SGA 2003-W-6701-SS Downloaded from – Slide 1 Dual Pathways of Asthmatic Inflammation CApacidad de SIngulair Oral en la

SGA 2003-W-6701-SS Slide 1Downloaded from – www.singulair.ae

Dual Pathways of Asthmatic Inflammation

CApacidad de SIngulair Oral en la Prevencion de Exacerbaciones Asmaticas

Montelukast with Inhaled Corticosteroids


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.

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


Airway Inflammation Persisted Despite Corticosteroid Use

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.

20,00010,000

1,000

100

10

1

Eosinophil 103/gsputum

Controlgroup

Mild to moderate

ICSlow-dose(n=10)

ICShigh-dose

(n=15)

OCS(n=10)

OCS ± ICS(n=7)

Severe asthma

p<0.01

p<0.001

p<0.001

p<0.01

In a clinical study of 74 patients


Leukotrienes

Other inflammatory mediators

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; Peters-Golden 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.

No Inflammation InflammationAsthma

Leukotrienes: Important in Early Asthma and Throughout the Disease


• 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.

Dual Pathways of Inflammation Actions of Corticosteroids


Dual Pathways of Inflammation Effects of the CysLT1 Receptor on Inflammatory Cells

EosinophilsLung Macrophage

Smooth- musclecell

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.

Monocytes


Dual Pathways of Inflammation Expression of the CysLT1 Receptor

Neutrophil

Monocyte

Macrophage

Basophil

Pluripotent hemopoieticstem cell

T CellsEosinophil

B Lymphocyte

CCR3

CD4+CD8+

CD19

M-CSF, GM-CSF, IL-3

LTC4, LTD4, LTE4

LN5

Mast Cell

LTC4

LTD4

LTE4

M-CSFGM-CSF

IL-5IL-3

GM-CSFLTC4

LTD4

LTE4

CD14

IL5Rβ

Represents the CysLT1 receptor

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

CysLT1R

CD34+



Dual Pathways of Inflammation Leukotrienes Are Powerful Inflammatory Mediators

Mediatorreceptor

Othermediators

CysLTreceptor CysLT


• Suppress many inflammatory mediators

• Suppress inflammatory processes– Via the leukotriene pathway– Via the steroid-sensitive pathway

LTRAs = leukotriene receptor antagonists


Dual Pathways of Inflammation Actions of LTRAs

Leukotrienes are highly specific but catalyze a massive inflammatory cascade


Dual Pathways of Inflammation Central Role of CysLTs in Asthma

Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16:304-309.

Inflammatory Cells (mast cells, eosinophils)

Sensory Nerves

(C fibers)

CysLTsEdema

BloodVessel

Decreased Mucus Transport

EosinophilInflux

Cationic Protein Release,Epithelial-Cell Damage

Contraction and Proliferation

Airway Smooth Muscle

Increased Mucus

Secretion

Airway Epithelium


p = NS between groups

Adapted from O’Shaughnessy KM et al Am Rev Respir Dis 1993;147:1472-1476.

18.720

16

12

8

4

0

Urinary LTE4

excretion(ng/mmol

creatinine)

18.4

PlaceboFluticasone propionate

Effect of Inhaled Fluticasone Propionate on Urinary LTE4 Excretion


*

*p<0.05 vs. baseline

Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149:953-959.

0.3

0.2

0.1

0

Urinary LTE4

(ng/mgcreatinine)

Post-allergen challenge

Baseline

ControlPrednisone

*

Effect of Oral Prednisone on Urinary LTE4 Excretion


n=14


Oral Prednisone Did Not Suppress CysLT Levels Recovered from BAL Fluid

BAL = bronchoalveolar lavage


80

70

60

50

40

30

20

10

0

BALlevels(pg/ml)

LTE4LTC4

Before prednisoneAfter prednisone

Eicosanoids in Asthmatics


*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.

14

12

10

8

6

4

2

0

SputumCysLT levels(ng/ml)

Controls(n=10)

6.4

All patients with asthma

(n=26)

9.4*

Patients with persistent

asthma(n=10)

11.4**

Patients with acute attacks

(n=12)

13*

Effect of ICS on Sputum Leukotriene Levels


LABA = long-acting beta2 agonist

Adapted from Currie GP et al Am J Respir Crit Care Med (in press).

Dual Pathways of Inflammation Long-Acting Beta2 Agonists Did Not Have Anti-inflammatory Effects

0

–100

–200

Change ineosinophils

( 106/L)from run-in

ICS + LABA + Montelukast

ICS +LABA ICS

ICS +Montelukast

p<0.05

p<0.05

LTRA montelukast further reduced inflammation when added to ICS


*p<0.05 compared with beclomethasone

Adapted from LaViolette M et al Am J Respir Crit Care Med 1999;160:1862-1868.

0.12

0.10

0.08

0.06

0.04

0.02

0

Eosinophilcounts(change

from baseline 103/µl)

Placebo Beclomethasone Montelukast+

beclomethasone

Montelukast

*

<1*

Treatment group

Dual Pathways of Inflammation LTRA Montelukast Further Reduced Asthmatic Inflammation

Complementary therapy that targets dual pathways of inflammation provided better control of inflammation


block steroid-sensitivemediators

blocks the effects of CysLTs

Inhaled steroidsMontelukast

Dual Pathways of Inflammation Montelukast Combined with a Steroid Affects the Dual Pathways of Inflammation

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.

