Der Markt für Biosimilars Zukunftschancen für mittelständische Unternehmen?

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1 Der Markt für Biosimilars Zukunftschancen für mittelständische Unternehmen? Dr. Urs C.H. Wiedemann InnovationsForum Hessen-Biotech 2007 IHK Frankfurt am Main, 20. Juni 2007

2 Das seit wenigen Jahren diskutierte Biosimilar-Konzept ist die Anwendung der Generika-Konzepts auf Biologicals Small Molecule Original Biological Original Upon patent expiration Upon patent expiration Abbreviated Drug Application with reference to pharmacological, toxicological and clinical studies of the original manufacturer and evidence of bioequivalence Abbreviated Drug Application? Small Molecule Generic Biosimilar Source: CEPTON Reduced price Reduced price? 2

3 Die Zeit der zweistellige Wachstumsraten des globalen Pharmamarktes ist vorbei aber einzelne Segmente haben weiterhin hohes Potential Market segmentation based on ex-manufacturer prices in top 8 countries, MAT Q4/2005 [$bn] Total Market* 414 $bn +5.7% growth Originally Protected 325 $bn +4.5% growth Never protected 55 $bn +12.7% growth Other: vitamins, etc. 34 $bn +6.5% growth Protected 248 $bn +11.3% growth Not Protected 77 $bn -13.0% growth Generics 54.2 $bn +12.7% growth Copy Products 0.4 $bn +1.4% growth Total Unprotected Market $bn -3.8% growth Ex-manufacturer prices *Excludes non-rx-bound Source: IMS MIDAS New Market Segmentation Feature, MAT Q4/2005,USA, Canada, France, Germany, Italy, Spain, UK, Japan 3

4 Seit einigen Jahren geht der Trend hin zu Spezialtherapeutika Biologicals haben hierin das größte Wachstumspotential % CAGR Biologicals +18% vs. Small Molecules +7% 401 8% 643 9% % * Shift in growth from mature to emerging markets from primary care to specialty care, especially driven by biologicals Specialist-driven products contributed 62% of total market growth Oncologics and autoimmune agents grew each by more than 20% Source: IMS / BioGeneriX / CEPTON * estimation 4

5 Seit ihrer Einführung in den 80er Jahren haben sich viele Biologicals zu Blockbustern entwickelt Global top selling Biologicals, 2005 Biological Indication $m Biological Indication $m Enbrel (Etanercept) Amgen Autoimmune/RA 3,657 Humira (Adalimumab) Abbott/Cambridge Autoimmune/RA 1,400 Remicade (Infliximab) Essex Autoimmune/RA 3,477 Pegasys/Copegus (Peginterferon alfa-2a) Roche HCV/B 1,374 Procrit/Eprex/Erypo (Epoetin alfa) J&J Aranesp (Darbepoetin alfa) Amgen Rituxan/Mabthera (Rituximab) Roche/Genentech Epogen (Epoetin alfa) Amgen Neulasta (Pegfilgrastim) Amgen Epogin/NeoRecormon (Epoetin beta) Roche/Chugai Herceptin (Trastuzumab) Roche/Genentech Avonex (Interferon beta 1a) Biogen Idec Anemia Anemia NHL/RA Anemia Cancer Anemia Cancer MS 3,324 3,273 3,154 2,455 2,288 1,710 1,629 1,543 Intron-A (Interferon alfa-2b) Schering-Plough Rebif (Interferon beta-1a) Serono Avastin (Bevacizumab) Roche/Genentech Neupogen (Filgrastim) Amgen Humalog (Insulinlispro) Lilly Betaseron/Betaferon (Interferon beta-1b) Schering Synagis (Palivizumab) Abbott/MedImmune Humulin (Insulin) Lilly HCV/B MS Cancer Cancer Diabetes MS RSV Diabetes 1,369 1,270 1,264 1,216 1,198 1,079 1,063 1,005 Source: IMS / DiCicco RA = Rheumatoid Arthritis NHL = Non-Hodgkin Lymphoma MS = Multiple Sclerosis HCV = Hepatitis C Virus 5

