2. Global COPD – the ever rising Burden
Approximately 210 million1
people have COPD
Summary of GOLD 2017 Update: For Educational Purpose Only 2
The global burden of COPD
cases in 2010 was estimated to
be 384 million2
GOLD 2011-16 GOLD 2017
83%
increase
1. World Health Organisation: Global surveillance, prevention and control of chronic respiratory diseases, 2007
http://www.who.int/respiratory/publications/global_surveillance/en/
2. Journal of Global Health 2015; 5(2) : 020415
• Global prevalence of COPD is 11.7%
• Currently 3 million annual deaths due to COPD.
• Deaths in 2030 might be 4.5 million deaths annually.
3. COPD in India – the ever rising Burden
1971 2011
14.84 million1
6.45 million
Burden has more than
doubled in these 4
decades
Crude estimates suggest that 30 million people suffer from COPD in India2
1. J Assoc Physicians India. 2012; 60 Suppl:14-16 I 2. J Assoc Physicians India. 2012; 60 Suppl:5-7
4. Evolution of COPD over the years
Persistent airflow
limitation that is usually
progressive
Chronic inflammatory
response
Persistent respiratory
symptoms
Airflow limitation
20172011Before 2011
5. COPD is a common, preventable and treatable
disease that is characterized by persistent
respiratory symptoms and airflow limitation
that is due to airway and/or alveolar
abnormalities usually caused by significant
exposure to noxious particles or gases
COPD, a common preventable and treatable
disease, is characterized 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
GOLD 2017: Updated COPD definition includes persistent
respiratory symptoms and airflow limitation
GOLD 20172GOLD 20161
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease
1. GOLD 2016
2. GOLD 2017
6. COPD patient
perspectives
Prim Care Respir J 2011; 20(3): 315-323
• 53% notably reduce physical activity for fear of breathing difficulties
• 60% have difficulty in walking up the stairs or walking due to COPD
• 54% are afraid of COPD worsening as the cold season comes
• 37% are always afraid of not having the medicine for COPD with
themselves
• 66% feel regular therapy with immediate results gives them
reasons for regular taking
Key findings:
Questionnaire-based survey performed in five European countries on patients with asthma and COPD
(n=719 patients; UK [n=153]; Germany [n=147]; France [n=145]; Italy [n=140]; Spain [n=134])
7. The COPD: Patient Experience Survey
Aims and Objectives: To gain insights on the impact of COPD in
Indian Patients with respect to Symptoms, activity limitation and
exacerbations
Data Collection
• Real world questionnaire based survey.
• Investigator administers the 15-item questionnaire to COPD
patients and fills the requisite data in the case report form.
• Total of 46 doctors (investigators across India) were involved
in this survey which gives 446 patients data.
Oral Presentation, Presented at NAPCON 2016
8. Breathlessness (77.14%) and cough (57.96%) were the most
troublesome symptoms experienced
0%
20%
40%
60%
80%
100%
Cough Breathlessness Tiredness Mucus on
coughing
Chest
pain/tightness
Weight loss Other
57.96%
77.14%
24.49%
32.65% 31.84%
7.76%
2.04%
Percentageofpatients
Troubling symptoms that patients experience
Bar chart for Frequency distribution for most troublesome
symptom that patient experience (n=245)
9. 33% had symptoms early in morning while
32% reported symptoms throughout the day
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Day time Night time Early morning Throughout 24 hours
20.41%
27.76%
33.47%
32.65%
Percentageofpatients
The part of the day when patient experience most symptoms
Oral Presentation, Presented at NAPCON 2016
10. 88.57% patients visited a doctor in the last one year for worsening of
symptoms, of which 47.47% visited the doctor for ≥3 times
0%
10%
20%
30%
40%
50%
None 1 - 2 times 3 - 4 times More than
4 times
11.43%
46.53%
28.16%
13.88%
Percentageofpatients
No. of times patients visited to doctor for worsening of
symptoms in last year due to COPD
Oral Presentation, Presented at NAPCON 2016
11. Nearly 50% patients were hospitalized atleast once in last year due
to COPD
0%
10%
20%
30%
40%
50%
None 1 time 2 or more
time
50.61%
33.88%
15.51%
Percentageofpatients
No. of times patients hospitalized in last year due to COPD
Oral Presentation, Presented at NAPCON 2016
15. Survey of newly diagnosed COPD PatiEnts
• Survey with 47 pulmonologists across India, data obtained on 247 newly
diagnosed COPD patients
Physicians and general practitioners being the first point of contact for all health related issues
including COPD need to identify COPD in the early stages.