Steroid-sensitive mediators

play a key role in asthmatic inflammation

CysLTsplay a key role in asthmatic inflammation

Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients

DUAL PATHWAY


Dual Pathways of Inflammation Airway Inflammation Correlated with Lung Function and Clinical Control

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.

0

–0.2

–0.4

–0.6

rS

FEV1

Daily symptomscore

PEFRvariability

–0.51

Absolute eosinophil countsECP concentrations

–0.36

–0.49 –0.51

–0.43

–0.52


• CysLTs and steroid-sensitive mediators are two important pathways of inflammation in asthma

• Corticosteroids do not block the leukotriene-mediated 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.

Summary Targeting Dual Pathways of Inflammation Improves Asthma Control


Capacity of Oral SINGULAIR to Prevent Asthma Exacerbations

CApacidad de SIngulair™ Oral en la Prevencion de

Exacerbaciones Asmaticas

SINGULAIR (montelukast sodium) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.


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.

• 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 studiesof 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

Rationale and Objective


PEFR = peak expiratory flow rate

Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211.

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)


Budesonide Turbuhaler 400–1600 µg qd

+ montelukast (n=326)

Budesonide Turbuhaler 400–1600 µg qd

+ placebo

(n=313)

qd = once daily

Inhaled short-acting beta2 agonists were permitted as needed.


CASIOPEA Study

Design

Period I

Weeks

Period II

Budesonide Turbuhaler

400–1600 µg/day

V1–2

V20

V24

V28

V516


FEV1 = forced expiratory volume in one second


• 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

CASIOPEA Study

Inclusion Criteria


*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


Montelukast Budesonide + Budesonide

(n=313) (n=326) Age, yr (range)* 44 ± 16 (18–79) 42 ± 15 (18–76)Gender, no.

Female 121 (39%) 124 (38%) Male 192 (61%) 202 (62%)

Duration of asthma, year* 13.8 ± 11.7 13.8 ± 11.4% of predicted FEV1* 81 ± 21 81 ± 19

Morning PEFR (L/min) 365 ± 108 373 ± 105Evening PEFR (L/min) 375 ± 108 382 ± 107Daytime asthma symptom score*,** 2.3 ± 0.8 2.2 ± 0.8Beta2-agonist use (puffs/day)* 3.3 ± 2.3 3.2 ± 2.5

Budesonide dose (µg/day), no.*** I. 400–800 202 (66%) 219 (69%) II. 801–1200 15 (5%) 18 (6%) III. 1201–1600 91 (30%) 80 (25%)

CASIOPEA Study

Baseline Characteristics of Patients



CASIOPEA Study

Montelukast + Budesonide Significantly Reduced Asthma-Exacerbation Days

4.8

3.1

Budesonide + placebo (n=308)

Montelukast + budesonide

(n=317)

Medianpercentageof asthma-

exacerbation days

5

4

3

2

1

0

35%p=0.03


p=0.67 (ns) across strata

Adapted from additional analysis of CASIOPEA study: asthma exacerbation days per budesonide dose strata and onset of action for beta agonist use

Regardless of ICS dose

CASIOPEA Study

Montelukast + Budesonide Reduced Asthma-Exacerbation Days

10

8

6

4

2

0

No. ofasthma

exacerbationdays

I (n=421)

Budesonide + placeboMontelukast + budesonide

II (n=33)

III (n=171)

Strata of ICS dose



CASIOPEA Study

Montelukast + Budesonide Significantly Increased Asthma-Free Days

42.3

66.1



(n=317)

Medianpercentageof asthma-free days

70

60

50

40

30

56%p=0.001


*The percentage of patients who awoke during the night because of asthma


CASIOPEA Study

Montelukast + Budesonide Significantly Reduced Nocturnal Awakenings

25.6

Least square mean % of

patientswith nocturnalawakenings*

35

30

25

20

32.2

20%p=0.01



(n=317)


*p = 0.05 vs. budesonide alone


CASIOPEA Study

Montelukast + Budesonide Significantly Reduced Beta2-Agonist Use*

% changefrom

baseline inbeta2-agonist

use

30

20

10

0

–10

–20

–30

–40

First 7 days in active treatment

Budesonide + placebo (n=313)Montelukast + budesonide (n=326)

Basal 1 2 3 4 5 6 7

A more rapid onset of action than budesonide + placebo


CASIOPEA Study

Montelukast + Budesonide Significantly Increased AM PEFR*

Tertiary endpoint: Morning PEFR

Mean adjusted by center and stratum

*p = 0.05 vs. budesonide alone


11.3

16.86



(n=317)

20

15

10

5

0

49%p=0.05

Least square mean change

in morningPEFR

(L/min)


% of Patients Most Common Budesonide + Montelukast + Adverse Events placebo (n=313) budesonide (n=326) Influenza 11 12Headache 9 11Upper respiratory infection 7 5Worsening asthma 5 7Epigastric pain/pyrosis 2 3Urinary tract infection 2 2Rhinitis 2 2Pharyngitis 1 2Bronchitis 1 2Total 41 44

No significant differences between groups


Montelukast + Budesonide Was Well Tolerated

Incidence of adverse events comparable to budesonide + placebo



• Montelukast added to patients’ usual dose of budesonide significantly improved asthma control (p0.05)– 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

CASIOPEA Study

Summary

Montelukast provided effective asthma control


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.

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


References

Please see notes page.


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

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SGA 2003-W-6701-SS Downloaded from – Slide 1 Dual Pathways of Asthmatic Inflammation CApacidad de SIngulair Oral en la