copd

1. COPD Today:
What is Different now
Dr. Vijay Kumar Agrawal
MBBS, MD, FCCP, FCCS, IDCCM
Metro Heart Institute with multispeciality
Faridabad

2. 2015 GOLD: Definition of COPD
COPD is a common preventable and
treatable disease, is characterised
by persistent airflow limitation
that is usually progressive and
associated with an enhanced
chronic inflammatory response in
the airways and the lung to
noxious particles or gases.
• It is increasingly recognized that
many patients with COPD have
systemic comorbidities that have a
major impact on quality of life and
survival
GOLD Guidelines 2015

3. Systemic inflammation in COPD
• COPD itself also has significant extrapulmonary (systemic)
effects.
• Inflammatory mediators in the circulation may contribute to
skeletal muscle wasting and cachexia, and may initiate or
worsen comorbidities such as :
• Ischemic heart disease
• Heart failure
• Osteoporosis
• Normocytic anemia
• Diabetes
• Metabolic syndrome and
• Depression
GOLD Guidelines 2015

4. COPD is an increasing problem
• Global prevalence of GOLD Stage II or higher COPD1
• men: 11.8%
• women: 8.5%
• overall: 10.1%
• >3 million deaths due to COPD in 20052
• 5% of all deaths globally
• total deaths projected to increase by more than 30% over next
10 years
• Considerable economic burden3

5. Burden of Disease- India
• The prevalence of COPD in India
according to INSEARCH I & II was
3.67%.
• The estimated burden of COPD in
India is about 15 million cases
• In India COPD causes about
500,000 deaths per year; hence
causes huge economic burden in
terms of direct & indirect costs
Lung India ,Aug 2013, Gupta et alS: Indian COPD guidelines VOL. 30;Issue 3

6. Risk Factors
• Cigarette smoking accounts for 85% of worldwide cases of COPD
• Approximately 25-50% smokers may develop COPD
 Inhaling noxious fumes – work related risks, air pollution (biomass fuel)

7. Situation In India
• In India where :
• 70%people use biomass
fuel for cooking purposes
compared to 20% who
smoke.
• Thus exposure to biomass
fuel may be a bigger risk
factor for COPD in India.

8. Vehicular Pollution
• Increasing in both rural and urban areas
• Traffic interruptions:
• Signals
• Traffic jams
• Railway crossings
• Diesel locomotives

9. Burning of Garbage
• Food
• Plastic
• Rubber
• Wood
• Organic matter

10. Indoor pollution
• Combustion of charcoal,
biomass or Kerosine
• Mosquito coils
• Incense Sticks

11. Chronic inflammation causes structural changes and
small airway narrowing in COPD
Inflammation
Inhaled noxious agents
(e.g. cigarette smoking, pollutants)
Lung damage
Airway narrowing
and fibrosis
Airway narrowing
and fibrosis
Mucus hypersecretion
(chronic bronchitis)
Mucus hypersecretion
(chronic bronchitis)
Alveolar wall destruction
(emphysema)
Alveolar wall destruction
(emphysema)

12. Barnes P.J., NEJM 2000; 343:269
COPD: Mechanism of Obstruction

13. Airflow limitation includes irreversible and
partially reversible components
• Irreversible components include1,2
• loss of elastic recoil due to alveolar destruction
• destruction of alveolar attachments which support and
maintain patency of small airways
• small airway fibrosis
• Partially reversible components include1,2
• accumulation of mucus
• smooth muscle hypertrophy
• bronchoconstriction2
1. GOLD 2008; 2. Brusasco. ERR 2006

14. Symptoms of COPD
CHRONIC COMPONENT
• Breathlessness (dyspnoea) on exertion
• Cough with or without sputum
• Chest tightness
• Wheeze
ACUTE COMPONENT
 An acute exacerbation of COPD is a sudden worsening of COPD
symptoms that typically lasts for several days

15. GOLD: COPD DIAGNOSIS
For Internal Training Purposes Only

16. GOLD: COPD Diagnosis
HISTORY OF EXPOSURE TO RISK
FACTORS
•Tobacco smoke
•Smoke from home cooking/heating fuels
•Occupational dusts and chemicals
SYMPTOMS
Dyspnea-progressive (worsens
over time and with exercise)
Chronic cough
Sputum1
SPIROMETRY REQUIRED TO DIAGNOSE COPD
Post-bronchodilator FEV1/FVC <0.70 confirms the presence of airflow limitation that is not fully
reversible2
1. Adapted from GOLD 2015; 2. Johannessen et al. 2006
FAMILY HISTORY OF
COPD
For Internal Training Pur3

17. Staging COPD – GOLD recommendations
STAGE Spirometric classification of COPD
severity based on post-bronchodilator
FEV1
Typical characteristics of each stage of COPD
Stage 1:
Mild
FEV1
/FVC <0.70
FEV1
≥80% predicted
• Chronic cough and sputum production may be present,
but not always.
• Individual often unaware of reduced lung function
• Few individuals seek medical attention
Stage 2:
Moderate
FEV1
/FVC <0.70
50%≤ FEV1
<80%
predicted
• Shortness of breath on exertion usually present
• Cough and sputum production sometimes present
• Stage at which individuals often seek medical
attention
Stage 3:
Severe
FEV1
/FVC <0.70
30%≤ FEV1
<50%
predicted
• Cough and sputum production frequently present
• Greater shortness of breath that impinges on patient QoL
• Reduced exercise capacity and fatigue
• Arterial hypoxaemia
• Weight loss
Stage 4:
Very severe
FEV1
/FVC <0.70
FEV1
<30% predicted or FEV1
<50%
predicted plus chronic respiratory failure
• Severe shortness of breath
• Respiratory failure may be present
• Clinical signs of heart failure may be present
• Patient quality of life severely impaired

