* A brighter future for allergic rhinitis patients Thursday 21 st March h h Leuven, Belgium

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1 * A brighter future for allergic rhinitis patients Thursday 21 st March h h Leuven, Belgium *Carr et al. A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis. J Allergy Clin Immunol. 2012; 129(5): Leung et al. MP29-02: A major advancement in the treatment of allergic rhinitis. J Allergy Clin Immunol. 2012; 129(5): 1216.

2 Agenda Welcome & Introduction Allergic rhinitis: the unmet medical need Shortfall in pathologic coverage of existing anti-rhinitis therapies: building the bridge to MP29-02 MP29-02: a breakthrough which may change the landscape of allergic rhinitis management Discussion & Closing Remarks Claus Bachert Wytske Fokkens The Netherlands Peter Hellings Belgium Claus Bachert Belgium All Claus Bachert

3 The allergic rhinitis landscape Most patients have moderate/severe Allergic Rhinitis European Survey 67.2% = moderate or severe 42.5% = persistent disease Many patients have mixed forms of Allergic Rhinitis Many patients are becoming polysensitized Evolution of treatment-resistant phenotypes Severe Chronic Upper Airway Disease (SCUAD) SCUAD - approx. 30% of AR patients Canonica et al, 2007; Settipane, 2001; Mosges & Klimek, 2007; Bousquet et al, 2009 Pie chart: data refers to non-infectious rhinitis; AR: Allergic Rhinitis

4 The allergic rhinitis landscape: Patients remain symptomatic on treatment 990 patients recruited by 161 GPs in France 72.5% were currently taking allergic rhinitis medication The vast majority of treated patients remain symptomatic Global discomfort caused by their AR during the previous week (VAS) There is a clear need for a new and more effective therapy Uncontrolled Bousquet et al, Int Arch Allergy Immunol, 2012; AR: allergic rhinitis; VAS: visual analogue scale

5 The allergic rhinitis landscape: Patients use multiple therapies in an attempt to achieve allergic rhinitis symptom control As many as 90% of patients in a recent survey - despite the fact that there is limited evidence to support this practice. Up to 90% of patients already take 2 or more rhinitis medications 60% of all AR patients are very interested in finding a new medication and 25% are constantly trying different medications to find one that works. There is a clear need for a new and more effective therapy AR: allergic rhinitis; Canonica et al, 2007; Schatz, 2007; Mullol et al, 2009; Demoly et al, 2002; Bousquet et al, 2012; Bousquet et al, 2008; Marple et al, 2007

6 Can MP29-02 change the landscape of AR management?.to the same extent as that seen in asthma management Fast relief: SABA Sustained relief: LABA Preventer: ICS Asthma Landscape Unmet medical need Most patients were taking SABA, LABA and ICS Convenient treatment needed to simplify asthma management as per recommendations Rhinitis Landscape Fast relief: anti-histamines Sustained & most effective relief: intranasal corticosteroids Unmet medical need Most patients have moderate to severe disease 20% SCUAD 75% of patients on unproven combination therapy More effective therapies urgently needed Many asthmatics now on LABA/ICS formulations MP29-02 a new paradigm for Allergic Rhinitis management AR: allergic rhinitis; SABA: short-acting beta-agonist; LABA: long-acting beta-agonist; ICS: inhaled corticosteroid; SCUAD: severe chronic upper airway disease

7 Allergic rhinitis: the unmet medical need Wytske Fokkens The Netherlands

8 Allergic rhinitis Magnitude of the problems 200 million Europeans have rhinitis!

9 Survey of rhinitis burden Data from Spain Patient reported symptoms (currently or frequently present) Mullol et al J Invest Alergy Investig Immunol 2009

10 Allergic Rhinitis impacts negatively on patients activities: Data from Finland The patient voice allergy survey In Sweden, the cost of rhinitis is 2.7 billion/yr in terms of lost productivity Valovirta et al, 2008, Hellgren et al, 2010

11 The situation has not improved over time: Data from the US Impact of current AR therapy on real life measures has not improved The majority of patients with Allergic Rhinitis felt irritable, tired and miserable in 2006 as well as in 2010 AIA, Allergies in America survey; AR, Allergic Rhinitis; NASAL, Nasal Allergy Survey Assessing Limitations. Meltzer et al, J Fam Pract; 2012; Nathan, Allergy Asthma Proc 2007

12 What is the allergic rhinitis burden today? New results from a healthcare survey in UK A new health survey including 1000 patients 1,000 Seasonal Allergic Rhinitis patients completed the survey 254 mild 746 moderate/severe patients (total nasal symptom score [TNSS]) 8/12, (incl. congestion score 2) Recruited through a patient panel The survey included questions on respondents Treatment Episode duration Impact of symptoms on productivity Absenteeism Pitman et al, 2012

