Efficacy of Montelukast in Asthma Patients with Allergic Rhinitis Slide 1 One Airway, One Disease, One Approach Slide 2 One Airway, One Disease Slide 3 Asthma and Allergic Rhinitis: Two Related Conditions Linked by One Common Airway Slide 4 Allergic Rhinitis and Asthma Have Similar Prevalence Patterns Slide 5 Many Patients with Asthma Have Allergic Rhinitis Slide 6 Allergic Rhinitis Is a Risk Factor for Asthma Slide 7 Allergic Rhinitis Increased the Risk of Asthma Attacks Slide 8 Allergic Rhinitis Doubled the Risk of ER Visits in Patients with Asthma Slide 9 Allergic Rhinitis Increased the Odds of Hospitalization for Asthma by 50% Slide 10 Allergic Rhinitis Increased the Number of Prescriptions for Rescue Therapy (SABA) in Patients with Asthma Slide 11 Both Asthma and Allergic Rhinitis Are Inflammatory Conditions  Slide 12 Allergic Rhinitis and Asthma Have Common Triggers Slide 13 Allergic Rhinitis and Asthma Share Common Inflammatory Cells and Mediators Slide 14 Allergic Rhinitis and Asthma Share a Similar Inflammatory Process and Occur in the Mucosa Slide 15 Symptoms Correlate with the Early- and Late-Phase Responses in Allergic Rhinitis and Asthma Slide 16 Patients with Allergic Rhinitis Experience Increased Bronchial Hyperresponsiveness Slide 17 Allergen Challenge to the Nose Increases Bronchial Hyperresponsiveness Slide 18 Many Patients with Asthma Have Nasal Inflammation Slide 19 Inflammatory Changes in the Nasal and Bronchial Mucosa Are Correlated Slide 20 Bronchial Allergen Challenge Increases a Marker of Inflammation (Eosinophils) in Nasal and Bronchial Tissues Slide 21 Bronchial Allergen Challenge Increases Systemic Markers of Inflammation Slide 22 Summary Slide 23 ARIA and IPAG Guidelines Recommend a Combined Approach to Managing Asthma and Allergic Rhinitis Slide 24 Role of Cysteinyl Leukotrienes Slide 25 Montelukast Combined with a Steroid Affects the Dual Pathways of Inflammation Slide 26 Inhaled Corticosteroids Do Not Affect Sputum Leukotriene Levels in Patients with Asthma Slide 27 Cysteinyl Leukotrienes Are Important Mediators of Nasal Obstruction Slide 28 Cysteinyl Leukotriene Challenge Increases Rhinorrhea in Allergic Rhinitis Slide 29 Role of Cysteinyl Leukotrienes in Early- and Late-Phase Allergic Response Slide 30 Correlation of Cysteinyl Leukotriene Release with Symptoms in Allergic Rhinitis Slide 31 Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Slide 32 Study Design and Objective Slide 33 Inclusion Criteria Slide 34 Endpoints Slide 35 Baseline Characteristics of Patients Slide 36 Montelukast Significantly Reduced Daily Rhinitis Symptoms Scores Slide 37 Montelukast Reduced Daily Rhinitis Symptoms Regardless of Asthma Status at Study Start Slide 38 Montelukast Improved Global Evaluations of Clinical Status and Quality of Life Slide 39 Montelukast Improved Asthma Control Slide 40 Conclusions Slide 41 COMPACT Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis Slide 42 Objective of COMPACT Study and Subanalysis Slide 43 Study Design Slide 44 Inclusion Criteria Slide 45 Montelukast + Budesonide Improved Morning PEF Progressively over 12 Weeks Slide 46 Definition of Groups in Analysis Slide 47 Statistical Analysis Slide 48 Baseline Characteristics of Patients Slide 49 Montelukast Provided Greater Improvements in Morning PEFR than Budesonide Slide 50 Montelukast Provided Greater Improvements in Morning PEFR than Budesonide in Patients Who Received Rhinitis Medications Slide 51 Conclusion Slide 52 Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Slide 53 Study Design and Objective Slide 54 Inclusion Criteria Slide 55 Endpoints Slide 56 Baseline Characteristics of Patients Slide 57 Montelukast Significantly Improved Daytime Asthma Symptom Scores (Primary Endpoint) Slide 58 Montelukast Significantly Improved Asthma Control Slide 59 Montelukast Significantly Improved Lung Function Slide 60 Montelukast Significantly Improved Global Evaluations of Allergic Rhinitis Slide 61 Tolerability Profile Slide 62 Conclusions Slide 63 Summary Slides 64–66 References Slide 67 Copyright Information Efficacy of Montelukast in Asthma Patients with Allergic Rhinitis One Airway, One Disease, One Approach SGA 2006-W-286990-SS

One Airway, One Disease Slide 2 Source: SGA 2004-W-6776-SS (Slide 2)

Frequently overlapping conditions Involvement of similar tissues One Airway, One Disease Asthma and Allergic Rhinitis: Two Related Conditions Linked by One Common Airway Source: SGA 2004-W-6776-SS (Slide 3) Frequently overlapping conditions Involvement of similar tissues Common inflammatory processes Common inflammatory cells Common inflammatory mediators Slide 3 In recent years there has been growing recognition of the epidemiologic, pathologic, and clinical links between asthma and allergic rhinitis. These diseases are frequent comorbidities, resulting in additional symptomatic burdens and higher socioeconomic costs in patients with both conditions.1 Both conditions are characterized by a strikingly similar underlying pathology; i.e., inflammation of the respiratory mucosa associated with the same allergic and pro-inflammatory mediators and cells.1,2 This slide kit will discuss the epidemiologic and pathologic links between these diseases and present data from clinical studies aimed at treating both conditions concomitantly. Adapted from Phillip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

Allergic Rhinitis Asthma Epidemiologic Links between Allergic Rhinitis and Asthma Allergic Rhinitis and Asthma Have Similar Prevalence Patterns Source: SGA 2004-W-6776-SS (Slide 4) Allergic Rhinitis Asthma UK Australia Canada Brazil USA South Africa Germany France Argentina Algeria China Russia UK Australia Canada Brazil USA South Africa Germany France Argentina Algeria China Russia Slide 4 Allergic rhinitis and asthma are highly prevalent worldwide, particularly in more developed countries that follow a “Western” lifestyle where the prevalence of both conditions is greatest.3-5 This slide shows 12-month prevalences of asthma and allergic rhinoconjunctivitis for selected participating centers in the International Study of Asthma and Allergies in Childhood (ISAAC). ISAAC is a systematic international comparison of the prevalence of asthma and allergies.3 This analysis looked at the relationship between asthma, allergic rhinoconjunctivitis, and atopic eczema by analyzing responses on one-page questionnaires completed by 463,801 children aged 13–14 years in 156 collaborating centers across 56 countries. The questionnaires included questions about symptoms over the previous 12 months. In addition, a video asthma questionnaire was used to ask children if their breathing had been like the breathing in the video.3 The association between atopic diseases and Western lifestyle may be attributable to a decreased incidence of certain infections in early childhood.4,5 It is thought that during early life, viral infections may selectively enhance the development of T-helper (Th)-1–type cells and thus inhibit proliferation of Th2 cells, which promote allergic sensitization.6 Because children in Western societies do not typically contract these early viral infections, normal maturation of the immune response is impaired while allergy-promoting Th2 responses persist.5,6 5 10 15 20 25 30 35 40 5 10 15 20 25 30 35 40 % prevalence % prevalence Study of worldwide prevalence of atopic diseases in 463,801 children 13–14 years of age. Children self-reported symptoms over 12 months using questionnaires. Adapted from the International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee Lancet 1998;351:1225–1232. SGA 2006-W-286990-SS

All asthmatic patients Epidemiologic Links between Allergic Rhinitis and Asthma Many Patients with Asthma Have Allergic Rhinitis Source: SGA 2004-W-6776-SS (Slide 5) Up to 80% of all asthmatic patients have allergic rhinitis Slide 5 Epidemiologic studies support the results of pathophysiologic and clinical studies showing an association between asthma and allergic rhinitis, demonstrating that among patients with asthma, 60% to 80% also have allergic rhinitis.7-10 Therefore, allergic rhinitis should be suspected, and treated if necessary, in patients with a diagnosis of asthma.7 All asthmatic patients Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; Sibbald B, Rink E Thorax 1991;46:895–901; Leynaert B et al J Allergy Clin Immunol 1999;104:301–304; Brydon MJ Asthma J 1996:29–32. SGA 2006-W-286990-SS

Allergic rhinitis increased the risk of asthma about threefold Epidemiologic Links between Allergic Rhinitis and Asthma Allergic Rhinitis Is a Risk Factor for Asthma Source: SGA 2004-W-6776-SS (Slide 6) Allergic rhinitis increased the risk of asthma about threefold 12 10 8 6 4 2 p<0.002 10.5 % of patients who developed asthma Slide 6 Allergic rhinitis is an important risk factor for asthma. In one long-term follow-up study, first-year college students with allergic rhinitis were approximately three times more likely to develop asthma over the ensuing 23 years than individuals without allergic rhinitis. This observed difference in the relative risk of developing asthma was significant between the two groups (p<0.002).11 In fact, allergic rhinitis may be an early manifestation of asthma. One large population-based study in Finland showed that the diagnosis of hay fever was almost always made before or concurrent with a diagnosis of asthma, but rarely thereafter.12 These associations reflect the shared atopy that underlies allergic rhinitis and asthma, thus explaining, at least in part, the frequent coexistence of these disorders.9 3.6 No allergic rhinitis at baseline (n=528) Allergic rhinitis at baseline (n=162) 23-year follow-up of first-year college students undergoing allergy testing; data based on 738 individuals (69% male) with average age of 40 years Adapted from Settipane RJ et al Allergy Proc 1994;15:21–25. SGA 2006-W-286990-SS

+ allergic rhinitis (n=893) Post Hoc Resource Use Analysis of IMPACT Allergic Rhinitis Increased the Risk of Asthma Attacks Source: SGA 2004-W-6776-SS (Slide 7—updated sourcing) 25 20 15 10 p=0.046 % of patients 21.3 17.1 Slide 7 The IMProving Asthma Control Trial (IMPACT) was a double-blind, multicenter clinical study of 1490 adults with chronic asthma who received montelukast plus fluticasone or salmeterol plus fluticasone for 48 weeks after an initial four-week run-in period with fluticasone alone. The primary objective was to compare the effect of therapy on the percentage of patients experiencing at least one asthma attack. This trial showed that 20% of patients treated with montelukast and fluticasone had at least one asthma exacerbation, compared to 19% in the salmeterol plus fluticasone group.13 A post hoc resource use analysis of IMPACT showed that over the one-year study period, the incidence of asthma attacks was significantly (p=0.046) higher among patients with both asthma and allergic rhinitis (21.3%) than among patients with asthma alone (17.1%). This difference represented an odds ratio of 1.35 for the group of patients with comorbid asthma and allergic rhinitis versus the group with asthma alone, with a 95% confidence interval (CI) of 1.03–1.77.14 Patients with asthma (n=597) Patients with asthma + allergic rhinitis (n=893) Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic rhinitis over 52 weeks Adapted from Bousquet J et al Clin Exp Allergy 2005;35:723–727. SGA 2006-W-286990-SS