18. GOLD 2015
Pharmacological management of COPD*
*Medications in each box are in alphabetical order, and not necessarily in order of preference. Other possible treatments are not shown, but can be used
alone or in combination with other options in the Recommended first choice and Alternative choice boxes. CAT, COPD Assessment Test; COPD, chronic
obstructive pulmonary disease; GOLD, Global initiative for chronic Obstructive Lung Disease; HRQoL, health-related quality of life; ICS, inhaled
corticosteroids; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council; PDE-4i,
phosphodiesterase type 4 inhibitor; SABA, short-acting β2-agonist; SAMA, short-acting muscarinic antagonist
Based on combined assessment of airflow limitation, symptoms and exacerbation risk
Risk
Exacerbationhistory
Risk
GOLDclassificationof
airflowlimitation
4
2
1
3
GOLD Group C
ICS + LABA, or LAMA
LAMA + LABA or
LAMA + PDE-4i or
LABA + PDE-4i
LAMA or LABA
LAMA /LABA
SAMA or SABA p.r.n..
LAMA or
LABA or
SABA + SAMA
ICS + LABA +/or LAMA
ICS + LABA + LAMA or
ICS + LABA + PDE-4i or
LAMA + LABA or
LAMA + PDE-4i
Recommended first choice
Alternative choice
GOLD Group D
GOLD Group A GOLD Group B
Reference. Adapted from GOLD. 2015.
1 (not leading
to hospital
admission)
Symptoms
CAT ≥10CAT <10
mMRC 0−1 mMRC ≥2
Breathlessness
≥2
or ≥1 leading
to hospital
admission

19. Risk-to-benefit ratio of inhaled
corticosteroids in patients with
COPD

20. COPD Is Not Asthma
• The pathobiology of airflow obstruction in COPD is unknown,
but it is associated with inflammation that intensifies during
exacerbations.
• Airway inflammation in COPD is characterised by increased
numbers of :
• Neutrophils
• Macrophages and
• CD8+ T lymphocytes, with increased levels of the cytokine
interleukin 8, and is largely unresponsive to corticosteroids
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

21. Effect of ICS on COPD exacerbations
• The guideline recommendations for the use of ICS in COPD are
largely based on their preventive effect on exacerbations.
• In early studies evaluating the use of ICS in COPD, it was found
that the group of patients most likely to benefit from the ICS
were those with :
• More severe COPD and a
• History of recurrent exacerbations
• A more recent systematic review by the Cochrane
collaboration of trials comparing LABA and ICS concluded that
the two therapies conferred similar benefits across most
outcomes, including exacerbations.
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

22. Effect of ICS on mortality
• With regard to survival (the primary objective of the TORCH
study):
• The effect of the salmeterol/fluticasone combination
narrowly failed to reach statistical significance.
• The addition of fluticasone did not offer additional benefit over
the LABA alone (13.5%).
• The hazard ratio for the combination compared with
fluticasone was significant (p=0.007), suggesting that the LABA
might be conferring a protective effect.
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

23. Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

24. Risks of ICS for COPD patients
• Patients with COPD are at an increased risk of pneumonia and
the risks may be further increased by the use of ICS.
• In a large case-control study, current ICS use was associated
with a 70% increase in the rate of hospitalisation for
pneumonia.
• The risk increased with ICS dose, with the use of fluticasone
1,000μg/day (or equivalent) more than doubling the risk of
hospitalisation for pneumonia
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

25. Pneumonia
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

26. Tuberculosis
• Immune suppression may also be involved in the link between
steroid use and increased risk of tuberculosis among COPD
patients.
• A case-control study found that ICS did not add to the risk of
tuberculosis in the presence of systemic steroids but :
• Increased the risk of tuberculosis among non-users of oral
corticosteroids, especially at doses equivalent to fluticasone
1,000μg/day
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

27. Osteoporosis And Fractures
• Patients with COPD are at high risk for osteoporosis and
fractures because of lifestyle factors (e.g. smoking, sedentary
lifestyle), systemic effects of the disease, and co-morbidities.
• Osteoporosis and low bone mineral density are common even
in milder stages of disease.
• A meta-analysis found that ICS use in COPD was associated
with a modest but statistically significant increase in fracture
risk.
• Each 500μg (beclometasone dipropionate equivalent) increase
in ICS dose was associated with a 9% increase in risk of
fractures
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

28. Oropharyngeal candidiasis and hoarseness
• A systematic review of studies of ICS use in COPD identified an
increased risk of oral thrush (relative risk 2.98, 95% CI 2.09 to
4.26) and hoarseness among ICS users.
• A Cochrane review of 47 primary studies similarly reported an
increased risk of oropharyngeal candidiasis (odds ratio 2.49,
95% CI 1.78 to 3.49) and hoarseness.
• The TORCH study reported rates per year of candidiasis of 0.7–
0.9 with fluticasone-containing treatment compared with 0.2
for salmeterol and placebo groups
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