Respirology 2014; 19 (Suppl. 3), 63–253 I P164 presented at NAPCON 2014
Key Finding: The first time a pulmonologist sees a COPD patient, the patient is
already in the severe stage of COPD
COPD in India – Delayed diagnosis?
16. Majority of the Indian doctors* reported that patients with COPD visit
them at moderate to severe stages of the disease
&90% of GPs-physicians of pulmonologists
Perspect Clin Res 2016;7:100-5
* *
Data was collated from 91 randomly selected GPs, physicians and pulmonologists through
questionnaire and face-to-face interviews, in 8 cities of India
COPD - Chronic Obstructive Pulmonary Disease
17. So what can be done to Improve patients’ daily lives?
– relieve symptoms and reduce the risk of exacerbations
• Fast onset of action
• Sustained 24 hour action
• Improve Airflow limitation
A reasonable approach to managing stable disease is
to try to maintain effective and continuous bronchodilation
18. Bronchodilators are essential to the management of COPD,
and are given to relieve or prevent symptoms, reduce
dynamic hyperinflation and improve lung function
Eur Respir Rev 2004; 13: 88, 22–27
19. Why provide bronchodilation?
• Airflow obstruction is a central feature of chronic obstructive
pulmonary disease (COPD).
http://advanceweb.com/web/reversibility_of_airflow_obstruction/focus_on_copd_issue2.html
20. Bronchodilators address airflow limitation by targeting
bronchoconstriction and reducing air trapping
Increased
mucociliary
clearance
Improved respiratory
muscle function
Smooth muscle relaxation
Reduced
hyperinflation
Bronchodilators
21. V
BD
Air flowDeflation
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
22. • But then which
bronchodilator?
• How many
bronchodilators?
- One or two
24. Many patients continue to experience breathlessness on
mono-bronchodilator therapy
• mMRC = modified Medical Research Council
FDC = fixed-dose combination • Prim Care Respir J. 2011;20(1):46-53
Real-world study of patients with COPD
On maintenance therapy with single
long-acting bronchodilator (n=1,072)
Majority of patients on
monotherapy were still breathless
This applied to all severity groups
More effective bronchodilation
would be beneficial
LABA/LAMA FDC could
address this need –
without having to add ICS
45
40
35
30
25
20
15
10
5
0
0 1 2 3 4
mMRC dyspnea scores
Patients(%)
<50%
≥80%
<80%
≥50%
25. Majority of COPD patients on
maintenance therapy still report
symptoms, leading to poor quality of life
and increased risk of exacerbations
Current therapies might be insufficient
for many COPD patients
Respir Med 2011;105:57-66
Eur Respir J 2015; 42:647-654
Need for Dual
Bronchodilation
26. Need of Dual bronchodilation
• Given the complexity of COPD, it is possible that a single drug may not possess all
necessary pharmacological activity to result in a desired therapeutic effect
• In patients not fully controlled with one long-acting bronchodilator, maximizing
bronchodilation (i.e. adding another bronchodilator with a different mechanism
of action) is the preferable option
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071575.pdf
27. Different distribution of muscarinic and beta2 -adrenergic receptors
along the bronchial tree
Multidisciplinary Respiratory Medicine 2014, 9:64
28. Mechanisms of bronchodilatory action of antimuscarinic agents and
beta2-adrenergic receptor agonists
Antimuscarinics
block the binding of
ACh to M3
muscarinic receptor
Leads to smooth
muscle relaxation
Inhibiting
smooth muscle
cell contraction
Beta2-receptor
agonists bind to
beta2-adrenergic
receptor
Induces cascade of
signal transduction
events
Multidisciplinary Respiratory Medicine 2014, 9:50
29. Don’t you feel ………………..
There is a high need of combining
LABA and LAMA to challenge COPD..
