Introduction. Jean Bousquet France

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2 Introduction Jean Bousquet France

3 The unmet medical need in allergic rhinitis management Disease management and efficacy assessment gaps Recommendation INS are recommended as the most effective treatment for AR ARIA recommends high quality, direct head to head studies EMA suggests the use of responder analyses (e.g. 50% response) to assess efficacy in a more clinically-relevant way Reality AR patients remain symptomatic on INS, even adding other AR medications to INS Direct head to head comparisons of active comparators is rare Responder analyses are rarely conducted and/or published INS: intranasal corticosteroids; AR: allergic rhinitis; EMA: European Medicines Agency

4 Aim of this symposium To utilise the MP29-02 clinical development programme to close both the efficacy and the assessment gaps in allergic rhinitis

5 MP29-02: A snapshot What is it? MP29-02 is a novel intranasal formulation of Azelastine hydrochloride and Fluticasone propionate in one nasal spray (total daily dose: 548/200 µg) It is an entirely new product for the treatment of allergic rhinitis It is not a simple fixed combination Where is it approved? MP29-02 has been approved by the FDA in May 2012 for SAR MP29-02 has been approved by the EU in January 2013 for moderate and severe SAR and PAR SAR: seasonal allergic rhinitis; PAR: perennial allergic rhinitis

6 Is MP29-02 the drug of choice for the treatment of allergic rhinitis? 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 1. Leung et a\, J Allergy Clinical Immunol 2013 AR: Allergic Rhinitis

7 Can MP29-02 change the landscape of AR management?.to the same extent as that seen in asthma management? Asthma Landscape Fast relief: SABA Sustained relief: LABA Preventer: ICS Unmet medical need Most patients were taking SABA, LABA and ICS Disease remained poorly controlled Improving asthma control became a primary focus Rhinitis Landscape Fast relief: anti-histamines Sustained & most effective relief: intranasal corticosteroids Unmet medical need Changing face of the disease 20% SCUAD 75% of patients on unproven combination therapy More effective therapies urgently needed Seretide or Symbicort represented a new paradigm for asthma management 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

8 A new breakthrough product in allergic rhinitis management 10.30h 10.35h Introduction 10.35h 10.55h Unmet medical need in allergic rhinitis Jean Bousquet France Jean Bousquet France 10.55h 11.15h 11.15h 11.30h MP29-02: the drug of choice for the treatment of allergic rhinitis MP29-02 vs marketed comparators: efficacy and safety Warner Carr USA Glenis Scadding UK 11.30h 11.45h MP29-02: long term efficacy and safety David Price UK 11.45h 12.00h Discussion and wrap-up All

9 Unmet medical need in allergic rhinitis Jean Bousquet France

10 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

11 Patients with moderate to severe impact (%) 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

12 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) 89% Rhinorrhea 82% Sneezing 82% Congestion 68% Itching 68% Ocular symptoms There is a clear need for a new and more effective therapy Uncontrolled Bousquet et al, 2012 AR: allergic rhinitis; VAS: visual analogue scale

13 Patients (%) 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 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; AR: allergic rhinitis;

14 Cellular infiltration Why does current therapy provide insufficient symptom control? Pathologic gaps with oral antihistamines Basophil Do not inhibit mast cell degranulation, leukotriene receptor interaction or inflammatory cell recruitment of the late phase

15 Why does current therapy provide insufficient symptom control? Pathologic gaps with intranasal corticosteroids Basophil Do not inhibit mast cell degranulation or leukotriene and histamine receptor interaction

16 rtnss (% Change from Baseline) Concurrent therapy with intranasal corticosteroids and oral anti-histamines is also not the answer Lack of additive effect: intranasal corticosteroids + oral antihistamine * p 0.02 vs PLA; p<0.01 vs LOR Anolik et al 2008 MFNS: mometasone furoate nasal spray; LOR: loratadine; PLA: placebo