29. Place of ICS in COPD treatment
guidelines

30. Place of ICS in COPD treatment guidelines
• Evidence-based guidelines support a limited role for ICS in
COPD treatment.
• According to global COPD guidelines, the use of an ICS in
combination with a LABA is appropriate for patients with :
• Higher risk, defined as GOLD stage 3 or 4 (severe or very
severe airflow limitation) and/or
• Frequent exacerbations
• A recent US/European clinical practice guideline found strong
evidence for the use of long-acting bronchodilator
monotherapy for:
• Symptomatic patients with FEV1 <60% predicted.
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

31. Place of ICS in COPD treatment guidelines
• The evidence was judged too weak to support a strong
recommendation for the broad use of combination therapy
(LABA and ICS) in these patients, and :
• Clinicians were advised to weigh the potential benefits and
harms of combination therapy on a case-by-case basis
• NICE guidelines recommended the LABA/ICS combination as an
option (alongside LAMA monotherapy) for patients with
FEV1 <50% predicted with exacerbations or breathlessness
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

32. Place of ICS in COPD treatment guidelines
(contd..)
• The recently updated GOLD guidelines include symptom
burden and exacerbation frequency for severity staging, as well
as airflow obstruction.
• Factors such as :
• Quality of life
• Exacerbations and co-morbidities, and their relative impact
on the patient's lifestyle, as well as
• Patient preference and the risk of side-effects of treatment,
should also be taken into account.
Price D et al. Primary Care Respiratory Journal (2012) 22, 92–100

33. Dual Bronchodilatation

34. Indacaterol + Glycopyrronium

35. Rationale of Dual
Bronchodilatation In COPD

36. Physiological Control of airway smooth muscle
Sympathetic nervous system: Bronchodilation
Parasympathetic nervous system: Bronchoconstriction

37. Long-acting Bronchodilators: The Cornerstone
of COPD Maintenance Therapy
• Two key classes of bronchodilators have been developed in COPD: β2-
agonists and muscarinic antagonists.
• Short-acting bronchodilators, such as ipratropium, albuterol, and
metaproterenol, have formed the cornerstone of initial COPD
therapy for the past two decades.
• Subsequently, long-acting bronchodilators were developed.
• The twice-daily LABAs salmeterol and formoterol first became
available for maintenance therapy of COPD more than 15 years ago.
• While the once-daily LAMA tiotropium has been available for 10
years and is the most widely prescribed maintenance monotherapy
bronchodilator in COPD
Tashkin DP et al. Respiratory Research. 2013;14(49)

38. Long-acting Bronchodilators
• Inhaled bronchodilators, as monotherapy or in combination, remain
the mainstay for patients in all categories.
• Long-acting bronchodilators, such as tiotropium, Glycopyrronium,
formoterol, and salmeterol, are proven to provide long-term
improvements in :
• Lung function
• Quality of life, and
• Exacerbations in patients with COPD
• Long-acting bronchodilators (e.g., tiotropium, salmeterol) also
reduce lung hyperinflation and dyspnea, and increase exercise
endurance
Tashkin DP et al. Respiratory Research. 2013;14(49)

39. Long-acting Bronchodilators (contd..)
• The once-daily LABA indacaterol, the once-daily LAMA
glycopyrronium, and twice-daily LAMA aclidinium represent
newer, recently licensed therapies.
Tashkin DP et al. Respiratory Research. 2013;14(49)

40. Combination Bronchodilation:
Rationale
• Guidelines recommend combination therapy involving two
long-acting bronchodilators with differing modes of action in
patients whose :
• COPD is not sufficiently controlled with monotherapy.
Tashkin DP et al. Respiratory Research. 2013;14(49)

41. Airway smooth muscle relaxation
• Airway smooth muscle relaxation (leading to bronchodilation)
can be achieved via two main routes:
• Inhibition of acetylcholine signaling via muscarinic
M3 receptors on airway smooth muscle with a muscarinic
antagonist, or
• Stimulation of β2-adrenoceptors with a β2-agonist.
• Targeting these two mechanisms of bronchoconstriction,
theoretically, has the potential to maximize the bronchodilator
response :
• Without increasing the dose of either component and
• Helps to overcome the inter- and intra-patient variability in
response to individual agents seen in COPD
Tashkin DP et al. Respiratory Research. 2013;14(49)

42. Airway smooth muscle relaxation (contd..)
• β2-agonists can amplify the bronchial smooth muscle relaxation
directly induced by the muscarinic antagonist by :
• Decreasing the release of acetylcholine via modulation of
cholinergic neurotransmission.
• Additionally, muscarinic antagonists have been demonstrated
to augment β2-agonist-stimulated bronchodilation by reducing
the bronchoconstrictor effects of acetylcholine.
Tashkin DP et al. Respiratory Research. 2013;14(49)

43. Muscarinic (cholinergic) receptors
• In smooth muscle
of all airways
• Higher density
in larger airways
β2-adrenergic receptors
• High concentration in
lung tissue
• Density in airway smooth
muscle does not change at
different airway levels
Barnes. PATS 2004
β2-agonists and muscarinic antagonists provide
bronchodilation with complementary modes and sites of
action
Muscarinic antagonists
• Prevent acetylcholine binding
to muscarinic receptors that
make muscle contract
β2-agonists
• Promote muscle relaxation
by binding to Beta 2
receptors

