Bulgaria Ewopharma MedReps Training Course 14 December 2010

Agenda 8.30-10.00 am Who is the allergic patient ? How the allergic patient is managed ? Why the allergic patient is underdiagnosed ? Why the allergic patient is undertreated ? Break 10.15 – 12.30 am Grass rationalisation, Posology - arguments to increase to 8 drops per day Patient follow up, Post graduate course presentation and arguments

Allergic patient: the current practice Who is the allergic patient ? How the allergic patient is managed ? Why the allergic patient is underdiagnosed ? Why the allergic patient is undertreated ?

Who is the allergic patient ? Epidemiology of respiratory allergic diseases ECHRS ISAAC Classification of respiratory allergic diseases ARIA GINA The natural course of allergic diseases

Allergic Rhinitis: prevalence in Europe Prevalence of AR in a population-based survey in 6 EU countries1: UK, Germany, France, Belgium, Italy and Spain AR European prevalence is 23%, of which 45% are undiagnosed1 26.0%1 29.8%2 500 million people suffer from AR worlwide 20.6%1 21.0%3 24.5%1 16.9%1 AR prevalence is quite high, with almost half of sufferers not being diagnosed. From those, a percentage have severe uncontrolled symptoms (target population for AIT). 21.5%1 1.Bauchau V., Durham S.R., Eur Respir J 2004:758-764 2.Bachert C. Allergy 2006: 61: 693-698 3.Brehl P. Ind Health 2003 Apr; 41 (2): 121-3

Masoli et al. Allergy 2004; 59(5): 469-78. Prevalence of clinical asthma in both adults and children : ISAAC Study Proportion of population (%) 10.1 2.5–5.0 7.6–10.0 0–2.5 5.1–7.5 No standardised data Masoli et al. Allergy 2004; 59(5): 469-78.

What is a severe allergic rhinitis ? Classification of allergic rhinitis*: New classification developed in 2001 by the ARIA consensus (Allergic Rhinitis and its Impact on Asthma) in order to characterise rhinitis and its impact on the quality of life according to its duration (intermittent or persistent) and the severity of the symptoms.  *Bousquet J. et al. Allergic Rhinitis and its Impact on Asthma (ARIA).Allergy 2008: 63 (Suppl. 86): 8–160 Intermittent Symptoms < 4 days per week or < 4 weeks Persistent > 4 days per week and > 4 weeks Slight • normal sleep • normal social and leisure activities • normal work and school life • symptoms causing minimal discomfort Moderate - Severe • sleep disturbed • disrupted social and leisure activities • disrupted work and school life • unpleasant symptoms

Profile of patients consulting the allergist REALIS survey: clinical and sensitization profile of patients consulting for respiratory allergies in France 80.3% moderate to severe patients N=2714 Allergists and pulmonologists recruited patients consulting for respiratory allergy and who were being tested for allergy for the first time (September 2007 - January 2008) The severity of allergic rhinitis or asthma was assessed by ARIA 2001 and GINA 2006 guidelines Among patients who were seen by a specialist, the majority (more than 8 in 10) had moderate to severe AR. ~ 80% of AR patients consulting an allergist have moderate-to-severe symptoms They have had allergic rhinitis symptoms during 4 to 5 years before they look for an allergy specialist M.Migueres et al. French REALIS survey. Abstract at XXVIII EAACI

Altered quality of life due to the allergic symptoms SLEEP & TIREDNESS 77 % of patients had sleep troubles 46 % of patients felt tired DAILY ACTIVITIES IMPAIRED LEARNING & COGNITIVE FUNCTIONS DISTURBED Impact on Allergic Respiratory Diseases WORK & SCHOOL PRODUCTIVITY < 90 % effectiveness at work < 93 % impaired classroom performance EMBARRASSMENT Adolescents embarassed to use inhalers

Allergic rhinitis is a risk factor for asthma WHO – Initiative 2000 ALLERGIC RHINITIS AND ITS IMPACT ON ASTHMA (ARIA) Allergic rhinitis has been defined by the WHO as major chronic disease of the airways Allergic rhinitis is a risk factor for asthma Expand the diagnosis: think of rhinitis in patients with asthma, think of asthma in patients with rhinitis WHO – Initiative 2000: Ein aktuelles Dokument der Weltgesundheitsorganisation WHO mit dem Titel „ALLERGIC RHINITIS AND IT´S IMPACT ON ASTHMA (ARIA)“ weist auf die enge Bezeihung zwischen einer Allergie an der Nase und der Lunge hin und fordert eine gemeinsame Behandlungsstrategie für beide Organsysteme. A common treatment strategy for rhinitis and asthma patients is recommended!