13 The AR symptom burden and its consequences: absenteeism and asthma treatment modification Impact on work productivity Work is negatively impacted by over 90% of patients when symptomatic Absenteeism due to SAR: 4.1 days/year Pitman et al, EAACI 2012; AR: allergic rhinitis; SAR: Seasonal Allergic Rhinitis Asthma treatment is affected if patients fail to take AR medication when symptomatic 53.7% of patients increased reliever 19.5% of patients increased preventer

14 rtnss or rtoss Impact of current therapy on overall symptom control Nasal & Ocular symptoms on treatment 96.2% of these patients were on treatment 70.5% were using multiple treatments (predominantly INS and oral anti-histamines) Still had a rtnss of 12.8/24 (i.e. 53% of total score) Still had a rtoss of 8.6/18 (i.e. 48% of total score) rtnss rtoss Allergic rhinitis was poorly controlled with current mono- and multiple-therapies Price et al, EAACI 2013 rtnss: reflective total nasal symptom score; rtoss: reflective total ocular symptom score; INS: intranasal corticosteroid

15 Why do patients co-medicate? Most patients use multiple therapies in an effort to control their symptoms Two thirds of all patients incl. in the survey reported using 2 AR medications 70.5% of moderate to severe patients 56.1% of mild patients % moderate/severe patients on 2 AR medications The need for faster and more effective treatment was the primary reason for co-medicating True for both moderate/severe and mild patients New allergic rhinitis therapy should provide better and faster nasal and ocular symptom relief Pitman et al, 2012; AR: Allergic Rhinitis

16 Many patients on intranasal corticosteroids and antihistamines have poor or partial symptom control White Clin Exp Allergy 1998

17 rtnss Change in rtnss Multiple therapies offer no additional benefits over intranasal corticosteroids alone Excellent symptom control after 2 weeks of intranasal corticosteroids in only 50% of patients Average change from baseline in rtnss for all 13 days of therapy FP FP + Montelukast Day Esteitie et al, 2010 rtnss: reflective total nasal symptom score; PAR: perennial allergic rhinitis; FP: fluticasone propionate; NS: not significant

18 What do Allergic Rhinitis patients want? Introduction to the world of Discrete Choice Experiments Discrete choice experiments are based on the premise that any good or service can be described by its characteristics (or attributes) Secondly, the extent to which an individual values a good or service can be described in terms of the levels of these characteristics The technique involves presenting individuals with choices of scenarios described in terms of attributes and associated levels Participants are asked to choose their preferred scenario Acaster et al, 2012

19 What do Allergic Rhinitis patients want? We asked them using a Discrete Choice Experiment (DCE) Same patients cohort who completed the healthcare survey 70.5% were taking multiple therapies Symptoms remained poorly controlled What do these patients want from an AR therapy? Patients were presented with 7 product characteristics each of which had 3 levels : 1. Maximum symptom relief (mild, moderate, complete) 2. Time to maximum relief (3, 7, 14 days) 3. Time to first dose benefit (0.5, 3, 8 hours) 4. Risk of side effects (2%, 5%, 10%) 5. Administration method (tablet, nasal spray, both) 6. Frequency of medication (once, twice, three times/day) 7. Monthly out-of-pocket cost ( 15, 30, 45). Patients were asked to imagine that they paid the full cost of this prescription medication Patients were presented with 19 pairs of potential Allergic Rhinitis products (based on the above characteristics) and asked to choose between them Acaster et al, 2012

20 An Example Choice Set Patients were presented with 19 of these and asked to pick A or B LEVELS Attribute Treatment A Treatment B Maximum treatment symptom relief Complete relief Mild improvement Time to achieve maximum treatment symptom relief 7 days 14 days Time to feel a benefit after first dose 3 hours 8 hours Side effects 10 in in 100 Administration method Tablet Nasal spray Frequency of medication Twice a day Three times a day Cost per month 15 per month 30 per month Which treatment do you prefer? A. B. Acaster et al, 2012

21 DCE Results: moderate to severe SAR patients Attribute Odds Ratio P Value WTP Treatment relief: complete vs. mild Treatment relief: moderate vs. mild Time to maximum relief: per day Time to first dose benefit: per hour 6.63 < < < < Side effects: per 1% 0.98 < Administration: tablets vs. nasal spray Administration: tablets & nasal spray vs. nasal spray Frequency of medication: times /day < < Cost: 1 / month increase 0.96 <0.01 Treatment efficacy drives patient preference for rhinitis treatment Most of these patients (70.5%) were taking multiple AR treatments Patients still want more efficacious treatments which provide complete or substantial treatment relief Patients where willing to pay 43/month to receive such a medication Acaster et al, 2012 DCE: discrete choice experiment; SAR: Seasonal Allergic Rhinitis; AR: allergic rhinitis; WTP: willingness to pay