44. Dual Bronchodilatation in COPD
For Internal Training Purposes Only

45. LABA therapy significantly reduces
exacerbations
1. Siler et al. Am J Respir Crit Care Med 2010;
2. Calverley et al. Lancet 2003; 3. Calverley et al. N Engl J Med 2007
Over 1 year2
20% reduction in the rate of moderate and severe exacerbations
(salmeterol 50 µg b.i.d. vs placebo p=0.003)
29% reduction in rate of exacerbations requiring oral corticosteroids placebo
(salmeterol 50 µg b.i.d. vs placebo p=0.0003)
Over 3 years3
15% reduction in annual rate of moderate and severe exacerbations
(salmeterol 50 µg b.i.d. vs placebo p<0.001)
20% reduction in annual rate of exacerbations requiring systemic corticosteroids
(salmeterol 50 µg b.i.d. vs placebo p<0.001)
3-month pooled data1
37% and 34% reductions in the rate of moderate and severe exacerbations
(indacaterol 150 µg [p=0.02] and 300 µg [p=0.008], respectively, vs placebo)

46. LAMA therapy significantly reduces
exacerbations
1. Brusasco et al. Thorax 2003; 2. Donohue et al. Chest 2002; 3. Casaburi et al. Eur Respir J 2002;
4. Vogelmeier et al. N Engl J Med 2011; 5. Vincken et al. Eur Respir J 2002;
6. Wedzicha et al. Am J Respir Crit Care Med 2008; 7. Tashkin et al. N Engl J Med 2008
1-year studies
14% reduction in rate of exacerbations vs placebo (p<0.05)3
11% reduction in rate of exacerbations vs salmeterol 50 µg b.i.d. (p=0.002;
POET study)4
24% reduction in exacerbations/patient/year vs ipratropium 40 µg q.d. (p = 0.006)5
2-year (INSPIRE) study6
No significant difference in exacerbation rate vs fluticasone/salmeterol 500/50 µg b.i.d.
6-month studies
Delayed time to first exacerbation vs salmeterol 50 µg b.i.d. and placebo, significantly
reduced exacerbation rate vs placebo but not salmeterol1
Numerically lower percentage of patients with exacerbations (36.8%) vs
salmeterol
50 µg b.i.d. (38.5%) and placebo (45.8%; not statistically significant)2
4-year (UPLIFT) study7
14% reduction in mean rate of exacerbations vs placebo (p<0.001)

47. Combining bronchodilators in COPD
• Current guidelines recommend adding a second bronchodilator to therapy
in moderate COPD in order to optimize the symptom benefit for patients1
• Combining bronchodilators of different pharmacologic classes may :
• Improve efficacy and
• Decrease the risk of side effects compared to increasing the dose of a
single bronchodilator1
• As airflow obstruction becomes more severe, a LAMA plus a LABA
combination has been advocated2
1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 (www.goldcopd.org);
2. Tashkin, Cooper. Chest 2004

48. Rationale for combining bronchodilators
• Bronchodilators are a cornerstone of COPD maintenance treatment
(GOLD)
• Patients on single long-acting bronchodilator therapy may still be
breathless and suffer from exacerbations
• Clinical data to date support the hypothesis that dual LABA/LAMA
bronchodilation improves outcomes vs monotherapies
• Combining bronchodilators may improve efficacy without increased
risk of adverse effects vs single bronchodilator
• Dual LABA/LAMA combination may differentially cover two
important disease components of COPD
• Treating symptoms and preventing exacerbations

49. Introduction of FDC of Indacaterol maleate and
Glycopyrronium bromide
• It is fixed dose combination of 2 globally approved and marketed drugs:
long acting β2-agonist (LABA) i.e Indacaterol maleate – QAB149 indicated
for COPD
long acting muscarinic antagonist (LAMA) i.e Glycopyrronium bromide
49

50. Indacaterol
| Presentation Title | Presenter Name | Date | Subject | Business Use Only50
Name: Indacaterol
It is a LABA.
Indication- Long-term, once-daily maintenance bronchodilator treatment of
airflow obstruction in patients with COPD, including chronic bronchitis and/or
emphysema.
Pharmacology:
• Pharmacokinetics
The median time to reach peak serum concentrations of indacaterol was
approximately 15 minutes after single or repeated inhaled doses.
Dose- 75-300 mcg

51. Glycopyrronium
| Presentation Title | Presenter Name | Date | Subject | Business Use Only51
Name: Glycopyrronium
It is a LAMA.
Indication- Maintenance bronchodilator treatment to relieve symptoms in adult
patients with chronic obstructive pulmonary disease (COPD).
Pharmacology:
• Pharmacokinetics
Rapidly absorbed and reached peak plasma levels at 5 minutes post dose.
Dose- 50 micrograms of glycopyrronium

52.  Indacaterol promote muscle relaxation
by binding to beta 2 receptors
 Glycopyrronium promotes muscle
relaxation by inhibiting the acetyl choline
release and blocking the muscarinic
receptors
| Presentation Title | Presenter Name | Date | Subject | Business Use Only52
Mechanism of Action of Dual Bronchodilatation
Glycopyrronium

53. Dose adjustment of Indacaterol in
the combination

54. • Metered dose  Delivered dose  Fine Particle Dose/Mass
• Delivered doses are usually in the range of 75-90 % of metered doses for capsule based DPI
• FPDs are very much dependent on formulation and delivery system, but never 100% of delivered dose
Fine Particle Dose (FPD) /
Fine Particle Mass (FPM)
(also referred to ‘lung dose’ or
‘respiratory dose’)
Delivered Dose (ex-
mouthpiece = label claim, e.g.
for Seebri®
Breezhaler®
and Ultibro®
Breezhaler®
)
Metered Dose
(for some capsule based
products = label claim,
e.g.Onbrez®
Breezhaler® ,
Foradil®
)
Definition of different doses and label
claims

