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The single largest independent vaccine company in the world.

The single largest independent vaccine company in the world. Thomas BAR Chloé CHARLES Elodie LE BIHAN Jérôme NUTTIN. This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques of Lille.

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The single largest independent vaccine company in the world.

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  1. The single largestindependent vaccine company in the world. Thomas BAR Chloé CHARLES Elodie LE BIHAN Jérôme NUTTIN

  2. This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques of Lille. The opinions expressed are our own and not necessarily those of Crucell.

  3. HistoricalBackground

  4. 1995 IntroGenedevelops PER.C6® Technology in full collaboration withLeidenUniversity. U-Bisys (1996) founds and developsMAbstract® (technology to derivefullyhuman antibodiesspecificallyagainst diseasedcells) 2000 2001 AdVactechnology 2002 Parnershipwith DSM (Per.C6)

  5. (1898) ChromaGenicsSTAR® (proteine production technology) Vivotif®(oral immunizationtyphoidfever) MoRu-Viraten®(measles and rubella) Inflexal®(first trivalent virosomal vaccine for active immunizationagainst influenza) 2006 2004 375 million € 4 million € 2001Crucell introducesAdVac®

  6. SBL Vaccin (1909) -Dukoral® cholera& E.coli oral vaccine -Vaccineagainst polio (IPV) 2006 39 million €

  7. ManagementCommittee • Dr. JaapGoudsmit • Positions at the Academic Medical Center at the University of Amsterdam and was Chairman of the Research • 2001: joined Crucell, Senior Vice President Vaccine Research • July 2002: management Committee member • Chief Scientific Officer and is responsible for all R&D activities Ronald Brus 1997: Executive Vice President Business Development 10/2000 – 02/2003: Chief Business Officer 03/2003 - 01/2004: Chief Operating Officer President and ChiefExecuticeOfficer JaapGoudsmit ChiefScientificOfficer René Beukema General Counsel and Corporate Secretary Cees de Jong ChiefOperating Officer Ronald Brus President and Chief Executive Officer BjörnSjöstrand ChiefBusiness Officer Leonard Kruimer ChiefFinancial Officer René BeukemaGeneral Counsel and Corporate Secretary

  8. Port folio products

  9. Technologies

  10. Technologies SAFETY SCALE YIELD CRXL + DSM: Percivia®

  11. Technologies • PER.C6 technology • Vaccine technology • Proteintechnology

  12. What is PER.C6®? • a human designer cell line for manufacturing of biopharmaceuticalsin serum-free defined medium. • a collaboration with DSM Biologics for the application of PER.C6® offers the total package • bio-manufacturing from cell line generation • a cell banks to large-scale manufacturing • PERCIVIA is the new PER.C6® Development Center, specialized for the expression of recombinant pharmaceutical proteins.  PERCIVIA is in the continuing improvement of PER.C6® baseline for material generation in support of pre-clinical and clinical research .

  13. What is PER.C6®? Single human retina-derived cell PERC 6® cell line immortalized can replicate indefinitely RecombinantDNA technology provides Humanglycosylation characteristics + Adenovirus 5 DNA Transfectionwith Ad 5 E1 genes produce antibodies that match humanphysiology. Master Cell Bank Expansion

  14. PERCIVIA CELL LINE • Cell Line Generation and culture • Compatible withbatch, fed batch • Compatible withXD™ Process • In ~ 2 weeks after inoculation: • viable cell concentration =100 – 150 X 106 cells/mL is achieved • volumetric productivity = 35 – 40 g/L of working volume

  15. PER.C6® Advantages • Safe • animal-derived component free and chemically defined • agreement of the FDA for clinical trial in phase III • Rapid development • High basic productivities but it can be improved (The XD™ PROCESS, batch and fed process) • Scalable • rising volume demands, performed up to a 20,000 L capacity • compatible with other cell culture technologies on the market • Highly characterized and fully documented • BMF(Biologics Master File) is maintained with annually filed updates, according to GLP • Wellprotected • Numerous patents (2024) • customers need access to the BMF AND PER.C6® cells only available under agreement from the alliance Crucell - DMS

  16. PER.C6® TechnologyAdvantages • Human-likeGlycosylation • Natural production of antibodies • that match human physiology (Betterglycosylation than Murine cell lines)

  17. Technologies • PER.C6 technology • Vaccine technology • Proteintechnology

  18. Vaccine technology • PER.C6 technology • AdVactechnology • Recombinant Paramyxovirus • Virosometechnology • Hansenulapolymorpha

  19. Vaccine technology1- PER.C6 technology Virus PER.C6 cell Virus reproduction Inactivated virus Human designer cell line for the development and large-scale manufacturing of biopharma products

  20. QUINVAXEM ®Fully liquid pentavalent vaccine for protection against five childhood diseases • First launched in 2006. • WHO’spre-qualified vaccine

  21. QUINVAXEM ®Fully liquid pentavalent vaccine for protection against five childhood diseases • Co–developed with Novartis which provides four of the five components • Crucell produce the vaccine at their Korean facilities. Berna BiotechKoreaCorp, HBsAg Novartis Germany, D, T, wP Novartis Italy, Hib 2006 2007 2008

  22. Vaccine technology2- AdVactechnology Used in combination with PER.C6®, to develop recombinant vaccines

  23. Vaccine technology3-Recombinant Paramyxovirus Recombinant measlesvectors: high and long-lived immune responsesagainstinsertedantigens

  24. Vaccine technology4-Virosometechnology Endocytosis Antigenproteolysis Antigenpresentation Stimulation of T cell T cell / B cellcooperation B cell direct activation

  25. Epaxal®Low dosage unique aluminum-free hepatitis A vaccine (0.25ml) • First product to be based on the virosome technology • Superior immunogenicity and local tolerability • Adults and children over the age of one, more than 40 countries.

