Clinical efficacy of montelukast in anti-inflammatory treatment of asthma and allergic rhinitis

Clinical efficacy of montelukast in anti-inflammatory treatment of asthma and allergic rhinitis Kim Hyun Hee, MD, PhD. Dept. of Pediatrics The Catholic University of Korea College of Medicine

Achieving asthma control In Real-world Understanding the reason for poor control

Uncontrolled Asthma Heavy burden on patients and their families Increased rates of hospitalizations and emergency room and other urgent care visits Activity limitations Night time awakenings Lost time from work and school Expensive, counting for most of asthma related health care cost

Need for Changes in Asthma Management - A Real Life Issue Many asthma patients remain uncontrolled: 94.7% did not meet all GINA criteria for asthma control a (AIRE Study) 1 51% did not meet criteria for asthma control despite the use of an ICS or an ICS + LABA (INSPIRE study) 2 a At the time of this study, GINA criteria for asthma control included the following: minimal chronic symptoms, minimal exacerbations, no emergency visits, minimal need for as-needed β agonists, no limitations in daily activities, and normal or near-normal lung function. GINA=Global Initiative for Asthma; AIRE=Asthma Insights and Reality in Europe; ICS=inhaled corticosteroids; LABA=long-acting β-agonists; INSPIRE=International Asthma Patient Insight Research. 1. Rabe KF et al. Eur Respir J. 2000;16:802 807. 2. Partridge MR et al. BMC Pulm Med. 2006;6:13. doi:10.1186/1147 2466-6-13. 3. Thomas M et al. Pediatrics. 2005;115(1):129 134. 4. Kang H-Y et al. Yonsei Med J. 2008;49(4):521 529. 5. Price D et al. Clin Exp Allergy. 2005;35:282 287. 6. LaForest L et al. Int Arch Allergy Immunol. 2005;136:281 286. 7. Valovirta E et al. BMC Pulm Med. 2006;6(suppl 1):S3. Slide 4

Predicting Poor Asthma Control 1 The wrong diagnosis Incorrect choice of inhaler or poor inhaler technique Smoking Patients beliefs and adherence Co-morbid rhinitis Individual variation in response to treatment 1. Achieving asthma control in practice: Understanding the reasons for poor control, Respiratory Medicine (2008) 102, 1681e1693

Smoking adversely impacts asthma control The prevalence of current smoking among patients with asthma varies by country from 15% to 25% 1,2 In retrospective cohort study of a large UK general practice database, Current smokers were almost 3 times more likely than non-smokers to be hospitalized for their asthma over a 12-month period 3 1. Annesi-Maesano I, Oryszczyn MP, Raherison C, et al. Increased prevalence of asthma and allied diseases among active adolescent tobacco smokers after controlling for passive smoking exposure. Clin Exp Allergy 2004; 34(7):1017-23 2. Hylkema MN, Sterk PJ, de Boer WI, Postma DS. Tobacco use in relation to COPD and asthma. Eur Respir J 2007;29(3):438-45 3. Price D, Zhang Q, Kocevar VS, Yin DD, Thomas M. Effect of a concomitant diagnosis of allergic rhinitis on asthma related healthcare use by adults. Clin Exp Allergy 2005;35 (3): 282-7

Smoking adversely impacts asthma control Barnes PJ et al. Lancet 2004;363:731-3

FEV 1, L Asthma Control Score Cigarette Smoking and Asthma Variability: Reduced Response to Oral Corticosteroids Placebo Prednisolone 3.0 P=0.605 P=0.386 P=0.019 5 P=0.865 P=0.108 P=0.004 4 2.5 2.0 3 2 1 0 0 1 Smokers n=14 Ex-Smokers n=10 Never-Smokers n=26 Smokers n=14 Ex-Smokers n=10 Never-Smokers n=26 1. Chaudhuri R et al. Am J Respir Crit Care Med. 2003;168:1308 1311, with permission from the American Thoracic Society. Slide 9

ICS therapy in Asthmatic smokers ICS therapy fails more often in smokers due to Different pattern of airway inflammation- neutrophilic inflammation Oxidative stress production which impairs the activity of HDAC2 Leukotriene production Fig. 1. Peak Expiratory Flow in non-smoking and smoking patients Fig.2. co-relation between smoking & urinary LTE4 1. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax 2002;57(3):226e30 (Fig. 1) 2. Cigarette smoking stimulates cysteinyl leukotriene production in man. Fauler J. and Frölich J.C. Eur J Clin Invest 1997; 27: 43-47 (Fig. 2)