6 Aktuell erfolgreiche Biologicals gehören nur einigen wenigen Klassen an dabei unterscheiden sie sich im Hinblick auf Wert & Volumen Major classes of Biologicals on the market, global sales 2005 [US $bn] Epeotin Anti-TNF Insulin Interferon beta G-CSF Interferon alfa Human Growth Hormones Herceptin Few kgs High Value Multi tons High Volume Source: DiCicco / BioCentury / own calculations / CEPTON 6

7 Ähnliche Biologicals gab es schon vor dem Aufkommen des Biosimilar Konzepts auf dem Markt allerdings keine generischen Substanzen Me too Biologicals Example Beta Interferon 1996 Beta Interferon 1b Betaferon (Schering) 1997 Beta Interferon 1a Avonex (Biogen) 1998 Beta Interferon 1a Rebif (Serono) (Rebif was granted same INN as Avonex because Serono never requested a new INN) Erythropoietin First generation: Same amino acid sequence, glycosylation varies and is different from endogenous EPO Next generation: Aranesp (Amgen) longer duration of action via glycoengineering of epo Roche development of CERA (Complex process: Pegylation of chemically synthesized 28-mer-N-terminal fragment and joining to EPO produced in mammalian cells Shire launched DynEpo in EU! In unregulated markets (like China, Eastern Europe, India and South America) Biologicals copy products since several years on the market e.g. Epoetin copies account for a total value of 700 $min 26 countries Source: DiCicco / CEPTON INN = International Nonproprietary Name by WHO 7

8 Der Markt der Biologicals ist immer noch dominiert durch Insuline und Vakzine das Wachstum kommt aus der Onkologie und Immunology The German Biologicals market, 2006 Number of approved Biologicals Interferons Coagulation Factors Other Recombinant Proteins Growth Factors Enzymes Other Hormones 12 8 Monoclonal AB 25 Vaccines Insulins 1) CAGR Source: Company reports / VFA / EvaluatePharma / BCG / CEPTON Sales contribution of Biologicals Immunology +15% Hematology +3% Other +43% Oncology +62% Total 25.4 bn 88% 12% Small Molecules CNS +7% 528 Biologicals Metabolic +3% 1) Infections +15% 8

9 Innerhalb der nächsten Jahre verlieren allein in Deutschland Biologicals im Wert von mehr als 300 Mio. Jahresumsatz ihren Patentschutz Patent expirations of products with German market sales >1 m, ex-manufacturer prices [ m] Date Substance m 2) Date Substance 2005 Fluticason /06 Levocabastin 05/05 Acamprosat /06 Tamsulosin Lamotrigine /06 Sertaconazol 06/05 Nafarelin 2.2 Bambuterol Mometason /06 Azithromycin Benazepril /06 Sumatriptan 07/05 Fosinopril /06 Filgrastim 1) 08/05 Cefpodoxim /06 Glanciclovir Cilazapril /06 Spirapril Terbinafin /06 Buserelin Amorolfin 10/05 Salmeterol Fosinopril +HCT Sertralin 43.2 Fentanyl patch /05 Lacidipin /05 Sevofluran 2.3 Lansoprazol 33.3 Glimeperid Epoetin beta 1) m 2) Date Substance m 3) /07 Levocetirizine Ceftibuten Tropisetron /07 Quetiapine /07 Didanosine Finasteride /07 Adapalene /07 Temozolomide /07 IFN beta 1b 1) /07 Factor IX 1) /07 Risperidone Date Substance m 3) 01/08 Fondaparin /08 Deferiprone /08 Alendronic acid115.7 Manidipine 1.4 IFNalfa con-1 1) /08 Imidapril /08 Fumaric acid /08 Octreotide 37.5 Bicalutamide 43.8 Lenograstim 1) /08 Piretanide Ramipril Fluvastatin /08 Ropinirole /08 Venlafaxine 82.8 Famciclovir 1.5 1) Biologicals m going off patent ) German audited sales ) German audited sales 2005 Source: Insight Health / CEPTON Date Substance m 3) Date Substance m 3) 02/09 Esomeprazole /10 Octocog alfa 1) /09 Gemcitabine 9.4 Benazepril /09 Eplerenone 4.5 +HCT 06/09 Orlistat 13.1 Lercanidipine 52.6 Tacrolimus /10 Desloratadine /09 Irinotecan 3.5 Losartan+HCT /09 Dydrogesterone 4.9 Felbamate Estradiol 04/10 Ribavirin 50.3 Estradiol /10 Levetiracetam 46.0 Norethisterone 07/10 Estradiol 24.8 Estrogens, /10 Anastrozole 87.2 conjugated + 09/10 Ropivacaine 1.4 Medroxyproges Danaparoid 3.0 terone acetate 10/10 Tacalcitol 2.3 Ethinylestradiol 4.3 Nebivolol Norethisterone Enfuvirtide /10 Hyaluronic acid 17.2 Penciclovir 2.1 Mizolastine 4.2 Follitropin α 1) 20.3 Insulin 85.6 Amfebutamone 1.4 LisPro 1) Pantoprazole Docetaxel /09 Losartan /10 Adalimumab 1) 59.7 Topiramate 25.5 Pramipexole /09 Fulvestrant 10.3 Risedronic acid 55.6 Choriogonadotropin alfa 1) /09 Imiquimod /09 Dorzolamide 13.5 Valaciclovir 2.5 Repaglinide m m m m m m 9