Why the allergic patient is underdiagnosed ? How the allergy diagnosis must be performed ? How the GPs diagnose the allergic diseases ? What’s going wrong with the allergy diagnosis ?

Diagnosis Process in Allergology Patient with suspected respiratory allergy symptoms Clinical history for allergy Allergy testing In allergy medicine, the diagnostic process itself is relatively simple but does need to follow a specific sequence. Firstly, one has to draw up a detailed medical profile of the patient on the basis of his or her clinical history and a detailed interview. This will enable the practitioner to broadly identify the allergen or group of allergens that are most likely to cause the patient's symptoms. During the patient interview, the practitioner seeks to establish the individual's personal medical history. Did he or she suffer from asthma or rhinitis as a child? And how about atopic dermatitis (an aggravating factor for the appearance of allergy)? In childhood, did the patient suffered from hypersensitivity to known allergenic foods? The second phase will then involve specific allergen testing.

Skin prick-tests method Allergens Stallerpoint®

Measurement of the skin reaction 15 – 20 minutes after testing Wheal diameter

How the GPs diagnose the allergic diseases ? Patient with suspected respiratory allergy symptoms Clinical history for allergy Stop In allergy medicine, the diagnostic process itself is relatively simple but does need to follow a specific sequence. Firstly, one has to draw up a detailed medical profile of the patient on the basis of his or her clinical history and a detailed interview. This will enable the practitioner to broadly identify the allergen or group of allergens that are most likely to cause the patient's symptoms. During the patient interview, the practitioner seeks to establish the individual's personal medical history. Did he or she suffer from asthma or rhinitis as a child? And how about atopic dermatitis (an aggravating factor for the appearance of allergy)? In childhood, did the patient suffered from hypersensitivity to known allergenic foods? The second phase will then involve specific allergen testing.

Why the allergic patient is underdiagnosed ? What’s going wrong with the allergy diagnosis ?

Consultation is not frequent “How recently have you been seen by a health care professional?” -Internet and telephone survey conducted in 2005 in general population from UK, Germany, Italy and Spain -N=2966 randomly selected adults with allergies Despite a high number of European population suffering from allergy, the consultation is not frequent. ~10% of the European population with rhinitis symptoms was never seen by a health care professional (nurse or doctor) for their condition Maurer M, Zuberbier T, Allergy 2007: 62: 1057-1063.

19% have consulted a specialist Only 1 patient over 5 consulted a specialist TNS STUDY: TNS survey conducted in France 2009. N= 623 subjects with AR symptoms from 2003 general population TYPE OF DOCTORS CONSULTED BY PATIENTS: 19% have consulted a specialist *Several consultations per doctor were possible **in France, a first consultation with a GP is mandatory before referral to a specialist When patients consult a doctor, the majority sees a GP. Only one patient in 5 consult a specialist. It is important to note that in France a patient must first be seen by a GP, who then decides if the patient should be referred to a specialist. In 94% of patients consulting a GP in 1st line treatment 19% consulted a specialist (13% an allergist**), in 2nd line treatment A.Didier et al. Unmet therapeutic needs in AR. Abstract at XXIX EAACI 2010

How the allergic patient is managed ? The allergen avoidance The pharmacotherapy The allergen immunotherapy (AIT)

The optimal management of the allergic patient The patient education Allergen avoidance Allergen Immunotherapy Pharmacotherapy

Why the allergic patient is undertreated ? The efficacy of the allergen avoidance ?

Allergen avoidance : recommended but a limited efficacy Mites: efficacy not well demonstrated Animals : patients can be sensitized without direct contact with pets Pollen: Unfeasible

Why the allergic patient is undertreated ? The efficacy of the pharmacotherapy ?

Therapy of Allergic Rhinitis ARIA Update 2007 WHO Intermittent symptoms Persistent symptoms Mild intermittent Severe intermittent Mild persistent Severe persistent Severity of Allergic Rhinitis patients Allergen and irritant avoidance Oral or local non-sedative H1-blocker Intra-nasal or oral decongestant Intranasal steroid Local cromone Specific Immunotherapy 11 % 35% 8% 46%

Current Symptomatic Treatments Rhinitis H1-Antihistamines Inhaled corticosteroids B2-agonists & Bronchodilators Antileucotriens Nasal corticosteroids Rhinitis Asthma Rhinitis Asthma Asthma