Patients with asthma + allergic rhinitis Allergic Rhinitis Worsens Asthma Allergic Rhinitis Doubled the Risk of ER Visits in Patients with Asthma Source: SGA 2004-W-6776-SS (Slide 8—updated sourcing) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 p=0.029 3.6 % of patients Slide 8 The post hoc resource use analysis of the IMPACT study revealed that over the one-year study period, the incidence of emergency room visits was more than twice as high among patients with both asthma and allergic rhinitis (3.6%) than among patients with asthma alone (1.7%). This significant (p=0.029) difference represented an odds ratio of 2.32 for the group of patients with comorbid asthma and allergic rhinitis versus the group with asthma alone (95% CI 1.12–4.8).14 1.7 Patients with asthma (n=597) Patients with asthma + allergic rhinitis (n=893) Post hoc analysis of medical resource use/asthma attacks in asthmatic patients with and without concomitant allergic rhinitis over 52 weeks ER=emergency room Adapted from Bousquet J et al Clin Exp Allergy 2005;35:723–727. SGA 2006-W-286990-SS

Patients with asthma + allergic rhinitis Retrospective Cohort Study of UK Mediplus Database Allergic Rhinitis Increased the Odds of Hospitalization for Asthma by 50% Source: SGA 2004-W-6776-SS (Slide 9—updated sourcing) 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 p<0.006 0.76 % of patients hospitalized annually 0.45 Slide 9 A retrospective cohort study was conducted to determine the incremental effect of allergic rhinitis on health-care resource use in adults with asthma. Data were analyzed from 27,303 adolescent or adult patients (16 to 55 years of age) with asthma who had one or more asthma-related office visits to a general practice in the UK. Medical resource use data were obtained from a database including more than 500 general practitioners.15 During the 12-month follow-up period, patients with documented allergic rhinitis were significantly more likely to be hospitalized for asthma than were patients with asthma alone (p=0.0058). Specifically, 0.76% of patients with comorbid asthma and allergic rhinitis required asthma-related hospitalizations, versus 0.45% of patients with asthma alone. Multivariate analysis demonstrated that this difference represented an odds ratio of 1.52 (95% CI 1.03–2.24), indicating that concomitant allergic rhinitis increased the odds of hospitalization for asthma by 50%.15 Patients with asthma (n=22,692) Patients with asthma + allergic rhinitis (n=4611) Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in general practice in the UK Adapted from Price D et al Clin Exp Allergy 2005;35:282–287. SGA 2006-W-286990-SS

+ allergic rhinitis (n=4611) Retrospective Cohort Study of UK Mediplus Database Allergic Rhinitis Increased the Number of Prescriptions for Rescue Therapy (SABA) in Patients with Asthma Source: SGA 2004-W-6776-SS (Slide 10—updated sourcing) 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5 2.4 p<0.0001 3.2 Annual prescriptions per patient Slide 10 The retrospective cohort study of 27,303 patients with asthma revealed that over the 12-month follow-up period, patients with allergic rhinitis filled significantly more prescriptions for short-acting beta2-agonists (SABA) than did patients with asthma alone (p<0.0001). The mean number of SABA prescriptions for patients with comorbid asthma and allergic rhinitis was 3.15 during the years, compared with a mean of 2.71 for patients with asthma alone.15 Correspondingly, multivariate analysis showed that a concomitant diagnosis of allergic rhinitis was a significant predictor of higher annual costs for asthma medications (p=0.0001).15 2.7 Patients with asthma (n=22,692) Patients with asthma + allergic rhinitis (n=4611) Analysis of health-care resource use in adults 16 to 55 years of age with asthma and allergic rhinitis in general practice in the UK SABA=short-acting beta2-agonists Adapted from Price D et al Clin Exp Allergy 2005;35:282–287. SGA 2006-W-286990-SS

Asthma is fundamentally a disease of inflammation One Airway, One Disease Both Asthma and Allergic Rhinitis Are Inflammatory Conditions Source: SGA 2004-W-6776-SS (Slide 11) Asthma is fundamentally a disease of inflammation Inflammation of the lower airways causes bronchoconstriction and airway hyperresponsiveness, resulting in asthma symptoms Allergic rhinitis is an IgE-mediated inflammatory disorder Inflammation of the nasal membranes in response to allergen exposure results in nasal symptoms Slide 11 Asthma is a chronic inflammatory disorder in which exposure to various stimuli results in airway obstruction and airflow limitation.16 Allergic rhinitis is an immunoglobulin E (IgE)–mediated inflammatory disorder in which exposure of the nasal membranes to allergens leads to nasal symptoms.7 Although allergic rhinitis and asthma traditionally have been diagnosed and managed as distinct upper- and lower-airway diseases, respectively, recent insights into their underlying pathophysiology have identified a continuum of inflammation within the upper and lower airways.17 Several new terms have been proposed to describe the ubiquitous airway inflammation observed in patients with concurrent allergic rhinitis and asthma. These include “one airway disease,”17 “allergic rhinobronchitis,”18 “united airways,”19 and “one linked airway disease,”20 among others. IgE=immunoglobulin E 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; Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149. SGA 2006-W-286990-SS

Insects (e.g., cockroach allergen) NSAIDs (e.g., aspirin) One Airway, One Disease Allergic Rhinitis and Asthma Have Common Triggers Source: SGA 2004-W-6776-SS (Slide 12) Outdoor allergens Pollens Molds Indoor allergens House-dust mites Animal dander Insects (e.g., cockroach allergen) NSAIDs (e.g., aspirin) Slide 12 Several of the same agents are known to trigger exacerbations of both allergic rhinitis and asthma.21 Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can induce bronchospasm or rhinitis in susceptible individuals.16,22 Sensitivity to indoor allergens is highly correlated with the presence of both allergic rhinitis and asthma.23 Exposure to house-dust mites can lead to sustained inflammation of the bronchi24 and perennial allergic rhinitis.25 Animal dander is another important indoor allergen implicated in both conditions.8,26 Insects such as cockroaches are often involved in both allergic rhinitis and asthma.16,27 Tobacco smoke, a major source of indoor pollution, can trigger asthma or allergic rhinitis whether the patient smokes or breathes in smoke from others.16,27 Common outdoor allergens in both conditions are pollens and molds.16,27 NSAIDs=nonsteroidal anti-inflammatory drugs 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; Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses, 2001. Pollen close-up image is a royality-free-image can be used in this piece without charge, but must be purchased to use anywhere else. Please see terms detailed in the photorights SGA2006-W-286900.doc. Dust mite close-up and insect images are rights-managed and are subject to the terms detailed in the photorights SGA2006-W-286900.doc. To use it in any other way without purchasing local rights is a licensing violation. SGA 2006-W-286990-SS

Inflammatory mediators One Airway, One Disease Allergic Rhinitis and Asthma Share Common Inflammatory Cells and Mediators Source: SGA 2004-W-6776-SS (Slide 13) Membrane-bound IgE Mast cell Preformed Mediators Cysteinyl leukotrienes Prostaglandins Platelet-activating factor Early-phase response Allergen Slide 13 The same immunologic processes are involved in the early- and late-phase responses seen in allergic rhinitis and asthma. The basis of both reactions is immediate hypersensitivity caused by a cascade of events that begins with sensitization and the generation of allergen-specific IgE when an allergen interacts with membrane-bound IgE on the surface of mast cells. This interaction triggers mast-cell degranulation; i.e., the release of preformed mediators (histamine and tryptase), cysteinyl leukotrienes, prostaglandins, and platelet-activating factor (PAF), which are directly responsible for the early-phase response. The late-phase response is provoked primarily by activation of mast cells or T cells, resulting in cytokine release. Cytokines influence a wide range of events associated with chronic inflammation, including eosinophil recruitment and the consequent release of cysteinyl leukotrienes and other newly generated inflammatory mediators.2,21,28 Whereas preformed and newly generated mediators of inflammation are similar in the upper and lower airway, their effects may differ in the different target organs.18 Eosinophils T cells Inflammatory mediators Late-phase response Cytokines Adapted from Casale TB et al Clin Rev Allergy Immunol 2001;21:27–49; Kay AB N Engl J Med 2001;344:30–37. SGA 2006-W-286990-SS

Eosinophil infiltration Shared Pathophysiology of Allergic Rhinitis and Asthma Allergic Rhinitis and Asthma Share a Similar Inflammatory Process and Occur in the Mucosa Source: SGA 2004-W-6776-SS (Slide 14) Allergic rhinitis Asthma Slide 14 Nasal and bronchial tissues share histologic similarities, including a pseudostratified epithelium with columnar, ciliated cells resting on a basement membrane in normal individuals.7 Not surprisingly, the inflammatory process is strikingly similar in these tissues: they are subject to eosinophil infiltration arising from the release of mediators such as cysteinyl leukotrienes and cytokines during the allergic or asthmatic response. Eosinophils may mediate the tissue damage observed in both conditions and may sustain and further potentiate the allergic and inflammatory response.2 Because there are differences in the structure of the mucosa in the upper and lower airways (i.e., the greater vascularity of nasal tissue, the presence of smooth muscle in the bronchi, and the greater degree of epithelial shedding in the lungs), inflammation in these target tissues induces the expression of a different set of symptoms in allergic rhinitis and asthma. These include bronchoconstriction in the lungs and vascular engorgement leading to nasal obstruction in the nose.2 Nasal mucosa Bronchial mucosa Eosinophil infiltration Eos=eosinophils; neut=neutrophils; MC=mast cells; Ly=lymphocytes; MP=macrophages Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149. SGA 2006-W-286990-SS