22 Implications of Discrete Choice Experiment Results Severity Patients Want Implication(s) Moderate to severe Complete or substantial treatment relief Current therapy is insufficient Patients not visiting GP but self-medicating with OTC treatments 1. Patient education required Encourage move away from self-medication and pharmacy led care towards physician led care 2. More effective AR therapy is required INS: intranasal steroid; OTC: over the counter; AR: allergic rhinitis

23 Conclusions AR has a negative impact on virtually every aspect of patients lives AR has a socioeconomic burden in terms of symptom burden, absenteeism, lost productivity and impact on asthma treatment The majority of patients use multiple therapies in an attempt to achieve faster and better symptom control Current therapy (even multiple therapies) provides insufficient symptom control DCE showed that patients taking multiple therapies still want more efficacious treatments which provide complete or substantial treatment relief We need to encourage move away from pharmacist led care to physician led care Clearly current therapy is not sufficient for many patients More effective treatments for allergic rhinitis are needed AR: allergic rhinitis; DCE: discrete choice experiment

24 Shortfall in pathologic coverage of existing anti-rhinitis therapies: building the bridge to MP29-02 Peter Hellings Belgium

25 Allergic rhinitis is poorly controlled with current mono- and multiple therapies: real life studies Patients with Severe Chronic Upper Airway Disease (SCUAD) are those with uncontrolled nasal and/or ocular symptoms and impaired quality of life despite treatment French retrospective survey 10-25% of patients defined as SCUAD A priori definition: visual analog score (VAS) of 5 and/or severe ocular symptoms Belgian survey 35% of allergic rhinitis patients remained uncontrolled in real life Bousquet et al, 2010; Hellings et al, 2012 Michiels E etl al., submitted 2013

26 rtnss or rtoss Allergic rhinitis is poorly controlled with current mono- and multiple therapies Nasal & Ocular symptoms on treatment Survey of 746 patients with moderate-tosevere AR 96.2% of these patients were on treatment 70.5% were on combination therapy (predominantly INS and oral antihistamines) rtnss rtoss Still had a rtnss of 12.8/24 and a rtoss of 8.6/18 Price et al, EAACI 2013; AR: alllergic rhinitis rtnss: reflective total nasal symptom score; rtoss: reflective total ocular symptom score; INS: intranasal corticosteroid

27 Low patient satisfaction with current allergic rhinitis therapy % of patients not satisfied with current therapy 66 % of patients are NOT satisfied with AR treatment Dissatisfaction was associated with: Female gender (OR 2.3) Co-morbidity (OR 2.3) Rhinitis severity (OR 1.4 ) Asthma severity (OR 2.0) Antihistamine use (OR 2.5) Ciprandi et al, 2001 AR: allergic rhinitis; OR: ordds ratio

28 Cure versus symptomatic treatment High expectations of treatment 40 % of patients demand cure and/or total suppression of symptoms Hellings P et al Clin Translational Allergy 2012

29 There are many medication classes available to treat allergic rhinitis Decongestants Corticosteroids Anti-histamines Rhinitis Anticholinergics Chromones Antileukotrienes

30 but there is lack of coverage of all symptoms A summary Symptom Nasal congestion Nasal Anticholinergic Decongestant Mast cell stabilizer Leukotriene Antagonist Oral antihistamine First line therapy Intranasal antihistamine Intranasal corticosteroid - + +/- +/- +/ Nasal pruritis / Rhinorrhoea Sneezing Ocular itching / Ocular watering Ocular redness / / No single medication class provides optimal relief from all symptoms

31 Pathology of Allergic Rhinitis the role of oral antihistamines: what they do Basophil Nasal Itch, Congestion?, Rhinorrhoea, Sneezing

32 Cellular infiltration Pathology of Allergic Rhinitis the role of oral antihistamines: what they don t do Congestion Rhinorrhoea Sneezing Nasal congestion Rhinorrhoea Nasal hypersensitivity Basophil Congestion Rhinorrhoea Rhinorrhoea Nasal Itch

33 Inhibit Cellular infiltration Pathology of Allergic Rhinitis the role of intranasal corticosteroids: what they do Nasal congestion Rhinorrhoea Nasal Basophil hypersensitivity

34 Pathology of Allergic Rhinitis the role of intranasal corticosteroids: what they don t do Do not inhibit mast cell degranulation or leukotriene and histamine receptor interaction Congestion Rhinorrhoea Sneezing Basophil Congestion Rhinorrhoea Rhinorrhoea Nasal Itch

35 Pathology of Allergic Rhinitis the role of intranasal antihistamines: what they do Congestion Rhinorrhoea Sneezing Nasal congestion Rhinorrhoea Nasal hypersensitivity Basophil Nasal Itch Congestion? Rhinorrhoea Sneezing Congestion Rhinorrhoea Rhinorrhoea Nasal Itch

