SGA 2003-W SS Slide 1 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.

SGA 2003-W SS 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 B. 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: ; 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

SGA 2003-W SS Slide 3 PEFR = peak expiratory flow rate Adapted from Vaquerizo MJ et al Thorax 2003;58: 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)

SGA 2003-W SS Slide 4 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: CASIOPEA Study Design Period I Weeks Period II Budesonide Turbuhaler 400–1600 µg/day V1 –2 V2 0 V2 4 V2 8 V5 16

SGA 2003-W SS Slide 5 FEV 1 = forced expiratory volume in one second Adapted from Vaquerizo MJ et al Thorax 2003;58: 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

SGA 2003-W SS Slide 6 *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: 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 ± ± 11.4 % of predicted FEV 1 *81 ± 2181 ± 19 Morning PEFR (L/min)365 ± ± 105 Evening PEFR (L/min)375 ± ± 107 Daytime asthma symptom score*, **2.3 ± ± 0.8 Beta 2 -agonist use (puffs/day)*3.3 ± ± 2.5 Budesonide dose (µg/day), no.*** I. 400– (66%)219 (69%) II. 801– (5%)18 (6%) III. 1201– (30%) 80 (25%) CASIOPEA Study Baseline Characteristics of Patients

SGA 2003-W SS Slide 7 Adapted from Vaquerizo MJ et al Thorax 2003;58: CASIOPEA Study Montelukast + Budesonide Significantly Reduced Asthma-Exacerbation Days Budesonide + placebo (n=308) Montelukast + budesonide (n=317) Median percentage of asthma- exacerbation days % p=0.03

SGA 2003-W SS Slide 8 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 No. of asthma exacerbation days I (n=421) Budesonide + placebo Montelukast + budesonide II (n=33) III (n=171) Strata of ICS dose

SGA 2003-W SS Slide 9 Adapted from Vaquerizo MJ et al Thorax 2003;58: CASIOPEA Study Montelukast + Budesonide Significantly Increased Asthma-Free Days Budesonide + placebo (n=308) Montelukast + budesonide (n=317) Median percentage of asthma- free days % p=0.001

SGA 2003-W SS Slide 10 *The percentage of patients who awoke during the night because of asthma Adapted from Vaquerizo MJ et al Thorax 2003;58: CASIOPEA Study Montelukast + Budesonide Significantly Reduced Nocturnal Awakenings 25.6 Least square mean % of patients with nocturnal awakenings* % p=0.01 Budesonide + placebo (n=308) Montelukast + budesonide (n=317)

SGA 2003-W SS Slide 11 *p = 0.05 vs. budesonide alone Adapted from Vaquerizo MJ et al Thorax 2003;58: CASIOPEA Study Montelukast + Budesonide Significantly Reduced Beta 2 -Agonist Use* % change from baseline in beta 2 -agonist use –10 –20 –30 –40 First 7 days in active treatment Budesonide + placebo (n=313) Montelukast + budesonide (n=326) Basal A more rapid onset of action than budesonide + placebo

SGA 2003-W SS Slide 12 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: Budesonide + placebo (n=308) Montelukast + budesonide (n=317) % p=0.05 Least square mean change in morning PEFR (L/min)

SGA 2003-W SS Slide 13 % 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: Montelukast + Budesonide Was Well Tolerated Incidence of adverse events comparable to budesonide + placebo

SGA 2003-W SS Slide 14 Adapted from Vaquerizo MJ et al Thorax 2003;58: 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

SGA 2003-W SS Slide 15 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: ; Bisgaard H Allergy 2001;56(suppl 66):7-11; Vaquerizo MJ et al Thorax 2003;58: 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

SGA 2003-W SS Slide 16 References Please see notes page.

SGA 2003-W SS Slide 17 CApacidad de SIngulair ™ Oral en la Prevencion de Exacerbaciones Asmaticas Capacity of Oral SINGULAIR to Prevent Asthma Exacerbations 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. Printed in USA VISIT US ON THE WORLD WIDE WEB AT