% 23% 34%

with one moderate with two moderate with one moderate with two moderate
exacerbation only* exacerbations only* exacerbation only* exacerbations only*
(Adjusted IRR† 1.17 (Adjusted IRR† 1.26 (Adjusted IRR † 1.23 (Adjusted IRR † 1.34
[95% CI 1.04, 1.33]) [95% CI 1.08, 1.46]) [95% CI 1.07, 1.42]) [95% CI 1.12, 1.60])

*Baseline = 12 months of prior history; †Adjusted for all baseline characteristics listed in Table 1; ‡Patients are registered at general practices in the UK, have a diagnosis of COPD, were over the age of 40 years, were smokers or ex-smokers and had data recorded from 2004
onwards
AECOPD, acute exacerbation of chronic obstructive pulmonary disease; CI, confidence interval; CV, cardiovascular; IRR, incidence rate ratio
1. Whittaker H, et al. Int J Chron Obstruct Pulmon Dis 2022;17:427–437; 2. Whittaker H, et al. Int J Chron Obstruct Pulmon Dis 2022;17:427–437 (supplementary material)
 Severe Exacerbations are Associated with Increased Mortality

1.0

0.9

0.8

Proportion surviving
0.7

0.6
Only 50% of patients were alive
0.5
within 3.6 years after their first 50%
0.4
severe exacerbationa
0.3

0.2

0.1

0
Severe exacerbations: hospitalization with a primary discharge 0 2 4 6 8 10 12 14 16 18
diagnosis of COPD
Time after first severe exacerbation (years)

Note: Figure adapted from Suissa S et al. Thorax. 2012;67:957-963 aCohort study that evaluated severe COPD exacerbations and their association with mortality in 73,106 patients with their first severe COPD exacerbation requiring hospitalization in the RAMQ from the Health Insurance Program of the Province of
Québec, Canada.
Suissa S et al. Thorax. 2012;67:957-963.
14
Even After Hospitalization Many Patients are Untreated For COPD

1st COPD Of these,

hospitalization
35%
had no maintenance
38%
had no maintenance
treatmenta history COPD treatmenta
prior to hospital during follow-upc
admissionb

Post Hospital
Pre-event
Index event Discharge

Retrospective cohort of Swedish inpatient secondary care from 2006-2015 hospitalized with a first severe COPD exacerbation (N=51,247). Index date defined as the date of first COPD hospitalization; aNo treatment with ICS, LAMA and/or LABA; bcollected during the 4-month period pre-
index for baseline; ccollected during the 4-month period during post-index. 15
Jansen C et al. Article and supplementary appendix. Int J Chron Obstruct Pulm Dis. 2020:15 2673-2682.
Identifying Patients at Risk of Exacerbations is Key to Optimizing
Their Management

A history of COPD
exacerbations is a strong predictor
of future exacerbations1,2

Increased dyspnea and productive

cough were associated with higher
exacerbation risk1,3

Patients with raised eosinophil counts

not on ICS were at higher risk of
exacerbating4

•
•
COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid
1. Müllerová H et al. BMJ Open. 2014;4:e006171; 2. Hurst JR et al. N Engl J Med. 2010;363:1128–1138; 3. Lindberg A et al. Respir Med. 2015;109:88–95; 4. Bafadhel M et al. Lancet Respir Med. 2018;6:117–
16
126.
Exacerbation Risk and Mortality Could Be Reduced
Through Transforming the COPD Care Pathway and Optimizing Disease Management

A combvination of approaches are required for optimal management of COPD

1 2 3 4
Identification of Disease assessment Optimum Follow-up of patients
patients with COPD and quantification of management of with COPD
future risk patients with COPD

Thorough phenotyping of Pharmacological and Regular follow-up to

Earlier diagnosis and
patients to identify non-pharmacological optimize pharmacological
targeted
those most at risk of treatments to prevent
case finding of patients
exacerbations and other exacerbations and and non-pharmacological
with COPD
conditions decrease risk of mortality intervention

Pullen R et al. Int J COPD. 2021;16:2301–2322

17
How does BREZTRI AEROSPHERE TM

clinical profile fit into COPD treatment

paradigm?