17 What is the allergic rhinitis burden in a matched MP29-02 clinical study patient population? A new health survey including 746 moderate/severe patients MP29-02 clinical study patient matching Reflective total nasal symptom score (rtnss): 8/12 Congestion score 2 Aim 1. To define the unmet medical need of AR patients matched to those in the MP29-02 clinical development programme 2. To use this information to show for the first time that a new treatment for AR management fills this unmet need and provides what patients want The survey included questions on respondents : Treatment Episode duration Impact of symptoms on productivity Absenteeism Pitman et al, 2012 AR: allergic rhinitis

18 The AR symptom burden and its consequences: absenteeism and asthma treatment modification Symptom episodes are short but occur several times during the season with negative impact: An average SAR symptom episode lasts 12.5 days Absenteeism due to SAR: 4.1 days/year 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 Pitman et al, 2012 AR: allergic rhinitis; SAR: Seasonal Allergic Rhinitis

19 Patients (%) Impact of seasonal allergic rhinitis on work productivity Impact on work productivity Work is negatively impacted by over 90% of patients when symptomatic Pitman et al, 2012

20 Patients (%) How do patients treat their AR and why do they comedicate? 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 % moderate/severe patients on 2 AR medications The need for faster and more effective treatment was the primary reason for co-medicating New allergic rhinitis therapy should provide better and faster nasal and ocular symptom relief Pitman et al, 2012; AR: Allergic Rhinitis

21 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 antihistamines) Still had a rtnss of 12.8/24 Still had a rtoss of 8.6/18 Allergic rhinitis was poorly controlled with current mono- and multiple-therapies Price et al, 2013 rtnss: reflective total nasal symptom score; rtoss: reflective total ocular symptom score; INS: intranasal corticosteroid

22 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 Concurrent therapy* New AR treatment Nasal congestion +/ Nasal pruritis Rhinorrhoea Sneezing Ocular itching Ocular watering Ocular redness INS + OAH or INS + LTRA AR: allergic rhinitis

23 Conclusions There is an unmet need in allergic rhinitis Allergic rhinitis (AR) is a challenge to treat and has a negative impact on virtually every aspect of patients lives Patients remain symptomatic on treatment since no medication class offers complete pathologic coverage There is a scarcity of direct head to head comparisons of active treatments and a need to assess efficacy in a more clinically relevant way The specific unmet needs of patients matched to those in a clinical development programme has been defined. These AR patients: Carry a high socioeconomic burden in terms of symptoms, absenteeism, lost productivity and impact on asthma treatment Use multiple therapies in an attempt to achieve faster and better symptom control Have insufficient symptom control (even those on multiple therapies) These patients would benefit from a new and more effective therapy AR: allergic rhinitis; DCE: discrete choice experiment

24 MP29-02: the drug of choice for the treatment of allergic rhinitis Warner Carr USA

25 MP29-02: a novel intranasal formulation of intranasal Fluticasone propionate and Azelastine hydrochloride Overview of Clinical Development programme 4 phase III, multi-centre, randomised, double-blind, placebo-controlled, parallel group trials (SAR trials) One long-term open-label safety study (chronic rhinitis trial) In all, 4,617 patients Objectives: To directly compare the efficacy and safety of MP29-02 with Azelastine and Fluticasone propionate nasal sprays in patients with moderate-to-severe SAR To assess the long-term safety of MP29-02 in patients with chronic rhinitis Hampel et al, 2010; Carr et al, 2012; Price et al, 2012; SAR: seasonal allergic rhinitis

26 MP29-02 clinical programme summary The largest body of evidence directly comparing the effectiveness of anti-rhinitis medications Study number Season N (ITT) Comparators MP-4001 MP-4002 MP-4004 MP /2008 Texas Cedar 2008 spring 2008 fall 2009 spring and summer 607 Marketed Comparators Astelin and generic Fluticasone 831 Regulatory studies Azelastine and 776 Fluticasone formulated in MP29-02 vehicle and 1791 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; Price et al, EAACI, 2012 FP: fluticasone propionate; ITT: intent to treat

27 MP29-02 study design: Seasonal Allergic Rhinitis Studies 1 spray/nostril bid Dymista NS Placebo run-in 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) Hampel et al, 2010; Carr et al, 2012 NS: nasal spray; TNSS: Total Nasal Symptom Score; TOSS: Total Ocular Symptom Score; bid: twice daily

