Transcript No Slide Title

Dual Pathways
of Asthmatic Inflammation
CApacidad de SIngulair Oral
en la Prevencion de Exacerbaciones Asmaticas
Montelukast with Inhaled Corticosteroids
Slide 1
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Importance of Inflammation in Asthma
• Asthma is fundamentally a disease of inflammation
• Inflammation causes bronchoconstriction and
airway hyperresponsiveness, resulting in symptoms
• Treating inflammation first in patients with mild to
moderate persistent asthma is an appropriate
treatment approach
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and
Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes
of Health, 1998; Bjermer L Respir Med 2001;95:703-719.
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Airway Inflammation Persisted
Despite Corticosteroid Use
In a clinical study of 74 patients
p<0.01
p<0.001
20,000
10,000
p<0.001
p<0.01
Eosinophil
 103/g
sputum
1,000
100
10
1
Control
group
ICS
low-dose
(n=10)
ICS
high-dose
(n=15)
Mild to moderate
OCS
(n=10)
OCS ± ICS
(n=7)
Severe asthma
ICS=inhaled corticosteroids; OCS ± ICS=received oral corticosteroids with or without ICS
Adapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.
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Leukotrienes: Important in Early Asthma
and Throughout the Disease
Other inflammatory mediators
Leukotrienes
No Inflammation
Asthma
Inflammation
This slide is an artistic rendition.
Adapted from Holgate ST, Peters-Golden M J Allergy Clin Immunol 2003;111(1 suppl):S1-S4; Holgate ST et al J Allergy
Clin Immunol 2003;111(1 suppl):S18-S36; Henderson WR Jr et al Am J Respir Crit Care Med 2002;165:108-116; PetersGolden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Varner AE, Lemanske RF Jr. In Asthma and
Rhinitis. Oxford, UK: Blackwell Science, 2000:1172-1185.
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Dual Pathways of Inflammation
Actions of Corticosteroids
• Suppression of a number of inflammatory mediators
– Cytokines
– Adhesion molecules
– Inducible enzymes
• Variable effects on inflammatory processes
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48.
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Dual Pathways of Inflammation
Effects of the CysLT1 Receptor
on Inflammatory Cells
Lung Macrophage
Eosinophils
Smoothmuscle
cell
Monocytes
PBMC
CysLT=cysteinyl leukotriene; PBMC=peripheral blood mononuclear cells
Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233.
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Slide 6
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Dual Pathways of Inflammation
Expression of the CysLT1 Receptor
CD19
LN5
B Lymphocyte
Macrophage
Mast Cell
Basophil
M-CSF
GM-CSF
CysLT1R
M-CSF, GM-CSF, IL-3
LTC4, LTD4, LTE4
CD34+
Pluripotent
hemopoietic
stem cell
IL-5
LTC4 IL-3
GM-CSF
LTD4
LTE4
IL5Rβ
Neutrophil
CCR3
Eosinophil
T Cells
CD8+
LTC4
LTD4
LTE4
CD14
Monocyte
Represents the
CysLT1 receptor
CD4+
Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233; Mellor et al Proc Natl Acad Sci USA
2001;98:7964-7969
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Dual Pathways of Inflammation
Leukotrienes Are Powerful
Inflammatory Mediators
CysLT
receptor
CysLT
Other
mediators
Mediator
receptor
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48.
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Dual Pathways of Inflammation
Actions of LTRAs
Leukotrienes are highly specific but catalyze
a massive inflammatory cascade
• Suppress many inflammatory mediators
• Suppress inflammatory processes
– Via the leukotriene pathway
– Via the steroid-sensitive pathway
LTRAs = leukotriene receptor antagonists
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48.
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Dual Pathways of Inflammation
Central Role of CysLTs in Asthma
Decreased Mucus Transport
Cationic Protein Release,
Epithelial-Cell Damage
Airway
Epithelium
Eosinophil
Influx
Increased
Mucus
Secretion
Edema
Blood
Vessel
CysLTs
Inflammatory Cells
(mast cells,
eosinophils)
Sensory
Nerves
(C fibers)
Contraction and
Proliferation
Airway Smooth Muscle
Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16:304-309.