18
The Phase III clinical programme of BREZTRI AEROSPHERETM

Two Phase III, multicentre, randomized, double-blind, parallel-group studies that assessed
the efficacy and safety of BUD/GLY/FORM in patients with COPD

KRONOS1 KRONOS extension study2

(24 weeks) (28 weeks)
N=1902a N=456
Dual primary endpoints:
• FEV1 AUC0-4 Evaluated bone and ocular safety as well as
other adverse events of special interest
• Change from baseline in pre-dose
trough FEV1

ETHOS3,4
(52 weeks)
N=8588a
Primary endpoint: rate of moderate or severe COPD exacerbations over 52 weeks

a Number of patients randomized.

AUC0-4 = area under the curve from 0-4 hours post-dose; BID = twice daily; BUD/GLY/FORM = budesonide/glycopyrronium/formoterol fumarate dihydrate; FEV1 = forced expiratory volume in 1 second.
1. Ferguson GT et al. Lancet Respir Med. 2018;6:747-758; 2. Kerwin EM et al. Respir Res. 2019;20:16; 3. Rabe KF et al. Respir Med. 2019;158:59-66;
4. Rabe KF et al. Online ahead of print. N Engl J Med. 2020.
 KRONOS study design

Phase III, randomized, double-blind, parallel-group, 24-week trial conducted in 4 countries

All MDI treatments were administered twice-daily via a single AEROSPHERETM inhaler

RANDOMIZATION BREZTRI AEROSPHERE 320/14.4/10 μg (ICS/LAMA/LABA) (N=640)

Follow-up
GLY/FORM MDI 14.4/10 μg (LAMA/LABA) (N=627) 14 days
SCREENING or
BUD/FORM MDIa 320/10 μg (ICS/LABA) (N=316) Safety
All patients were on open- extension
label ipratropium QID +/- ICS Open-label BUD/FORM DPI 400/12 μg (ICS/LABA) (N=319)

Double blind treatment period

Visit 1 2 3 4 5 6 7 8 9 10
Day -28 Day -21 Day -19
to -9 to -2 to -1 Day 1 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24

Assess bronchodilator
response

BUD/FORM MDI delivered via the AEROSPHERETM inhaler is not an available product.
a

DPI = dry powder inhaler; MDI = metered-dose inhaler; QID = four times daily.
Ferguson GT et al. Article and supplementary appendix. Lancet Respir Med. 2018;6:747-758.
© AstraZeneca 2020
KRONOS study population

Patient Moderate to very severe COPD with no requirement for a history of COPD exacerbations
population within the past year

40-80 years of age

Established clinical history of COPD and post-BD FEV1/FVC ratio <0.70
Current or former smoker (≥10 pack-year history)
Key Symptomatic (CAT ≥10)
inclusion On ≥2 inhaled maintenance therapiesa for COPD for ≥6 weeks prior to screening
criteria

FEV1 ≥25% to <80% of predicted normal

Current diagnosis of asthma

Key
Hospitalization due to poorly controlled COPD <3 months prior to, or during, screening
exclusion
Change in smoking status <6 weeks prior to, or during, screening
criteria
Acute worsening of COPDb
Included scheduled SABAs and/or SAMAs; bDefined as requiring OCS or antibiotics <6 weeks prior to screening with a <4-week washout and/or antibiotics prior to Visit 1 or during screening.
a

BD = bronchodilator; CAT = COPD assessment test; FVC = forced vital capacity; OCS = oral corticosteroid; SABA = short-acting beta agonist; SAMA = short-acting muscarinic antagonist.
Ferguson GT et al. Article and supplementary appendix. Lancet Respir Med.
Baseline characteristics were comparable across treatment groups

BUD/GLY/FORM GLY/FORM BUD/FORM Open-label

320/14.4/10 µg 14.4/10 μg MDI 320/10 μg BUD/FORM DPI
Characteristic (n=639) (n=625) (n=314) 400/12 µg (n=318)

