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1 ALLERGEN IMMUNOTHERAPY Blondeau Eloïse Boukhalfa Koussayla Tiquet Laure Vandaele Anaïs Stallergenes profile 2 • a European biopharmaceutical company • 7th largest pharmaceutical company in France. • specialized in the treatment of severe respiratory allergies by allergen immunotherapy • almost 500 000 patients benefit from the pharmaceutical company’s treatments every year • Over 1000 people now work at Stallergenes • Sales in 2011 : 235 M€ ; R&D : 20% of sales 3 RESPIRATORY ALLERGY A global public health challenge Respiratory allergy 4 Allergic rhinitis Rhinitis Sinusitis Conjunctivitis Asthma “during two or more consecutive days for more than 1 h” (ARIA 2008) Respiratory allergy 5 Classified according to symptom duration and severity : Due to : Indoor allergens Outdoor allergens Persistent rhinitis and asthma Intermittent rhinitis Impact on quality of life, sleep, school and work substancial indirect costs Allergy diagnostic 6 Consultation with an allergist : In-depth interview + physical examination Provisional identification of possible guilty allergen Skin testing (« Prick-test ») Sensitization confirmed or bordeline Blood test (specific IgE assay) Provocation test or bordeline Allergy diagnostic 7 Skin Prick Testing Allergy diagnostic 8 Intra dermal reaction inspection palpation measurement of transverse diameter in mm of induration Positive > 5 mm Allergy diagnostic 9 True Test Respiratory allergy : epidemiology 10 Increasing prevalence Western lifestyle countries Very common disease Developing countries Tends to be more common Probably underdiagnosed Allergic rhinitis ≈500 million people Annual total cost : 2 to 5 billion $ (USA, 2003*) (direct medical costs, co-morbidities, productivity losses, OTC medications) Asthma ≈300 million people * ARIA 2008 Allergy treatments 11 EVICTION • the primary recommended solution • to eradicate all contacts with the allergen • difficulty to put into practice (formal identity, pollens) SYMPTOMACTIC TREATMENTS ALLERGENIC IMMUNOTHERAPY • prescribed first line by the general practitioner • to reduce the severity of the symptoms and inflammation • recognised efficacy • no long-term benefits (symptoms return as soon as the treatment is stopped) • no impact on the natural progression of the disease. • the only treatment that prevent worsening of the allergy • to reduce the body’s sensitization to the allergen by progressively modulating the immune response to the allergen Allergen-specific immunotherapy : mechanism 12 Altered T-cell cytokine balance (shift to Th1) Induction of regulatory T-cells Reduction in specific IgE levels (long term) Induction of IgG blocking antibodies Reduced recruitment of effector cells (eosinophils, mast cells) J Clin Invest, 2004 Allergen-specific immunotherapy : indications 13 Clinically relevant specific IgE Symptoms of allergic rhinitis, conjunctivitis and/or asthma Poor response to pharmacotherapy/ allergen avoidance Adverse effects of medications Avoid long-term medication and its cost Coexisting allergic rhinitis and asthma Possible prevention of asthma Reactions to Hymenoptera stings Systemic reaction : respiratory, cardiovascular… Older than 16 years with systemic reaction limited to the skin Adapted from J Allergy Clin Immunol., 2007 14 STALLERGENES A step by step construction History 15 1962 Creation of Stallergenes in Lyon within the Institut Mérieux 1980 German market working with a distributor 1974 established in Paris + international operations in the Benelux countries and North Africa 1988 first automated production chain for NPP (Named Patient Product) Name Patient Product NPP 16 APSI : “Allergène Préparé Spécialement pour un Individu” NPPs still are not subject in all countries to a specific regulatory framework regarding pharmaceutical registration. Automated distribution lines Automated encapsulation