Score for nasal symptoms Time post-challenge (hours) One Airway, One Disease Symptoms Correlate with the Early- and Late-Phase Responses in Allergic Rhinitis and Asthma Source: SGA 2004-W-6776-SS (Slide 15) Score for nasal symptoms Sneezing Nasal pruritus Congestion Rhinorrhea Immediate (early) phase Late phase Upper Airways (Allergic rhinitis) Antigen challenge 1 3–4 8–12 24 Time post-challenge (hours) Slide 15 The slide illustrates the similar pattern and time course of early- and late-phase responses in allergic rhinitis and asthma. Approximately one hour after allergen provocation, patients with allergic rhinitis experience a peak in symptoms, while patients with asthma experience a steep decline in lung function (measured by forced expiratory volume in one second [FEV1]). Several hours later, a sustained period of symptoms occurs in patients with allergic rhinitis and reduced lung function affects patients with asthma. Within 12 to 24 hours, both types of reactions typically resolve.29,30 During the early-phase response, symptoms in patients with allergic rhinitis typically consist of sneezing, rhinorrhea, and conjunctivitis;28 patients with asthma experience wheezing, coughing, and shortness of breath in addition to objectively demonstrable changes in lung function.29 During the late-phase response, patients with allergic rhinitis experience sustained nasal congestion,28 and patients with asthma experience a fall in lung function similar to that observed in the early-phase response.29 100 Lower Airways FEV1 (% change) (Asthma) 50 1 2 3 4 5 6 7 8 9 10 24 Time (hours) FEV1=forced expiratory volume in one second Adapted from Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford: Blackwell Science, 2000:1172–1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604. SGA 2006-W-286990-SS

Prevalence of bronchial hyperresponsiveness* Clinical Links between Allergic Rhinitis and Asthma Patients with Allergic Rhinitis Experience Increased Bronchial Hyperresponsiveness Source: SGA 2004-W-6776-SS (Slide 16) Prevalence of bronchial hyperresponsiveness* 60 50 40 30 20 10 (n=27) p<0.02 48 % of patients Slide 16 Many examples of “communication” between the nose and lungs link allergic rhinitis and asthma. One such example is the bronchial hyperresponsiveness observed in patients with allergic rhinitis. The prevalence of bronchial hyperresponsiveness (defined as a provocation dose [PD] of carbachol causing a 20% decrease in FEV1 [PD20] <1 mg) was evaluated during and out of pollen season in 27 nonasthmatic patients with seasonal allergic rhinitis plus hay fever. Bronchial hyperresponsiveness increased significantly, from 11% out of pollen season to 48% during pollen season (p<0.02). Thus, the expression of allergic symptoms, even when confined to the nose, is associated with bronchial hyperreactivity in the lungs.31 11 Out of season In season Study of bronchial hyperreactivity in patients (mean age 20 years) with hay fever; challenges were performed in the fall of one year and approximately six months later. *PD20 <1 mg after carbachol challenge PD=provocation dose Adapted from Madonini E et al J Allergy Clin Immunol 1987;79:358–363. SGA 2006-W-286990-SS

Geometric mean PC20 (methacholine, mg/ml) Clinical Links between Allergic Rhinitis and Asthma Allergen Challenge to the Nose Increases Bronchial Hyperresponsiveness Source: SGA 2004-W-6776-SS (Slide 17) Change from baseline in PC20* Placebo (n=5) Allergen (n=5) 3 2 p=0.0009 Geometric mean PC20 (methacholine, mg/ml) p=0.011 Slide 17 A crossover study further established the relationship between allergic rhinitis and lower-airway dysfunction. Patients were studied on two days separated by two weeks. On the first study day, 10 patients with allergic rhinitis and asthma randomly received nasal challenge with either allergen or placebo. Thirty minutes and 4.5 hours after challenge, bronchial hyperresponsiveness was determined through methacholine-challenge testing. The endpoint of post-challenge (PC)20 measures the methacholine dose required to decrease FEV1 by 20%. Therefore, lower PC20 values denote greater hyperresponsiveness. Two weeks later, patients were crossed over to the alternate challenge group (allergen or placebo). Lower-airway responsiveness to methacholine was comparable at baseline on both study days. The geometric mean log2 PC20, however, was significantly lower in patients receiving allergen challenge to the nose than in the group receiving placebo 30 minutes (p=0.011) and 4.5 hours post-challenge (p=0.0009).32 This finding supports the observations described on the previous slide by demonstrating a causal relationship between nasal allergen challenge and the onset of bronchial hyperresponsiveness. The persistent changes in bronchial reactivity in this study most likely reflect the action of inflammatory products that reached the lower airways through either postnasal drainage or the systemic circulation.32 Baseline 0.5 hour post-challenge 4.5 hours post-challenge Randomized, crossover two-day investigation of the relationship between allergic rhinitis and lower airway dysfunction in patients with allergic rhinitis and asthma (mean age 31.4 years) PC=post-challenge *Lower PC20 values indicate greater hyperresponsiveness Adapted from Corren J et al J Allergy Clin Immunol 1992;89:611–618. SGA 2006-W-286990-SS

Eosinophils/ field of nasal biopsy Clinical Links between Allergic Rhinitis and Asthma Many Patients with Asthma Have Nasal Inflammation Source: SGA 2004-W-6776-SS (Slide 18) Eosinophil counts in the nasal mucosa 18 16 14 12 10 8 6 4 2 (n=9) (n=8) (n=10) Eosinophils/ field of nasal biopsy Slide 18 In a recent study of 27 non-atopic patients, eosinophil counts in nasal biopsy specimens from asthmatic patients (with or without rhinitis symptoms) were consistently and significantly greater than those in normal controls (p<0.001). Of the 27 patients who participated, nine patients had both asthma and allergic rhinitis, eight had asthma without allergic rhinitis, and 10 were healthy non-atopic control subjects. These findings support the hypothesis that asthma and rhinitis are clinical expressions of the same entity.33 p<0.001 p<0.001 Rhinitis No rhinitis Control Asthmatic Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in non-atopic subjects 20 to 66 years of age Bars represent median values. Adapted from Gaga M et al Clin Exp Allergy 2000;30:663–669. SGA 2006-W-286990-SS

Asthmatic nasal mucosa eosinophils Clinical Links between Allergic Rhinitis and Asthma Inflammatory Changes in the Nasal and Bronchial Mucosa Are Correlated Source: SGA 2004-W-6776-SS (Slide 19) 40 35 30 25 20 15 10 5 (n=17) Asthmatic nasal mucosa eosinophils Slide 19 A recent study included 27 non-atopic patients: nine patients had both asthma and allergic rhinitis, eight had asthma without allergic rhinitis, and 10 were healthy non-atopic control subjects. There was a strong linear correlation between eosinophilia in the nasal mucosa and in the bronchial mucosa of the 17 asthmatic patients (r=0.851, p<0.001). The airway epithelium in patients with asthma therefore appears to be inflamed all along its length, further supporting the hypothesis that asthma and rhinitis are clinical expressions of the same entity.33 r=0.851, p<0.001 5 10 15 20 25 30 Asthmatic bronchial mucosa eosinophils Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in atopic subjects 20 to 66 years of age Adapted from Gaga M et al Clin Exp Allergy 2000;20:663–669. SGA 2006-W-286990-SS

Clinical Links between Allergic Rhinitis and Asthma Bronchial Allergen Challenge Increases a Marker of Inflammation (Eosinophils) in Nasal and Bronchial Tissues Source: SGA 2004-W-6776-SS (Slide 20) Nasal tissue (lamina propria) Bronchial tissue (subepithelial layer) b 100 80 60 40 20 a 1600 1200 800 400 Eosinophils (number cells/ mm2) d c Slide 20 Allergic rhinitis and asthma are linked by clinical evidence of an inflammatory response in the lower airways, as well as by inflammation of the nasal mucosa after bronchial allergen challenge in nonasthmatic patients with allergic rhinitis. In a recent study, nasal and bronchial biopsy and blood samples were obtained from eight nonasthmatic patients with allergic rhinitis (age 21–31 years) and eight nonasthmatic, nonallergic controls (age 18–29 years) immediately before and 24 hours after segmental allergen bronchoprovocation. Nasal biopsies were obtained at baseline and at 1 and 24 hours after challenge. Eosinophils, markers of mucosal allergic inflammation, were counted in the biopsy specimens and blood samples.34 In the nasal lamina propria, eosinophil counts did not differ significantly in the allergic and control groups at baseline. Twenty-four hours after bronchial allergen challenge, however, eosinophils in the nasal tissues of allergic patients had increased significantly from baseline (p=0.04). In the bronchial subepithelium, the number of eosinophils in the allergen-challenged segment also rose significantly from baseline 24 hours after challenge (p=0.002).34 In this study, segmental allergen bronchoprovocation produced a widespread allergic response that included the nose and bronchial tissue in patients with allergic rhinitis.34 a T0 T24 T0 Unchallenged left lung Allergen- challenged right middle lobe Control patients (n=8) Allergic patients (n=8) T24 Evaluation of allergic inflammation in the upper and lower airways after bronchial challenge in nonasthmatic allergic rhinitis patients vs. controls (age range 18–31 years) T0= before challenge; T24=24 hours post-challenge ap<0.05; bp<0.01; cp=0.001; dp=0.002 Adapted from Braunstahl G-J et al Am J Respir Crit Care Med 2000;161:2051–2057. SGA 2006-W-286990-SS

Peripheral blood eosinophils (106 cells/L) Clinical Links between Allergic Rhinitis and Asthma Bronchial Allergen Challenge Increases Systemic Markers of Inflammation Source: SGA 2004-W-6776-SS (Slide 21) * Control patients (n=8) Allergic patients (n=8) 600 500 400 300 200 100 ** Peripheral blood eosinophils (106 cells/L) Slide 21 The study discussed on the previous slide also showed that bronchial allergen challenge in individuals with allergic rhinitis increased inflammatory cells (eosinophils) in the blood from baseline (p<0.05) and compared with nonallergic controls (p<0.01). Together with the inflammatory response observed throughout the upper and lower respiratory tract in allergic patients, this finding suggests a systemic inflammatory effect.34 T0 T24 Evaluation of allergic inflammation in the upper and lower airways after bronchial challenge in nonasthmatic allergic rhinitis patients vs. controls (age range 18–31 years) T0= before challenge; T24=24 hours post-challenge *p<0.05; **p<0.01 Data presented as median ± range Adapted from Braunstahl G-J et al Am J Respir Crit Care Med 2000;161:2051–2057. SGA 2006-W-286990-SS