Age, mean (SD), years 64.9 (7.8) 65.1 (7.7) 65.2 (7.2) 65.9 (7.7)
Male, % 72.0 68.8 71.3 74.2
Race, White / Asian / Black / Other, % 51.5 / 44.4 / 3.6 / 0.5 48.2 / 45.6 / 6.1 / 0.2 50.0 / 45.2 / 4.8 / 0 51.3 / 44.3 / 4.4 / 0
Current smoker, % 40.1 41.1 36.6 38.4
Pack-years smoked, median (range), no. 45.0 (10.0-256.0) 45.0 (10.0-171.0) 45.0 (10.0-192.0) 45.0 (10.0-180.0)
Eosinophils, ≥150 cells/mm3, % 50.9 53.4 51.9 50.6
Exacerbation history, 0 (past 12 months), % 73.4 75.7 74.8 73.6
Postbronchodilator FEV1, mean (SD), % predicted 50.2 (14.3) 50.2 (13.8) 50.0 (14.0) 50.7 (13.8)
COPD severity, moderate / severe / very severe, % 48.5 / 43.0 / 8.1 49.0 / 42.7 / 8.3 49.0 / 42.4 / 8.3 50.3 / 43.4 / 6.3
Reversible to albuterol, % 44.8 42.6 41.4 44.0
Use of ICS at screening, % 72.6 71.5 71.7 70.8
CAT score at screening, mean (SD) 18.7 (6.4) 18.1 (6.1) 18.4 (6.6) 18.0 (6.4)

Note: All treatments were administered BID.

mITT = modified intent-to-treat; SD = standard deviation.
Ferguson GT et al. Lancet Respir Med. 2018;6:747-758. © AstraZeneca 2020
 BREZTRI significantly improved morning predose trough FEV1
vs. dual therapies
Over 24 weeks, BUD/GLY/FORM
resulted in FEV1 increases of:
Adjusted mean (SE) change from baseline

in morning predose trough FEV1 (mL)a

180

160
22 mL
vs.
140 LAMA/LABAb
95% CI: 4 to 39
120 p=0.0139

100

80 74 mL
vs.
60
ICS/LABA MDIc
95% CI: 52 to 95
40
p<0.0001
20

0 // //
Day 1 4 8 12 16 20 24 12-24 0-24
0-24
Week
BREZTRI GLY/FORM BUD/FORM MDI BUD/FORM DPI
320/14.4/10 μg 14.4/10 μg 320/10 μg 400/12 μg

Note: All treatments were administered BID.

a
mITT population; bPrimary endpoint EU/Canada approach; cPrespecified secondary endpoint EU/Canada approach. 23
Ferguson GT et al. Article and supplementary appendix. Lancet Respir Med. 2018;6:747-758.
BREZTRI significantly improved FEV1 AUC0-4 vs. ICS/LABA

Over 24 weeks, BUD/GLY/FORM

resulted in FEV1 AUC0–4 differences of:
Adjusted mean (SE) FEV1 AUC0-4 (mL)a

350
330
104 mL
310 vs.
290 ICS/LABA MDI
95% CI: 77 to 131
270 p<0.0001

250
230
210
91 mL
vs.
190 ICS/LABA DPI
170 95% CI: 64 to 117
p<0.0001
150 // //
Day 1 4 8 12 16 20 24 12-24 0-24
0-24

Week
BREZTRI GLY/FORM BUD/FORM MDI BUD/FORM DPI
320/14.4/10 μg 14.4/10 μg 320/10 μg 400/12 μg

Note: All treatments were administered BID.

a
mITT population. 24
Ferguson GT et al. Lancet Respir Med. 2018;6:747-758.
BREZTRI powerfully protects symptomatic patients from moderate to severe
exacerbations vs GLY/FORM in a majority of patients without a recent
exacerbation history1-3
Annual rate of moderate/severe exacerbations 1,2

In KRONOS, 74% of
patients did not report
an exacerbation in the
previous 12 months2

a
BREZTRI vs GLY/FORM MDI: Annual rates: 0.46 vs 0.95 (RR 0.48, 95% CI 0.37–0.64; p<0.0001).1,2 bBREZTRI vs BUD/FORM MDI: Annual rates 0.46 vs 0.56 (RR 0.82; 95% CI 0.58–1.17; p=0.2792).1,2
1. BREZTRI AEROSPHERE SmPC; 2. Ferguson GT et al. Lancet Respir Med. 2018;6:747-758; 3. Data on File, AstraZeneca Veeva Approval ID: REF-54777. 25
BREZTRI significantly reduces COPD Severe exacerbation led to
hospitalizations vs GLY/FORM1

Annual rate of severe exacerbations resulting in COPD hospitalisation or death 1

a
BREZTRI vs GLY/FORM MDI: Annual rates: 0.05 vs 0.13 (RR 0.36, 95% CI 0.18–0.70; unadjusted p=0.0026).1 The p-value is unadjusted because it was not included in the Type 1 error control plan for
the KRONOS study.2 bBREZTRI vs BUD/FORM MDI: Annual rates 0.05 vs 0.05 (RR 0.85; 95% CI 0.34–2.13; p=0.7363).1
26
1. Data on File, AstraZeneca Veeva Approval ID: REF-54777; 2. Ferguson GT et al. Lancet Respir Med. 2018;6:747-758. Supplementary Appendix.
BREZTRI: Fast onset within 5 minutes1a