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Effect of Inhaled Fluticasone Propionate
on Urinary LTE4 Excretion
20
18.7
18.4
16
Urinary LTE4
excretion
(ng/mmol
creatinine)
12
8
4
0
Fluticasone
propionate
Placebo
p = NS between groups
Adapted from O’Shaughnessy KM et al Am Rev Respir Dis 1993;147:1472-1476.
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Slide 11
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Effect of Oral Prednisone on Urinary
LTE4 Excretion
0.3
Urinary LTE4
(ng/mg
creatinine)
Control
Prednisone
*
*
0.2
0.1
0
Baseline
Post-allergen
challenge
*p<0.05 vs. baseline
Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149:953-959.
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Oral Prednisone Did Not Suppress CysLT
Levels Recovered from BAL Fluid
Eicosanoids in Asthmatics
80
70
Before prednisone
After prednisone
60
BAL
levels
(pg/ml)
50
40
30
20
10
n=14
0
LTC4
LTE4
BAL = bronchoalveolar lavage
Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149:953-959.
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Effect of ICS on Sputum Leukotriene Levels
14
13*
11.4**
12
9.4*
10
Sputum
CysLT levels 8
(ng/ml)
6
6.4
4
2
0
Controls
(n=10)
All patients
with asthma
(n=26)
Patients with
persistent
asthma
Patients with
acute attacks
(n=12)
(n=10)
*p<0.02 vs. normal individuals; **p<0.05 vs. normal individuals
Adapted from Pavord ID et al Am J Respir Crit Care Med 1999;160:1905-1909.
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Dual Pathways of Inflammation
Long-Acting Beta2 Agonists Did Not Have
Anti-inflammatory Effects
LTRA montelukast further reduced inflammation when
added to ICS
ICS + LABA +
Montelukast
ICS +
Montelukast
ICS +
LABA
ICS
0
Change in
eosinophils
( 106/L) –100
from run-in
–200
p<0.05
p<0.05
LABA = long-acting beta2 agonist
Adapted from Currie GP et al Am J Respir Crit Care Med (in press).
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Dual Pathways of Inflammation
LTRA Montelukast Further Reduced
Asthmatic Inflammation
Complementary therapy that targets dual pathways of
inflammation provided better control of inflammation
0.12
*
0.10
Eosinophil
0.08
counts
(change
0.06
from
baseline
0.04
 103/µl)
0.02
<1*
0
Placebo
Montelukast
Beclomethasone
Montelukast
+
beclomethasone
Treatment group
*p<0.05 compared with beclomethasone
Adapted from LaViolette M et al Am J Respir Crit Care Med 1999;160:1862-1868.
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Dual Pathways of Inflammation
Montelukast Combined with a Steroid
Affects the Dual Pathways of Inflammation
CysLTs
Steroid-sensitive
mediators
play a key role
in asthmatic
inflammation
play a key role
in asthmatic
inflammation
Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients
Montelukast
Inhaled steroids
blocks the
effects of
CysLTs
block
steroidsensitive
mediators
DUAL PATHWAY
The slide represents an artistic rendition.
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Bisgaard H Allergy
2001;56(suppl 66):7-11.
SGA 2003-W-6701-SS
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Dual Pathways of Inflammation
Airway Inflammation Correlated with Lung
Function and Clinical Control
FEV1
PEFR
variability
Daily symptom
score
0
–0.2
rS
–0.4
–0.36
–0.43
–0.6
–0.51
–0.49
–0.51
–0.52
Absolute eosinophil counts
ECP concentrations
FEV1 = forced expiratory volume in one second; PEFR = peak expiratory flow rate; rS = Spearman’s rank coefficient of
correlation; ECP = eosinophilic cationic protein
Adapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.
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Summary
Targeting Dual Pathways of Inflammation
Improves Asthma Control
• CysLTs and steroid-sensitive mediators are
two important pathways of inflammation in asthma
• Corticosteroids do not block the leukotrienemediated pathway of inflammation
• Treating dual pathways of inflammation in
the airway of asthmatic patients may provide
better control of inflammation and effective
asthma control
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Bisgaard H Allergy
2001;56(suppl 66):7-11.