28 MP29-02 trial patients at screening Patients had moderate to severe Seasonal Allergic Rhinitis 1,2 12 years old with a 2-year history of Seasonal Allergic Rhinitis (SAR) Positive skin prick test to relevant pollen Moderate-to-severe SAR Defined by ARIA guidelines Defined by baseline rtnss (at least 8/12) and nasal congestion score (at least 2/3) at screening visit itnss of 8 at time point zero At randomisation patients demonstrated: Baseline rtnss of (max =24) Baseline rtoss of (max =18) The majority of allergic rhinitis patients attending their doctor have moderate-to-severe disease 3 1.Hampel et al, 2010; 2. Carr et al, 2012; 3. Canonica et al, 2007 ARIA: Allergic Rhinitis and its impact on asthma; rtnss: reflective total nasal symptom score; rtoss: reflective total ocular symptom socre

29 Endpoints Primary 1,2 Reflective total nasal symptom score [rtnss] (AM + PM) Maximum score = 24 Key secondary 1,2 Onset of action 4h instantaneous TNSS [itnss] Reflective total ocular symptom score [rtoss] (AM + PM) Maximum score = 18 Individual nasal and ocular symptoms Nasal: congestion; itching; rhinorrhoea; sneezing Ocular: itching, redness, watering Post hoc 2 rtnss by patient baseline severity Substantial treatment response 50% reduction from baseline in rtnss 1 point remaining for EACH nasal symptom (i.e. complete/almost complete symptom relief) 1. Hampel et al, 2010; 2. Carr et al, 2012

30 MP29-02: rationale for a meta-analysis

31 Rationale for meta-analysis MP4002/MP4004/MP4006 Decided to: Pool the results from studies MP4002/MP4004/MP4006 since: Same active comparators not commercially available Same study design Similar inclusion exclusion criteria Same endpoints MP 4001 study Active comparators are commercially available Rationale for this study separation is further endorsed by PK findings AZE: azelastine; FP: fluticasone propionate; PK: pharmacokinetic

32 Studies MP4002/MP4004/MP4006 have the same active comparators PK Study 3282 (FP) design Healthy subjects Treatments Dymista Dymista without Azelastine Generic FP (Bohringer ingelheim) 3 period, 6 sequence cross-over (William s design) Single dose (2 sprays per nostril = 200 µg fluticasone) 24 hour observational period 14 day wash-out LLOQ 0.25 pg/ml (FF: 10 pg/ml; FP: pg/ml) PK: pharmacokinetic; FP: fluticasone propionate; LLoQ: lower limit of quantification; FF: fluticasone furoate

33 Mean serum concentration (pg/ml) PK Study 3282 (FP) Plasma concentrations (Per Protocol, n=19) Scheduled time (hours) The result is a more efficient intranasal absorption Plasma levels are much below the threshold for systemic side effects PK: pharmacokinetic; FP: fluticasone propionate; LLoQ: lower limit of quantification; BI: Boehringer Ingelheim

34 LS Mean Change from Baseline in rtnss Consistent benefit of MP29-02 across ALL SEASONS Spring Autumn Spring & Summer MP FP AZE PLA rtnss baseline ranges were: MP4002: ; MP4004: ; MP4006: Carr et al, 2012 MP4002: p=0.034 vs Dymista ; p=0.001 vs Dymista ; * p<0.001 vs Dymista ; MP4004: p=0.038 vs Dymista ; p=0.032 vs Dymista ; * p<0.001 vs Dymista ; MP4006: p=0.029 vs Dymista ; p=0.001 vs Dymista ; * p<0.001 vs Dymista AZE: Azelastine; FP: Fluticasone propionate; rtnss: reflective Total Nasal Symptom Score