In the KRONOS study, the time to onset of actionb on Day 1 was within 5 minutes

a
BREZTRI AEROSPHERE is NOT a rescue medication and does NOT replace fast-acting inhalers to treat acute symptoms. 2b
Time to onset is defined as the first post-dose time point where the mean
change from baseline in FEV1 exceeded 100 mL. 27
1. Ferguson GT et al. Lancet Respir Med. 2018;6:747-758; 2. BREZTRI AEROSPHERE SmPC.
Adverse events that occurred in ≥2% of patients in any group
(safety population) in the KRONOS study
The safety profile of BUD/GLY/FORM was comparable to the profiles of GLY/FORM and BUD/FORM

BREZTRI GLY/FORM BUD/FORM Open-label BUD/FORM

320/14.4/10 µg 14.4/10 μg MDI 320/10 μg DPI 400/12 µg
(n=639) (n=625) (n=314) (n=318)

% % % %
Nasopharyngitis 8 7 8 9
URTI 10 6 6 7
COPD 3 5 3 4
Bronchitis 3 2 4 3
Muscle spasms 3 1 5 2
Dysphonia 3 1 5 2
Hypertension 2 2 3 1
Dyspnoea 1 1 3 3
Back pain 1 2 1 3
Nausea 1 <1 1 2

The percentages of patients with confirmed pneumonia (by a Clinical Endpoint Committee) were low and similar across
treatment groups: BUD/GLY/FORM, 1.9%; GLY/FORM, 1.6%; BUD/FORM MDI, 1.9%; BUD/FORM DPI, 1.3%.

Notes: All treatments were administered BID. URTI = upper respiratory tract infection
Ferguson GT et al. Lancet Respir Med. 2018;6:747-758.
 ETHOS study design

Phase III, randomized, double-blind, parallel-group, 52-week trial conducted in 26 countries1,2

All treatments were administered twice-daily via a single AEROSPHERETM inhaler

BREZTRI AEROSPHERE 320/14.4/10 μg (ICS/LAMA/LABA) (N=2157)

BUD/GLY/FORM MDI 160/14.4/10 (ICS/LAMA/LABA) (N=2137)

SCREENING
GLY/FORM MDI 14.4/10 μg (LAMA/LABA) (N=2143)
All patients were on open-
RANDOMIZATION

label ipratropium QID +/- ICS2 BUD/FORM MDIa 320/10 μg (ICS/LABA) (N=2151)

Double blind treatment period Follow-up

Visit 1 2 3 5 6b
7 8b 9b 10 11b 12 13b 14
Week2 −4 4 4 12 16 20 24 28 36 44 52 54
Assess 0
8
bronchodilator
response
aBUD/FORM MDI delivered via the AEROSPHERETM inhaler is not an available product; bVisit conducted via telephone contact; all
other visits were conducted in-clinic.
1. Rabe KF et al. Online ahead of print. N Engl J Med. 2020; 2. Rabe KF et al. Respir Med. 2019;158:59-66.
ETHOS study population

Patient Moderate to very severe COPD with a history of moderate or severe COPD exacerbation(s)
population within the past year1,2

40-80 years of age

Established clinical history of COPD and post-BD FEV1/FVC ratio <0.70
Current or former smoker (≥10 pack-year history)
Symptomatic (CAT ≥10)
Key On ≥2 inhaled maintenance therapiesa for COPD for ≥6 weeks prior to screening
inclusion
criteria FEV 1≥25% to <65% of predicted normal

History of moderate or severe COPD exacerbations in the 12 months prior to screening:

• ≥1 moderate or severe if post-BD FEV1 <50% of predicted normal
• ≥2 moderate or ≥1 severe if post-BD FEV1 ≥50% of predicted normal

Key Current diagnosis of asthma

exclusion COPD due to α1 antitrypsin deficiency
criteria Any significant uncontrolled conditions other than COPD

a Included scheduled SABAs and/or SAMAs.