55. Dose adjustment of indacaterol in combination
120 µg indacaterol 47 µg indacaterol
Metered dose Delivered dose
85 µg indacaterol
43 µg glycopyrronium
47 µg indacaterol
21 µg glycopyrronium
44 µg glycopyrronium 21 µg glycopyrronium
Fine particle dose
150 µg indacaterol
Indacaterol
Label claim:
150 µg indacaterol
50 µg glycopyrronium
Glycopyrronium
Label claim:
44 µg glycopyrronium
110 µg indacaterol
50 µg glycopyrronium
Indacaterol and Glycopyrronium
Label claim:
85 µg indacaterol
43 µg glycopyrronium
55

56. Place of Indacaterol +Glycopyrronium
in the Therapeutic Armamentarium
| Presentation Title | Presenter Name | Date | Subject | Business Use Only56
• GOLD guidelines recommend LABA+LAMA for Group B, C and D
• Indian standard of care is LABA+LAMA for patients who
continue to have symptom on monotherapy, except for those
with frequent exacerbations
• Currently there is no available FDC formulation of a long acting
β2-agonist and long acting muscarinic antagonist (world wide)

57. Clinical Studies
| Presentation Title | Presenter Name | Date | Subject | Business Use Only57
QVA 149 in studies corresponds to Indacaterol +Glycopyrronium ( Indacaterol + G

58. A2303 SHINE: Study design
• Pivotal safety and efficacy study (USA, EU, Latin America, Asia)
• 2,144 COPD patients randomized; 2,135 full analysis set
Prescreening Run-in period
Open-label tiotropium 18 μg q.d. via Handihaler (n=483)
Placebo via Breezhaler (n=234)
Indacaterol 150 μg q.d. via Breezhaler (n=477)
Glycopyrronium 50 μg q.d. via Breezhaler (n=475)
Indacaterol +Glycopyrronium 110/50 μg q.d. via Breezhaler (n=475)
Day -21 to Day -15 Day -14 to Day -1 Day 1 to Day 184
Prerandomization period
Visit 1 Visit 2
Randomization
Visit 3
26-week, multicenter, randomized, double-blind, parallel-group, placebo and
active-controlled (open-label tiotropium) study
q.d. = once daily; USA = United States of America; EU = European Union
Permitted concurrent treatment = inhaled corticosteroids and short-acting β2-agonists as needed
Bateman et al. ERJ 2013
58

59. A2303 SHINE: Study objectives
• Primary objective
• To examine superiority of Indacaterol +Glycopyrronium over indacaterol and glycopyrronium
alone for trough FEV1 at Week 26 in patients with moderate-to-severe COPD
• To compare (non-inferiority) Indacaterol +Glycopyrronium vs open-label tiotropium 18 µg
(lung function)
• Lung function: standardized AUC; early, peak response and trough response,
24-hour serial spirometry (subgroup of patients)
• Safety/tolerability over 26 weeks
• Cardiovascular safety
Bateman et al. ERJ 2013
AUC = area under the curve; FEV1 = forced expiratory volume in 1 second; TDI = Transition Dyspnea Index;
SGRQ = St George’s Respiratory Questionnaire
59

60. Once-daily Indacaterol +Glycopyrronium
provided significant 24-hour
improvement in FEV1versus open-label
tiotropium 18 µg
Bateman et al. ERJ 2013;
Bateman et al. ERJ 2012
60

61. TreatmentdifferencesintroughFEV1atthe
endofDay1(mL)
**
*
**
*
**
*
**
* **
*
Differences vs placebo
Indacaterol
+Glycopyrroni
um vs OL
tiotropium 18
µgFEV1 = forced expiratory volume in 1 second; q.d. = once daily
Trough refers to the mean of the values at 23 h 15 min and 23 h 45 min post-dose.
Data are presented as least squares mean differences with 95% confidence intervals; ***p<0.001.
Indacaterol +Glycopyrronium improved mean trough
FEV1
vs placebo and OL tiotropium 18 µg on Day 1
Bateman et al. ERJ 2013;
Bateman et al. ERJ 2012
Indacaterol +Glycopyrronium vs
OL tiotropium 18 µg
61

62. Once-daily Indacaterol +Glycopyrronium demonstrated a rapid
onset of action at first dose versus open-label
tiotropium 18 µg, sustained through 26 weeks
Bateman et al. ERJ 2013;
Bateman et al. ERJ 2012
62

63. Indacaterol +Glycopyrronium improved FEV1 at 5 minutes
post-dose vs placebo and OL tiotropium 18 µg (Day 1, Week
26)
∆=70 mL
p<0.001
∆=290 mL
p<0.001
∆=120 mL
p<0.001
∆=130 mL
p<0.001
FEV1 = forced expiratory volume in 1 second; q.d. = once daily; OL = open-label;
Values are least squares mean ± standard error; Data versus indacaterol and
glycoyrronium is not presented here.
Bateman et al. ERJ 2013
1.1
0
63