30. Life Sci 1993; 52:2145-60
Aqueous
biphase
Hydrophilic
(water soluble)
Not retained by lipophilic
part of cell membrane
Fast removal by diffusion
Lipophilic (fat soluble)
Retained in lipophilic
part of cell membrane
Slow release from cell
membrane
Partially hydrophilic,
partially lipophilic
Some retained in lipophilic
part of cell membrane
Slow release from cell
membrane
Salbutamol Formoterol Salmeterol
Lipophilicity – reason for long duration of action
Lipophilic (fat soluble)
Retained in raft domain
of lipid membrane
Ultra slow release from
cell membrane
24 hours duration of
action3
Indacaterol2
31. Mode of action of Indacaterol
31
Smooth
muscle cell
Smooth muscle
cell relaxation
Activates Protein
kinase
Decreases
intracellular Ca
2+
Indacaterol
β2 receptor
32. Pharmacokinetic profile
Pharmacokinetic parameters Indacaterol
Bioavailability 43%–45%
Onset of action 5 mins
Time to Cmax Approximately 15 minutes
Protein binding 94–96%
Half-life 40–56 hours
Metabolism Hepatic
Elimination Faeces: approximately 90% (54% as
unchanged drug)
Urine: <2% (as unchanged drug)
32
P & T 2012; 37:86–98
33. Rapid onset of action - 5 mins
33
Randomized, double-blind, single
dose, crossover study;
n= 89 patients with moderate-to-
severe COPD
Placebo, Salmeterol/Fluticasone,
Salbutamol, Indacaterol
Int J Chron Obstruct Pulmon Dis. 2010; 5:311-8
Onset of action
**p < 0.01
***p< 0.001
FEV15minspostdose(L)
PBO: Placebo, S+F: Salmeterol + Fluticasone, Salb: Salbutamol, Ind: Indacaterol
Fast onset of action, similar to that of
salbutamol and faster than that of
salmeterol-fluticasone
34. Sustained 24 hour bronchodilation
Pulm Pharmacol Ther. 2011; 24:162-8
Randomized, multicenter, placebo-
controlled, crossover study
n= 68 patients with moderate-to-
severe COPD
Placebo, Salmeterol, Indacaterol
Evaluation:
24-h post-dose (trough) FEV1 after
14 days
Duration of action
Superior bronchodilation
compared with placebo across the
24-h period, superior FEV1
compared with salmeterol at
many post-baseline time points p < 0.001 for indacaterol vs. placebo at all time points; p < 0.05 for
salmeterol vs. placebo at all time points; †p < 0.05 for indacaterol vs.
salmeterol
200 ml more than placebo
90 ml more than salmeterol
35. Efficacy irrespective of the time of dosing
35
Time of dosing
Respir Med 2010; 104:1869-76
Randomized double-blind,
crossover study
n=96 patients with moderate-to-
severe COPD
Indacaterol 300 mcg o.d. dosed
PM or AM, salmeterol 50 mcg
b.i.d. or
placebo, each for 14 days
24 hour bronchodilation,
not affected by the
dosing time Trough FEV1 measured 24 hours after indacaterol; 12 hours after salmeterol
*: p<0.01
#: p<0.001
# #
#
36. Indacaterol overview
• Indacaterol is a novel, fast-acting, inhaled, once-daily LABA with:1–4
• fast onset of action
• sustained 24-hour duration of bronchodilator efficacy
• superior improvements in FEV1 versus placebo and formoterol
• effective control of symptoms
• acceptable safety and tolerability profile
• delivery via a reliable and easy to use single-dose dry powder inhaler
LABA = long-acting β2-agonist
1. Feldman et al. BMC Pulm Med 2010;
2. Donohue et al. Am J Respir Crit Care Med 2010;
3. Kornmann et al. Eur Respir J 2011;
4. Dahl et al. Thorax 2010
37. Dose adjustment of Indacaterol in Nistami