Higher LTE 4 concentration in Asthmatic smokers The level of LTE 4 / creatinine (pg/mg) were increased in asthmatic subjects compared to COPD and controls, p<0.0001 for asthma (Fig. 1) The level of LTE 4 / creatinine (pg/mg) were increased in asthmatic smokers compared to non-smokers, P<0.0001 (Fig. 2) Fig. 1. LTE4/creatinine concentration between control subjects Fig. 2. LTE4/creatinine concentration between control subjects 1. Gaki E, Papatheodorou G et al. Leukotriene E4 in urine in patients with asthma and COPD- effect of smoking habit, Resp Medicine 2008 Each symbol represents one individual. Horizontal bars represent mean values. S: smoking, NS: non-smoking, ES: Ex-smoking.

am PEF (L/min) Greater response of Montelukast in Smokers Montelukast showed greater response than ICS in asthmatic smokers 20 15 ** *** * 10 5 0 Montelukast Beclomethasone Non-Smokers Smokers N=83 1. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med. 2007;175:783-90 AJRCCM 2006

Role of LTRA in Asthmatic Smokers The LTRA montelukast seems to have some effect in smokers with asthma, as shown by a recently performed pilot study These results need to be confirmed in larger clinical trials

Number of Subjects (n=72) PRICE Results: 6-Week ICS Period 18 16 14 12 10 8 6 4 2 0 1 1 2 4 9 16 11 13 2 20 10 0 10 20 30 40 50 60 4 2 FEV 1, % Change a 3 54% of subjects determined to be responders (n=39) 46% of subjects categorized as non-responders (n=33) 1 1 Baseline Parameters b FEV 1 % predicted Responders (n=39) Non-responders (n=33) P Value 68.5 ± 10.4 77.5 ± 8.8 <0.001 FEV 1 /FVC 0.65 ± 0.1 0.76 ± 0.1 <0.001 2 a FEV 1 distribution response to ICS over short-term 6-week trial. Bars represent 5% increments in FEV 1 response. b Mean ± standard deviation. Reprinted from Martin RJ et al. The Predicted Response to Inhaled Corticosteroid Efficacy (PRICE) trial. J Allergy Clin Immunol. 2007;119:73 80. Copyright 2007 American Academy of Allergy, Asthma & Immunology, with permission from Elsevier. Slide 16

PRICE Results: 16-Week Double-Blind Trial a Responders: Those who remained on ICS treatment maintained asthma control. Those randomized to placebo had worse asthma control. Non-responders: It did not matter whether patients continued ICS treatment or switched to placebo. ACQ results did not differ between treatment groups. ACQ=asthma control questionnaire. a Asthma control measured by mini ACQ and stratified by FEV 1 response. Martin RJ et al. J Allergy Clin Immunol. 2007;119:73 80. Slide 17

CLIC Primary Outcome: FEV 1 Response FEV 1 Change With Montelukast Sodium 7.5% MT response 40 30 20 10 0 10 Concordance Correlation 0.55 (0.43, 0.65) Montelukast sodium alone n=6 (5%) Both medications n=22 (17%) Multicenter, randomized, double-blind, cross-over Primary long-term Tx for ped asthma N = 144, 6~17yr 16wks, cross-over MONK 5mg vs FP 100mg bid inh 20 30 40 Neither medication n=69 (55%) Fluticasone propionate alone n=29 (23%) 7.5% FP response 50 50 40 30 20 10 0 10 20 30 40 FEV 1 Change With Fluticasone Propionate MT=montelukast sodium; FP=fluticasone propionate. Reprinted from Szefler SJ et al. J Allergy Clin Immunol. 2005;115:233 242, with permission from the American Academy of Allergy, Asthma, and Immunology. Slide 18

CLIC: Difference in Asthma Control (Days-per-Week Response) a Participants Better response to fluticasone propionate (n=36) Better response to montelukast sodium (n=15) 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 a Difference in asthma control days between fluticasone propionate and montelukast sodium (fluticasone minus montelukast sodium) for individual participants. Each line designates a single participant. An asthma control day was defined as a day with no daytime or nighttime asthma symptoms, no rescue albuterol for asthma symptoms or peak flow less than 80% of personal best, no asthma health care use, and no asthma-related absences from school or work. Reprinted from Zeiger RS et al. J Allergy Clin Immunol. 2006;117:45 52, with permission from the American Academy of Allergy, Asthma, and Immunology. Slide 19

Summary in variability in Tx response Clinicians should expect variability in treatment response to clinical, physiologic, and inflammatory indicators of response for ICSs and LTRAs in all patients incl. children and adults Low pulmonary function, bronchodilator response and airway hyperresponsiveness are associated with a favorable response to ICS eno level are associated with a favorable response to ICSs in children but not adults Younger age, higher urinary leukotriene levels and shorter duration of disease are linked to a favorable response to LTRAs in children Adult patients with asthma who smoke might have a favorable response to LTRAs over ICSs

The MONtelukast In Chronic Asthma (MONICA) study Efficacy of montelukast in asthma patients inadequately controlled on an ICS or an ICS + LABA Slide 21