Shared Pathophysiology of Allergic Rhinitis and Asthma Summary Source: SGA 2004-W-6776-SS (Slide 22) Allergic rhinitis and asthma share several pathophysiologic characteristics Common triggers Similar inflammatory cascade on exposure to allergen Cysteinyl leukotrienes are common mediators in upper and lower airway diseases Similar pattern of early- and late-phase responses Infiltration by the same inflammatory cells (e.g., eosinophils) Several potential connecting pathways, including systemic transmission of inflammatory mediators Slide 22 Many potential mechanisms may link allergic rhinitis and asthma. These conditions share several common triggers, including both indoor and outdoor allergens.16,27 Similar immunologic processes underlie the inflammatory cascade on exposure to allergen,28 resulting in similar patterns of early- and late-phase responses.29,30 Histologic studies have confirmed that nasal and bronchial mucosa have a similar structure. Both tissues are subject to infiltration by the same inflammatory mediators during the allergic or asthmatic response.2 Several potential connecting pathways between these two diseases have been proposed, including the systemic transmission of inflammatory mediators between the upper and lower airways.35 Leukotrienes play a role in both upper (allergic rhinitis) and lower (asthma) airway diseases.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; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21:27–49; Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001; Kay AB N Engl J Med 2001;344:30–37; Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford, UK: Blackwell Science, 2000:1172–1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604; Togias A Allergy 1999;54(suppl 57): 94–105. SGA 2006-W-286990-SS

Patients with allergic rhinitis should be evaluated for asthma One Airway, One Disease ARIA and IPAG Guidelines Recommend a Combined Approach to Managing Asthma and Allergic Rhinitis Source: SGA 2004-W-6776-SS (Slide 23 Revised) Patients with allergic rhinitis should be evaluated for asthma Patients with asthma should be evaluated for allergic rhinitis A strategy should combine the treatment of upper and lower airways in terms of efficacy and tolerability Slide 23 In light of the associations between asthma and allergic rhinitis, recent guidelines developed by the Allergic Rhinitis and its Impact on Asthma (ARIA) Workshop Expert Panel, in collaboration with the World Health Organization, recommended strategies to integrate the diagnosis and treatment of allergic rhinitis and asthma. Specific emphasis was placed on the need to evaluate patients with allergic rhinitis for asthma and to evaluate patients with asthma for allergic rhinitis. When these diseases coexist, a combined treatment strategy should be used.7 Because optimal management of rhinitis may improve coexisting asthma, consideration should be given to the effectiveness of treatment for both conditions.7 For example, corticosteroids and antileukotrienes have efficacy in both conditions; alpha-adrenergic antagonists are effective only in the treatment of allergic rhinitis; beta-adrenergic antagonists are effective only in the treatment of asthma; and antihistamines are less effective in asthma than in allergic rhinitis.7 The route of administration also deserves consideration; orally administered drugs may affect both nasal and bronchial symptoms.7 Caution should be exercised in the use of intranasal plus inhaled corticosteroids because of possible additive side effects.7 The ARIA guidelines acknowledge that the prevention or early treatment of nasal inflammation may help to control asthma, but this possibility requires further study.7 Guidelines from the International Primary Care Airways Group (IPAG) in the United States concur that patients with asthma should be appropriately evaluated for allergic rhinitis; optimal management of rhinitis may improve coexisting asthma.36 ARIA=Allergic Rhinitis and its Impact on Asthma; IPAG=International Primary Care Airways Groups Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; International Primary Care Airways Group, Los Angeles, California, USA, MCR Vision, 2005. SGA 2006-W-286990-SS

Source: SGA 2004-W-6776-SS (Slide 24) Cysteinyl Leukotrienes—Important Mediators of Both Asthma and Allergic Rhinitis Slide 24 SGA 2006-W-286990-SS

Steroid-sensitive mediators (e.g., cytokines) Cysteinyl leukotrienes Cysteinyl Leukotrienes in Asthma: Dual Pathways of Inflammation Montelukast Combined with a Steroid Affects the Dual Pathways of Inflammation Source: SGA 2004-W-6776-SS (Slide 25) Steroid-sensitive mediators (e.g., cytokines) Cysteinyl leukotrienes Montelukast Inhaled steroids Slide 25 Cysteinyl leukotrienes and steroid-sensitive mediators are two important pathways of inflammation in asthma.37,38 • Airway inflammation and asthma symptoms often persist despite treatment with inhaled steroids and long-acting beta2-agonists.39-42 • Steroids do not block the formation of leukotrienes in the airways of asthmatics.40,43-45 Therefore, treating dual pathways may provide complementary benefits—better control of inflammation and effective asthma control—compared with treating only the steroid-sensitive pathway.46 Inhibit steroid- sensitive mediators (e.g., cytokines) Blocks cysteinyl leukotrienes The slide represents an artistic rendition. Adapted from Diamant Z, Sampson AP Clin Exp Allergy 1999;29:1449–1453; Barnes PJ Am J Respir Crit Care Med 1996;154:S21–S27; Claesson H-E, Dahlén S-E J Intern Med 1999;245:205–227; Price DB et al Thorax 2003;58:211–216. SGA 2006-W-286990-SS

All patients with asthma Cysteinyl Leukotrienes—Mediators of Asthma Inhaled Corticosteroids Do Not Affect Sputum Leukotriene Levels in Patients with Asthma Source: SGA 2004-W-6776-SS (Slide 26) 14 12 10 8 6 4 2 13* Sputum cysteinyl leukotriene levels (ng/ml) 11.4** 9.4* Slide 26 A study in healthy and asthmatic nonsmoking adults investigated concentrations of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) in the sputum. Leukotriene levels were significantly higher in asthmatic patients (9.4 ng/ml) than in normal individuals (6.4 ng/ml). Moreover, the levels increased with disease severity (11.4 ng/ml in patients with persistent asthma and 13.0 ng/ml in patients with recent acute exacerbations) despite the daily use of inhaled corticosteroids.47 These results support other evidence that corticosteroids do not block the formation of leukotrienes in asthmatics.40,43-45 6.4 Controls (n=10) All patients with asthma (n=26) Patients with persistent asthma (n=10) Patients with acute attacks (n=12) Study of the use of induced sputum to assess airway eicosanoid production in 10 healthy and 26 asthmatic adults (mean age 40 to 57 years in each treatment group) *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. SGA 2006-W-286990-SS

Source: SGA 2004-W-6776-SS (Slide 28) Cysteinyl Leukotrienes—Mediators of Asthma Cysteinyl Leukotrienes Are Important Mediators of Nasal Obstruction 150 125 100 * % change in NAR Slide 27 A nasal-provocation study was conducted to examine the role of LTD4 in the nasal symptoms of allergic rhinitis. Sixty adult patients with house dust–induced allergic rhinitis were assigned to nasal provocation with LTD4 (n=14), histamine (n=14), antigen (n=18), or a nonactive control solution (n=14). Nasal airway resistance (NAR) was expressed as the ratio of peak NAR with the active agent to peak with the control solution. The endpoint of concentration (threshold) was the minimum concentration of the active agent required to produce an increase of at least 20% in sneezing, nasal secretion, or NAR compared with nonactive control provocation.48 LTD4 had longer-lasting effects on NAR than histamine. After histamine challenge (n=11), NAR increased once at 1 hour (p<0.05 vs. baseline) and returned to baseline between one and three hours on average. As shown in the slide, after LTD4 challenge (n=7), in contrast, NAR increased significantly at 30 minutes (p<0.05) and did not return to baseline for 11 hours. Moreover, LTD4 was a stronger mediator of nasal response than histamine, as reflected by a threshold concentration approximately 5000-fold lower than that of histamine. Thus, LTD4 plays an important role in nasal allergy by inducing strong and long-lasting nasal blockage.48 Challenge (n=7) 1/2 1 3 5 7 9 11 Hour LTD4 was approximately 5000 times more potent than histamine in mediating nasal responses Study to examine the clinical significance of LTD4 vs. antigen and histamine in adult patients (mean age 25.0–26.4 in each group). Nasal provocations were carried out with serially increasing doses of LTD4, histamine, or antigen. *p<0.05 vs. baseline NAR=nasal airway resistance Adapted from Okuda M et al Ann Allergy 1988;60:537–540. SGA 2006-W-286990-SS

Nasal secretion (10-2 g/min) Source: SGA 2004-W-6776-SS (Slide 28) Cysteinyl Leukotrienes—Mediators of Both Asthma and Allergic Rhinitis Cysteinyl Leukotriene Challenge Increases Rhinorrhea in Allergic Rhinitis 1.00 0.75 0.50 0.25 (n=8) Nasal secretion (10-2 g/min) Slide 28 A nasal-provocation study was conducted to examine the role of LTD4 in the nasal symptoms of allergic rhinitis. Sixty adult patients with house dust–induced allergic rhinitis were assigned to nasal provocation with LTD4 (n=14), histamine (n=14), antigen (n=18), or a nonactive control solution (n=14). Nasal airway resistance (NAR) was expressed as the ratio of peak NAR with the active agent to peak with the control solution. The endpoint of concentration (threshold) was the minimum concentration of the active agent required to produce an increase of at least 20% in sneezing, nasal secretion, or NAR compared with nonactive control provocation.48 LTD4 was also shown to play a role in nasal secretion (rhinorrhea) in these patients with allergic rhinitis. While the average amount of secretion was less with LTD4 (0.28±0.36 g with a threshold concentration of 210–1.4 µg/ml) than with antigen or histamine, the duration of nasal secretion was comparable to that with topical antigen and longer than that observed with histamine.48 ~5 ~10 ~15 ~20 Time (minutes) Study to examine the clinical significance of LTD4 vs. antigen and histamine in adult patients (mean age 25.0–26.4 in each group). Nasal provocations were carried out with serially increasing doses of LTD4, histamine, or antigen. Adapted from Okuda M et al Ann Allergy 1988;60:537–540. SGA 2006-W-286990-SS

Score for nasal symptoms Time post-challenge (hours) Cysteinyl Leukotrienes—Mediators of Asthma Role of Cysteinyl Leukotrienes in Early- and Late-Phase Allergic Response Source: SGA 2004-W-6776-SS (Slide 29) Early phase Histamine, cysteinyl leukotrienes, prostaglandins, thromboxanes, heparin, proteases, PAF (predominant) Late phase Cysteinyl leukotrienes, cytokines (predominant) Score for nasal symptoms Sneezing Nasal pruritus Congestion Rhinorrhea Cysteinyl leukotrienes Slide 29 Initial exposure to an allergen leads to the formation of allergen-specific IgE antibodies, which bind to high-affinity receptors on mast cells and basophils.20 Allergic inflammation is subsequently triggered when the IgE molecules on the surface of mast cells become crossbound by allergen, resulting in mast cell degranulation.20 This early phase of the allergic response is characterized by the release of inflammatory mediators, e.g., histamine, leukotrienes (including cysteinyl leukotrienes), prostaglandins, thromboxanes, as well as heparin, proteases, and platelet-activating factor.49 Among these mediators, the cysteinyl leukotrienes and histamine are particularly important.16 Within an hour of allergen exposure, cysteinyl leukotrienes and histamine increase in nasal secretions, corresponding to the emergence of symptoms.30,50-52 While the role of histamine is well known, clinical studies now indicate that cysteinyl leukotrienes also mediate the characteristic symptoms of allergic rhinitis, including nasal congestion, sneezing, and rhinorrhea.48,50,53,54 Several hours after the early allergic response, a late-phase reaction may also occur.49 This phase is characterized by the influx of inflammatory cells and the release of mediators (including leukotrienes and cytokines) that promote and prolong the inflammatory response.49,50,55 During the late-phase reaction, the release of cysteinyl leukotrienes coincides with the recurrence of nasal symptoms.50 Cysteinyl leukotrienes are therefore involved in both early- and late-phase reactions. Antigen challenge 1 3–4 8–12 24 Time post-challenge (hours) PAF=platelet-activating factor Adapted from Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599–S604; Rachelevsky G J Pediatr 1997;131:348–355; Rouadi P, Naclerio R. SRS-A to Leukotrienes: The Dawning of a New Treatment. S Holgate, S Dahlen, eds. Oxford, England: Blackwell Science, 1997; Creticos PS et al N Engl J Med 1984;31:1626–1630. SGA 2006-W-286990-SS