120 µg indacaterol 47 µg indacaterol
Label
claim
Dose that
leaves the mouthpiece
85 µg indacaterol
43 µg glycopyrronium
47 µg indacaterol
21 µg glycopyrronium
Fine particle dose
150 µg indacaterol
Onbrez® Breezhaler ®
Label claim:
150 µg indacaterol
110 µg indacaterol
50 µg glycopyrronium
Nistami® Inhaler®
Label claim:
Indacaterol
Glycopyrronium
FOR MEDICAL EDUCATION AND INTERNAL USE ONLY
39. Glycopyrronium - MOA
• Competitive muscarinic receptor
antagonist
• Bronchodilates the airways by
inhibiting acetylcholine induced
bronchoconstriction in bronchial
smooth muscle cells
Drugs (2013) 73:741–753International Journal of COPD 2012:7 729–741
40. M3 receptor is thought to be the prime mediator of cholinergic
bronchoconstriction
M2 receptor protects against bronchoconstriction and has a role in
cardiac function (e.g. blocking of M2 receptor may increase heart rate)
Ideal Muscarinic antagonist should have high
affinity for the M3 (and M1) receptor, but low
affinity for the M2 receptor
Drugs (2013) 73:741–753
Characteristics of an ideal Muscarinic antagonist
41. Glycopyrronium shows greater selectivity/affinity for the M3 receptors
over the M2 receptors than tiotropium
Expert Rev. Clin. Pharmacol. 6(5), 503–517 (2013)
More the selectivity of M3 over M2
Better the receptor occupancy of
M3 over M2
More faster rate of action
Reach equilibrium faster
42. Glycopyrronium has a faster dissociation from the M2 receptors versus
M3 receptors as compared to tiotropium
Expert Rev. Clin. Pharmacol. 6(5), 503–517 (2013)
Faster the dissociation from M2
Lesser the chances of cardiac side
effects
43. Pharmacokinetics
• Rapidly absorbed following inhalation
• Peak plasma levels at 5 min post-dose
• Absolute bioavailability - 45%
• Terminal elimination phase after inhalation (t1/2: 33–57 h)
• Pharmacokinetic steady state - 1 week
Expert Rev. Clin. Pharmacol. 6(5), 503–517 (2013)
44. Glycopyrronium shows rapid onset of action in 5 mins as compared to Tiotropium
with sustained 24 hrs of action from day 1
Significant improvement in Lung Function in
5 mins post dose compared to Tiotropium
46 ml
P=0.0015
n = 1888 GOLD moderate COPD patients; once-
daily Glyco 50 μg Tio 18 mcg or placebo
Curr Med Res Opin. 2014 Mar;30(3):493-508
Glycopyrronium is superior to placebo at all assessed time points
(p<0.01), superior to tiotropium at 5, 15 and 30 min, 1 and 2 h (p<0.05)
Eur Respir J. 2012 Nov; 40(5): 1106–1114.
45. Glycopyrronium shows similar efficacy as compared to that of Tiotropium
International Journal of COPD 2015:10 111–123
Table - Treatment differences with glycopyrronium versus placebo and tiotropium in the GLOW studies and SHINE trial
46. • Glycopyrronium is a novel, selective, fast-acting, inhaled, once-daily
LAMA with:1–3
• sustained 24-hour duration of bronchodilator efficacy
• improvement in FEV1 versus placebo
• fast onset of action
• effective control of symptoms
• acceptable safety and tolerability profile
• delivery via a reliable and easy to use single–dose dry powder inhaler
Glycopyrronium Overview
1. D’Urzo et al. Respir Res 2011;
2. Kerwin et al. Eur Respir J 2012;
3. Beeh et al. Int J COPD 2012LAMA = long-acting muscarinic antagonist
47. So what happens when this
ultra LABA and novel LAMA are
combined?