10 Weltweit ist das Potential der Biologicals, die ihren Patentschutz aktuell verlieren, 18 Mrd. US$ p.a. attackiert durch einige wenige Unternehmen Market potential Current main targets for Biosimilar attack ~18 $bn already off patent or soon off patent Biologicals are a major growth driver expected to continue to grow with +18% p.a. Somatropin: Genotropin (Pfizer), Norditropin (Novo Nordiks) Erythropoietin: Epogen (Amgen), Procrit (J&J), Recomon (Roche) Filgrastim: Neupogen (Amgen) Interferon beta: Avonex (Biogen Idec), Rebif (Serono), Betaferon (Schering) Interferon alpha: Roferon A (Roche), Intron A (Schering- Plough/Biogen), Alferon N (Interferon Sciences) Most active players Source: CEPTON 10

11 Insbsondere große Generikahersteller und einige Specialty-Pharma- Hersteller sind aktiv auf dem Gebiet der Biosimilars Omnitrop first approved EU-Biosimilar, launched in May 2006 in Germany File Epo Biosimilar in EU; further products in pipeline Valtropin (Biopartners) has already received approval in EU BUT! EMEA issued negative opinion about CMC of IFN-α2a application due to quality concerns & differences to Roche s Roferon A Strategic development partnership with Biopartners (IFN-α2a, IFN-β, Epo, CSF) Biosimilar development in cooperation with VC funded BIOCEUTICALS AG Filed registration for Epo on (Epo-zeta EU-market size 1.2 bn 1) ) Projects in pipeline: Filgrastim, Interferon beta-1a Epo-similar registered in Croatia ( ) Collaboration with Mayne & Barr to develop Filgrastim Acquisition of Sicor to strengthen biosimilar development & manufacturing capabilities Take-over of Isreal development team focused on biologicals from Serono (ex InterPharm Labs Ltd.) Filed Epo Biosimilar in EU Indications: Anemia (Epo), MS (IFN-β), Neutropenia (CSF), Source: Company reports / CEPTON 1) STADA estimation based on data from several market research companies 11

12 Aber die Komplexität der Moleküle wirft die Frage auf, ob ein generisches Konzept überhaupt für Biologicals möglich ist Characteristics of Small Molecules and Biologicals Small Molecule Pharmaceuticals Simple molecules Small molecular mass Very well defined Easy to characterize Chemical Synthesis Biologicals Complex molecules Large molecular mass ( x) Less well defined Difficult to characterize Biotechnological production process dependent on living cells Original Me Too Generic? Biosimilar? Source: CEPTON 12