1. Rabe KF et al. Respir Med. 2019;158:59-66; 2. Rabe KF et al. Online ahead of print. N Engl J Med. 2020.
Primary and secondary endpoints

Primary
endpoint Rate of moderate or severe COPD exacerbations (efficacy estimand)

Exacerbations Symptoms
• Rate of moderate or severe COPD • Change from baseline in average daily rescue
exacerbations (attributable estimand) medication use over 24 weeks
• Rate of severe COPD exacerbations • TDI focal score over 24 weeks (ex-US only)
Secondary
endpoints • Time to first moderate or severe COPD • Change from baseline in EXACT total score over
exacerbation 52 weeks (ex-US only)
• Change from baseline in SGRQ total score over 24
Mortality weeks (ex-US only)
• Time to death (all cause) • Percentage of patients achieving ≥4 units in SGRQ
total score at Week 24 (US only)

EXACT = Exacerbations of Chronic Pulmonary Disease Tool; SGRQ = St. George’s Respiratory Questionnaire; TDI = Transitional Dyspnea Index.
Rabe KF et al. Respir Med. 2019;158:59-66.
Baseline characteristics were comparable across treatment groups

BREZTRI BUD/GLY/FORM GLY/FORM BUD/FORM

320/14.4/10 µg 160/14.4/10 µg 14.4/10 μg 320/10 μg
Characteristic (n=2137) (n=2121) (n=2120) (n=2131)

Age, mean (SD) years 64.6 (7.6) 64.6 (7.6) 64.8 (7.6) 64.6 (7.6)
Male, % 59.0 61.2 58.7 60.0
Race, White, % 85.1 84.1 85.3 85.2
Current smoker, % 42.6 40.8 40.4 40.5
Pack-years smoked, mean (SD), no. 47.0 (25.1) 47.9 (25.8) 48.4 (26.5) 47.1 (26.3)
Eosinophils, ≥150 cells/mm3, % 59.8 59.3 60.0 60.7
Exacerbation history, 1 / ≥2 (past 12 months), % 44.0 / 55.9 43.9 / 56.0 42.8 / 57.1 42.8 / 57.1
Postbronchodilator FEV1, mean (SD), % predicted 43.6 (10.3) 43.1 (10.4) 43.5 (10.2) 43.4 (10.4)
COPD severity, moderate / severe / very severe, % 28.7 / 61.1 / 10.2 28.5 / 59.9 / 11.6 28.1 / 61.0 / 10.8 28.8 / 60.2 / 10.9
Reversible to albuterol, % 30.7 29.8 31.6 30.7
Use of ICS at screening, % 79.8 81.5 80.5 80.0
CAT score at screening, mean (SD) 19.7 (6.5) 19.6 (6.6) 19.5 (6.6) 19.5 (6.5)
Therapy at entry, Triple / ICS-LABA / LAMA-LABA, % 39.1 / 30.9 / 14.7 39.5 / 31.6 / 13.1 39.8 / 31.1 / 13.5 39.0 / 31.5 / 14.3

Note: All treatments were administered BID.

Rabe KF et al. Article and supplementary appendix. Online ahead of print. N Engl J Med. 2020.
BREZTRI powerfully protects symptomatic patients with a recent exacerbation
history from moderate to severe exacerbations vs dual therapies in a
symptomatic patient population1
Annual rate of moderate/severe exacerbations 1

In ETHOS, 100% of
patients reported an
exacerbation in
the previous 12 months

a
BREZTRI vs GLY/FORM MDI: Annual rates: 1.08 vs 1.42 (RR 0.76, 95% CI 0.69–0.83; p<0.001). bBREZTRI vs BUD/FORM MDI: Annual rates 1.08 vs 1.24 (RR 0.87; 95% CI 0.79–0.95; p=0.003).1
1. Rabe KF et al. N Engl J Med. 2020;383:35-48. 33
BREZTRI significantly reduces COPD hospitalisations vs BUD/FORM1

Annual rate of severe exacerbations resulting in COPD hospitalisation or death 1

a
BREZTRI vs GLY/FORM MDI: Annual rates: 0.13 vs 0.16 (RR 0.80, 95% CI 0.66–0.97; p=0.02). bBREZTRI vs BUD/FORM MDI: Annual rates 0.13 vs 0.15 (RR 0.84; 95% CI 0.69–1.03; p=0.09).
1. Rabe KF et al. N Engl J Med. 2020;383:35-48.
34
BREZTRI Significantly Reduced Risk of All-Cause Mortality vs. LAMA/LABAa
in the Original and Final Retrieved Datasets1,2
3 ETHOS:* Time to all-cause mortality1† Hazard ratio for risk of death with
GLY/FORM
18/9.6 µg‡ BREZTRI 320 was1:
Final retrieved dataset
Kaplan-Meier cumulative