36 Pathology of Allergic Rhinitis the role of intranasal antihistamines: what they don t do Do not inhibit mast cell recruitment or leukotriene receptor interaction Basophil

37 Clinical consequence of pathologic coverage gaps Oral antihistamine vs intranasal antihistamine Symptom relief deficit with oral antihistamines 2 week, doubleblind, randomized trial N=360 moderate to severe SAR patients AZE (2 sprays/nostril bd) vs CET (10 mg once daily) * p=0.049 vs CET; ** p=0.01 vs CET Oral antihistamines fall short for nasal congestion & sneezing relief vs intranasal antihistamine Berger et al AAAI 2006;97: AZE: azelastine; CET: cetirizine; SAR: seasonal allergic rhinitis

38 Azelastine in rhinitis Nasal obstruction Mucosal edema Mucosal inflammation Gehano et all ORL 2001

39 Azelastine in rhinitis Substance P and azelastine responders vs non-responders Excellent response group (n=16) Poor response group (n=4) Shinoda et al Am J Rhinol 1997

40 Clinical consequence of pathologic coverage gaps Oral anti-histamine vs intranasal corticosteroid Symptom relief deficit with oral antihistamines 4 week, doubleblind, doubledummy, parallel group trial N=351 SAR patients TAA (220 µg) vs LOR (10 mg) once daily * p<0.05 vs LOR Oral antihistamines fall short for congestion, sneezing & nasal itch relief vs an intranasal corticosteroid Condemi et al AAAI 2000;84:533-8 TAA: triamcinolone acetonide aqueous nasal spray; LOR: lortatadine

41 Clinical consequence of pathologic coverage gaps Intranasal anti-histamine vs corticosteroid (I) Symptom relief deficit with intranasal antihistamines Individual nasal symptoms 14-day,randomized, double-blind, placebocontrolled study N=610 moderate-tosevere SAR patients AZE (1 spray/nostril bd) FP (1 spray/nostril bd) PLA (1 spray/nostril bd) Outcomes rtnss rtoss Individual symptoms * p vs PLA; p= vs AZE Intranasal antihistamines fall short for congestion & rhinorrhoea relief vs an intranasal corticosteroid Hampel et al, AAAI 2010;105: AZE: azelastine; FP: fluticasone propionate; PLA: placebo

42 Clinical consequence of pathologic coverage gaps Intranasal anti-histamine vs corticosteroid (II) Symptom relief deficit with intranasal corticosteroids Individual ocular symptoms * p vs PLA Intranasal corticosteroids fall short for ocular itching & watering relief vs an intranasal antihistamine Hampel et al, AAAI 2010;105: AZE: azelastine; FP: fluticasone propionate; PLA: placebo

43 Clinical consequences of pathologic gaps: a summary Symptom Focus on antihistamines and intranasal corticosteroids Oral antihistamine Intranasal antihistamine Intranasal corticosteroid Nasal congestion +/ Nasal pruritis Rhinorrhoea Sneezing Ocular itching Ocular watering Ocular redness No single medication class provides optimal relief from all symptoms

44 Combination therapy is not the answer Lack of additive benefit with combination therapy Several studies have examined the benefit of combining a nasal steroid with an oral antihistamine or leukotriene antagonist in rhinitis 1-4 Intranasal corticosteroids plus oral antihistamines (or leukotriene antagonist) combinations Mometasone + loratadine 1 Fluticasone + loratadine 2 Fluticasone + levocetirizine 3 Fluticasone + cetirizine, and fluticasone + montelukast 4 None of these studies concluded that the combination was better than nasal steroids alone 1. Anolik et al AAAI 2008;100: Ratner PH, et al. J Fam Pract. 1998;47: Barnes ML, et al. Clin Exp Allergy. 2006;36: Di Lorenzo G, et al. Clin Exp Allergy. 2004;34:

45 Combination therapy with intranasal corticosteroids and oral antihistmaines is not the answer Lack of additive effect: intranasal corticosteroids + oral antihistamine * p 0.02 vs PLA; p<0.01 vs LOR Anolik et al AAAI 2008;100: MFNS: mometasone furoate nasal spray; LOR: loratadine; PLA: placebo

46 Combination therapy is not the answer Clinical consequences of pathologic gaps: a summary Symptom Oral antihistamine Intranasal antihistamine Intranasal corticosteroid Combination therapy* Nasal congestion +/ Nasal pruritis Rhinorrhoea Sneezing Ocular itching Ocular watering Ocular redness Multiple therapies do not provide optimal relief from all symptoms INS + OAH or INS + LTRA INS: intranasal corticosteroid; OAH: oral antihistamine; LTRA: leukotriene antagonists