lines Automated labelling lines History 17 1989 Merger of Stallergenes with the Allergen Division Institut Pasteur 1993 Acquisition of Stallergenes by Wendel Investissement 1992 expansion of Stallergenes in Greece, Spain, Portugal and Turkey History 18 1994 Launch of Staloral® (allergen immunotherapy by sublingual delivery) Advantages of sublingual route 19 SUBCUTANEOUS ROUTE SUBLINGUAL ROUTE Injection Under the tongue Administered in a medically controlled environment (Systemic reactions) At home Initiation phase : 13 weeks Initiation phase : 11 days Maintenance phase : 3 to 5 years Maintenance phase : 3 to 5 years Systemic AE (14 %) : urticaria, anaphylaxis Local AE : itching (Rare systemic AE) Approved Not approved by FDA in the USA but accepted and widely used in Europe Low dose Dose of allergen is greater than subcutaneous immunotherapy Efficacy of sublingual immunotherapy 20 Wilson et al. (2005) systemic review of literature in Cochrane, Medline, Embase library . 22 clinical studies, a total of 979 patients double-blinded, placebo-controlled, parallel-group studies Symptoms SMD = -0.34 (-0.69,-0.15) p= 0.002 medication requirements SMD = -0.43 (-0.63,-0.23) p= 0.00003 Highly significant reduction in symptoms as well as definite decrease in medicine intake for symptoms BUT sublingual immunotherapy equals the efficacy of subcutaneous immunotherapy is not clear. Long-lasting effect of SLIT in children with asthma due to house dust mite 21 V.Di Rienzo, F.Marcucci, P.Puccinelli, S.Parmiani, F.Frati, L.Sensi, GW Canonica, G. Passalacqua Clin Exp Allergy, 2003 35 SLIT + drugs 60 Children No More SLIT Mean = 8.5 yrs Asthma/ rhinitis 25 only drugs 0 5 YEARS 10 Long-lasting effect of SLIT in children with asthma due to house dust mite 22 0.001 n No asthma 0.001 40 NS 0.001 0.001 1 1 4 30 2 20 10 The study demonstrates that SLIT is effective in 32efficacy children and that it31maintains the clinical 31 for 4 to 5 years after discontinuation 24 23 24 SLIT CTRL BASELINE 4 SLIT 17 CTRL END SLIT 3 SLIT CTRL 10 YEARS Asthma Staloral® 23 Sublingual solution with allergenic extracts for ITS One vial contains 10 mL of a solution at: 10 ; 100 or 300 IR/Ml of one of the allergen products. IR : Index of Reactivity 24 Allergenicity The allergen extract contains 100 IR/mL Skin prick-test (Stallerpoint®) : wheal diameter of 7 mm in 30 patients sensitized Staloral® 25 Type I allergies for the classification of Gell and Coombs, including rhinitis, conjunctivitis, rhinoconjunctivitis, asthma (minor to moderate) of seasonal or per-year. Dose journalière 300 300 IR/ml 200 10 IR/ml 100 100 IR/ml During 3 years 0 1 3 5 7 9 11 13 15 17 19 INITIATION MAINTENANCE ALLERGEN EXTRACTS: 26 ACARIENS: Acarus siro (3.a); Blomia tropicalis (3.a); POLLENS DE GRAMINEES: Chiendent pied-de-poule (Cynodon dactylon (L.) Pers.) (3.d) ; Dactyle aggloméré (Dactylis Dermatophagoides farinae (3.d); Dermatophagoides pteronyssinus (3.d); Glyciphagus domesticus (3.a);Lepidoglyphus destructor (3.b); Tyrophagus putrescentiae(3.a) glomerata L.) (3.d); Fétuque des prés (Festuca pratensis Hudson.) (3.a), Fléole des prés , (Phleum pratense L.) (3.d); Flouve odorante (Anthoxanthum odoratum L.) (3.d); Houlque laineuse (Holcus lanatus L.) (3.a); Ivraie vivace (Lolium perenne L.) (3.d), Pâturin des prés (Poa pratensis L.) (3.d), 5 graminées (pollen de dactyle aggloméré, de fléole des prés, de flouve odorante, d’ivraie vivace, de pâturin des prés) (3.d) ; Seigle (Secale cereale L.) (3.c). POLLENS D’ARBRES : Aulne glutineux (Alnus glutinosa (L.) Gaertn.) (3.d) ; Bouleau blanc (Betula pendula Roth.) (3.d); Charme (Carpinus betulus L.) (3.a) ; Châtaignier (Castanea sativa Mill.) (3.a) ; Chêne pédonculé (Quercus robur L.) (3.a) ; Cyprès d’Italie (Cupressus sempervirens L.) (3.c) ; Frêne élevé (Fraxinus excelsior L.)