MONICA 1 Study Design and Methods Design Multicenter, open-label, prospective study Objective To assess the impact of montelukast added to an ICS or an ICS + LABA in patients with uncontrolled asthma Setting Subjects recruited by office-based pulmonary specialists at 290 sites in Germany Patient population Patients aged 18 years with mild to moderate persistent asthma uncontrolled by ICS or ICS + LABA therapy Treatment 6 months of therapy with montelukast 10 mg once daily in addition to current asthma treatment a a Concomitant medications included short-acting β-agonists, ICS, LABA, fixed combinations of ICS and LABA, theophylline, or, in some cases, oral corticosteroids. 1. Virchow JC et al. Respir Med. doi:10.1016/j.rmed.2009.11.022. Slide 22

MONICA 1 Effective End Points Primary ACT scores Secondary German version of the validated MiniAQLQ Other Lung function (assessed by FEV 1 and PEF) ACT=asthma control test; MiniAQLQ=MiniAsthma Quality of Life Questionnaire. 1. Virchow JC et al. Respir Med. doi:10.1016/j.rmed.2009.11.022. Slide 23

MONICA 1 Baseline Characteristics of Patients Characteristic Value Total number of patients treated 1,681 Mean ± SD age, y 45.7 ± 15.9 Men, % of patients 34 Women, % of patients 66 Lung function (FEV 1 or PEF) <80% of predicted, % of patients 36 Daytime symptoms >2 times/week, % of patients 72 Rescue medication use >2 times/week, % of patients 57 Exacerbations 1x/y, % of patients 45 Uncontrolled asthma despite ICS or ICS + LABA, % of patients 95 SD=standard deviation. 1. Virchow JC et al. Respir Med. doi:10.1016/j.rmed.2009.11.022. Slide 24

Patients in Each ACT Category, % MONICA 1 Improvements in ACT Scores With Add-On Montelukast 100 75 1.2 13.9 25.0 7.2 41.8 11.4 47.5 ACT Scores 25 (Completely controlled) 20 24 (Well controlled) 16 19 (Poorly controlled) <16 (Uncontrolled) 50 25 57.5 27.2 21.7 0 Baseline (n=1,681) 21.0 Month 3 (n=1,477) Primary end point: Mean ACT score improved significantly between baseline (14.6 ± 4.6) and Month 6 (19.4 ± 4.4) with add-on montelukast (P<0.0001). 1. Virchow JC et al. Respir Med. doi:10.1016/j.rmed.2009.11.022. 17.6 Month 6 (n=1,303) Slide 25

Mean Score MONICA 1 Improvements in MiniAQLQ With Add-On Montelukast 6 5 Baseline (n=1,605) Month 3 (n=1,409) Month 6 (n=1,261) 5.0 a 5.3 a 4 4.0 3 2 1 0 ICS or ICS + LABA ICS or ICS + LABA + Montelukast ICS or ICS + LABA + Montelukast a P<0.0001 vs baseline. 1. Virchow JC et al. Respir Med. doi:10.1016/j.rmed.2009.11.022. Slide 26

FEV 1, L PEF, L/s MONICA 1 Improvements in Lung Function With Add-On Montelukast Baseline Month 3 Month 6 3 2.46 2.61 a 2.60 a 7 6 5.76 6.20 a 6.22 a 2 5 4 1 3 2 0 a P<0.0001 vs baseline. (n=1,445) (n=1,057) (n=914) ICS or ICS + LABA ICS or ICS + LABA + Montelukast ICS or ICS + LABA + Montelukast 1 0 (n=967) (n=669) (n=563) ICS or ICS + LABA ICS or ICS + LABA + Montelukast ICS or ICS + LABA + Montelukast Lung function measurements were performed at the investigator s discretion; thus, not all patients had data for these parameters. 1. Virchow JC et al. Respir Med. doi:10.1016/j.rmed.2009.11.022. Slide 27

Physicians/Patients at Month 6, % MONICA 1 Global Improvements in Asthma With Add-On Montelukast 100 75 83.2 83.4 Very much better/better No improvement 50 25 15.3 15 0 Physicians a Patients a N not stated. 1. Virchow JC et al. Respir Med. doi:10.1016/j.rmed.2009.11.022. Slide 28

MONICA 1 Summary and Conclusions This real-world study showed that 6 months of add-on therapy with montelukast was effective in patients already receiving an ICS or an ICS + LABA who had uncontrolled asthma symptoms. Asthma control (Months 3 and 6): significant improvements in ACT score (P<0.0001 vs baseline) (primary end point) Quality of life (Months 3 and 6): significant improvements in the MiniAQLQ score (P<0.0001 vs baseline) Lung function (Months 3 and 6): significant improvements in FEV 1 and PEF (P<0.0001 vs baseline for both comparisons) Asthma status (Month 6): improvements in global assessment by 83% of patients and physicians 1. Virchow JC et al. Respir Med. doi:10.1016/j.rmed.2009.11.022. Slide 29