BUD/GLY/FORM
160/18/9.6 µg‡ 0.51 (95% CI 0.33, 0.80),
2 49% unadjusted P=0.0035 ‡
incidence1 (%)

BUD/FORM
320/9.6 µg‡ RR versus GLY/FORM
BREZTRI (18/9.6 µg§, N = 2,120)
320/18/9.6 µg
1 Final retrieved dataset

0.72 (95% CI 0.44, 1.16),

28% P=0.172 versus BUD/FORM
RR (320/9.6 µg§, N = 2,131)
+ censored
0
0 4 8 12 16 20 24 28 32 36 40 44 48 Original dataset
Number of patients at risk:
52 We eks % Mortality║
BREZTRI 2137 2136 2134 2131 2130 2127 2123 2122 2118 2112 2106 2103 2100 2075 1.4 (n=30)
BUD/GLY/FORM‡ 2121 2121 2120 2118 2110 2104 2102 2101 2098 2087 2084 2076 2072 2062 2.1 (n=44)‡
GLY/FORM‡ 2120 2117 2112 2106 2100 2097 2095 2089 2086 2082 2077 2069 2067 2045 2.6 (n=56)‡
BUD/FORM‡ 2131 2127 2122 2120 2118 2116 2110 2108 2102 2099 2097 2094 2088 2075 1.9 (n=40)‡

*ETHOS was a Phase 3, randomised, double-blind, multicentre, parallel-group trial in patients with moderate-to-very-severe COPD over 52 weeks (N=8509). The primary endpoint of the rate of moderate or severe
COPD exacerbations was met;2 †Time to death (all cause) was evaluated as a secondary endpoint in the ETHOS trial; the data presented are an additional mortality analysis using the final retrieved dataset unless stated
otherwise; ‡ Significant; P-values in the original dataset are unadjusted owing to an endpoint earlier in the hierarchy of Type 1 error control tests did not reach statistical significance1; ¶ BUD/GLY/FORM 320/18/9.6 μg (N
= 2,137) demonstrated a 22% reduction in death from any cause versus BUD/FORM (320/9.6 μg†, N = 2,131) HR 0.78 (95% CI 0.47, 1.30) ARR 0.3%; ¶. ARR, absolute risk reduction; BUD, budesonide; CI, confidence
interval; FORM, formoterol fumarate; GLY, glycopyrrolate; RR, risk reduction

1. Martinez FJ, et al. Am J Respir Crit Care Med 2021;203:553–564; 2. Rabe KF, et al. N Engl J Med 2020; 383:35–48
 Class Review Triple Fixed Dose Combination

• TFDC Vs LAMA/ LABA Reduction in Moderate or Severe Exacerbation.

• TFDC Vs LAMA/LABA Reduction in Severe Exacerbation related to Hospitalization.
• TFDC Vs ICS/LABA Reduction in Severe Exacerbation related to Hospitalization.
• ICS intraclass difference in risk of Pneumonia.

36
 ICS/LAMA/LABA reduces the rate of COPD exacerbations
compared with LAMA/LABA1-4
ICS/LAMA/LABA vs. LAMA/LABA1-4 ICS/LAMA/LABA vs. LAMA/LABA1-4
Moderate or severe exacerbations Severe exacerbations

-34%
-24% -16% RR, 0.66
RR, 0.76; 95% CI, 0.56-0.78;
RR: 0.84
1.6
95% CI, 0.69-0.83; -25% 0.2 95% CI, 0.69-1.03;
p<0.001

-64%
p<0.001
RR, 0.75; p=0.09
Exacerbation rate (events/year)

Exacerbation rate (events/year)

-52%
95% CI, 0.70-0.81;
1.4 p<0.001 0.18 RR: 0.36
RR, 0.48; 95% CI, 0.18-0.70;
95% CI, 0.37-0.64;
0.16 unadjusted
1.2 p<0.0001 p=0.0026†
0.14 -21%
1 -15% RR, 0.79;
RR, 0.85; 0.12 95% CI, 0.55-1.13;
95% CI, 0.72-1.0; p=0.19
0.8 p=0.043 0.1