35 Δ Placebo LS Mean Change from Baseline rtnss Δ Placebo LS Mean Change from Baseline rtnss Δ Placebo LS Mean Change from Baseline rtnss Δ Placebo LS Mean Change from Baseline rtnss Significantly greater baseline rtnss reduction MP4002 (n=831) MP4004 (n=776) p=0.034 vs MP29-02; p=0.002 vs MP29-02 MP4006 (n=1791) p=0.038 vs MP29-02; p=0.032 vs MP29-02 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 Carr et al, 2012 rtnss: reflective Total Nasal Symptom Score; FP: Fluticasone propionate; AZE: Azelastine; PLA: placebo

36 Δ Placebo LS Mean Change from Baseline: Individual symptom score MP29-02 targets all the different nasal symptoms of Allergic Rhinitis Carr et al, 2012 * p vs MP29-02; p vs MP29-02; p= vs MP29-02 MP29-02 (n=848) ;AZE: Azelastine (n=847); FP: Fluticasone propionate (n= 846); Placebo (n= 857)

37 LS Mean change from Baseline in itnss MP29-02 has a rapid onset of action Within 30 minutes Time (mins) Onset of action defined as first consecutive significance versus placebo Onset of action for FP was >240 mins Carr et al, 2012 * p vs placebo (Study MP4004); itnss: instantaneous total nasal symptom score

38 LS Mean Change from Baseline in rtoss (Delta placebo) MP29-02 effectively relieves overall ocular symptoms ITT Symptomatic patients BL TOSS 8 Carr et al, 2012; Data on file; p vs MP29-02 rtoss: reflective total ocular symptom socre; FP: fluticasone propioante; AZE: azelastine

39 Δ Placebo LS Mean Change from Baseline: Individual symptom score MP29-02 targets all the different ocular symptoms of Allergic Rhinitis p= vs MP29-02 p= vs MP29-02 p= vs MP29-02 Carr et al, 2012 MP29-02 (n=848) ;AZE: Azelastine (n=847); FP: Fluticasone propionate (n= 846)

40 rtnss (LS mean change from baseline) Effective regardless of symptom severity Carr et al, 2012 * p vs all active treatments; p <0.04 vs MP29-02; p< 0.01 vs MP29-02 rtnss: reflective Total Nasal Symptom Score; RQLQ: Rhinitis Quality of Life Questionnaire; FP: Fluticasone propionate; AZE: Azelastine; PLA: placebo

41 % Patients % Patients Treatment response with MP29-02 Substantial response (A) 50% rtnss reduction Complete/near-to-complete response (B) 1 pt left in each nasal symptom More MP29-02 patients achieved this response and up to 3 days faster than FP and up to 5 days faster than AZE More MP29-02 patients achieved this response and up to 5 days faster than FP and up to 7 days faster than AZE Carr et al, 2012 AZE: Azelastine; FP: Fluticasone propionate ; PLA: placebo.responder rate = % of patients who achieved the specified response

42 These results have been published in JACI Take home messages Prior to MP29-02, no clinical development program has demonstrated additional benefit over two currently recommended first-line AR therapies in moderate-tosevere patients Patients with moderate-to-severe SAR achieved better control and were controlled earlier with MP29-02 than with recommended medications according to guidelines The results are consistent among different parameters, including ocular symptoms, and across various allergy seasons MP29-02 provided benefits for all patients, providing significantly greater symptom relief than Fluticasone propionate or Azelastine monotherapy regardless of disease severity Carr et al, 2012 JACI: Journal of Allergy & Clinical Immunology; AR: Allergic Rhinitis; SAR: Seasonal Allergic Rhinitis

43 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 AR: Allergic Rhinitis

44 MP29-02 versus marketed comparators: efficacy & safety Glenis Scadding UK

45 MP29-02 versus commercially available first line therapy The treatment effect of MP29-02 becomes even more striking when comparing it to commercially-available FP the Meda Fluticasone propionate preparation masks the real world effects of MP29-02

46 LS Mean Change from Baseline in rtnss: (Delta Placebo) rtnss LS Mean Change from Baseline MP29-02 most effectively treats overall nasal symptoms MP29-02 provided significantly greater nasal symptom relief than FP or AZE Superiority of MP29-02 apparent from day 1 and sustained p< vs Mp29-02; p= vs MP29-02 * p 0.04 vs MP29-02 Meltzer et al, 2013 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