Early-phase allergic response Late-phase allergic response Cysteinyl Leukotrienes—Mediators of Asthma Correlation of Cysteinyl Leukotriene Release with Symptoms in Allergic Rhinitis Source: SGA 2004-W-6776-SS (Slide 30) Early-phase allergic response (within minutes) Late-phase allergic response (within 4+ hours) Predominant mediator types Cysteinyl leukotrienes Histamine Cytokines Most commonly associated allergy symptoms Sneezing Nasal itching Rhinorrhea Nasal obstruction Prolonged nasal obstruction Slide 30 The slide shows the correlation of cysteinyl leukotriene release with symptoms in allergic rhinitis.7,20,48,50,56-58 The early phase of an allergic response begins within minutes of exposure to an allergen.7,20 During this phase, numerous inflammatory mediators are released in nasal secretions, including cysteinyl leukotrienes, histamine, prostaglandins, and thromboxanes.7,16,49,59 The most common early-phase symptoms are sneezing, nasal itching, rhinorrhea, and nasal obstruction.7,30,59 The late-phase allergic response, which occurs in 30% to 40% of patients, begins within at least four hours and peaks six to 12 hours after the initial response.7,20 This phase is characterized by the release of cysteinyl leukotrienes and cytokines in nasal secretions,7,49,50 and is associated with prolonged nasal obstruction.7 Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558; Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; Sibbald B, Rink E Thorax 1991;46:895–901; Leynaert B et al J Allergy Clin Immunol 1999;104:301–304; Brydon MJ  Asthma J 1996:29–32; Vignola AM et al Allergy 1998;53:833–839; Meltzer EO Ann Allergy Asthma Immunol 2000;84:176–185; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21:27–49; Settipane GA Arch Intern Med 1981;141:328–332; Magnan A et al Eur Respir J 1998;12:1073–1078; Yssel H et al Clin Exp Allergy 1998;5:104–109, discussion 17–18. SGA 2006-W-286990-SS

Source: SGA 2004-W-6776-SS (Slide 31) Efficacy of Montelukast in Asthma Patients with Seasonal Allergic Rhinitis Slide 31 SGA 2006-W-286990-SS

Double-blind treatment Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Study Design and Objective Source: SGA 2004-W-6776-SS (Slide 32) Period I Single-blind run-in Period II Double-blind treatment Montelukast* (n=415) Placebo Placebo (n=416) Slide 32 Based on evidence of the linked pathophysiology of allergic rhinitis and asthma, and the role of cysteinyl leukotrienes in both conditions, recent investigations have focused on the effects of cysteinyl leukotriene blockade in the treatment of patients with both conditions.1 Recently, a prospective, randomized, double-blind, multicenter, parallel-group study was conducted during the spring and fall in the United States and Europe to evaluate the efficacy of montelukast in improving the symptoms of seasonal allergic rhinitis in patients with asthma and seasonal allergic rhinitis.1 After a three- to five-day single-blind placebo run-in period, patients were randomized to receive two weeks of treatment with oral montelukast 10 mg (n=415) or placebo (n=416) once daily at bedtime.1 Short-acting beta2-agonists were permitted in both groups.1 –3 to 5 days 2 weeks To evaluate the efficacy of montelukast in improving the symptoms of allergic rhinitis in patients with active asthma and active allergic rhinitis during the allergy season *10 mg once daily at bedtime Short-acting beta2-agonists were used as needed in both groups. Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

1-year history (dyspnea, wheezing, chest tightness, cough) Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Inclusion Criteria: Active Asthma and Daily Rhinitis Symptoms Source: SGA 2004-W-6776-SS (Slide 33) Asthma 1-year history (dyspnea, wheezing, chest tightness, cough) 1 of 4 criteria for active asthma Asthma symptoms  once weekly Reversible airway obstruction History of methacholine hyperresponsiveness 1-year history of exercise-induced bronchoconstriction Stable dose of inhaled corticosteroid and/or long-acting beta2-agonist use Allergic Rhinitis 2-year clinical history (rhinitis symptoms worsening during allergy season) Daily rhinitis symptoms at least mild to moderate during placebo run-in Positive skin test to 3 allergens active during study season Slide 33 The study enrolled patients 15 to 85 years of age with a clinical history of active asthma of at least one year and a clinical history of seasonal allergic rhinitis of at least two years. Eligible patients met at least one of four criteria for active asthma: asthma symptoms at least once weekly, reversible airway obstruction (>12% increase in FEV1 after inhaled short-acting beta2-agonist), a history of methacholine airway hyperresponsiveness, or at least a one-year history of exercise-induced bronchoconstriction. Patients on a stable dose of inhaled corticosteroid and/or inhaled long-acting beta2-agonist were eligible. During the placebo run-in period, patients had to demonstrate at least mild to moderate daily rhinitis symptoms (daytime nasal congestion, rhinorrhea, sneezing, and itching and nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings). Additionally, patients were required to demonstrate a positive skin test (wheal diameter 3 mm greater than control) to at least three allergens that were active during the study season.1 Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

Composite Daily Rhinitis Symptom Score Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Endpoints Source: SGA 2004-W-6776-SS (Slide 34) Composite Daily Rhinitis Symptom Score Daytime nasal symptoms Congestion Rhinorrhea Pruritus Sneezing Nighttime symptoms Difficulty falling asleep Nighttime awakenings Nasal congestion on awakening Slide 34 During the run-in and treatment periods, patients completed a daily diary in which they assigned a score to each of their allergic rhinitis symptoms on a four-point scale in which 0=none, 1=mild, 2=moderate, and 3=severe. The mean changes in these symptoms from pretreatment baseline values were analyzed over the two-week treatment period.1 The primary endpoint in this trial was the daily rhinitis symptoms score, a composite of daytime nasal symptoms scores (average of scores for nasal congestion, rhinorrhea, sneezing, and itching, each rated on a 0 to 3 scale), nighttime symptoms scores (average of nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings, each rated on a 0 to 3 scale).1 Additional endpoints included global evaluations of asthma, in which patients and physicians individually assessed the clinical status of asthma at the end of the treatment period, and the frequency of as-needed use of short-acting beta2-agonists during treatment.1 Secondary allergic rhinitis endpoints were the rhinoconjunctivitis quality-of-life score, completed before randomization and at the end of treatment, which consisted of the average of scores of seven individual domains (nasal symptoms, eye symptoms, non–nose/eye symptoms, activity, sleep, emotions, and practical problems) graded by patients on a six-point scale, and global evaluations of allergic rhinitis, in which patients and physicians individually assessed the clinical status of allergic rhinitis at the end of the treatment period relative to study entry on a six-point scale.1   (0–3 scale, mild to severe) Secondary/other endpoints Rhinoconjunctivitis quality of life Patients’ and physicians’ global evaluations of allergic rhinitis Patients’ and physicians’ global evaluations of asthma As-needed beta2-agonist use Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Baseline Characteristics of Patients Source: SGA 2004-W-6776-SS (Slide 35) Montelukast (n=415) Placebo (n=416) Age (year) Mean±SD Range 33.013.2 15–78 33.613.7 15–80 Gender (% of patients) Male Female 36% 64% 35% 65% Duration of allergic rhinitis (years) 19.611.9 19.012.2 Duration of asthma (years) 17.512.2 16.511.9 Inhaled corticosteroid therapy at baseline (% of patients) 38% 43% Asthma symptoms once weekly (% of patients) 90% 93% Asthma symptoms twice weekly (% of patients) 57% 62.5% Season studied (% of patients) Spring Fall 84% 16% 85% 15% FEV1 (% predicted) Daily rhinitis symptoms score 1.750.42 1.770.42 Slide 35 The treatment groups were similar at baseline with respect to demographic and clinical characteristics. The mean age of patients was approximately 33 years in each group; approximately two-thirds of each group were female, and the vast majority of patients in each group were studied in the spring. Mean duration of allergic rhinitis was 19.3 years (mean±SD 19.6±11.9 for montelukast and 19.0±12.2 for placebo) and mean duration of asthma was 17.0 years at baseline (mean±SD 17.5±12.2 for montelukast and 16.5±11.9 for placebo) . Patients had mild to moderate asthma, with mean FEV1 in each group of 84%. About 41% of patients were using inhaled corticosteroids. Mean daily rhinitis symptoms scores were similar in the two groups.1 Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

Daily rhinitis symptoms Daytime nasal symptoms Nighttime symptoms Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Significantly Reduced Daily Rhinitis Symptoms Scores* Source: SGA 2004-W-6776-SS (Slide 36) Daily rhinitis symptoms Daytime nasal symptoms Nighttime symptoms –0.1 –0.2 –0.3 –0.4 –0.5 Change from baseline (mean) –11.8% –11% –18.2% –10.5% Slide 36 During the two-week active treatment period, montelukast significantly improved the primary endpoint of daily rhinitis symptoms score (p0.001 vs. placebo), producing a mean reduction of 0.35±0.48 (18%) from baseline, versus a mean reduction of 0.25±0.46 (11%) from baseline with placebo. Montelukast also significantly reduced the two individual components of the primary endpoint; i.e., the daytime nasal symptoms score and the nighttime symptoms score (both, p0.001 vs. placebo).1 –18% p0.001 –18.7% p0.001 p0.001 Placebo (n=416) Montelukast (n=415) Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15 to 85 years of age with allergic rhinitis during the allergy season *Scored on a 4-point scale Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Reduced Daily Rhinitis Symptoms Regardless of Asthma Status at Study Start Source: SGA 2004-W-6776-SS (Slide 37) Treatment difference: montelukast minus placebo (LS meanSE) Greater Effect –0.1 Slide 37 Montelukast was effective in patients with mild asthma included in this study. Analysis showed that the effects of montelukast on the daily rhinitis symptoms score were consistent across subgroups defined by asthma status at study entry (i.e., patients taking vs. not taking inhaled corticosteroids, patients with asthma symptoms twice weekly vs.<twice weekly; patients with FEV1 <80% vs. 80% of predicted; and patients with 12% vs. <12% beta2-agonist reversibility).1 –0.2 Yes No  twice weekly <twice weekly <80% 80% 12% <12% –0.3 n=335 n=490 n=495 n=330 n=316 n=503 n=427 n=392 On inhaled corticosteroids Asthma symptoms FEV1 % predicted Beta2-agonist reversibility Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15–85 years of age with allergic rhinitis during the allergy season LS=least-squares Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