Total rhinitis score: Nasal Mometasone % MFNS 100mcg/QD MFNS 200mcg/QD 79 Placebo 75 75 71 70 63 59 60 53 53 44 45 Mean improvement from baseline 36 34 29 Slide 21: Safety and tolerability of grass pollen tablet sublingual immunotherapy The oral mucosa contains a limited number of proinflammatory cells, such as mast cells, which probably contributes to the absence of anaphylactic reactions with sublingual immunotherapy the basis of the therapy’s excellent safety profile. In this study all treatment doses were well-tolerated and as in previous studies of sublingual immunotherapy there were few serious and no fatal adverse events. The slide shows the treatment-emergent adverse events with an incidence of more than 5% in the safety population. These were almost all local reactions related to direct oral contact with the allergen and mainly occurred at the beginning of the treatment course during the initiation phase. They were seen rarely or were absent from the placebo treated group. All local reactions resolved without medical intervention. Other frequently reported adverse events were headache and nasopharyngitis the incidence of which was similar across all treatment groups including the placebo group. Can we say something about formulation or adjuvants improvements underway here to reduce these AEs? The number of patients reporting “severe” AEs was similar in each of the active treatment groups, 10 for 100 IR and 500 IR and 8 for 300 IR. Not all patients experiencing severe adverse events left the study, only 3 withdrew from the 100 IR, 6 from the 300 IR and 8 from the 500 IR. No patients withdrew from the placebo group because of treatment-emergent adverse events. One patient in the 300 IR group and two in the 500 IR group experienced serious adverse events but these were not related to the study medication. Time (day) * p0.01 relative to placebo Van Drunen et al., Allergy 2005: 60 (Suppl. 80): 5-19

Total rhinitis score : Nasal Mometasone MFNS 50mcg/QD MFNS 100mcg/QD 60 MFNS 200mcg/QD MFNS 800mcg/QD Placebo 50 40 Improvement in total nasal symptom scores 30 20 10 Baseline 3 7 14 21 28 Endpoint Time (day) Van Drunen et al., Allergy 2005; 60 (Suppl. 80): 5-19

Rhinitis symptoms in seasonal AR Montelukast vs. placebo and Loratadin Daytime nasal symptoms Daily composite (daytime nasal & night-time) Night-time symptoms -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 -9% -16% -22% -8% -20% -15% -9% -16% -20% Change from baseline (0-3 scale; LS mean  SE) Placebo Montelukast Loratadine Philip et al., Clin Exp Allergy 2002; 32: 1020-1028

A patient uncontrolled and not satisfied by the pharmacotherapy 35-40 % of patients receiving optimal standard symptomatic treatment experience poor symptom control The level of patient dissatisfaction are high with these medications

What are the unmet needs ? Patient satisfaction / perception Patient expectation: a long term efficacy

What are the unmet needs ? Patient satisfaction / perception

Allergic Rhinitis Management Good 100% Medium Bad 75% 50% 25% 0% Nasal corticosteroid regular regular intermittent intermittent Anti-histamine regular intermittent regular intermittent How do patients feel after their symptomatic treatment (anti H1, corticosteroid) ? White et al. , Clin Exp Allergy1998

everybody knows this word. The paradox of allergy „Allergy“ everybody knows this word. Only 10 per cent of allergic patients are treated correctly.

symptomatic treatments 48 % have bad quality of life Allergic Rhinitis and unmet therapeutic needs TNS 2009: 623 subjects with AR/ 2003 individuals from general population Control with symptomatic treatments Quality of life Three quarters of patients who have consulted a doctor within the last 12 months remain uncontrolled despite the use of symptomatic treatments. Half of those uncontrolled patients have a bad quality of life. 73% remain uncontrolled (19% of total population) 48 % have bad quality of life (13% of total population) 19% of allergic rhinitis patients remain uncontrolled and 13% have a poor quality of life despite using symptomatic treatments A.Didier et al. Unmet therapeutic needs in allergic patients . Abstract at XXIX EAACI 2010

Unsatisfied needs Symptomatic treatment Social and financial impact No long term efficacy No effect on the disease modifying Lack of compliance Dissatisfaction Social and financial impact Cost of the disease Quality of life decrease Chronicity of the disease Resignation

What are the unmet needs ? Patient expectation: a long term efficacy

Why AIT can satisfy the unmet needs ? Immunomodulatory effect Long term and sustained effect

Definition Specific immunotherapy is the repeated administration of allergen products to allergic subjects to activate immunomodulatory mechanisms and provide sustained relief of symptoms during subsequent natural allergen exposure WHO Guideline 1998 EMEA Guideline 2008

Immunomodulatory effect of AIT Natural exposure to the allergen Lymphocytes B IgE IL- 4 CPA Th2 Lymphocytes T Mastocytes AIT Allergy T reg Lymphocytes T regulator