47 There is a clear unmet need for a new treatment for AR with broad pathologic coverage which provides optimal relief from all nasal and ocular symptoms Symptom Oral antihistamine Intranasal antihistamine Intranasal corticosteroid Combination therapy* New AR treatment Nasal congestion +/ Nasal pruritis Rhinorrhoea Sneezing Ocular itching Ocular watering Ocular redness INS + OAH or INS + LTRA AR: allergic rhinitis

48 What about allergic rhinitis patients expectations and preferences? Expectations of an anti-allergic treatment 43% expected a suppression of allergy symptoms 12% expected to be cured from their allergy 20% expected both symptom suppression and allergy cure Patients preference for allergic rhinitis treatment 30% preferred nasal spray 25% preferred oral treatment 16% preferred combination treatment Patients have high expectations from treatment and prefer a nasal spray over oral treatment Hellings et al, 2012

49 Conclusions The underlying pathology of rhinitis is complex There are many medication classes available to treat it However, no single rhinitis medication class targets all pathologic pathways of allergic rhinitis As a consequence: No single medication class provides optimal relief from all symptoms Use of combination therapy provides no additional benefit over intranasal corticosteroids alone Patients have high expectations from their allergic rhinitis medication There is a clinical need for a new AR treatment with broad pathologic coverage which provides effective relief from both nasal and ocular symptoms thus meeting patient expectations AR: allergic rhinitis

50 MP29-02: a breakthrough product which may change the landscape of allergic rhinitis management Claus Bachert Belgium

51 The ARIA guidelines Intranasal corticosteroids are considered the most effective treatment for Allergic Rhinitis There is a need for high-quality, direct head-to-head comparison studies to further substantiate current treatment recommendations (European Medicines Agency) Bousquet et al, 2008; Brozek et al, 2010; ARIA: allergic rhinitis and its impact on asthma

52 A large direct, head-to-head clinical development programme has been undertaken for a new AR treatment MP29-02 is a novel intranasal formulation of AZE and FP in one nasal spray (total daily dose: 548/200 µg) Study number Season N (ITT) Comparators MP /2008 Texas Cedar 607 Marketed Comparators Astelin and generic Fluticasone MP-4002 MP spring 2008 fall Regulatory studies Azelastine and Fluticasone formulated in MP spring and summer 1791 MP29-02 vehicle and applied in same device MP-4000 Chronic rhinitis 1 yr study in India 612 Marketed FP (Safety Study) Hampel et al, 2010; Carr et al, 2012; Meltzer et al, 2012; Price et al, EAACI, 2012 AR: allergic rhinitis; AZE: azelastine; FP: fluticasone propionate; ITT: intent to treat

53 Seasonal Allergic Rhinitis Study Design 1 spray/nostril bid Placebo run-in MP29-02 Fluticasone propionate NS Azelastine NS Placebo Day 7 Screening Day 1 Randomisation Day 7 Visit Day 14 Visit Symptom qualification period Daily TNSS/TOSS Daily Assessment (AM & PM) NS: nasal spray; TNSS: Total Nasal Symptom Score; TOSS: Total Ocular Symptom Score; bid: twice daily Hampel et al, 2010; Carr et al, 2012; Meltzer et al, 2012

54 Inclusion Criteria Patients had moderate to severe Seasonal Allergic Rhinitis (SAR) 12 years old with a 2-year history of SAR Positive skin prick test to relevant pollen Moderate-to-severe SAR Defined by ARIA guidelines Defined by baseline rtnss, nasal congestion scores and rtoss At randomisation patients demonstrated: Baseline rtnss of (max =24) Baseline rtoss of (max =18) The majority of randomized patients with Allergic Rhinitis have moderateto-severe disease ARIA: Allergic Rhinitis and its impact on asthma; rtnss: reflective total nasal symptom score; rtoss: reflective Total Ocular Symptom Score; Hampel et al, 2010

55 Selected Endpoints Reflective total nasal symptom score (rtnss) Comprising nasal congestion, itching rhinorrhoea & sneezing (max =24) Reflective total ocular symptom score (rtoss) Comprising ocular itching, redness & watering (max = 18) Individual nasal and ocular symptoms Reflective total of 7 symptom score (rt7ss) The rhinoconjunctivitis symptom complex Maximum score = 42 Substantial treatment response 50% reduction from baseline in rtnss (suggested by EMA) 1 point remaining for EACH nasal symptom (i.e. complete/near to complete symptom relief) EMA: European Medicines Agency

56 Change from baseline in rtnss over time P<0.04 vs MP29-02 Hampel et al, 2010 MP29-02 (n=153); FP: Fluticasone propionate (n=151); AZE: azelastine (n=152); PLA: placebo (n=151); rtnss: reflective Total nasal symptom score); Results expressed as LS mean change from baseline