13 Insbesondere wenn Biologicals der 2. und 3. Generation nachgeahmt werden sollen, muss der Geschäftsmodell hinterfragt werden Classification of Biologicals Small Molecules Peptides Protein Substitutes also Glycosylated Derivatized Proteins Pegylated, Antibodies, Customized Proteins, Nucleic acids Vaccines Blood products Tissue engineering Increasing complexity Increasing regulatory requriements Increasing dependence on production process Decreasing fit to classical pharmaceutical business model 1st Generation 2nd Generation 3rd Generation Source: CEPTON 13

14 Eine Reihe von Hürden müssen überwunden werden, um erfolgreich auf dem Gebiet der Biosimilars zu sein Hurdles for the Biosimilar business model 5 Marketing & Sales Requirements 1 Production Process 4 Development Costs 2 Scientific Issues 3 Regulatory Requirements Source: CEPTON 14

15 Eine Reihe von Hürden müssen überwunden werden, um erfolgreich auf dem Gebiet der Biosimilars zu sein Hurdles for the Biosimilar business model 5 Marketing & Sales Requirements 1 Production Process 4 Development Costs 2 Scientific Issues 3 Regulatory Requirements Source: CEPTON 15

16 Der biotechnologische Herstellungsprozess stellt die größte Eintrittsbarriere dar auch nach Patentablauf 1 Challenges Production process Manufacturers are not obliged to disclose production process Biosimilar manufacturers have to elaborate own production process Production is complicated and dependent on living cells implying heterogeneity Highly demanding quality assurance processes Production plants have to undergo extensive certification procedures by regulatory authorities Regulatory requirements continue to increase In comparison to generic small molecule production costs are high Source: Handelsblatt / CEPTON 16

17 Der Fall Eprex verdeutlicht, wie abhängig und anfällig Biologicals vom Herstellungsprozess sind kleine Veränderungen haben große Folgen 1 The Eprex case Example Change in EMEA Regulation: ban of human protein ingredients Substitution of human serum albumin by Sorbitol 80 in Eprex formulation Use of coated syringes in order to avoid leachates from rubber syringe stoppers and potentially associated immunogenicity Increase in incidence of adverse effects: PRCA 1) 1) Pure Red Cell Aplasia Source: Boven K. et al. (2005) Nephrol Dial Transplant 20(Suppl 3): iii33-iii40 / CEPTON 17

18 Eine Reihe von Hürden müssen überwunden werden, um erfolgreich auf dem Gebiet der Biosimilars zu sein Hurdles for the Biosimilar business model 5 Marketing & Sales Requirements 1 Production Process 4 Development Costs 2 Scientific Issues 3 Regulatory Requirements Source: CEPTON 18

19 Die Anforderungen an das wissenschaftliche Know-how im Unternehmen sind hoch 2 Challenges Scientific issues Handle scientific issues related to the production process Establish own cell line and secure stability Ensure quality assurance of production process Meet requirements of demanding Pharmacovigilance process Support marketing and sales in scientific product detailing Source: CEPTON 19

20 Eine Reihe von Hürden müssen überwunden werden, um erfolgreich auf dem Gebiet der Biosimilars zu sein Hurdles for the Biosimilar business model 5 Marketing & Sales Requirements 1 Production Process 4 Development Costs 2 Scientific Issues 3 Regulatory Requirements Source: CEPTON 20

21 Als Folge sind die Anforderungen der Zulassungsbehörden ebenfalls hoch wenn sie überhaupt schon spezifiziert sind 3 Challenges Regulatory requirements General Guidline on Biosimilars: Guideline on Similar Biological Medicinal Products (CHMP/437/04) Due to complexity and heterogeneity of products individual guidelines for selected product classes: Insulin Somatropin G-CSF Epoetin IFN-alpha Currently no regulation of Biosimilar approval process Approval of Follow-on-Biologics via Hatch- Waxmann Provision Omnitrope approved only after legal actions initiated by Sandoz But FDA considers this an exception: Molecule not glycosylated, clear mode of action, Ongoing discussion on FDA policy concerning Biosimilars Source: EMEA / FDA / CEPTON 21