64. 1.8
FEV1 = forced expiratory volume in 1 second; OL = open-label; Values are least squares mean ± standard error
“Peak FEV1” defined as the highest value within the first 4 hours after dosing.
1.7
1.6
1.5
1.4
1.3
1.2
PeakFEV1(L)
∆=330 mL, p<0.001
∆=130 mL, p<0.001
∆=130 mL, p<0.001
∆=200 mL, p<0.001
∆=200 mL, p<0.001
∆=210 mL, p<0.001
∆=120 mL, p<0.001
1.31
1.51 1.51 1.52
1.64
0
Indacaterol +Glycopyrronium improved peak FEV1 vs placebo and OL
tiotropium 18 µg over 4 hours post-dose at Week 26
Bateman et al. ERJ 2013;
Bateman et al. ERJ 2012
OL tiotropium
18 μg q.d.
n=480
Indacaterol
+Glycopyrroniu
m
110/50 μg q.d.
n=474
Glycopyrronium
50 μg q.d.
n=473
Indacaterol
150 μg q.d.
n=476
Placebo
n=232
64

65. Once-daily Indacaterol +Glycopyrronium
provided clinically significant
improvements in dyspnea versus open-label
tiotropium 18 µg
Bateman et al. ERJ 2013
65

66. More patients on Indacaterol +Glycopyrronium had a clinically
important1
improvement in TDI focal score versus OL tiotropium 18 µg
at Week 26
1
Clinically important difference in TDI focal score is defined as a ≥1-point improvement
(Witek, Mahler. Eur Respir J 2003); TDI = Transition Dyspnea Index; OL = open-label
Bateman et al. ERJ 2013
Indacaterol +Glycopyrronium
110/50 μg q.d.
n=474
OL tiotropium
18 μg q.d.
n=480
Glycopyrronium
50 μg q.d.
n=473
Indacaterol
150 μg q.d.
n=476
66

67. Indacaterol +Glycopyrronium improved health
status and the ability
to perform daily activities versus open-label
tiotropium 18 µg
Bateman et al. ERJ 2013;
Welte et al. AJRCCM 2013
67

68. Values are least squares mean ± standard error; **p<0.05;
SGRQ = St George’s Respiratory Questionnaire; q.d. = once daily; OL = open-label
Indacaterol +Glycopyrronium improved SGRQ total score
vs placebo and OL tiotropium 18 µg at Week 26
Improvement
Bateman et al. ERJ 2013
∆=–3.01**
OL tiotropium
18 μg q.d.
n=480
Indacaterol +Glycopyrronium
110/50 μg q.d.
n=474
Glycopyrronium
50 μg q.d.
n=473
Indacaterol
150 μg q.d.
n=476
Placebo
n=232
68

69. Once-daily Indacaterol +Glycopyrronium
demonstrated an acceptable
overall safety and tolerability profile
Bateman et al. ERJ 2013
69

70. The incidence of adverse events was similar
between Indacaterol +Glycopyrronium , OL tiotropium 18 µg ,
glycopyrronium and indacaterol over 26 weeks
Preferred term, n (%)
Indacaterol
+Glycopyrr
onium
(n=474)
Placebo
(n=232)
Indacaterol
(n=476)
Glycopyrronium
(n=473)
OL tiotropium
18 µg
(n=480)
COPD exacerbation 137 (28.9) 91 (39.2) 153 (32.1) 150 (31.7) 138 (28.8)
Nasopharyngitis 31 (6.5) 23 (9.9) 35 (7.4) 46 (9.7) 40 (8.3)
Cough 26 (5.5) 8 (3.4) 38 (8.0) 18 (3.8) 21 (4.4)
Upper respiratory tract infection 20 (4.2) 13 (5.6) 32 (6.7) 20 (4.2) 24 (5.0)
Oropharyngeal pain 17 (3.6) 7 (3.0) 7 (1.5) 10 (2.1) 10 (2.1)
Upper respiratory tract
infection (viral) 15 (3.2) 7 (3.0) 11 (2.3) 13 (2.7) 12 (2.5)
Upper respiratory tract
infection (bacterial) 10 (2.1) 13 (5.6) 13 (2.7) 15 (3.2) 22 (4.6)
Lower respiratory tract infection 9 (1.9) 5 (2.2) 15 (3.2) 7 (1.5) 12 (2.5)
Back pain 8 (1.7) 5 (2.2) 11 (2.3) 17 (3.6) 8 (1.7)
Incidence of adverse events in ≥3% of patients in any
group
Bateman et al. ERJ 2013
OL = open-label
70

71. A2313 ILLUMINATE: Study design
• Safety and efficacy study
• 523 COPD patients randomized; 522 full analysis set
q.d. = once daily; b.i.d. = twice daily; EU = European Union; *Salbutamol “as needed” could be given
throughout the study as rescue medication; Patients with a history of COPD exacerbations requiring
treatment with antibiotics, systemic corticosteroids or hospitalization were excluded from the study
Double-blind treatment period
(26 weeks)*
26-week, multicenter, randomized, double-blind, parallel-group,
double-dummy study
Day –21 to
Day –15
Day 1 to Day 184
Prerandomization period
30-day post-safety
follow-up
Prescreening
WASHOUT
Run-in period
Indacaterol +Glycopyrronium 110/50 μg q.d. via
Breezhaler (n=258)
Fluticasone/salmeterol 500/50 µg
b.i.d. via Accuhaler (n=264)
Day –14 to
Day –1
Visit 1 Visit 2 Visit 3
Visit 3 to Visit 7
Randomization
Vogelmeier et al. Lancet Respir Med 2013.
71