  26. Inflexal® V Virosomaladjuvanted influenza (all age groups) • Based upon the virosome technology • Introduced in 1997, Registered in 43 countries • Licensed for all age groups (up from 6 months). • Vaccine’s antigen composition follows yearly WHO recommendations. • Extensive market experience (more than 40 million doses) confirming its safety profile.

  27. Vaccine technology5-Hansenulapolymorpha

  28. Hepavax-Gene®Recombinant hepatitis B vaccine   • Immunogenic component: recombinant hepatitis B surface antigen (HbsAg) • One of the WHO’spre-qualified vaccines. • The prevention of this disease with a vaccine is clearly preferable to the difficult prospect of trying to cure it. • It is considered to be the first vaccine against a major human cancer

  29. Purchased vaccines • Vivotif®: first oral vaccine againsttyphoidfever • MoRu-Viraten®: vaccine againstmeasle and rubella • Inflexal® • Epaxal®: vaccine againstHepatitis A • Hepavax-Gene® By acquisition of Berna Biotech By acquisition of SBL • Dukoral®: oral vaccine against cholera and E.Coli

  30. MoRu-Viraten® Vaccine for protection againstmeasles and rubella (all age groups) • Marketed since 1986 . • All age groups: children, adolescents and adults. Vivotif®Unique oral typhoid vaccine • Live attenuated typhoid fever vaccine. • Only oral vaccine against Salmonella entericaserovarTyphi(S. typhi). • Adults and children over the age of five. • Licensed in over 30 countries.

  31. DUKORAL®Internationally licensed oral vaccine against cholera (and ETEC) • First licensed in 1991 and licensed in over 60 countries. • Recommendedsince 2001 by the WHO for immunisation against cholera (V.choleraeserogroup O1) in endemic areas. • WHO’spre-qualified vaccines. • Adults and children from two years of age. • Over 10 million doses of Dukoral® have been supplied with very few adverse events reported. • Protective efficacy against cholera of approximately 85%.

  32. DUKORAL®Internationally licensed oral vaccine against cholera (and ETEC) • Oral vaccine • The most efficient way of eliciting an intestinal IgA response • Killedbacterialcells and cholera toxine B subunit • Create an anti-bacterialresponse and an anti-toxinresponse • Synergistic action of Ig A antibodies

  33. Vaccin licensees and partners(total=14)

  34. Technologies • PER.C6 technology • Vaccine technology • Proteintechnology

  35. STAR®technology • STAR®-elements are DNA elements in the human genome that are able to counteract epigenetic gene repression • STAR®-elements improve both productivity and yield of antibodies and therapeutic proteins. DNA encoding gene Expression of the gene Introduction of STAR®-elements mammalian celllines Number of clones

  36. STAR®technology Key features and advantages • Useful for the production of recombinant human antibodies and proteins • Identify stable high producing mammalian cell lines • Established mammalian cell banks for antibody and protein production • Effective on mammalian cell lines such as • Crucell's own PER.C6 cell line • the Chinese hamster ovary (CHO) line Licensing

  37. MAbstract®technology • MAbstract® technology can be used to • rapidly select monoclonal specificities • identification of neutralizingantibodies • identify unique targets on proteins, viruses, bacteria • large antibody phage display libraries • Exclusive license to research, develop and commercialize antibodies with MedImmune (AstraZeneca) • MAbstract® technology uses the “phage-display technology”

  38. MAbstract®technology Humandonor lymphocytes Extraction Antibodygenes Insertion Libraries of phages expressing antibodies Bacteriophages Exposition Target an entire pathogen or an isolated antigen Isolation of the relevant phages/antibodies Fully Humain Antibody Antibodyready for PER.C6® clone generation Preclinicaltesting Selection Optimisation

  39. Proteinproducts Prolastin Proteinindicated for hereditarydeficiency of alpha-1 proteinaseinhibitor. Cofact (prothrombincomplex ) Marketing and distribution agreement withSanquin. Flu monoclonal antibody CR6261 Potential therapy against seasonal and pandemic flu Rabies monoclonal antibody CL184 • combination of twohuman monoclonal antibodies • usingCrucell'sMAbstract® and PER.C6® technology

  40. Pipeline

  41. Pipeline

  42. Pipeline Key developments • Seasonal flu vaccine being developed with sanofipasteur using the PER.C6® technology entered into Phase II clinical trials. • Discovery of human monoclonal antibodies for the treatment of the H5N1 pandemic flu virus. • Preliminary data from Phase I tuberculosis trial indicates highest immune responses ever. • Rabies monoclonal antibody cocktail was granted Fast Track status by the U.S. Food and Drug Administration (FDA).

  43. Tuberculosis The world’s second deadliest infectious disease. 1.7 million people died from tuberculosis in 2006 (WHO). Current vaccine, is not very effective in preventing pulmonary tuberculosis Problem of extensively drug-resistant tuberculosis (XDR-TB)

  44. Tuberculosis • Collaboration with the Aeras Global Tuberculosis Vaccine Foundation • Development of a recombinant tuberculosis vaccine based on: - AdVac® vaccine technology - PER.C6® manufacturing technology. • Phase I trials with very promising results. - US: trial completed and demonstrated safety - SA: trial showed highest CD8-cell immune response, toleration • Phase II (SA) study started in october 2008

  45. Rabies Using MAbstract® and PER.C6® technology, discovery of a human monoclonal antibody cocktail for the post-exposure treatment of rabies Exclusive collaboration agreement with sanofipasteur. Antibody cocktail entered a Phase II clinical trial in the US in March 2008. Study completed, positive preliminary results.

  46. Financial overview

  47. Revenues

  48. 2008 : Net profit €14.6 mln

  49. Technology and Research Development

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