Global evaluations of allergic rhinitis* Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Improved Global Evaluations of Clinical Status and Quality of Life Source: SGA 2004-W-6776-SS (Slide 38) Global evaluations of allergic rhinitis* 5 4 3 2 1 p0.001 p0.001 Placebo (n=416) Montelukast (n=415) Treatment score (mean±SD) 2.77 Slide 38 Montelukast had a significant effect on patient and physician global evaluations of the patients’ clinical status with respect to allergic rhinitis at the end of treatment. The effects of montelukast on these scores were significantly greater than those of placebo (both, p0.001).1 Montelukast significantly improved rhinoconjunctivitis quality-of-life scores, producing mean reductions from baseline of 0.73±1.14 versus 0.55±1.10 in the placebo group (p<0.01). These results reflect overall improvement in many aspects of daily life affected by allergic rhinitis, including symptoms, activity, sleep, emotions, and practical problems.1 2.76 2.39 2.41 Patients Physicians Montelukast significantly improved rhinoconjunctivitis quality-of-life scores versus placebo (p<0.01) Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15–85 years of age with allergic rhinitis during the allergy season *Scored on a 6-point scale Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

Global evaluations of asthma* Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Montelukast Improved Asthma Control Source: SGA 2004-W-6776-SS (Slide 39) Global evaluations of asthma* 2.8 2.6 2.4 2.2 Placebo (n=416) Montelukast (n=415) Treatment score (mean) p<0.01 p<0.05 2.52 2.52 Slide 39 As with global evaluations of allergic rhinitis, montelukast had significantly greater effects on global evaluations of asthma by patients (p<0.01) and physicians (p<0.05) versus placebo.1 During double-blind treatment, montelukast significantly reduced the number of puffs per day of as-needed short-acting beta2-agonist use in the complete study cohort of patients with mild asthma, and in the subgroup of patients who used beta2-agonists during the baseline run-in period (p0.005).1 Although the effects of therapy on FEV1 were not measured because the focus of the trial was relief of rhinitis symptoms, the results with these lung function endpoints show that montelukast provided relief from asthma in these comorbid patients.1 2.34 2.28 Patients Physicians Montelukast significantly reduced beta2-agonist use (p0.005 vs. placebo) Multicenter study of the effects of montelukast 10 mg on allergic rhinitis in asthmatic patients 15–85 years of age with allergic rhinitis during the allergy season *Scored on a 6-point scale Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

In asthmatic patients with concomitant seasonal allergic rhinitis, Clinical Study of Asthma Patients with Concomitant Seasonal Allergic Rhinitis Conclusions Source: SGA 2004-W-6776-SS (Slide 40) In asthmatic patients with concomitant seasonal allergic rhinitis, montelukast demonstrated significant improvements in Allergic Rhinitis Daily rhinitis symptoms score (average of the daytime nasal symptoms score and the nighttime symptoms score)a Rhinoconjunctivitis quality of lifeb Global evaluations of allergic rhinitis by patient and by physiciana Asthma Global evaluations of asthma by patientb and by physicianc Beta2-agonist used Slide 40 This randomized, parallel-group, double-blind study demonstrated that montelukast significantly improved seasonal allergic rhinitis symptoms in asthma patients with concomitant seasonal allergic rhinitis.1 Two weeks of treatment with montelukast produced significant improvements versus placebo in many of the study endpoints. Improvements in allergic rhinitis included the daily rhinitis symptoms score, an average of the daytime nasal symptoms score and the nighttime symptoms score (primary endpoint) (p0.001), the rhinoconjunctivitis quality-of-life score (p<0.01), as well as global evaluations of allergic rhinitis by patients and physicians (p0.001). Asthma endpoints were also improved, including global evaluations of asthma by patients (p<0.01) and physicians (p<0.05), and as-needed short-acting beta2-agonist use (p0.005).1 The beneficial effects of montelukast on allergic rhinitis endpoints observed in this study are consistent with the findings from previous studies of montelukast in the treatment of allergic rhinitis.1,60-64 The effects of montelukast on the symptoms of seasonal allergic rhinitis in patients with active asthma may be attributable to amelioration of the systemic inflammation that underlies both conditions.1 The authors of this study concluded that the use of montelukast in asthma patients with concomitant allergic rhinitis provides clinicians with an option that provides overall clinical benefits.1 ap0.001 vs. placebo; bp<0.01 vs. placebo; cp<0.05 vs. placebo; dp0.005 vs. placebo Adapted from Philip G et al Curr Med Res Opin 2004;20:1549–1558. SGA 2006-W-286990-SS

NEW Efficacy of Montelukast in Asthma Patients with Concomitant Allergic Rhinitis—COMPACT Subanalysis Slide 41 SGA 2006-W-286990-SS

Objective of COMPACT Study and Subanalysis Source: SGA 2004-W-6776-SS (Slide 41 with REVISED SOURCING) To determine whether adding montelukast 10 mg to budesonide (800 µg) would provide greater benefits than doubling the dose of budesonide (to 1600 µg) in Adult patients with asthma (OVERALL COMPACT study) Adult patients with asthma and allergic rhinitis (SUBANALYSIS) Slide 42 The Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) study was a randomized clinical trial designed to compare the efficacy of adding the leukotriene receptor blocker montelukast to inhaled budesonide (400 µg twice daily) versus doubling the dose of budesonide (800 µg twice daily) in adults with chronic asthma.41 After the trial was completed, a post hoc analysis was conducted to determine whether treatment with montelukast plus budesonide, compared to budesonide alone, provided additional benefits in the subgroup of asthma patients who had concomitant allergic rhinitis.65 COMPACT=Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy Adapted from Price DB et al Thorax 2003;58:211–216; Price DB et al Allergy 2006; in press. SGA 2006-W-286990-SS

COMPACT Study Study Design Source: SGA 2004-W-6776-SS (Slide 42) Montelukast 10 mg once daily + Budesonide 400 µg twice daily (n=448) Budesonide 400 µg twice daily Budesonide 800 µg twice daily + Oral placebo montelukast (n=441) Slide 43 The COMPACT study began with a single-blind, four-week run-in period during which all patients received budesonide 400 µg twice daily. Patients were then randomized to receive 12 weeks of double-blind treatment with either montelukast 10 mg once daily plus budesonide 400 µg twice daily, or budesonide 800 µg twice daily plus oral placebo montelukast.41 1 4 8 12 16 Weeks Period I Run-in (4 weeks) Single-blind Period II Active treatment (12 weeks) Double-blind Adapted from Price DB et al Thorax 2003;58:211–216. SGA 2006-W-286990-SS

COMPACT Study Inclusion Criteria NEW Age 15 to 75 years Asthma of at least one year’s duration Asthma not optimally controlled (judged by investigator) Regular inhaled corticosteroid use* Baseline FEV1 ≥50% of predicted at visits 1 and 3 Beta2-agonist reversibility ≥12% in FEV1 Beta2-agonist use ≥1 puff/day during the last two weeks of run-in period Slide 44 Eligible patients were 15 to 75 years of age and had asthma for at least one year, which, judged by the investigator, was not optimally controlled despite the regular use of an inhaled corticosteroid at doses of 600 to 1200 µg/day of budesonide, beclomethasone, triamcinolone, or flunisolide, or of 300 to 800 µg/day of fluticasone. Patients were nonsmokers or ex-smokers (stopped at least six months and <12 pack year history). Patients were also required to have a baseline FEV1 value ≥50% of predicted at visits 1 and 3 and beta2-agonist reversibility of ≥12% in FEV1, and to have used at least one puff/day of a beta2-agonist during the last two weeks of the run-in period.41 *Dose range: 600–1200 µg/day of budesonide, beclomethasone, triamcinolone, flunisolide, or 300–800 µg/day of fluticasone Adapted from Price DB et al Thorax 2003;58:211–216. SGA 2006-W-286990-SS

Days after randomization COMPACT Study Montelukast + Budesonide Improved Morning PEF Progressively over 12 Weeks Source: SGA 2004-W-6776-SS (Slide 43) 440 430 420 410 400 390 380 Montelukast 10 mg + budesonide 800 µg (n=448) Budesonide 1600 µg (n=441) Morning PEF* (L/min) Slide 45 Morning peak expiratory flow rate (PEF) was the prespecified primary endpoint of COMPACT. Both montelukast with budesonide and budesonide alone treatment groups showed progressive improvements in morning PEF over the 12-week trial. Addition of montelukast to budesonide was at least as effective as doubling the dose of budesonide over the last 10 weeks of the 12-week treatment period. In addition, changes in morning PEF during the first three days of treatment demonstrated a rapid onset of effect and significantly greater efficacy for the montelukast with budesonide group (p<0.001).41 –14 –7 7 14 21 28 35 42 56 63 70 77 84 Days after randomization PEF=peak expiratory flow rate *Mean measurement before administration of study medication Adapted from Price DB et al Thorax 2003;58:211–216. SGA 2006-W-286990-SS

Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Definition of Groups in Analysis Source: SGA 2004-W-6776-SS (Slide 45 REVISED) Asthma+AR Patients with asthma and allergic rhinitis, defined by both positive patient history and confirmed physician diagnosis Asthma–AR Patients with asthma but without both a patient history and physician diagnosis of allergic rhinitis Slide 46 In this subanalysis of COMPACT, asthma patients were classified as having concomitant allergic rhinitis if they had both a positive patient history and a confirmed physician diagnosis of allergic rhinitis. Patients without these two designations were classified as asthma patients without allergic rhinitis.65 In addition, a subgroup of patients with asthma and allergic rhinitis who were taking medications (including intranasal steroids and antihistamines) to control the symptoms of allergic rhinitis was analyzed.65 Adapted from Price DB et al Allergy 2006; in press. SGA 2006-W-286990-SS