72. A2313 ILLUMINATE: Study objectives
• Primary endpoint
• To demonstrate superiority of Indacaterol +Glycopyrronium 110/50 μg
OD. vs fluticasone/salmeterol 500/50 μg b.i.d. in terms of standardized
FEV1 AUC0–12h following 26 weeks of treatment in patients with moderate-
to-severe COPD
• Secondary endpoints
• To evaluate the effect of Indacaterol +Glycopyrronium 110/50 μg O.D.
as compared to fluticasone/salmeterol 500/50 μg b.i.d. in terms of:
• Standardized FEV1 AUC0–12h following 12 weeks of treatment
• FVC at all timepoints following 12 and 26 weeks of treatment
• TDI focal score following 12 and 26 weeks of treatment
Vogelmeier et al. Lancet Respir Med 2013.
AUC = area under the curve; q.d. = once daily; b.i.d. = twice daily; FEV1 = forced expiratory
volume in 1 second; FVC = forced vital capacity; TDI = Transition Dyspnea Index; Patients
with a history of COPD exacerbations requiring treatment with antibiotics, systemic
corticosteroids or hospitalization were excluded from the study
72

73. Once-daily Indacaterol + Glycopyrronium
provided significant 24-hour improvement in
FEV1 versus salmeterol / fluticasone
Vogelmeier et al. Lancet Resp Med 2013.
73

74. FEV1 = forced expiratory volume in 1 second; q.d. = once daily; b.i.d. = twice daily; Trough refers to
the mean of the values at 23 h 15 min and 23 h 45 min pre-dose; Values are least squares mean
± standard error; *Patients with COPD exacerbations requiring treatment with antibiotics and/or
systemic corticosteroids or hospitalization in the year prior to randomization were excluded
Vogelmeier et al. Lancet Resp Med 2013
∆=92 mL
p<0.0001
∆=103 mL
p<0.0001
1.52
1.61
1.50
1.60
Week 12 Week 26
Pre-doseFEV1
1.7
1.6
1.5
1.40
Indacaterol +Glycopyrronium provided significant
improvement in FEV1 vs salmeterol/fluticasone at
Week 26 Salmeterol/fluticasone
50/500 μg b.i.d.* (n=258)
Indacaterol +Glycopyrronium
110/50 μg q.d. (n=264)
74

75. Once-daily Indacaterol +Glycopyrronium
demonstrated a rapid onset of action versus
salmeterol/fluticasone
Vogelmeier et al. Lancet Resp Med 2013.
75

76. Indacaterol +Glycopyrronium improved FEV1 at 5 minutes and 30
minutes post-dose vs salmeterol/fluticasone* (Day 1, Week 12,
Week 26)
FEV1 = forced expiratory volume in 1 second; Values are least squares mean (95% CI);
p<0.0001 at all timepoints; *Patients with COPD exacerbations requiring treatment with antibiotics
and/or systemic corticosteroids or hospitalization in the year prior to randomization were excluded
FEV1treatmentdifferenceIndacaterol
+Glycopyrroniumvssalmeterol/fluticasone
Vogelmeier et al. Lancet Resp Med 2013
76

77. Indacaterol +Glycopyrronium improved peak FEV1 vs
salmeterol/fluticasone over 4 hours post-dose at Day 1, Week 12 and
Week 26
∆=66 mL
p<0.0001
∆=145 mL
p<0.0001
∆=155 mL
p<0.0001
Day 1 Week 12 Week 26
PeakFEV1
1.9
1.8
1.7
1.6
1.5
1.69
1.68
1.67
1.76
1.82
1.82
“Peak FEV1” defined as the highest value within the first 4 hours after dosing.
Values are least squares mean ± standard error; *Patients with COPD exacerbations requiring treatment with
antibiotics and/or systemic corticosteroids or hospitalization in the year prior to randomization were excluded
0
Vogelmeier et al. Lancet Respir Med 2013.
Salmeterol/fluticasone*
50/500 μg b.i.d. (n= 264)
Indacaterol +Glycopyrronium
110/50 μg q.d. (n=258)
77

78. Once-daily Indacaterol +Glycopyrronium
provided clinically significant improvements in
dyspnea versus salmeterol/fluticasone
Vogelmeier et al. Lancet Resp Med 2013.
78

79. Indacaterol + Glycopyrronium improved TDI focal
score vs salmeterol/fluticasone at Week 26
Values are least squares mean ± standard error; b.i.d. = twice daily; TDI = Transition Dyspnea Index;
q.d. = once daily; *Patients with COPD exacerbations requiring treatment with antibiotics and/or
systemic corticosteroids or hospitalization in the year prior to randomization were excluded
Fluticasone/salmeterol
500/50 μg
Indacaterol +Glycopyrronium
110/50 μg
∆=0.58, p=0.025
∆=0.76, p=0.003
IncreasefrombaselineinTDIfocalscore
Fluticasone/salmeterol
500/50 μg b.i.d.
Indacaterol +Glycopyrronium
110/50 μg q.d.
Vogelmeier et al. Lancet Resp Med 2013
0
Salmeterol/fluticasone*
50/500 μg b.i.d. (n=264)
Indacaterol +Glycopyrronium
110/50 μg q.d. (n=258)
79

80. Indacaterol +Glycopyrronium reduced COPD
symptoms and the need for rescue medication
use versus salmeterol/fluticasone
Vogelmeier et al. Lancet Resp Med 2013
80