57 Overall change from baseline in rtnss (delta placebo) p< vs MP29-02; p= vs MP29-02 Hampel et al, 2010 MP29-02 (n=153) FP: fluticasone propionate (n=151); AZE: azelastine (n=152); rtnss: reflective total nasal symptom score Data presented as LS mean change from baseline delta placebo with 95% CI

58 Overall change from baseline in individual nasal symptom scores: congestion and nasal itch Congestion Nasal Itch p= vs MP29-02; p= vs MP29-02 p= vs MP29-02; p= vs MP29-02 Hampel et al, 2010 MP29-02 (n=153); FP: Fluticasone propionate (n=151); AZE: azelastine (n=152) Results expressed as LS mean change from baseline (delta placebo) with 95% CI

59 Overall change from baseline in individual nasal symptom scores: Rhinorrhea and sneezing Runny nose Sneezing p= vs MP29-02; p< vs MP29-02 p= vs MP29-02; p< vs MP29-02 Hampel et al,2 010 MP29-02 (n=153) FP: Fluticasone propionate (n=151); AZE: azelastine (n=152) Results expressed as LS mean change from baseline (delta placebo) with 95% CI

60 Overall change from baseline in rtoss (delta placebo) p= vs MP29-02; p= vs MP29-02 Hampel et al, 2010 MP29-02 (n=153); FP: Fluticasone propionate (n=151); AZE: azelastine (n=152); rtoss: reflective Total Ocular Symptom Score; Data presented as LS mean change from baseline delta placebo with 95% CI

61 Overall change from baseline in individual ocular symptom scores Itching Watering Redness p= vs MP29-02 p= vs MP29-02 p= vs MP29-02 p= vs MP29-02 p= vs MP29-02 p= vs MP29-02 Hampel et al, 2010 MP29-02 (n=153);fp: Fluticasone propionate (n=151); AZE: azelastine (n=152) Data presented as LS mean change from baseline delta placebo with 95% CI

62 Overall change from baseline in rt7ss (delta placebo): rhinitis symptom complex p= vs MP29-02; p= vs MP29-02 Data on file MP29-02 (n=153); FP: Fluticasone propionate (n=151); AZE: azelastine (n=152); rt7ss: Total of 7 symptom scores (All nasal pluis all ocular symptoms); Results expressed as LS mean change from baseline (delta placebo) with 95% CI

63 Overall change from baseline in rtnss: in those with more and in those with less severe disease Most AR patients have moderate-to-severe disease More severe patients Less severe pateints p= vs MP29-02; p= vs MP29-02 MP29-02 (n=77); FP (n=64); AZE (n=68) p= vs Dymista ; p= vs Dymista MP29-02 (n=76); FP (n=87); AZE (n=84) Data on file FP: fluticasone propionate; AZE: Azelastine;AR: allergic rhinitis; rtnss: reflective Total Nasal Symptom Score Results expressed as LS mean change from baseline (delta placebo) with 95% CI

64 Proportion of patients achieving 50% reduction in nasal symptoms and time taken to achieve this response More MP29-02 patients achieve substantial symptom relief (1 in every 2 patients) And achieve this level of control up to 6 days faster than either FP or AZE Relevance: A substantial response with up to 6 day s time advantage over first-line therapy is relevant since an AR episode lasts 12.5 days on average Substantial nasal symptom reduction is achieved by more MP29-02 patients and up to 6 days earlier than existing first-line therapy Bachert et al. EAACI 2011, AZE: Azelastine; FP: Fluticasone propionate; PLA: placebo; AR: allergic rhinitis Responder rate = % of patients with a 50% or more reduction in Total Nasal Symptom Score

65 Proportion of patients achieving 1 pt remaining in each nasal symptom and time taken to achieve this response 1 out of 6 MP29-02 patients achieve complete or near-tocomplete symptom relief Relevance: Complete symptom relief is what patients want AZE: Azelastine; FP: Fluticasone propionate; PLA: placebo Data on file; Responder Rate = % of patients with a score of 1 for every nasal symptom

66 4002/4004/4006 represent regulatory studies where MP29-02 was compared to non-commercially available comparators Study number Season N (ITT) Comparators MP-4001 MP-4002 MP-4004 MP /2008 Texas Cedar 2008 spring 2008 fall 2009 spring and summer Marketed Comparators Astelin and generic Fluticasone Regulatory studies Azelastine and Fluticasone formulated in MP29-02 vehicle and applied in same device MP-4000 Chronic rhinitis 1 yr study in India 612 Marketed FP (Safety Study) Hampel et al, 2010; Carr et al, 2012; Meltzer et al, 2012; Price et al, EAACI, 2012 AR: allergic rhinitis; FP: fluticasone propionate; ITT: intent to treat