(3.b); Génévrier de Ashe (Juniperus ashei Buchholz) (3.c); Hêtre (Fagus sylvatica L.) (3.a); Marronnier d'inde (Aesculus hippocastanum L.) (3.a); Mimosa (Acacia dealbata link..) (3.a); Noisetier (Corylus avellana L.) (3.d); Olivier (Olea europaea L.) (3.c) ; Peuplier blanc (Populus alba L.) (3.a) ; Platane hybride (Platanus hispanica x Mill ex Munchh..) (3.a) ; Robinier faux-acacia (Robinia pseudoacacia L.) (3.a) ; Saule marsault (Salix caprea L.) (3.a) ; Sureau noir (Sambucus nigra L.) (3.a) ; Tilleul à petites feuilles (Tilia cordata Mill.) (3.a) ; Troène (Ligustrum vulgare L.) (3.a) POLLENS D’HERBACEES : Ambroisie à feuilles d'armoise MOISISSURES : Alternaria alternata (3.c) ; Botrytis cinerea (3.a) ; Pleospora herbarum (3.a) PHANERES : phanères de chat (3.c) ; phanères de cheval (3.b) : phanères de chien (3.b) ; phanères de cobaye (3.a) ; phanères de (Ambrosia artemisiifolia L.) (3.d) ; Amarante réfléchie (Amaranthus retroflexus L.) (3.a); Armoise commune (Artemisia vulgaris L.) (3.b); Chénopode blanc Chenopodium album L.) (3.a); Colza (Brassica napus L.) (3.a); Marguerite (Chrysanthemum leucanthemum L.) (3.a); Ortie dioïque (Urtica dioïca L.) (3.a); Pariétaire de Judée (Parietaria judaica L.) (3.c) ; Pariétaire officinale (Parietaria officinalis L.) (3.c); Pissenlit (Taraxacum officinale Web.) (3.a) ; Plantain lancéolé (Plantago lanceolata L.) (3.a); Solidage du canada (Solidago Canadensis L.) (3.a); Soude salsovie (Salsola kaliL.) (3.a) hamster (3.a) ; phanères de lapin (3.a). INSECTES : blatte germanique (3.b) ; moustique (3.b) Process of standardization of Staloral300. 27 Sieving Drying Storage Process of standardization of Staloral300. 28 Extraction Purification Process of standardization of Staloral300. 29 Ajustement of dosage of the allergen Standardization in IR History 30 1999 Purchase of Bayer Pharma’s Allergy division the world’s number 2 company in its market. 1995 Creation of a subsidiary in Germany and purchase of a laboratory in Belgium 1997 Creation of a subsidiary in Italy and in Central Europe (Czech Republic and Slovakia); Establishment in Antony (Paris area) 1999 Opening of a subsidiary in Spain. History 31 2000 Pursuit of international development in South Africa, Australia, New Zealand and Poland. 2003 The Stalair program 2001 Stallergenes enters the Middle East markets 2007 Development of a first product candidate as part of the Enhanced Allergens program Development of recombinant allergens 32 produced by genetic engineering complex biological extracts products that are purer and have better features The Stalair programm 33 Phase I Oralair® Actair® Stalair® rBet v1 Ragweed pollen Japanese cedar pollen Phase II Phase III •Sublingual grass pollen immunotherapy tablets •Marketed in Germany , Europe, Australia, Russia… •Dust mite immunotherapy tablet •Phase III adult (Europe). Current phase III study in children •Recombinant birch pollen allergen •Phase IIb/III clinical trial •aimed primarily at the US market •early stage of development •aimed primarily at the Japanese market •early stage of development Approved Oralair® 34 Phase IIb/III : Optimal dose of SLIT with a 5–grass pollen tablet for seasonal allergic rhinitis 35 628 adults (18-45 years) With seasonal grass pollen– related allergic rhinitis 10 % of asthma Optimal dose, efficacy, and safety of once-daily SLIT with a 5–grass pollen tablet for seasonal allergic rhinitis, Alain Didier and al, Rhinitis, sinusitis, and upper airway disease, 2007 . RTSS : Rhinoconjunctivitis Total Symptom Score 36 Sneezing Watery eyes Rhinorrhea RTSS Ocular pruritus Nasal congestion Nasal pruritus Results of the study 37 RTSS 300-IR / 500-IR ≠ Placebo P = 0.0001 Improvement (Mean) 300-IR : 37.0 % 500-IR : 35.3 % The 300-IR/500-IR doses both demonstrated significant efficacy compared with placebo The risk-benefit ratio favors the use of 300-IR tablets for clinical practice History 38 2008 24/01/08 : market authorization in Germany for Oralair® 5-grass-pollen SLIT tablets in pediatric allergic rhinoconjunctivitis 39 278 children of 5-17 years With seasonal grass pollen– related allergic rhinitis 21.4 % of asthma Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis, Ulrich Wahn and al, Rhinitis, sinusitis, and upper airway disease, 2008. Results of the study 40 RTSS Improvement 300-IR ≠ Placebo Mean : 28.0 % P = 0.001 Median : 39.3 % 5-grass-pollen SLIT tablets (300 IR) reduce RTSS in children and adolescents with grass pollen–related rhinoconjunctivitis History 41 2009 19/01/09 : paediatric marketing authorization in Germany for Oralair®. 