47 LS Mean Change from Baseline (Delta Placebo) LS Mean Change from Baseline (Delta Placebo) LS Mean Change from Baseline (Delta Placebo) LS Mean Change from Baseline (Delta Placebo) Patients treated with MP29-02 experience significant relief from all their nasal symptoms Better than intranasal Fluticasone or Azelastine Nasal Congestion Nasal Itch p= vs MP29-02; p= vs MP29-02 p= vs MP29-02; p= vs MP29-02 Rhinorrhea Sneezing p= vs MP29-02; p< vs MP29-02 p= vs MP29-02; p< vs MP29-02 Meltzer et al, 2013 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

48 LS Mean Change from Baseline in rtnss (Delta Placebo) MP29-02: the most effective option regardless of severity Most AR patients have moderate-to-severe disease More severe Less severe p= vs MP29-02; p= vs MP29-02 MP29-02 (n=77); FP (n=64); AZE (n=68) p= vs MP29-02; p= vs MP29-02 MP29-02 (n=76); FP (n=87); AZE (n=84) Meltzer et al, 2013 AR: allergic rhinitis; AZE: Azelastine; FP: Fluticasone propionate; rtnss: reflective Total Nasal Symptom Score Results expressed as LS mean change from baseline (delta placebo) with 95% CI

49 LS Mean Change from Baseline in rtoss (Delta Placebo) MP29-02 is also more effective than intranasal steroids in treating the symptoms of conjunctivitis ITT Symptomatic patients BL TOSS 8 p= vs MP29-02; p= vs M)29-02 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) Meltzer et al, 2013 rtoss: reflective total ocular symptom score; ITT: intent to treat; AZE: Azelastine; FP: Fluticasone propionate; BL: baseline. Results expressed as LS mean change from baseline (delta placebo) with 95% CI

50 LS Mean Change from Baseline (Delta Placebo) Patients treated with MP29-02 experience significant relief from all their ocular symptoms Better than intranasal Fluticasone or Azelastine 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 Meltzer et al, 2013 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

51 rt7ss LS Mean Change from Baseline (Delta Placebo) rt7ss LS Mean Change from Baseline MP29-02 most effectively treats the entire rhinitis symptom complex (both nasal & ocular symptoms) Twice as effective as intranasal FP or AZE in relieving both nasal & ocular symptoms Superiority of MP29-02 apparent from day 1 and sustained Day p= vs MP29-02; p= vs MP29-02 ; * p vs MP29-02 ; Meltzer et al, 2013 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

52 % Patients MP29-02: superior in providing faster and substantial symptom relief ( 50% reduction in nasal symptoms) FP AZE PLA 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 (p=0.0284) or AZE (p=0.0223) Day 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 Meltzer et al, 2013; 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

53 % Patients MP29-02: More patients will be symptom-free than first-line therapy 1 out of 6 MP29-02 patients achieve complete or near-to-complete symptom relief Days faster than FP or AZE Relevance: Complete symptom relief is what patients want Day Meltzer et al, 2013 AZE: Azelastine; FP: Fluticasone propionate; PLA: placebo Responder Rate = % of patients with a score of 1 for every nasal symptom

54 MP29-02 is well tolerated (14 day trials) MP4001 TRAE n(%) MP29-02 (n=153) AZE (n=152) FP (n=153) PLA (n=151) Dysgeusia 11 (7.2) 3 (2.0) 0 0 Epistaxis 6 (3.9) 3 (2.0) 6 (3.9) 5 (3.3) Headache 3 (2.0) 1 (0.7) 5 (3.3) 1 (0.7) MP4002 MP29-02 (n=207) AZE (n=208) FP (n=207) PLA (n=210) Dysgeusia 5 (2.4) 7 (3.4) 2 (1.0) 1 (0.5) Epistaxis 2 (1.0) 4 (1.9) 5 (2.4) 2 (1.0) Headache 1 (0.5) 1 (0.5) 5 (2.4) 3 (1.4) MP4004 MP29-02 (n=195) AZE (n=194) FP (n=189) PLA (n=200) Dysgeusia 4 (2.1) 14 (7.2) 1 (0.5) 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) MP4006 MP29-02 (n=451) AZE (n=449) FP (n=450) PLA (n=451) Dysgeusia 21 (4.7) 23 (5.1) 1 (0.2) 0 Epistaxis 8 (1.8) 5 (1.1) 5 (1.1) 8 (1.8) Headache 6 (1.3) 9 (2.0) 6 (1.3) 2 (0.4) Hampel et al, 2010; Carr et al, 2012; Meltzer et al, 2012 TRAE: treatment related adverse event; AZE: azelastine; FP: fluticasone propionate; PLA: placebo