67 Significantly greater baseline rtnss reduction MP4002 (n=831) MP4004 (n=776) p=0.034 vs MP29-02; p=0.002 vs MP29-02 p=0.038 vs MP29-02; p=0.032 vs MP29-02 MP4006 (n=1971) Meta-analysis (n=3398) p=0.029 vs MP29-02; p<0.016 vs MP29-02 p=0.001 vs MP29-02; p<0.001 vs MP29-02 rtnss: reflective Total Nasal Symptom Score; FP: Fluticasone propionate; AZE: Azelastine; PLA: placebo Carr et al, J Allergy Clin

68 Editor s choice J Allergy Clin Immunol MP29-02 : A major advancement in the treatment of Allergic Rhinitis MP29-02 : can be considered the drug of choice for the treatment of Allergic Rhinitis Treatment differences even greater versus marketed comparators (i.e study MP4001) AR: Allergic Rhinitis

69 What about long-term efficacy? Study number Season N (ITT) Comparators MP-4001 MP-4002 MP-4004 MP /2008 Texas Cedar 2008 spring 2008 fall 2009 spring and summer Marketed Comparators Astelin and generic Fluticasone Regulatory studies Azelastine and Fluticasone formulated in MP29-02 vehicle and applied in same device MP-4000 Chronic rhinitis 1 yr study in India 612 Marketed FP (Safety Study) Hampel et al, 2010; Carr et al, 2012; Meltzer et al, 2012; Price et al, EAACI, 2012 AR: allergic rhinitis; FP: fluticasone propionate; ITT: intent to treat

70 Change from baseline in rtnss over time: chronic rhinitis patients (PAR and NAR) P<0.05 vs FP Consistent statistical superiority over FP up to and incl. week 28 with treatment difference maintained for 52 weeks rtnss: reflective Total Nasal Symptom Score; PAR: perennial allergic rhinitis; NAR: non-allergic rhinitis; FP: Fluticasone propionate; Price et al, EAACI 2012

71 Time to first response: 100% PM rtnss reduction from baseline (first 28 days) chronic rhinitis patients P = vs MP29-02 More patients treated with MP29-02 were symptom-free free and achieved this response days earlier than those treated with FP rtnss: reflective total nasal symptom score; ITT: intent to treat; FP: fluticasone propionate Data on file

72 Conclusions A large direct, head to head clinical development programme has been undertaken for a new allergic rhinitis treatment (MP29-02) MP29-02 should fill the unmet medical need in AR since: It is more effective than commercially available first-line therapies in combating overall nasal symptoms (rtnss), overall ocular symptoms (rtoss), each of the individual symptoms and the overall rhinitis symptom complex (rt7ss) It provides benefits for all patients, providing significantly greater symptom relief vs FP or AZE regardless of disease severity More patients achieved substantial symptom relief or complete/near to complete symptom relief and did so days earlier. It is considered the drug of choice and a major advancement in the treatment of AR by Editors of J Allergy Clin Immunol It is more effective than intranasal FP for long-term treatment of chronic rhinitis AR: allergic rhinitis; rtnss: reflective total nasal symptom score; rtoss: reflective ocular symptom score; rt7ss: reflective total of 7 symptom scores; FP: fluticasone propionate; AZE: azelastine

73 MP29-02 provides superior relief for the most common symptoms associated with AR Symptom Oral antihistamine Intranasal antihistamine Intranasal corticosteroid Combination therapy* MP29-02 Nasal congestion +/ Nasal pruritis Rhinorrhoea Sneezing Ocular itching +/ Ocular watering +/ Ocular redness +/ INS + OAH or INS + LTRA AR: allergic rhinitis

74 Wrap up and discussion

75 Can MP29-02 change the landscape of AR management?.to the same extent as that seen in asthma management Fast relief: SABA Sustained relief: LABA Preventer: ICS Asthma Landscape Unmet medical need Most patients were taking SABA, LABA and ICS Convenient treatment needed to simplify asthma management as per recommendations Rhinitis Landscape Fast relief: anti-histamines Sustained & most effective relief: intranasal corticosteroids Unmet medical need Most patients have moderate-to-severe disease 20% SCUAD 75% of patients on unproven combination therapy More effective therapies urgently needed Many asthmatics now on LABA/ICS formulations MP29-02 a new paradigm for Allergic Rhinitis management SABA: short-acting beta-agonist; LABA: long-acting beta-agonist; SCUAD: severe chronic upper airway disease