81. Indacaterol +Glycopyrronium significantly reduced daytime
symptoms vs salmeterol/fluticasone over 26 weeks
∆=2.50%
p=0.049
Patients used an electronic diary to record data on symptoms and rescue medication use; Values
are least squares mean; *Patients with COPD exacerbations requiring treatment with antibiotics
and/or systemic corticosteroids or hospitalization in the year prior to randomization were excluded;
b.i.d. = twice daily; q.d. = once daily
Percentageofdays
(Weeks1–26)
Vogelmeier et al. Lancet Resp Med 2013
Indacaterol +Glycopyrronium
110/50 μg q.d. (n=258)
Salmeterol/fluticasone*
50/500 μg b.i.d. (n=264)
81

82. Indacaterol +Glycopyrronium reduced daily rescue
medication use vs salmeterol/fluticasone over 26 weeksChangefrombaselineinrescue
medicationuse(puffsperday)
Values are least squares mean ± standard error; *Patients with COPD exacerbations
requiring treatment with antibiotics and/or systemic corticosteroids or hospitalization in
the year prior to randomization were excluded; b.i.d. = twice daily; q.d. = once daily
∆=–0.39, p<0.019
Vogelmeier et al. Lancet Resp Med 2013
Salmeterol/fluticasone*
50/500 μg b.i.d. (n=264)
Indacaterol +Glycopyrronium
110/50 μg q.d. (n=258)
82

83. Once-daily Indacaterol +Glycopyrronium
demonstrated an acceptable overall safety and
tolerability profile
Vogelmeier et al. Lancet Resp Med 2013
83

84. The incidence of adverse events was similar between
Indacaterol +Glycopyrronium and salmeterol/fluticasone over
26 weeks
Preferred term, n (%)
Indacaterol
+Glycopyrronium
(n=258)
Salmeterol/fluticasone
(n=264)
COPD worsening (including exacerbation) 44 (17.1) 62 (23.5)
Nasopharyngitis 37 (14.3) 29 (11.0)
Headache 9 (3.5) 10 (3.8)
Back pain 7 (2.7) 3 (1.1)
Upper respiratory tract infection (bacterial) 7 (2.7) 2 (0.8)
Hypertension 6 (2.3) 4 (1.5)
Cough 5 (1.9) 5 (1.9)
Dyspnea 5 (1.9) 4 (1.5)
Oropharyngeal pain 5 (1.9) 4 (1.5)
Periodontitis 4 (1.6) 1 (0.4)
Muscle spasms 1 (0.4) 10 (3.8)
Dysphonia 0 5 (1.9)
Pneumonia 0 4 (1.5)
Sinusitis 0 6 (2.3)
Vogelmeier et al. Lancet Resp Med 2013
Incidence of adverse events in ≥1% of patients in any group
84

85. Summary
• Once-daily Indacaterol +Glycopyrronium 110/50 µg demonstrated
• Significantly better and clinically relevant improvements in lung
function compared with SFC twice daily with significant symptomatic
benefits in patients with moderate-to-severe COPD
• Significant improvement in dyspnea versus SFC at Weeks 12 and 26
• Significant reduction in symptoms versus SFC over 26 weeks
• Significant reduction in rescue use versus SFC over 26 weeks
• Numerical reduction in moderate to severe COPD exacerbations over
26 weeks
• The safety profile of both Indacaterol +Glycopyrronium and SFC were acceptable, with the
overall incidence of adverse events being similar between the two groups
Vogelmeier CF, et al. Lancet Resp Med. 2012
SFC = salmeterol/fluticasone
85

86. Prescribing Information
• Therapeutic class: Combination of a long acting β2-agonist (Indacaterol
maleate and a long acting muscarinic antagonist (Glycopyrronium bromide.
• Indication: Indicated to relieve symptoms and reduce exacerbations in
patients with chronic obstructive pulmonary disease (COPD)
• Dosage Form & Strength: Dry inhalation powder hard capsules with inhaler
Indacaterol maleate and glycopyrronium bromide (fixed dose combination)
110/50 microgram
• Dosage: 110/50 microgram Indacaterol maleate and glycopyrronium
bromide dry inhalation powder hard capsules; once daily administered via
single-dose dry powder inhaler

87. Pharmacokinetics
Metabolism- After oral administration of radiolabelled indacaterol in a
human, unchanged indacaterol was the main component in serum,
accounting for about one third of total drug-related AUC over 24 hours.
A hydroxylated derivative was the most prominent metabolite in serum.
In vitro the UGT1A1 isoform is a major contributor to the metabolic
clearance of indacaterol.
Hydroxylation resulting in a variety of mono- and bis-hydroxylated
metabolites and direct hydrolysis resulting in the formation of a
carboxylic acid derivative (M9) were seen by Glycopyrronium.
.
87

88. Elimination
• Indacaterol serum concentrations declined in a multi-phasic
manner with an average terminal half-life ranging from 45.5 to
126 hours.
• Glycopyrronium plasma concentrations declined in a multi-
phasic manner.
• The mean terminal elimination half-life was much longer after
inhalation (33 to 57 hours) than after intravenous (6.2 hours)
and oral (2.8 hours) administration

89. Pharmacodynamics (PD)
• The combination of indacaterol and glycopyrronium showed a
rapid onset of action within 5 minutes after dosing
• The effect remains constant over the whole 24 h dosing
interval
• There was no evidence for tachyphylaxis over time when
compared to placebo or its monotherapy components.

90. Special populations
• A population pharmacokinetic analysis of data in COPD
patients after inhalation indicated no significant effect of age,
gender and (lean body) weight on the systemic exposure to
indacaterol and glycopyrronium.

91. Thank You !