55 MP4001 Conclusions (I) MP29-02 versus marketed comparators The efficacy of MP29-02 is more apparent compared to commerciallyavailable first line therapy (vs non-commercially available comparators used in studies MP4002, MP4004 and MP4006 [i.e. the JACI publication]). MP29-02 is more effective than commercially available first-line therapies in combating overall nasal symptoms (rtnss), overall ocular symptoms (rtoss) as well as each of the individual symptoms. MP29-02 provides benefits for all patients, providing significantly greater symptom relief vs FP or AZE regardless of disease severity AR: Allergic Rhinitis; rtnss: reflective Total Nasal Symptom Score; rtoss: reflective total ocular symptom score; FP: Fluticasone propionate; AZE: Azelastine

56 MP4001 Conclusions (II) MP29-02 versus marketed comparators In AR patients with moderate to severe rhinoconjunctivitis, MP29-02 is more effective than either FP or AZE More MP29-02 patients achieved substantial and complete/near-to-complete nasal symptom relief and achieved it days earlier than patients treated with firstline therapy MP29-02 is well tolerated MP29-02 is the drug of choice for the treatment of allergic rhinitis AR: Allergic Rhinitis;; FP: Fluticasone propionate; AZE: Azelastine

57 MP29-02: long-term efficacy and safety David Price UK

58 MP4000 long term study Objective and efficacy endpoint The primary objective of study MP4000 was to evaluate the safety and tolerability of MP29-02 with chronic use over a 1-year period in subjects with chronic allergic or non-allergic rhinitis. Changes from baseline in the PM 12h rtnss to every 4 week treatment interval were also analysed (ANCOVA) for treatment differences between MP29-02 and commercial FP nasal spray. FP: fluticasone propionate; rtnss: reflective total nasal symptom score; ANCOVA: analysis of covariance

59 MP4000 inclusion criteria Male and female subjects, years of age with a history of chronic rhinitis symptoms due to allergic or non-allergic perennial rhinitis or non-allergic vasomotor rhinitis. who were likely to benefit from continuous therapy with MP29-02 nasal spray or FP nasal spray. Subjects with a seasonal allergic component were also included, provided that they had significant symptoms outside of the allergy season during the year. Subjects on a stable dose of subcutaneous immunotherapy were included. FP: fluticasone propionate

60 Chronic rhinitis study design: 1 year Design: randomized, open-label, active controlled, parallel group study in subjects with chronic allergic or non-allergic rhinitis. 1-week screening period preceded the 12-month treatment period. Qualified subjects were randomized in a 2:1 ratio to treatment with MP29-02 nasal spray 1 spray per nostril twice daily or FP nasal spray 2 sprays per nostril once daily. Visits at Months 1, 3, 6, 9, and 12. FP: fluticasone propionate