SGA 2003-W-6701-SS
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CApacidad de SIngulair™ Oral
en la Prevencion de
Exacerbaciones Asmaticas
Capacity of Oral SINGULAIR to
Prevent Asthma Exacerbations
SINGULAIR (montelukast sodium) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Slide 20
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Rationale and Objective
• Rationale
•
– Leukotrienes are powerful inflammatory mediators
that are not blocked by steroids in the airways of
asthmatic patients
– LTRAs can further reduce inflammation and improve
symptoms when added to ICS therapy
• Additive effects on peripheral blood eosinophils,
a marker of inflammation, shown in clinical studies
of LTRAs + ICS
– Effects of ICS + leukotriene-modifying treatment on
reducing asthma exacerbations, a prominent goal of
asthma therapy, must be evaluated
Objective
– To evaluate the addition of oral montelukast to
patients’ usual dose of inhaled budesonide in the
treatment of adults with mild to moderate asthma
Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and
Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of
Health, 1998; Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; discussion S43-S48;
LaViolette M et al Am J Respir Crit Care Med 1999;160:1862-1868; Bisgaard H Allergy 2001;56(suppl 66):7-11.
SGA 2003-W-6701-SS
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CASIOPEA Study
Primary Endpoint
% of Asthma Exacerbation Days
Defined as a day when any of the following occurred
• Awake all night (awake all night or recurrent episodes
of awakening)
• Increase from baseline in symptom score of >50%
• Increase from baseline in beta-agonist use of >70%
(minimum increase 2 puffs/day)
• Decrease from baseline of >20% in morning PEFR
• Morning PEFR <180 l/min
• Asthma attack (unscheduled medical care for asthma)
PEFR = peak expiratory flow rate
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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CASIOPEA Study
Design
Period I
Period II
Budesonide Turbuhaler 400–1600 µg qd
Budesonide
Turbuhaler
+ montelukast (n=326)
400–1600 µg/day
Budesonide Turbuhaler 400–1600 µg qd
+ placebo
(n=313)
V1
–2
V2
0
V2
4
V2
8
V5
16
Weeks
qd = once daily
Inhaled short-acting beta2 agonists were permitted as needed.
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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CASIOPEA Study
Inclusion Criteria
• Non-smoking asthmatic patients 18–70 years of age
• Prior treatment with a clinically stable dose of ICS
equivalent to budesonide 400–1600 µg/day
• FEV1 55% of predicted
• Reversible airway obstruction (12% increase
from baseline)
• Minimum total daytime asthma symptom score
of 64 (of possible 336)
• 1 puff/day of beta2 agonist
FEV1 = forced expiratory volume in one second
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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CASIOPEA Study
Baseline Characteristics of Patients
Age, yr (range)*
Gender, no.
Female
Male
Duration of asthma, year*
% of predicted FEV1*
Morning PEFR (L/min)
Evening PEFR (L/min)
Daytime asthma symptom score*,**
Beta2-agonist use (puffs/day)*
Budesonide dose (µg/day), no.***
I. 400–800
II. 801–1200
III. 1201–1600
Budesonide
(n=313)
Montelukast
+ Budesonide
(n=326)
44 ± 16 (18–79)
42 ± 15 (18–76)
121 (39%)
192 (61%)
13.8 ± 11.7
81 ± 21
365 ± 108
375 ± 108
2.3 ± 0.8
3.3 ± 2.3
124 (38%)
202 (62%)
13.8 ± 11.4
81 ± 19
373 ± 105
382 ± 107
2.2 ± 0.8
3.2 ± 2.5
202 (66%)
15 (5%)
91 (30%)
219 (69%)
18 (6%)
80 (25%)
*Mean ± SD
**Mean of scores to four questions, each rated on a scale of 0 (best) to 6 (worst)
***44 (14%) and 35 (11%) patients on placebo and montelukast, respectively, received 400 µg/day
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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CASIOPEA Study
Montelukast + Budesonide
Significantly Reduced Asthma-Exacerbation Days
5
Median
percentage
of asthmaexacerbation
days
4.8
4
3.1
3
35%
p=0.03
2
1
0
Budesonide +
placebo
(n=308)
Montelukast +
budesonide
(n=317)
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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CASIOPEA Study
Montelukast + Budesonide
Reduced Asthma-Exacerbation Days
Regardless of ICS dose
Budesonide + placebo
Montelukast + budesonide
10
8
No. of
asthma
exacerbation
days
6
4
2
0
p=0.67 (ns) across strata
