1. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 1 Dual Pathways of Asthmatic Inflammation CApacidad de SIngulair Oral en la Prevencion de Exacerbaciones Asmaticas Montelukast with Inhaled Corticosteroids

2. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 2 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

3. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 3 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. 20,000 10,000 1,000 100 10 1 Eosinophil  10 3 /g sputum Control group Mild to moderate ICS low-dose (n=10) ICS high-dose (n=15) OCS (n=10) OCS ± ICS (n=7) Severe asthma p<0.01 p<0.001 p<0.01 In a clinical study of 74 patients

4. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 4 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 InflammationInflammationAsthma Leukotrienes: Important in Early Asthma and Throughout the Disease

5. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 5 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

6. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 6 Dual Pathways of Inflammation Effects of the CysLT 1 Receptor on Inflammatory Cells Eosinophils Lung Macrophage Smooth- muscle cell 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

7. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 7 Dual Pathways of Inflammation Expression of the CysLT 1 Receptor Neutrophil Monocyte Macrophage Basophil Pluripotent hemopoietic stem cell T Cells Eosinophil B Lymphocyte CCR3 CD4+ CD8+ CD19 M-CSF, GM-CSF, IL-3 LTC 4, LTD 4, LTE 4 LN5 Mast Cell LTC 4 LTD 4 LTE 4 M-CSF GM-CSF IL-5 IL-3 GM-CSF LTC 4 LTD 4 LTE 4 CD14 IL5Rβ Represents the CysLT 1 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 CysLT 1 R CD34+

8. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 8 Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48. Dual Pathways of Inflammation Leukotrienes Are Powerful Inflammatory Mediators Mediator receptor Other mediators CysLT receptor CysLT

9. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 9 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. Dual Pathways of Inflammation Actions of LTRAs Leukotrienes are highly specific but catalyze a massive inflammatory cascade

10. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 10 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) CysLTs Edema Blood Vessel Decreased Mucus Transport Eosinophil Influx Cationic Protein Release, Epithelial-Cell Damage Contraction and Proliferation Airway Smooth Muscle Increased Mucus Secretion Airway Epithelium

11. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 11 p = NS between groups Adapted from O’Shaughnessy KM et al Am Rev Respir Dis 1993;147:1472-1476. 18.7 20 16 12 8 4 0 Urinary LTE 4 excretion (ng/mmol creatinine) 18.4 PlaceboFluticasone propionate Effect of Inhaled Fluticasone Propionate on Urinary LTE 4 Excretion

12. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 12 * *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 LTE 4 (ng/mg creatinine) Post-allergen challenge Baseline Control Prednisone * Effect of Oral Prednisone on Urinary LTE 4 Excretion

13. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 13 n=14 Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149:953-959. Oral Prednisone Did Not Suppress CysLT Levels Recovered from BAL Fluid BAL = bronchoalveolar lavage Adapted from Dworski R et al Am J Respir Crit Care Med 1994;149:953-959. 80 70 60 50 40 30 20 10 0 BAL levels (pg/ml) LTE 4 LTC 4 Before prednisone After prednisone Eicosanoids in Asthmatics

14. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 14 *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 Sputum CysLT 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

15. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 15 LABA = long-acting beta 2 agonist Adapted from Currie GP et al Am J Respir Crit Care Med (in press). Dual Pathways of Inflammation Long-Acting Beta 2 Agonists Did Not Have Anti-inflammatory Effects 0 –100 –200 Change in eosinophils (  10 6 /L) from run-in ICS + LABA + Montelukast ICS + LABA ICS ICS + Montelukast p<0.05 LTRA montelukast further reduced inflammation when added to ICS

16. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 16 *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 Eosinophil counts (change from baseline  10 3 /µl) PlaceboBeclomethasone 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

17. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 17 block steroid- sensitive mediators 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 CysLTs play a key role in asthmatic inflammation Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients DUAL PATHWAY

18. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 18 Dual Pathways of Inflammation Airway Inflammation Correlated with Lung Function and Clinical Control FEV 1 = forced expiratory volume in one second; PEFR = peak expiratory flow rate; r S = 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 rSrS FEV 1 Daily symptom score PEFR variability –0.51 Absolute eosinophil counts ECP concentrations –0.36 –0.49 –0.51 –0.43 –0.52

19. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 19 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

20. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 20 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.

21. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 21 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 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 Rationale and Objective

22. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 22 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)

23. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 23 Budesonide Turbuhaler 400–1600 µg qd + montelukast (n=326) Budesonide Turbuhaler 400–1600 µg qd + placebo (n=313) qd = once daily Inhaled short-acting beta 2 agonists were permitted as needed. Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211. CASIOPEA Study Design Period I Weeks Period II Budesonide Turbuhaler 400–1600 µg/day V1 –2 V2 0 V2 4 V2 8 V5 16

24. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 24 FEV 1 = forced expiratory volume in one second Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211. 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 FEV 1  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 beta 2 agonist CASIOPEA Study Inclusion Criteria

25. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 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. Montelukast Budesonide + Budesonide (n=313) (n=326) Age, yr (range)*44 ± 16 (18–79) 42 ± 15 (18–76) Gender, no. Female121 (39%)124 (38%) Male192 (61%)202 (62%) Duration of asthma, year*13.8 ± 11.713.8 ± 11.4 % of predicted FEV 1 *81 ± 2181 ± 19 Morning PEFR (L/min)365 ± 108373 ± 105 Evening PEFR (L/min)375 ± 108382 ± 107 Daytime asthma symptom score*, **2.3 ± 0.82.2 ± 0.8 Beta 2 -agonist use (puffs/day)*3.3 ± 2.33.2 ± 2.5 Budesonide dose (µg/day), no.*** I. 400–800202 (66%)219 (69%) II. 801–1200 15 (5%)18 (6%) III. 1201–1600 91 (30%) 80 (25%) CASIOPEA Study Baseline Characteristics of Patients

26. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 26 Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211. CASIOPEA Study Montelukast + Budesonide Significantly Reduced Asthma-Exacerbation Days 4.8 3.1 Budesonide + placebo (n=308) Montelukast + budesonide (n=317) Median percentage of asthma- exacerbation days 543210543210 35% p=0.03

27. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 27 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. of asthma exacerbation days I (n=421) Budesonide + placebo Montelukast + budesonide II (n=33) III (n=171) Strata of ICS dose

28. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 28 Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211. CASIOPEA Study Montelukast + Budesonide Significantly Increased Asthma-Free Days 42.3 66.1 Budesonide + placebo (n=308) Montelukast + budesonide (n=317) Median percentage of asthma- free days 70 60 50 40 30 56% p=0.001

29. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 29 *The percentage of patients who awoke during the night because of asthma Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211. CASIOPEA Study Montelukast + Budesonide Significantly Reduced Nocturnal Awakenings 25.6 Least square mean % of patients with nocturnal awakenings* 35 30 25 20 32.2 20% p=0.01 Budesonide + placebo (n=308) Montelukast + budesonide (n=317)

30. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 30 *p = 0.05 vs. budesonide alone Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211. CASIOPEA Study Montelukast + Budesonide Significantly Reduced Beta 2 -Agonist Use* % change from baseline in beta 2 -agonist use 30 20 10 0 –10 –20 –30 –40 First 7 days in active treatment Budesonide + placebo (n=313) Montelukast + budesonide (n=326) Basal1234567 A more rapid onset of action than budesonide + placebo

31. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 31 CASIOPEA Study Montelukast + Budesonide Significantly Increased AM PEFR* Tertiary endpoint: Morning PEFR Mean adjusted by center and stratum *p = 0.05 vs. budesonide alone Adapted from Vaquerizo MJ et al Thorax 2003;58:204-21. 11.3 16.86 Budesonide + placebo (n=308) Montelukast + budesonide (n=317) 20 15 10 5 0 49% p=0.05 Least square mean change in morning PEFR (L/min)

32. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 32 % of Patients Most Common Budesonide +Montelukast + Adverse Events placebo (n=313) budesonide (n=326) Influenza1112 Headache 911 Upper respiratory infection 7 5 Worsening asthma 5 7 Epigastric pain/pyrosis 2 3 Urinary tract infection 2 2 Rhinitis 2 2 Pharyngitis 1 2 Bronchitis 1 2 Total4144 No significant differences between groups Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211. Montelukast + Budesonide Was Well Tolerated Incidence of adverse events comparable to budesonide + placebo

33. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 33 Adapted from Vaquerizo MJ et al Thorax 2003;58:204-211. 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 CASIOPEA Study Summary Montelukast provided effective asthma control

34. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 34 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

35. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 35 References Please see notes page.

36. SGA 2003-W-6701-SS Downloaded from – www.singulair.aewww.singulair.ae Slide 36 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