27/11/09 : European approval for the Oralair® tablet in Europe 2010 19/04/10 : positive resultats of the phase III « Oralair » in USA Partnership-Oralair 42 Partnership of development and marketing in Canada (2007) Partnership of marketing in Russia and CEI (2009) Oralair® 43 ORALAIR 100 IR & 300 IR sublingual tablets Initiation treatment ORALAIR 300 IR sublingual tablets Continuation treatment Oralair® 44 THERAPEUTIC INDICATIONS : Treatment of grass pollen allergic rhinitis •with or without conjunctivitis •in adults, adolescents and children above the age of 5 •with clinically relevant symptoms, •confirmed by a positive cutaneous test and/or •a positive titre of the specific IgE to the grass pollen. Pharmacotherapeutic group: Allergen extracts, grass pollen. ATC code: V01AA02 Actair® 45 THERAPEUTIC INDICATION : allergic rhinitis to dust mites Phase IIb/III : Safety and Efficacy Study of SLIT in House Dust Mite Allergic Rhinitis 46 Placebo 486 adults (18-50 years) House dust mite-related allergic rhinitis 300 IR 500 IR 12 months The results are positive but not published Pediatric Phase III : Study of SLIT in House Dust Mite Allergic Rhinitis 47 Placebo 471 children (5-17 years) House dust mite-related allergic rhinitis 300 IR 36 months About 1 year after the start the committee of experts (DSMB) recommanded termination of the study The study is terminated in 04/07/2011 Actair® 48 History 49 September 2010 an exclusive partnership with Shionogi The agreement signed in Japan 50 the tablet against Japanese cedar pollen Actair® (immunotherapy tablet against dust mites) This agreement is financially satisfactory: € 24 million upfront, € 46 million of development milestones plus royalties on sales History 51 November 2010 Transfer of the 47% shareholding held by Wendel Group in Stallergenes SA to Ares Life Sciences I SARL Ares Life Sciences : a new majority shareholder 52 10/11/2010 : Wendel transfers its 47% shareholding to Ares Life Sciences (a 300 million € benefit for Wendel) Ares manages its own funds origins in the pharmaceutical industry and in biology Public offering by Ares Life Sciences (march 2011) significant financial resources Goal = international expansion, particularly in USA Invaluable support and experience Leadership transition : a consequence ? 53 Albert SAPORTA Chairman and chief executive officer (since 1999) Non executive chairman (01/2012) Managing director (since 2002) Leaves the company (10/2011) Former Executive Vice-President of the Merck-Serono Group Managing director (10/2011) Louis CHAMPION Roberto GRADNIK History 54 January 2011 Stallergenes opens a new raw material production unit in Amilly (Loiret). A new raw material production unit situated in Amilly an investment of € 6 million 55 dedicated to the harvest and treatment of grass pollens (Oralair®, allergic immunotherapy treatments) The area of cultivation will reach150 hectares in the next few years, allowing Stallergenes to produce half of its grass pollen requirements. importance of quality assurance and standardisation an extension of its dustmite production activities ? World's leading producer of grass pollens and house dust mites Development in the United States 56 The VO61.08 trial conducted with Oralair® : positive May 2011 : subsidiary in US (Boston) Stallergenes is preparing for a