76 Back up slides

77 Overall change from baseline in rtoss: ITT and ocular symptomatic subpopulation (BL TOSS 8) ITT Symptomatic patients BL TOSS 8 p= vs MP29-02; p= vs MP29-02 MP29-02 (n=153); FP (n=151); AZE (n=152) p= vs MP29-02; p= vs MP29-02 MP29-02 (n=128); FP (n=125); AZE (n=118) rtoss: reflective total ocular symptom score; ITT: intent to treat; AZE: Azelastine; FP: Fluticasone propionate; BL: baseline. Data on file; Results expressed as LS mean change from baseline (delta placebo) with 95% CI

78 Number of symptom free days experienced by chronic rhinitis patients during 1 years treatment Days available Days symptom-free Difference Population MP29-02 FP MP29-02 FP MP FP ITT (88.2) (106.6) (114.5) (116.6) 25.9 days Allergic patients (87.5) (106.3) (118.1) (117.8) 23.9 days Patients taking MP29-02 experienced significantly more symptom-free days than those on FP Chronic patients: 8.4% more symptom-free days (p=0.0005) PAR patients: 7.3% more symptom-free days (p=0.0122) ITT: Intent to Treat; FP: fluticasone propionate; PAR: perennial allergic rhinitis

79 Overview of treatment-related, treatment-emergent adverse events (safety population) 14 days A representative SAR study Study MP4004 MP29-02 (n=195) FP (n=189) AZE (n=194) PLA (n=200) Any adverse event 20 (10.3) 10 (5.3) 24 (14.9) 9 (4.5) Dysgeusia 4 (2.1) 1 (0.5) 14 (7.2) 1 (0.5) Epistaxis 3 (1.5) 3 (1.6) 3 (1.6) 5 (2.5) Headache 5 (2.6) 4 (2.1) 4 (2.1) 1 (0.5) Cough 2 (1.0) 0 (0.0) 1 (0.5) 0 (0.0) Nasal discomfort 1 (0.5) 0 (0.0) 2 (1.0) 0 (0.0) Nausea 1 (0.5) 0 (0.0) 0 (0.0) 2 (1.0) Oropharyngeal pain 1 (0.5) 0 (0.0) 2 (1.0) 0 (0.0) Mucosal erosion 2 (1.0) 0 (0.0) 0 (0.0) 0 (0.0) SAR: seasonal allergic rhinitis; FP: fluticasone propionate; AZE: azelastine; PLA: placebo

80 Treatment-related adverse events (safety population) 52 weeks Treatment-related adverse eventª MP29-02 (N=404) Number of subjects (%) FP (N=207) Any event 38 (9.4) 23 (11.1) Dysgeusia 10 (2.5) 1 (0.5) Epistaxis 5 (1.2) 1 (0.5) Headache 4 (1.0) 9 (4.3) Cough 4 (1.0) 0 (0.0) Blood cortisol increased 2 (0.5) 1 (0.5) Weight increased 2 (0.5) 1 (0.5) Glucose tolerance impaired 2 (0.5) 1 (0.5) Acne 2 (0.5) 0 (0.0) Vomiting 2 (0.5) 0 (0.0) Rhinitis 2 (0.5) 0 (0.0) The proportion of subjects with a treatment-emergent adverse event was similar for both treatment groups There was no evidence for an accumulation of adverse events over time or any occurrence of late adverse reactions FP: fluticasone propionate

81 Eye examination findings (safety population) 52 weeks Subjects, n (%) MP29-02 (n=404) FP (n=207) Evidence of glaucoma at screening 0 (0.0) 0 (0.0) Evidence of glaucoma at 6 months 1 (0.2) 0 Evidence of glaucoma at 12 months /ET 0 (0.0) 0 (0.0) Evidence of posterior sub-capsular cataract at screening 0 2 (1.0)ª Evidence of posterior sub-capsular cataract at 6 months 3 (0.7) 0 (0.0) Evidence of posterior sub-capsular cataract at 12 months ET 1 (0.2) 3 (1.4) The incidence of abnormal ocular findings on ophthalmologic examination was low for both groups FP: fluticasone propionate; ET: end of trial

82 Serum cortisol concentrations (sub-group of safety population) 52 weeks Fasting Serum Cortisol Baseline value for 6-month assessment 6 months MP29-02 Mean ± SD (n) ± 4.20 (154) ± 4.55 (154) FP Mean ± SD (n) ± 4.65 (78) ± 4.62 (78) Change from baseline to 6 months ± 5.14 (154) ± 5.32 (78) Baseline value for 12 month/et assessment 12 months/et ± 4.21 (137) ± 4.87 (137) ± 4.53 (73) ± 4.65 (73) Change from baseline to 12 months/et ± 5.53 (137) ± 4.96 (73) Mean fasting serum cortisol was similar between treatment groups at baseline, Month 6, and Month 12 There was no appreciable reduction in serum cortisol from baseline following 12 month s continuous treatment with either MP29-02 or FP FP: fluticasone propionate; ET: end of trial; SD: standard deviation