0.6 0.08
0.06
0.4
0.04
0.2 0.02
0 0
KRONOS a ETHOS IMPACT TRIBUTE KRONOS a ETHOS IMPACT TRIBUTE
(BREZTRI) (BREZTRI)

Coloured bars = ICS/LAMA/LABA; grey bars = LAMA/LABA Coloured bars = ICS/LAMA/LABA; grey bars = LAMA/LABA

†
p-values for this endpoint are considered unadjusted as it was not included in the type I error control strategy; a secondary endpoint.
1. Ferguson GT et al. Lancet Respir Med. 2018;6:747-758; 2. Rabe KF et al. N Engl J Med. 2020;383:35-48; 3. Lipson DA et al. N Engl J Med. 2018;378:1671-1680; 4. Papi A et al.
Lancet. 2018;391:1076-1084.
BREZTRI significantly reduced the rate of Severe COPD
exacerbations compared with dual therapy1-5

ICS/LAMA/LABA vs. ICS/LABA1-5

-20%
0.18 RR: 0.80
95% CI: 0.66 to 0.97
NS

Exacerbation rate (events/year)

p=0.02 RR: 0.87
95% CI: 0.76-1.01
0.16 p=0.06

0.14
0.12
0.1
NS
0.08 NS
RR: 0.49
95% CI: 0.24, 1.03
RR: 0.85 p=0.061

0.06
95% CI: 0.34 to 2.13
p=0.7363

0.04
0.02 Not
0 Studied
KRONOS ETHOS IMPACT FULFIL TRIBUTE
a
(BREZTRI) (BREZTRI)

Coloured bars = ICS/LAMA/LABA; grey bars = ICS/LABA

†
p-values for this endpoint are considered unadjusted as it was not included in the type I error control strategy; a secondary endpoint.
1. Ferguson GT et al. Lancet Respir Med. 2018;6:747-758; 2. Rabe KF et al. N Engl J Med. 2020;383:35-48; 3. Lipson DA et al. N Engl J Med. 2018;378:1671-1680; 4. Papi A et al.
Lancet. 2018;391:1076-1084; 5. Lipson DA et al. Am J Respir Crit Care Med. 2017;196:438-446; 6.
Intraclass Difference in Pneumonia Risk with Fluticasone and Budesonide in COPD,
A systematic Review of Evidence from Direct – Comparison Studies

 Relative risk (RR) ratio across 5 included studies (57,199

patients) was 1.13 (95% CI: 1.09–1.19), representing a
13.5% increased risk of pneumonia among fluticasone
users compared to budesonide users.

 Similarly, summary RR ratio for serious pneumonia implied a

14.4% increased risk of serious pneumonia among
fluticasone users compared to budesonide users (pooled
RR: 1.14; 95% CI: 1.09–1.20).

 There is likely a clinically important intraclass

difference in the risk of pneumonia between fluticasone-
and budesonide-containing inhaled medications in COPD.

This review investigated whether there is an intraclass difference in risk of pneumonia between inhaled fluticasone and budesonide, the 2 most used ICS in COPD. A search of the medical
literature was conducted in PubMed and Embase for the period of 01/01/69–05/31/19. The summary relative risk (RR) ratio across 5 included studies (57,199 patients) has been assessed.
BREZTRI demonstrated efficacy and safety in patients with and without a
recent history of COPD exacerbations

BREZTRI significantly reduced the rate of moderate or severe COPD exacerbations

compared with LAMA/LABA1,2 and ICS/LABA2 regardless of exacerbation history1,2

BREZTRI significantly reduced the rate of severe exacerbations by 20% vs. ICS/LABA in
ETHOS and by 64% vs. LAMA/LABA in KRONOS 1,2

BREZTRI provided a significant reduction in all-cause mortality of 49% vs. LAMA/LABA2

49%
(unadjusted p=0.00353,a)

BREZTRI reduced symptoms and improved quality of life vs. dual therapies2 with a
lung function benefitb within 5 minutes1

The incidence of AEs with BREZTRI is consistent with the safety profiles of its
well-established components1,2

a p-values for this endpoint are considered unadjusted because of results higher in the testing hierarchy for the rate of severe exacerbation; bTime to onset of action.
1. Ferguson GT et al. Lancet Respir Med. 2018;6:747-758; 2. Rabe KF et al. Article and supplementary appendix. Online ahead of print. N Engl J Med. 2020;
34 3. Martinez FJ et al. Abstract. Am J Respir Crit Care Med. 2020;201:A4214.
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Thank you

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