22 Eine Reihe von Hürden müssen überwunden werden, um erfolgreich auf dem Gebiet der Biosimilars zu sein Hurdles for the Biosimilar business model 5 Marketing & Sales Requirements 1 Production Process 4 Development Costs 2 Scientific Issues 3 Regulatory Requirements Source: CEPTON 22

23 Der Vorteil der Entwicklungszeiten für Biologicals hat sich in den letzten Jahren im Verhältnis zu den Small Molecules nivelliert 4 Challenges Total development times for small molecule and biologial products approved in the US Years Biological quick wins already addressed Increasing regulatory requirements and raised premarket safety bar Biologicals Small Molecules Source: Tufts Center for the Study of Drug Development / CEPTON 23

24 Infolge der fordernden Zulassungsbedingungen sind die Entwicklungskosten für Biosimilars um Größenordnungen höher als für Generika 4 Challenges Development costs [US $m] x Complete dossier necessary Required clinical studies to prove safety and efficacy comparable to requirements for original manufacturer 60 Necessary Patient numbers 300 1,000 (in comparison to 0 100) 40 In EU only centralized procedure ,5 5 Small Molecule Generic Biosimilar x higher development costs Source: Expert estimations / CEPTON 24

25 Eine Reihe von Hürden müssen überwunden werden, um erfolgreich auf dem Gebiet der Biosimilars zu sein Hurdles for the Biosimilar business model 5 Marketing & Sales Requirements 1 Production Process 4 Development Costs 2 Scientific Issues 3 Regulatory Requirements Source: CEPTON 25

26 Der Vertrieb von Biosimilars stellt ebenfalls hohe Anforderungen an die Organisation kein generisches Vertriebsmodell 5 Challenges Marketing & Sales requirements Product complexity Demanding detailing Post-marketing surveillance requirements Costumer I would have to be convinced of the efficacy, MS is an important disease, and I find it hard to believe there will be a lot of generics on the market Dr. Coyle, Director of the MS Case Center and Chair of Neurology at the School of Medicine Stony Brook, NY Altogether higher M&S cost in comparison to generic model Source: CEPTON 26

27 Speziell für komplexere Biologicals muss die Tragfähigkeit des Biosimilar-Geschäftmodells hinterfragt werden Comparison of generic and biosimilar business model Schematic 100% 100% % 80% 60% % 80% 60% 40% 40% 20% 20% 0% Original Generic 0% Original Biosimilar Sustainability of Business model ( ) Low cost structure Unlikely that original manufacturer drops price too High development, production and marketing costs Original manufacturer will likely reduce price Source: CEPTON 27

28 Trotz eines Preisnachlasses von 25%, konnte Omnitrope innerhalb eines Jahres nach Launch noch keine Marktrelevanz erringen A first view onto the Omnitrope launch monthly audited sales Germany [ m] 6.0 MAT* Mar Genotropin (Pfizer) / mg Norditropin (Novo) / mg Saizen (Serono) / mg Humatrope (Lilly) / mg Zomacton (Ferring) / mg Nutropinaq (Ipsen) n.d. Jan Feb 2006 Mar Apr May Jun Jul Aug Sep Oct Noc Dec Jan Feb 2007 Mar Omnitrope (Sandoz) / mg Source: Insight Health NPI / CEPTON * Moving annual total 28

29 Die Erfolgsfaktoren eines Biosimilar-Unternehmens spiegeln mehr die eines Biotech als die eines Generika-Players wieder Key success factors for Biosimilar business strategy Specialty Pharma marketing or access to strong co-promotion/- marketing partner Biotechnological production know-how and assets Development expertise and financial support Is there a difference to an original manufacturer? Strong scientific and patent expertise Handling of demanding regulatory requirements Source: CEPTON 29

30 Expansion means complexity and complexity decay. C. Northcote Parkinson Source: CEPTON 30

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