Analysis of covariance (ANCOVA) model used to test each endpoint Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Statistical Analysis Analysis of covariance (ANCOVA) model used to test each endpoint Treatment and study site used as factors Appropriate baseline values used as covariate Slide 47 In the post hoc analysis of asthma patients with coexisting allergic rhinitis, treatment comparisons were based on analysis of covariance (ANCOVA); in this model, corresponding baseline values were included as a covariate and the treatment group and study site as factors.65 Adapted from Price DB et al Allergy 2006; in press. SGA 2006-W-286990-SS

Asthma + allergic rhinitis (n=410) Asthma (n=479) Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Baseline Characteristics of Patients Source: SGA 2004-W-6776-SS (Slide 46 REVISED) Asthma + allergic rhinitis (n=410) Asthma (n=479) Age (year, median) 43 45 Gender (% of patients) Male Female 42 58 38 62 Race (% of patients) White Black Asian Other 78 1 6 15 76 <1 4 19 FEV1 (% of predicted, mean) 69 67 History of atopic dermatitis (% of patients) 12 Slide 48 The subgroup analysis of COMPACT included patients with a history and diagnosis of asthma and allergic rhinitis (n=410) and patients with asthma but no history or diagnosis of allergic rhinitis (n=479). The treatment groups were similar at baseline with respect to demographic and clinical characteristics. The median age was 43 years in the comorbidity group and 45 years in the asthma group, both treatment groups had approximately the same proportion of male and female patients, and three quarters of each group were white. At baseline, lung function was similar in the two groups; i.e., a mean FEV1 value of 69% of predicted in the comorbidity group and 67% of predicted in the asthma group. A history of atopic dermatitis was noted in 19% of patients in the comorbidity group and in 12% of the asthma group.65 Adapted from Price DB et al Allergy 2006; in press. SGA 2006-W-286990-SS

Asthma + Allergic Rhinitis Patients Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Montelukast Provided Greater Improvements in Morning PEFR than Budesonide Source: SGA 2004-W-6776-SS (Slide 47 REVISED) 50 40 30 20 10 Asthma + Allergic Rhinitis Patients Montelukast (n=216)* Budesonide (n=184)** LS mean ±SE change from baseline (L/min) Slide 49 In the subgroup of asthma patients with allergic rhinitis in the COMPACT study, the mean increase from baseline in morning PEFR was significantly (p=0.028) higher in the montelukast + budesonide group (33.5 L/min; 9.2%) than in the budesonide alone group (24.1 L/min; 6.0%).65 The primary endpoint of the COMPACT study was morning PEF. p=0.028 4 8 12 Weeks The primary endpoint of the COMPACT study was morning PEF LS=least squares *Montelukast 10 mg once daily + budesonide 400 µg twice daily; **Budesonide 800 µg twice daily Adapted from Price DB et al Allergy 2006; in press. SGA 2006-W-286990-SS

Asthma + Allergic Rhinitis Patients Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Montelukast Provided Greater Improvements in Morning PEFR than Budesonide in Patients Who Received Rhinitis Medications* NEW 60 40 20 –20 Asthma + Allergic Rhinitis Patients p=0.017 LS mean ±SE change from baseline (L/min) Slide 50 A post hoc analysis of the subgroup of asthma patients with allergic rhinitis who received medications for allergic rhinitis in COMPACT showed that the mean increase from baseline in morning PEFR was significantly (p=0.017) higher in the montelukast + budesonide group (52.1 L/min; 21%) than in the budesonide alone group (7.8 L/min; 1.9%).65 Montelukast (n=33)** Budesonide (n=23)*** 4 8 12 Weeks *Intranasal steroids, antihistamines, or other treatments for rhinitis; **Montelukast 10 mg once daily along with budesonide 400 µg twice daily; ***Budesonide 800 µg twice daily Adapted from Price DB et al Allergy 2006; in press. SGA 2006-W-286990-SS

In the subgroup of asthma patients from the COMPACT Subanalysis of Asthma Patients with Concomitant Allergic Rhinitis in COMPACT Conclusion Source: SGA 2004-W-6776-SS (Slide 48 REVISED) In the subgroup of asthma patients from the COMPACT study who had concomitant allergic rhinitis The addition of montelukast to budesonide provided significantly greater improvements in lung function than doubling the dose of budesonide (p<0.05) Slide 51 The subgroup analysis of the COMPACT study showed that for asthma patients who had concomitant allergic rhinitis, adding montelukast to budesonide provided significantly greater benefit in improving lung function than doubling the dose of budesonide (p<0.05).65 Adapted from Price DB et al Allergy 2006; in press. SGA 2006-W-286990-SS

NEW Efficacy of Montelukast in Asthma Patients with Seasonal Aeroallergen Sensitivity Slide 52 SGA 2006-W-286990-SS

Period I Placebo run-in Period II Double-blind Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Study Design and Objective NEW To assess the treatment effect of montelukast 10 mg vs. placebo on daytime asthma symptoms as measured by daily diaries during a three-week treatment period Montelukast (n=225)* Placebo Placebo (n=230) Slide 53 A multicenter, randomized, double-blind, parallel-group study was conducted at 69 centers in the United States to compare the treatment effect of montelukast (10 mg in the evening) versus placebo during the spring allergy season in adults with chronic asthma with seasonal aeroallergen sensitivity. In addition to the study medications, albuterol was allowed as needed throughout the study.66 Patients who had been taking asthma controller medications discontinued these during a washout period of at least 10 days before entering the placebo run-in period. All patients were required to have a placebo run-in period of at least four days (period I) to assess inclusion criteria, to obtain baseline symptom scores and frequency of beta2-agonist use for analysis, and to evaluate patient competence in completing electronic diary entries and compliance with study medication. Patients whose asthma worsened during the washout or run-in period and who (in the opinion of the investigator) required prohibited therapy were excluded from randomization.66 Eligible patients were randomized to receive either oral montelukast (10 mg once daily in the evening) or matching placebo during period II, a three-week, double-blind treatment period. During this period, patients used an electronic diary to record daytime symptoms, nighttime symptoms, inhaled beta2-agonist use, and asthma attacks.66 Day –14 Day –4 Week 0 Week 3 Washout Period I Placebo run-in Period II Double-blind *10 mg once daily in the evening Albuterol was used as needed in both groups. Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

Baseline FEV1 ≥60% predicted NEW Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Inclusion Criteria ≥18 years of age Clinical history of chronic asthma (≥1 year) active during allergy season Predetermined level of asthma symptoms (32 points per week on 0–6 point daily scale) Baseline FEV1 ≥60% predicted Airway reversibility (FEV1 increase ≥12% after beta2-agonist use) Positive skin-prick test reaction to at least two geographically relevant seasonal aeroallergens Nonsmokers for ≥1 year; smoking history of ≤10 pack-years Slide 54 Eligible patients were ≥18 years of age and had at least a one-year history of chronic asthma that was symptomatic during the allergy season. Additionally, patients were required to report a predetermined level of asthma symptoms (≥32 points/week on a 0- to 6-point daily scale) and beta2-agonist use (≥1 puff/day) during the run-in period. At randomization or within the year preceding randomization, patients were required to have a baseline FEV1 60% of predicted and airway reversibility of at least 12% (as demonstrated by FEV1 after inhaled beta2-agonist administration). Eligible patients had documented sensitivity to seasonal aeroallergens as demonstrated by a positive skin-prick test reaction (wheal ≥3 mm greater than the saline control) to at least two geographically relevant seasonal aeroallergens at the first study visit or within the preceding year. In addition, patients were required to be nonsmokers for at least one year with a smoking history of no more than 10 pack-years.66 Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Endpoints NEW Primary Daytime asthma symptoms Secondary Nighttime symptoms – AM and PM peak expiratory flow rate (PEFR) Beta2-agonist use Exploratory Global assessments of change in allergic rhinitis symptoms over the study course Slide 55 The primary endpoint used to determine asthma control was the change from baseline to week 3 in daytime asthma symptom scores. Patients assessed their symptoms by answering the following four questions on a seven-point scale from a validated questionnaire on daytime asthma symptoms and activity limitations: How often did you experience asthma symptoms today? (0=none of the time, 6=all of the time) How much did your asthma symptoms bother you today? (0=not at all bothered, 6=severely bothered) How much activity could you do today? (0=more than usual activity, 6=less than usual activity) How often did your asthma affect your activities today? (0=none of the time, 6=all of the time). Daily scores were calculated as average scores for the four questions; average scores for the baseline period and treatment period were calculated using all the daily scores in the period.66 Secondary endpoints included nighttime asthma symptoms, morning and evening peak expiratory flow rate (PEFR), inhaled beta2-agonist use, asthma attacks, and discontinuations due to asthma.66 Additionally, the investigators assessed an exploratory endpoint: the change in allergic rhinitis symptoms over the course of the study. At study end, patients were asked to make the following global assessment: Compared to study entry, allergic rhinitis symptoms at study end (nasal itching, sneezing, runny nose, and nasal congestion) were 0=very much better, 1=moderately better, 2=a little better, 3=unchanged, 4=a little worse, 5=moderately worse, or 6=very much worse. In addition, responses were collapsed into categories of 0, 1, 2=better, 3=no change, and 4, 5, 6=worse.66 Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

History of allergic rhinitis (%) 99.6 99.1 FEV1 (% predicted)* Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Baseline Characteristics of Patients NEW Variable Montelukast (n=225) Placebo (n=230) Age, year: mean (range) 35.5 (18–66) 36.8 (18–76) Gender (% female) 72.4 67.8 Race (%) White Black Hispanic Other 80.0 11.6 6.2 2.2 82.6 9.1 5.7 2.6 History of allergic rhinitis (%) 99.6 99.1 FEV1 (% predicted)* 83.3 (12.3) 82.2 (13.6) Beta2-agonist reversibility (%)* 19.8 (9.2) 20.7 (11.2) Daytime symptom score (0–6 scale)* 2.6 (0.8) Nighttime symptom score (0–3 scale)* 0.6 (0.5) Beta2-agonist use (puffs/day)* 3.1 (1.8) 3.0 (1.9) AM peak expiratory flow rate (L/min)* 366.7 (93.8) 367.0 (94.8) PM peak expiratory flow rate (L/min)* 370.5 (93.9) 374.1 (92.8) Slide 56 Of the 455 randomized patients, 225 received montelukast and 230 received placebo. The treatment groups were well matched at baseline with respect to demographic and clinical characteristics. The mean ages in the montelukast and placebo groups were 35.5 and 36.8 years, respectively. Approximately two-thirds of each treatment group were female, and the vast majority of patients were white. More than 99% of patients in each group had a history of allergic rhinitis. Clinical characteristics for the two groups (including FEV1, beta2-agonist reversibility, daytime and nighttime symptoms scores, beta2-agonist use, morning and evening PEFR) were similar.66 *Mean (SD) Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