The MARS study (Montelukast combined with fixed Associations in Real life Survey) Efficacy of montelukast in asthma patients inadequately controlled on an ICS + LABA Slide 30

MARS 1 Study Design and Methods Design Multicenter, open-label, prospective, observational study Objective Evaluate the impact of add-on therapy with montelukast in patients with asthma who were uncontrolled on current ICS + LABA treatment a Setting Outpatients enrolled by general practitioners in Belgium Patient population Patients 4 years of age with mild to moderate asthma who were symptomatic despite ICS + LABA therapy Treatment 2 months of montelukast 4 mg, 5 mg, or 10 mg once daily at bedtime added to an ICS + LABA a Budesonide + formoterol turbohaler or fluticasone + salmeterol dry-powder inhaler. 1. Korn D et al. Curr Med Res Opin. 2009;25(2):489 497. Slide 31

MARS 1 Efficacy End Point Primary End Point: Change in mean ACQ score a from baseline to Month 2 Subgroup analyses of change in mean ACQ score based on Presence of allergic rhinitis symptoms ICS + LABA dose level Type of ICS + LABA combination ACQ=Asthma Control Questionnaire. a ACQ score calculated as the sum of 6 items on a questionnaire rated from 0 (best) to 6 (worst). 1. Korn D et al. Curr Med Res Opin. 2009;25(2):489 497. Slide 32

MARS Baseline 1 Characteristics of Patients Characteristic Value Total number of patients evaluated 5,769 Mean ± SD age, y 41 ± 21 Patients aged <15 y, % 14.3 Patients aged 15 y, % 85.7 Males, % of patients 53 Females, % of patients 47 Patients with concomitant allergic rhinitis, % 42 ICS + LABA a dosage stratum, % of patients Low dose Medium dose High dose Patients with partially controlled b asthma, % 38 Patients with uncontrolled c asthma, % 62 21 48 31 a Budesonide + formoterol turbohaler or fluticasone + salmeterol dry-powder inhaler; b ACQ score 1.50; c ACQ score >1.50. 1. Korn D et al. Curr Med Res Opin. 2009;25(2):489 497. Slide 33

ACQ Score MARS Improvement 1 in ACQ Scores (Primary End Point) 2.5 2.0 1.97 1.5 1.0 1.05 a 0.5 0 Baseline (before montelukast) Month 2 (after montelukast) a P<0.001 vs baseline. N=5,769. 1. Korn D et al. Curr Med Res Opin. 2009;25(2):489 497. Slide 34

Mean (SD) ACQ Score MARS Improvements 1 in ACQ Scores in Patients With Asthma and Allergic Rhinitis (Subgroup Analysis) 3.0 Baseline (before montelukast) Month 2 (after montelukast) 2.5 2.0 a 1.5 a,b 1.0 0.5 0 Asthma With Allergic Rhinitis (n=2,442) Asthma Without Allergic Rhinitis (n=3,327) a P<0.001 vs baseline; b P<0.001 vs patients without allergic rhinitis. N=5,769. 1. Korn D et al. Curr Med Res Opin. 2009;25(2):489 497. Slide 35

MARS 1 Summary and Conclusions This real-world study showed that add-on therapy with montelukast was effective in achieving asthma control in patients already receiving an ICS + LABA but who were still symptomatic. Significant improvement in mean ACQ scores in the total study cohort (primary end point) (P<0.001) Significant improvement in mean ACQ scores in the following subgroups: Patients with and without allergic rhinitis at baseline (P<0.001) Patients in all strata of ICS + LABA dosage (low, medium, and high) (P<0.001) Patients receiving ICS + LABA treatment (either budesonide + formoterol turbuhaler or fluticasone + salmeterol dry-powder inhaler) (P<0.001) 1. Korn D et al. Curr Med Res Opin. 2009;25(2):489 497. Slide 36

Conclusion Uncontrolled asthma is highly prevalent in patients despite the use of standard asthma medications. Smoking, individual variation in response to treatment can cause poor asthma control. Several real-world efficacy studies have shown that montelukast improves asthma control in patients whose asthma symptoms are uncontrolled on an ICS or an ICS + LABA

Dual Pathways of Inflammation Montelukast Combined With a Steroid Affects the Dual Pathways of Inflammation CysLTs play a key role in asthmatic inflammation Steroid-sensitive mediators play a key role in asthmatic inflammation Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients Montelukast blocks the effects of CysLTs Inhaled steroids block steroidsensitive mediators DUAL PATHWAY The slide represents an artistic rendition. CysLT = cysteinyl leukotriene Slide 38 Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):s37-s42; Bisgaard H Allergy 2001;56(suppl 66):7-11.

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