61 MP4000 subject baseline characteristics Chronic rhinitis Age (yrs) 12 to < 18 [n (%)] 18 to <65 [n (%)] 65 [n (%)] MP29-02 (n=404) 32.8 (11.5) 28 (6.9) 373 (92.3) 3 (0.7) FP (n=207) 35.3 (11.5) 8 (3.9) 196 (94.7) 3 (1.4) Gender Male n (%) 240 (59.4) 110 (53.1) Race n (%) Asian Black 404 (100.0) 0 (0.0) 206 (99.5) 1 (0.5) Height (in) 63.8 (3.9) 63.9 (3.9) Weight (lb) (29.1) (26.8) PM rtnss 3.84 (2.49) 3.87 (2.32) Overall RQLQ score 2.06 (1.05) 2.23 (1.06) Disease duration (yrs) 5.9 (5.0) 6.3 (6.4) PAR sub-population: MP29-02 (n=278); FP (n=145) FP: fluticasone propionate; rtnss: reflective total nasal symptom score; RQLQ: rhinitis quality of life questionnaire; PAR: perennial allergic rhinitis

62 LS Mean change from Baseline in rtnss MP29-02 most effectively relieves overall nasal symptoms: chronic rhinitis patients MP29-02 versus marketed comparator P<0.05 vs MP29-02 Week Price et al, EAACI 2012 rtnss: reflective Total Nasal Symptom Score; FP: Fluticasone propionate

63 LS Mean change from Baseline in rtnss MP29-02 most effectively relieves overall nasal symptoms: PAR patients MP29-02 versus marketed comparator P<0.05 vs MP29-02 Week Data on file PAR: Perennial Allergic Rhinitis; rtnss: reflective Total Nasal Symptom Score; FP: fluticasone propionate

64 % Patients More MP29-02 patients first achieve 100% rtnss reduction and days faster: chronic rhinitis patients Time to first response: 100% PM rtnss reduction from baseline ITT Population 1 in 2 MP29-02 patients by Day 7 1 in 3 MP29-02 patients by Day 3 Twice as many MP29-02 patients symptom free on Day 1 Day Lieberman et al, EAACI 2013 rtnss: reflective total nasal symptom score; ITT: intent to treat; FP: fluticasone propionate;

65 % Patients More MP29-02 patients first achieve 100% rtnss reduction and days faster: PAR patients Time to first response: 100% PM rtnss reduction from baseline Same pattern observed PAR Population P = vs MP29-02 Day Lieberman et al, EAACI 2013 rtnss: reflective total nasal symptom score; PAR: perennial allergic rhinitis; FP: fluticasone propionate

66 Patients treated with MP29-02 experienced more symptom-free days Population Days available Days symptom-free Difference MP29-02* FP MP29-02* FP MP29-02*- 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 experience 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) Lieberman et al, EAACI 2013 ITT: Intent to Treat; FP: fluticasone propionate; PAR: perennial allergic rhinitis; NAR: non-allergic rhinitis

67 Overview of TEAEs and TRAEs (safety population) 52 weeks Number of AE reported MP29-02 (N=404) FP (N=207) All TEAEs All TRAEs Number (%) of subjects with AE All TEAEs 188 (46.5) 92 (44.4) Mild 136 (33.7) 67 (32.4) Moderate 47 (11.6) 25 (12.1) Severe 5 (1.2) 0(0.0) All TRAEs 38 (9.4) 23 (11.1) Mild 29 (7.2) 16 (7.7) Moderate 9 (2.2) 7 (3.4) Severe 0 (0.0) 0 (0.0) Number (%) of subjects with SAE 3 (0.7) 1 (0.5) Number (%) of subjects with AE leading to discontinuation 11 (2.7) 6 (2.9) Number (%) of deaths 0 (0.0) 0 (0.0) The proportion of subjects with a TEAEs or TRAEs was similar for both groups Most of these events were mild in nature Data on file AE: adverse event; TEAE: treatment emergent adverse event; TRAE: treatment-related adverse event; SAE: serious adverse event; FP: fluticasone propionate

68 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. Price et al, SERIN 2013 FP: fluticasone propionate

69 Other safety outcomes No appreciable changes in laboratory values were observed. Nasal examination findings were unremarkable The incidences and intensity of epistaxis, nasal irritation, mucosal oedema, nasal discharge, mucosal erythema, bleeding and crusting were comparably low in the two treatment groups Reduced following 6 and 12 months treatment with either Dymista or FP There were no nasal mucosal ulcerations or perforations Ocular examination findings were unremarkable. No patient developed glaucoma in either group and the incidence of cataracts was low for both groups (0.2% for MP29-02; 1.4% for FP) There were no significant differences between groups in fasting AM serum cortisol levels following 12 months continuous treatment with MP29-02 (-0.08 mcg/dl) or FP (-1.04 mcg/dl) Data on file FP: fluticasone propionate