Recruitment and activation of mast cells and eosinophils Allergen Immunotherapy: from the immunological effects to the symptomatic effect Recruitment and activation of mast cells and eosinophils Nasal, ocular and bronchial hyperreactivity AIT decrease Symptoms Use of antiallergic drugs

Allergen Immunotherapy AIT is the only treatment that modifies the natural evolution of allergy One allergy Two allergies Several allergies Allergen Immunotherapy Allergic Asthma Allergic Rhinitis

Why the allergist is the expert ? Diagnosis AIT indications Patient management and follow-up

Diagnostic Approach In Allergology Allergy History Skin Tests/ IgE Symptoms Moderate/severe Poor QOL Positive

AIT Indication Pathway Allergy History Skin Tests/ IgE Symptoms Moderate/severe Poor QOL D I AGNOS S Positive Indication for AIT ? Contra indications: Immunoptahologic diseases Severe asthma - Malignancy - Treatment withβ-blockers - Chronic mouth disease - Pregnancy: avoid initiaition of immunotherapy during pregnancy NO YES Age ≥ 4 yrs old SLIT with pollens mixtures or 2 non related allergens SLIT with one allergen

Which Allergen for AIT ? Monosensitization Polysensitization A patient with moderate/severe symptoms during/after allergen exposure A patient with an altered quality of life due to the allergic symptoms A patient not improved and not satisfied by the pharmacotherapy A patient accurately diagnosed For allergic respiratory diseases Monosensitization Polysensitization

What are the key success factors for AIT ? Patient Information Patient’s Action Plan Patient Follow-Up Patient Doctor Relationship

Key success factors for AIT Patient information = Patient Education Patient should understand : His/her allergic disease The goals of SIT The disease modifyer effect of SIT Why 3-5 years of SLIT ? The onset of action of SLIT The importance of compliance for the success of SLIT

BREAK 15 minutes

Agenda 10.15 – 12.30 am Grass rationalisation Posology - arguments to increase to 8 drops per day Patient follow up Post graduate course: presentation and arguments

Grass rationalisation 5 Grasses / 4 cereals mixture: is it still relevant ? High level of allergens cross-reactivity between 5 grasses and cereals 5 grasses alone is sufficient to treat the allergic patient sensitized to grass pollen and cereal pollen.

Rationale to increase to 8 drops per day

STALORAL pollen: The optimal posology Currently:STALORAL 4 press/day = 120 IR/day ORALAIR clinical trial: 100 IR/day = No efficacy 300 IR/day = Efficacy STALORAL 8 press/day = 240 IR/day STALORAL 10 press/day = 300 IR/day ?

Minimal Maintenance dose: SLIT - pollen Pollen season 1st year Pre-seasonal IT Co-seasonal Withdraw SLIT for 6 months 3 – 4 MONTHS 2 Months Minimal Maintenance dose: 300 IR / 4 press/day Initial phase 9-11 days Maintenance phase 5 – 6 months

Patient follow up

Patient Information/Communication Give the right message to the patient !! “Allergy is a chronic disease not curable by pharmacotherapy alone..” “Rhinitis will develop into asthma in 50 % of the patients..” “You may develop new allergic sensitizations..” “The only way to affect the disease is by immune intervention..” “ SIT is a three years treatment but compared to lifelong drug intake..” “ Efficacy of SIT persists longtime after cessation “ “ SIT would positivily affect your quality of life…”

Key success factors for SIT Patient Information/Education needs from the doctor Time Conviction / Enthousiasm/Persuasion To be done at regular intervals (not a one shot issue)

Patient compliance: a major issue Factors of non-compliance : Daily intake Treatment duration: 3-5 years

Key success factors for AIT Patient compliance: a major issue Patient Follow-Up Optimal patient follow-up SIT efficacy assessment

An optimal follow-up for a patient treated with perennial SLIT Build-up maintenance (Year 1) 5 visits Start Visit Visit Visit Visit Visit 12th month 1st month 3rd month 6th month 9th month Go/No Go maintenance (Year 2) 3 visits Visit Visit Visit 16th month 20th month 24th month maintenance (Year 3) 3 visits Visit Visit Visit 28th month 32th month 36th month Stop

An optimal follow-up for a patient treated with seasonal SLIT Build-Up maintenance (année 1) 3 visits Start Go/No Go Visit Visit Visit Pollen season 3-4 months post-season 3-4 months before season maintenance (Year 2) 3 visits Build-Up Pollen season 3-4 months post-season 3-4 months before season maintenance (Year 3) 3 visits Build-Up Pollen season 3-4 months post-season 3-4 months before season STOP