I
II
III
(n=421)
(n=33)
(n=171)
Strata of ICS dose
Adapted from additional analysis of CASIOPEA study: asthma exacerbation days per budesonide dose strata and onset
of action for beta agonist use
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CASIOPEA Study
Montelukast + Budesonide
Significantly Increased Asthma-Free Days
70
66.1
60
Median
percentage
of asthmafree days
56%
p=0.001
50
42.3
40
30
Budesonide +
placebo
(n=308)
Montelukast +
budesonide
(n=317)
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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CASIOPEA Study
Montelukast + Budesonide
Significantly Reduced Nocturnal Awakenings
35
32.2
Least square 30
mean % of
patients
with nocturnal
awakenings* 25
25.6
20%
p=0.01
20
Budesonide +
placebo
(n=308)
Montelukast +
budesonide
(n=317)
*The percentage of patients who awoke during the night because of asthma
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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CASIOPEA Study
Montelukast + Budesonide
Significantly Reduced Beta2-Agonist Use*
30
Budesonide + placebo (n=313)
Montelukast + budesonide (n=326)
20
% change
from
baseline in
beta2-agonist
use
10
0
–10
–20
A more rapid onset of action
than budesonide + placebo
–30
–40
Basal
1
2
3
4
5
6
7
First 7 days in active treatment
*p = 0.05 vs. budesonide alone
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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CASIOPEA Study
Montelukast + Budesonide
Significantly Increased AM PEFR*
Tertiary endpoint: Morning PEFR
20
16.86
Least square 15
mean change
in morning
10
PEFR
(L/min)
11.3
49%
p=0.05
5
0
Budesonide +
placebo
(n=308)
Montelukast +
budesonide
(n=317)
Mean adjusted by center and stratum
*p = 0.05 vs. budesonide alone
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-21.
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Montelukast + Budesonide
Was Well Tolerated
Incidence of adverse events comparable to budesonide + placebo
% of Patients
Budesonide +
Montelukast +
placebo (n=313)
budesonide (n=326)
Most Common
Adverse Events
Influenza
Headache
Upper respiratory infection
Worsening asthma
Epigastric pain/pyrosis
Urinary tract infection
Rhinitis
Pharyngitis
Bronchitis
Total
11
9
7
5
2
2
2
1
1
41
12
11
5
7
3
2
2
2
2
44
No significant differences between groups
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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CASIOPEA Study
Summary
Montelukast provided effective asthma control
• Montelukast added to patients’ usual dose of
budesonide significantly improved asthma control
(p0.05)
– Effective control regardless of patients’
budesonide dose
• Faster onset of action than budesonide + placebo,
evident from day 1
• Montelukast + budesonide was well tolerated, with
a tolerability profile comparable to budesonide +
placebo
Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.
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Slide 33
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Conclusions
• CysLTs and steroid-sensitive mediators comprise
dual pathways of inflammation in asthma
• Corticosteroids at any dose do not block
leukotrienes in the airways of asthmatic patients
• In clinical studies, complementary therapy with
the LTRA montelukast and ICS effectively reduced
inflammation and improved symptom control in
patients with mild to moderate persistent asthma
Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Currie GP et al
Am J Respir Crit Care Med (in press); LaViolette M et al Am J Respir Crit Care Med 1999;160:1862-1868; Bisgaard H
Allergy 2001;56(suppl 66):7-11; Vaquerizo MJ et al Thorax 2003;58:204-211.
SGA 2003-W-6701-SS
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References
Please see notes page.
SGA 2003-W-6701-SS
Slide 35
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Montelukast with Inhaled Corticosteroids
Targeting Dual Pathways
of Asthmatic Inflammation
Before prescribing, please consult
the manufacturers’ prescribing information.
Merck does not recommend the use of any product
in any different manner than as described
in the prescribing information.
Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved.
4-05 SGA 2003-W-6701-SS
Printed in USA
VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
SGA 2003-W-6701-SS
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