70 Long-term summary I In chronic rhinitis patients MP29-02 reduced PM rtnss from baseline significantly more than FP, from Day 1 up to and including week 28 with treatment difference maintained for 52 weeks. Consistent significance was lost post-week 28 due to loss of sample power due to decreasing sample size (ICH guideline E1A) and not due to reduced treatment effect During the first month of treatment more chronic rhinitis patients first became symptom-free on MP29-02 and did so days faster than FP patients. 1 in 2 MP29-02 patients first achieved 100% response by Day 7 (Day 16 for FP) Similar pattern observed in PAR sub-population rtnss: reflective total nasal symptom score; FP: fluticasone propionate; PAR: perennial allergic rhinitis; NAR: non-allergic rhinitis

71 Long-term efficacy summary Patients treated with MP29-02 experienced approximately 1 months more symptom-free days than those treated with FP 25.9 more symptom free days in ITT population (8.4% more than FP [p=0.0005]) 23.9 more symptom free days in PAR population (7.3% more than FP [p=0.0122]) MP29-02 has an excellent safety profile with no safety signal which would preclude its long-term use These results affirm MP29-02 s broad therapeutic spectrum and confirm its consistent superiority over an intranasal corticosteroid FP: fluticasone propionate; PAR: perennial allergic rhinitis; NAR: non-allergic rhinitis

72 MP29-02 is a new AR therapy and not a simple fixed dose combination Jean Bousquet France

73 MP29-02 clinical development programme summary Regulators requested studies versus marketed AND reformulated comparators thus already acknowledging the likely influence of formulation/device on clinical 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 607 Marketed Comparators Astelin and generic Fluticasone 831 Regulatory studies Azelastine and 776 Fluticasone formulated in MP29-02 vehicle and 1791 applied in same device Hampel et al, 2010; Carr et al, 2012; Price et al, EAACI, 2012 FP: fluticasone propionate; ITT: intent to treat

74 Mean serum concentration (pg/ml) MP29-02 is a new product for AR managment The Evidence: FP in MP29-02 has a different PK profile than commercial FP Scheduled time (hours) FP in MP29-02 has a different PK profile than commercial FP Therefore the term fixed combination is misleading it is a new product with its own product characteristics e.g. PK profile PK: pharmacokinetic; FP: fluticasone propionate; LLoQ: lower limit of quantification; BI: Boehringer Ingelheim

75 % Patients % Patients MP29-02 is a new product for AR management The Evidence: FP in MP29-02 has a different clinical profile than commercial FP 50% response: MP29-02 versus commercial FP and AZE 50% response: MP29-02 versus non-commercial FP and AZE FP AZE PLA FP AZE PLA Day Commercial FP and commercial AZE are not different Day Non commercial FP is different This is the FP in MP29-02 FP in MP29-02 has a different PK profile and a different clinical profile evidenced by differences in the 50% rtnss response curves AZE: azelastine; FP: fluticasone propionate; rtnss: reflective total nasal symptom score

76 Discussion and wrap-up

77 Is MP29-02 the drug of choice for the treatment of allergic rhinitis? 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 AR: Allergic Rhinitis

78 Can MP29-02 change the landscape of AR management?.to the same extent as that seen in asthma management Asthma Landscape Fast relief: SABA Sustained relief: LABA Preventer: ICS Unmet medical need Most patients were taking SABA, LABA and ICS Disease remained poorly controlled Improving asthma control became a primary focus Rhinitis Landscape Fast relief: anti-histamines Sustained & most effective relief: intranasal corticosteroids Unmet medical need Changing face of the disease 20% SCUAD 75% of patients on unproven combination therapy More effective therapies urgently needed Seretide or Symbicort represented a new paradigm for asthma management 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

79 Thank you