pre-BLA in the context of a BLA (Biological License Application) with the FDA. Marketing of 3 products : Oralair ®, Actair ®, Ragweed pollen tablet An international presence 57 Market focused in Europe (mainly in Germany, France, Spain and Italy Sales of Stallergenes : 96% in Europe Market and competitors 58 Current Market of 750 M€ Market in 2022 : 3.5 B€ 60% of the world market is shared by Stallergenes and ALK-Abello Just three pure players : Stallergenes , ALK-Abello and Allergy Therapeutics ALK-Abello is yet in USA AMM of GRAZAX (ALK-Abello) in France Great performance in a difficult context 59 Capturing market share thanks to Oralair® Great performance in a difficult context 60 European market trends : 3% decrease in S1 2011 • German rebate • Regulatory pressure in the Netherlands • Very low pollen season in 2010 • Economical crisis in southern Europe (Spain, Italy, Greece) Stallergenes : 4% increase of market share • Lesser presence in Germany and Netherlands • Oralair success : resisting better than competition in Germany + increasing global sales in other countries Products 61 Information and services 62 MEETINGS with doctors in their surgeries to international scientific conventions. VARIED MEANS OF COMMUNICATION: telephone assistance, teaching materials, training, postgraduate teaching programmes AN INTERACTIVE WEB SITE with a reserved area for healthcare professionals and a medical document database Information and services 63 AN INTERACTIVE WEB SITE An area dedicated to the general public and patients APSI - deferred payment systems, -a voice server to follow on a daily basis the preparation of their treatment, -the sending of SMS to notify them of the shipment date of their treatment. 64 FINANCIAL ANALYSIS Evolution of turnover (Sales) 65 250,000,000 225,000,000 9% 200,000,000 12% Chiffres d'affaires 175,000,000 13% 150,000,000 16% 125,000,000 16% 100,000,000 2006 2007 2008 2009 2010 2011 R&D investment 66 R&D investment :170 million in 7 years (since 2004) Investments carried out in France, in collaboration with competent public scientific organisations :CNRS, INSERM, CEA, the Institut Pasteur, INRA, CEMAGEF Gross Margin 67 255,000,000 205,000,000 77,64% CA 155,000,000 Chiffres d'affaires Marge brute 105,000,000 55,000,000 5,000,000 2006 2007 2008 2009 2010 Net Income 68 250,000,000 200,000,000 150,000,000 Chiffres d'affaires Résultat net 100,000,000 50,000,000 14,2%CA 2006 2007 2008 2009 2010 EBITDA 69 250,000,000 200,000,000 150,000,000 Chiffres d'affaires EBITDA 100,000,000 50,000,000 2006 2007 2008 2009 2010 ROTA (%) – Economic returns 70 R.E Actifs Resultat = EBIT Total Net Assets 120 100 80 60 40 48.09 35.86 32.98 30.47 32.92 2006 2007 2008 2009 20 0 2010 EBIT ROTA (%) Total capitaux investis ROE (%) – Financial returns 71 Capitaux propres R.F = Resultat RNC Capitaux propres 140 120 100 80 RNC ROE CP 60 40 34.67 27.7 24.09 23 21.61 23.55 2006 2007 2008 2009 2010 20 0 2005 Share Price 72 AMMORALAIR Allemagne PIII + ACTAIR UE Supply of Ares 59 €/share Arret de PIII ACTAIR SWOT 73 STRENGHT •Stalair® : 5 major allergens in the world •Satisfactory clinical data •Leading producer of pollen & dust mite •Global extension •Development contract with Japan •Potential disease modifying WEAKNESS •Laboratory without experience for the process approval and administrative procedures •ALK already present in the US •Depending on the pollen season •High cost treatment SWOT 74 OPPORTUNITIES •Growing awareness of allergic rhinitis •Sublingual IT still lacking from many countries •Limited competition •Generic products excluded from this market •High-technology for the extraction of natural products THREAT •Reduction in health spending by the States •Slow approval procedures •Increased administrative costs related to the process of approvals Trophies of Stallergenes 75 BFM AWARDS 2009 Trophée des industriels 2010 76 THANKS FOR YOUR ATTENTION !