49. GOLD 2017 on Dual bronchodilation
• Combining bronchodilators with different mechanisms and duration
of action may increase the degree of bronchodilation with a lower risk
of side effects compared to increasing the dose of a single
bronchodilator
Summary of GOLD 2017 Update: For
Educational Purpose Only
50. Summary of GOLD 2017 Update: For
Educational Purpose Only
51
Bronchodilator
Continue, Stop or try
alternative class of
bronchodilator
Evaluate effect
GROUP A
GOLD 2017
(highlighted pathways in green indicate preferred treatment options)
Low Risk,
Less Symptoms
LAMA or LABA
LABA+LAMA
Persistent
Symptoms
GROUP B
GOLD 2017
(highlighted pathways in green indicate preferred treatment options)
Low Risk,
More Symptoms
51. Summary of GOLD 2017 Update: For
Educational Purpose Only
52
GOLD 2017
LAMA
LABA+LAMA ICS+LABA
Further
Exacerbation(s)
GROUP C
(highlighted pathways in green indicate preferred treatment options)
High Risk,
Less Symptoms
ICS+LABA+LAMA
ICS+LABA
Further
Exacerbation(s)
LABA+LAMALAMA
Further
Exacerbation(s)
Persistent
Symptoms/ Further
Exacerbation(s)
Consider Roflumilast, if
patient has
chronic bronchitis and FEV1
< 50% predicted
Consider Macrolide
(in former Smokers)
GROUP D
(highlighted pathways in green indicate preferred treatment options)
High Risk,
More Symptoms
GOLD 2017
52. Bronchodilators in Stable COPD
• Inhaled bronchodilators are central in management of symptoms
• LABA and LAMA improve lung function, dyspnea, health status and
reduces exacerbation rates
• Combination therapy with LAMA and LABA reduces exacerbations
(versus monotherapy or ICS/LABA)
• Combination therapy with LAMA and LABA increases FEV1 and
reduces symptoms (versus Monotherapy)
Summary of GOLD 2017 Update: For
Educational Purpose Only
54. Summary of GOLD 2017 Update: For
Educational Purpose Only
55
GOLD 2017
LAMA
LABA+LAMA ICS+LABA
Further
Exacerbation(s)
GROUP C
(highlighted pathways in green indicate preferred treatment options)
High Risk,
Less Symptoms
ICS+LABA+LAMA
ICS+LABA
Further
Exacerbation(s)
LABA+LAMALAMA
Further
Exacerbation(s)
Persistent
Symptoms/ Further
Exacerbation(s)
Consider Roflumilast, if
patient has
chronic bronchitis and FEV1
< 50% predicted
Consider Macrolide
(in former Smokers)
GROUP D
(highlighted pathways in green indicate preferred treatment options)
High Risk,
More Symptoms
GOLD 2017
Long term treatment with ICS/LABA may be considered in frequent
exacerbators
55. Despite recommendations, ICS is often used in early-stage COPD
• ICS plus LABA recommended for use only in patients in Groups C and D1
• However, many patients in Groups A and B are treated with ICS2,3
1. GOLD 2014
2. Small M et al. Thorax 2012;67(Suppl. 2):A144–5
3. Higgins V et al. COPD8 2012 (Poster)
Data were drawn from the Adelphi Respiratory Disease Specific Programme, a large multinational (France, Germany, Italy,
Spain, UK, USA) cross-sectional survey generating real-world data based on actual clinical practice N=1,508.2,3
GOLD Group C
13 patients
54% using ICS
739 patients
38% using ICS
152 patients
33% using ICS
604 patients
51% using ICS
GOLD Group D
GOLD Group A GOLD Group B
56. Can we withdraw ICS in patients at low risk exacerbation who gets
stabilized after taking long acting bronchodilators?
• Withdrawal of inhaled corticosteroids can be safe in COPD patients at low risk of exacerbation.
• In OPTIMO1 & WISDOM2 trials COPD patients, on maintenance therapy with bronchodilators &
ICS, FEV1>50% predicted, & <2 exacerbations/year were evaluated after withdrawing ICS
• OPTIMO Trial – Did not observe any deterioration of lung function symptoms, & exacerbation
rate between the two groups at baseline and at 6 months
• WISDOM Trial – No difference in exacerbation rate
1. N Engl J Med. 2014 Oct 2;371(14):1285-94
2. Respir Res. 2014 Jul 8;15:77
57. No difference was found at 6 months for CAT and FEV1 between the groups
Mean (SE) of FEV1 % predicted (A) and of CAT score (B) at T6 in the two groups of patients who were switched to long acting
bronchodilators or continued their treatment with ICS. Respir Res. 2014 Jul 8;15:77
58. No difference was found at 6 months for no. of exacerbations per patient
between the groups
Mean (SE) exacerbation rate expressed as exacerbation/patient/6 months at the end of the study (T6) in the two groups of
patients who were switched to long acting bronchodilators (NO ICS) OR continued the treatment with ICS
Respir Res. 2014 Jul 8;15:77
59. WISDOM Trial
N Engl J Med. 2014 Oct 2;371(14):1285-94
In patients with severe COPD receiving tiotropium plus
salmeterol, the risk of moderate or severe
exacerbations was similar among those who
discontinued inhaled glucocorticoids and those who
continued glucocorticoid therapy.