Content of follow-up visits One month after starting 3 months 6 months 9 months 12 months Safety Staloral intake Safety Staloral intake Compliance Compliance Efficacy Compliance Satisfaction Efficacy Compliance Satisfaction Efficacy Willingness to continue

SIT efficacy assessment is based only the clinical parameters Reduction of symptoms Rhinitis Conjunctivitis Asthma Reduction of anti-allergic drugs intake Improvement of Quality of life Compliance Satisfaction Efficacy Willingness to continue

Efficacy Assessment using a color-coded VAS (1/3) Symptoms : Before SLIT Good Average Bad How was your daytime rhinitis condition ? How was your nighttime rhinitis condition ? How was your daytime asthma condition ? How was your nighttime asthma condition ? Green area Orange area Red area

Efficacy Assessment using a color-coded VAS ((2/3) Symptoms 6 months later Good Average Bad How was your daytime rhinitis condition ? How was your nighttime rhinitis condition ? How was your daytime asthma condition ? How was your nighttime asthma condition ? Green area Orange area Red area

Efficacy Assessment using a color-coded VAS (3/3) Symptoms 12 months later Good Average Bad How was your daytime rhinitis condition ? How was your nighttime rhinitis condition ? How was your daytime asthma condition ? How was your nighttime asthma condition ? Green area Orange area Red area

Rescue Medication for allergic rhinitis Efficacy Assessment ? Rescue Medication for allergic rhinitis H1-Antihistamine Nasal Steroids % 100 - 25% - 50 % 50 - J0 9 M 12 M Months

Rescue Medication for allergic asthma Efficacy Assessment ? Rescue Medication for allergic asthma β2-agonists Inhaled Steroids % 100 - 25% - 50 % 50 - J0 9 M 12 M Months

Items Quality of life Efficacy Assessment ? SLEEP & TIREDNESS DAILY ACTIVITIES IMPAIRED (sport, work, school) WORK & SCHOOL PRODUCTIVITY LEARNING & COGNITIVE FUNCTIONS DISTURBED

After 12 months of SIT: Efficacy assessment % ≥ 50 % Months At least 50 % reduction of symptoms and rescue medicaction use and a significant QOL improvement should be achieved at 12 months

After 36 months of SIT: Stop & Follow-Up ≥ 50 % 70 -80 % ≥ 80 % Stop and follow-up Months At least 80 % reduction of symptoms and rescue medicaction use and a significant QOL improvement should be achieved at 36 months

SIT efficacy assessment ≥ 50 % 70 -80 % ≥ 80 % SIT Stop Month

Sustained long term efficacy of SIT ≥ 80 % SIT Stop Month Years

Add one or two additionals years if necessary ≥ 50 % 60 -80 % Months

Post - SIT : Patient follow-up year 2nd year 3rd year 4th year 5th year A visit once a year

After 12 months of SIT: a key milestones STOP ? Symptoms weakly improved No change in rescue medications QOL not improved Compliance poor Safety average / bad Patient/parent not satisfied

After 12 months of SIT: Why to stop ? % Months Less than 50 % reduction of symptoms and rescue medicaction use and a poor QOL improvement have been achieved at 12 months

After 12 months of SIT: a key milestones Before taking the decision to Stop, Check: Compliance : vials renewal; missing periods : changes in personal or familial conditions , cost issue, willingness to pursue the treatment Environmental changes: increase in allergenic load/ Co-factors irritant Co-morbidities : not treated If none of these factors are found, go-back to the diagnosis and recheck the indications

Key Message To be successful SLIT needs: A good indication The best candidate An optimal patient management

Post graduate course presentation and arguments Objectives Contents Organisation

Post graduate course presentation and arguments (1) STALLERGENES Post Graduate Course An Essential Half-Day Training Course On : Sublingual Immunotherapy in Practice

Post graduate course What The Course Will Cover ? A stepwise approach for the indications of SLIT The place of SLIT in the treatment of allergic respiratory diseases The key factors to make SLIT a success The compliance/adherence issue and how to tackle it

Post graduate course : the agenda Welcome – Introduction 15’ The basics of SLIT : recall 15’ Workshop 1 : Choosing the right patient for SLIT 60’ Coffee Break 15’ Workshop 2 : Managing the patient optimally 60’ The patient follow-up handbook 15’ Interactive Quizz 15’ Take-home messages 15’ 3 hours 30 duration

Post graduate course Who Should Attend ? Allergists Experience with SLIT: at least 1 year 10 to 15 attendees/ session

Post graduate course : Meeting Date 2011 March 2011 Varna Plovdiv Sofia