Change from baseline (LS mean±SE) NEW Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Montelukast Significantly Improved Daytime Asthma Symptom Scores (Primary Endpoint) Montelukast (n=223) Placebo (n=229) 0.1 Change from baseline (LS mean±SE) –0.1 –0.2 Slide 57 Montelukast met the primary endpoint of the study: improvement in daytime asthma symptom scores. The slide shows the mean change from baseline in daytime asthma symptom scores for each treatment group. The improvement from baseline in the montelukast group was significantly greater than that in the placebo group (p=0.002; least-squares [LS] mean difference: −0.20; 95% CI: −0.34, −0.07).66 –0.34 –0.3 –0.4 –0.5 –0.54 –0.6 p=0.002 –0.7 Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

Beta2-agonist use (puffs/day)a Nighttime symptom scorea NEW Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Montelukast Significantly Improved Asthma Control Beta2-agonist use (puffs/day)a Nighttime symptom scorea –0.1 –0.2 –0.05 –0.3 –0.4% (–0.6 to –0.2) –0.07% (–0.12 to –0.02) –0.4 Change from baseline (mean)b –0.10 –0.5 Slide 58 Compared to patients receiving placebo, montelukast improved asthma control as assessed by beta2-agonist use and nighttime symptom score. The montelukast group used beta2-agonists significantly less frequently (p=0.003) and had significantly fewer nighttime asthma symptoms (p<0.001) during the three-week treatment period.66 –0.6 –0.17% (–0.22 to –0.12) –0.7 –0.8% (–1.0 to –0.6) –0.15 –0.8 –0.9 –0.20 p<0.001c p=0.003c Placebo (n=416) Montelukast (n=415) aA negative change from baseline indicates a favorable outcome for this endpoint. bAdjusted mean change (95% confidence interval [CI]) from baseline and treatment differences (95% CI) from ANOVA model with effects for treatment, center, and baseline value. cNo adjustment for multiple tests was made. Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

(L/min)a Change from baseline (mean)b NEW Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Montelukast Significantly Improved Lung Function AM PEFR (L/min)a PM PEFR (L/min)a 20 p<0.001c 15 17.2% (11.3 to 23.1) p<0.001c Change from baseline (mean)b 10 11.3% (5.5 to 17.1) Slide 59 Compared to patients receiving placebo, montelukast improved lung function as assessed by PEFR throughout the day. The montelukast group had significantly greater improvement in morning and evening PEFR (p<0.001) during the three-week treatment period.66 5 1.3% (–4.4 to 7.0) –5 –2.0% (–7.7 to 3.6) Placebo (n=416) Montelukast (n=415) aA positive change from baseline indicates a favorable outcome for this endpoint. bAdjusted mean change (95% CI) from baseline and treatment differences (95% CI) from ANOVA model with effects for treatment, center, and baseline value. cNo adjustment for multiple tests was made. Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

Montelukast (n=205) Placebo (n=218) Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Montelukast Significantly Improved Global Evaluations of Allergic Rhinitis NEW 6.0 5.0 4.0 3.0 2.0 1.0 Score* (LS mean±SE) Slide 60 Of 455 randomized patients, 423 had active allergic rhinitis symptoms (within the three weeks before randomization), as determined by the investigator. The improvement (indicated by a lower score) in global allergic rhinitis symptoms with montelukast was significantly greater than with placebo (LS mean difference −0.25; 95% CI: −0.50, 0.00; p=0.054).66 p=0.054 2.40 2.15 Montelukast (n=205) Placebo (n=218) *Seven-point scale in which higher scores indicate more deterioration in symptoms since the start of the study. Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

2.2% (5 patients) with montelukast 3.0% (7 patients) with placebo Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Tolerability Profile Montelukast comparable to placebo in proportion of patients with clinical and laboratory adverse events Similar incidence of discontinuations due to non–drug-related clinical adverse events 2.2% (5 patients) with montelukast 3.0% (7 patients) with placebo Slide 61 Montelukast was well tolerated. Based on data from 454 patients included in the safety analysis, montelukast was comparable to placebo in the incidence of clinical and laboratory adverse events. Only five patients (2.2%) receiving montelukast discontinued therapy due to clinical adverse events compared with seven patients (3.0%) for placebo. No treatment discontinuation was considered drug related by the investigator.66 Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

 Daytime symptom score  Beta2-agonist use Clinical Study of Asthma Patients with Concomitant Aeroallergen Sensitivity Conclusions NEW In patients with chronic asthma and seasonal aeroallergen sensitivity, montelukast 10 mg provided significant improvement in asthma control when compared to placebo  Daytime symptom score  Beta2-agonist use  Nighttime asthma symptom score  AM and PM PEFR  Global asthma evaluations Montelukast 10 mg was well tolerated Slide 62 The results of this study showed that compared to placebo, montelukast provided significant improvement in asthma control during allergy season in patients with chronic asthma and seasonal aeroallergen sensitivity. Furthermore, incidences of clinical and laboratory adverse events and of discontinuations due to clinical adverse events were similar in the two treatment groups; no treatment discontinuation was considered drug related. The investigators concluded that montelukast is an effective and well-tolerated therapeutic option for these patients.66 Adapted from Busse WW et al Ann Allergy Asthma Immunol 2006;96:60–68. SGA 2006-W-286990-SS

Montelukast in Asthma Patients with Concomitant Allergic Rhinitis Summary Source: SGA 2004-W-6776-SS (Slide 49 sourcing updated) Allergic rhinitis and asthma are inflammatory disorders that have been linked epidemiologically, pathophysiologically, and clinically as “one airway disease” Allergic rhinitis increases morbidity, therapeutic needs, and use of health-care resources in patients with asthma ARIA and IPAG recommend a combined strategy for the management of coexistent allergic rhinitis and asthma when possible Cysteinyl leukotrienes are mediators of both allergic rhinitis and asthma The cysteinyl leukotriene modifier montelukast has been shown to improve lung function, symptoms, and quality of life in asthma patients with concomitant seasonal allergic rhinitis Slide 63 Allergic rhinitis and asthma are inflammatory disorders that have been linked epidemiologically, pathophysiologically, and clinically as “one airway disease.”7,16,21 The clinical importance of this association has been established in outcomes research showing that the presence of allergic rhinitis increases morbidity, drug costs, and use of health-care resources in patients with asthma.14,15 Therefore, current guidelines, for example, from ARIA and IPAG, recommend a combined strategy for the management of coexistent allergic rhinitis and asthma.7,36 In light of the importance of cysteinyl leukotrienes as mediators of both allergic rhinitis and asthma, recent investigations have focused on the effects of cysteinyl leukotriene blockade in the treatment of patients with both conditions.1 In clinical studies, the cysteinyl leukotriene receptor antagonist montelukast was shown to improve lung function, symptoms, and quality of life in asthma patients with concomitant seasonal allergic rhinitis.1,65 Therefore, in asthma patients with seasonal allergic rhinitis, montelukast represents a therapeutic option that provides overall clinical benefits.1 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; Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S148–S149; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21:27–49; Philip G et al Curr Med Res Opin 2004;20: 1549–1558; Price DB et al. Presentation at the World Allergy Organization Biannual Meeting, September 2003, Vancouver, British Columbia, Canada; International Primary Care Airways Group, Los Angeles, California, USA, MCR Vision, 2005. SGA 2006-W-286990-SS

References Please see notes page. References Phillip G, Nayak AS, Berger WE et al. The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergy rhinitis. Curr Med Res Opin 2004;20:1549–1558. Casale TB, Lazarus SC. Immunobiology of asthma and rhinitis: Pathogenic factors and therapeutic options. Am J Respir Crit Care Med 1999;160:1778–1787. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:1225–1232. Matricardi PM, Rosmini F, Riondino S et al. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: Epidemiological study. BMJ 2000;320: 412–417. Ceuppens J. Western lifestyle, local defenses and the rising incidence of allergic rhinitis. Acta Otorhinolaryngol Belg 2000;54:391–395. Martinez FD. Role of viral infections during childhood: Could they be protective? Thorax 1994;49:1189–1191. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic Rhinitis and its Impact on Asthma. ARIA. WHO Initiative. J Allergy Clin Immunol 2001;108:S147–S334. Sibbald B, Rink E. Epidemiology of seasonal and perennial rhinitis: Clinical presentation and medical history. Thorax 1991;46:895–901. Leynaert B, Bousquet J, Neukirch C et al.  Perennial rhinitis: An independent risk factor for asthma in nonatopic subjects: Results from the European Community Respiratory Health Survey.  J Allergy Clin Immunol 1999;104:301–304. Brydon MJ.  Patient audit for allergy, asthma and rhinitis.  Asthma J 1996:29–32. Settipane RJ, Hagy GW, Settipane GA. Long-term risk factors for developing asthma and allergic rhinitis: A 23-year follow-up study of college students. Allergy Proc 1994;15:21–25. Huovinen E, Kaprio J, Laitinen LA et al. Incidence and prevalence of asthma among adult Finnish men and women of the Finnish Twin Cohort from 1975 to 1990, and their relation to hay fever and chronic bronchitis. Chest 1999;115:928–936. Bjermer L, Bisgaard H, Bousquet J et al. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: One year, double blind, randomised comparative trial. BMJ 2003;327:891–895. Bousquet J, Gaugris S, Sazonov Kocevar V et al. Increased risk of asthma attacks and emergency visits among asthma patients with allergic rhinitis: A subgroup analysis of the improving asthma control trial. Clin Exp Allergy 2005;35:723–727. Price D, Zhang Q, Sazonov Kocevar V et al. Effect of a concomitant diagnosis of allergic rhinitis on asthma-related health care use by adults. Clin Exp Allergy 2005;35:282–287. 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. Grossman J. One airway, one disease. Chest 1997;111:S11–S16. Simons FE. Allergic rhinobronchitis: The asthma-allergic rhinitis link. J Allergy Clin Immunol 1999;104:534–540. Vignola AM, Chanez P, Godard P et al. Relationships between rhinitis and asthma. Allergy 1998;53:833–839. Meltzer EO. Role for cysteinyl leukotriene receptor antagonist therapy in asthma and their potential role in allergic rhinitis based on the concept of ‘one linked airway disease.’ Ann Allergy Asthma Immunol 2000;84:176–185. Casale TB, Amin BV. Allergic rhinitis/asthma interrelationships. Clin Rev Allergy Immunol 2001;21:27–49. References Please see notes page. SGA 2006-W-286990-SS

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Efficacy of Montelukast in Asthma Patients with Allergic Rhinitis One Airway, One Disease, One Approach 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. Slide 67 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 © 2006 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 3-07 SGA 2006-W-286990-SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com Copyright © 2006 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 3-07 SGA 2006-W-286990-SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com SGA 2006-W-286990-SS