Crucell

The single largest independent vaccine company in the world.

Thomas BARChlo CHARLESElodie LE BIHANJrme NUTTIN119 mars 2009To develop, produce and market vaccines and antibodies that prevent or treat infectious diseases.

119 mars 20092This is an independent study performed by students from the Facult des Sciences Pharmaceutiques of Lille.

The opinions expressed are our own and not necessarily those of Crucell.2HistoricalBackground19 mars 20093

31995 IntroGene develops PER.C6 Technology in full collaboration with Leiden University.U-Bisys (1996)founds and develops MAbstract (technology to derive fully human antibodiesspecifically against diseased cells)2000

2001 AdVac technology2002 Parnership with DSM (Per.C6)4initial public offering4ChromaGenics STAR (proteine production technology)20042001Crucell introduces AdVac

Vivotif(oral immunization typhoid fever)MoRu-Viraten (measles and rubella) Inflexal (first trivalent virosomal vaccine for active immunization against influenza)

(1898)2006375 million

4 million 5Berna Biotech AG 1981 Berna Biotech registers Vivotif, the first live-attenuated vaccine for oral immunization against typhoid fever; 1987 Berna Biotech register MoRu-Viraten, the vaccine for protection against measles and rubella; Berna Biotech registers Inflexal V, first trivalent virosomal vaccine for active immunization against influenza)

5

SBL Vaccin (1909)-Dukoral cholera& E.coli oral vaccine-Vaccine against polio (IPV) 200639 million 66

ManagementCommittee

Jaap GoudsmitChief Scientific Officer Cees de JongChief Operating OfficerRen BeukemaGeneral Counsel and Corporate SecretaryRen BeukemaGeneral Counsel and Corporate SecretaryBjrn SjstrandChief Business Officer Leonard KruimerChief Financial OfficerRonald Brus President and Chief Executive Officer

Ronald Brus1997: Executive Vice President Business Development

10/2000 02/2003: Chief Business Officer

03/2003 - 01/2004: Chief Operating Officer

President and Chief Executice Officer

Dr. Jaap Goudsmit

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

719 mars 2009Dr. Ronald Brus is Crucells President andChief Executive Offi cer. He has beena member of Crucells Management

1989: professor at the University of Amsterdam and the Academic Medical Center Institute for Infectious Diseases and the Institute for Science Education

Committee since the Companysincorporation and was formerly ChiefOperating Offi cer (March 2003 toJanuary 2004) and Chief Business Offi cer(October 2000 to February 2003). Priorto that, he was Executive Vice PresidentBusiness Development after joining theCompany in 1997. From 1994 to 1996 hewas product planning physician at ForestLaboratories in New York and from 1990to 1994 he was Medical Director forZambon B.V. He holds a medical degreefrom the University of Groningen,the Netherlands.Dr. Brus is Chairman of the

Dr. Jaap Goudsmit is Crucells ChiefScientifi c Offi cer and is responsible for allR&D activities. He became a member ofCrucells Management Board in January2004. He joined Crucell in 2001 as SeniorVice President Vaccine Research andbecame a member of CrucellsManagement Committee in July 2002.Prior to that, he held various positionsat the Academic Medical Center at theUniversity of Amsterdam and wasChairman of the Research Institute forInfectious Diseases and the Institute forScience Education. Since 1989 he hasbeen a professor at the University ofAmsterdam and the Academic MedicalCenter. He holds a medical degree anda PhD from the University of Amsterdam,7Port folio products819 mars 20098Technologies19 mars 20099

9TechnologiesCRXL + DSM: PerciviaSAFETY SCALE YIELD1019 mars 2009ADN ds des cellules vivantes et on leur fait produire des mdicaments grande chelle1970: human insulin gene in bacteria, dc production dinsuline, contre le diabte1980: milian cells1990: on produit des cellules qui se rpliquent indfinitivement. On utilise le gne E1 des adnovirus (rplication et rendement de production augmentent). Donc tt a sert, ds un premier temps pr faire de la thrapie gnique.Puis on a dcouvert que ces cellules avaient un domaine dutilisation plus large. En effet, on a dcouvert que les virus humains se rpliquaient trs bien ds les PER.C6 cells. RELIABLY, SAFELY, EASILY AND LOW COST. Dc dvp de vaccins contre influenza et (whest measles).Aussi pr les vaccins recombinants, pr AIDS, EBOLA, MALARIA, pr lesquels les techniques traditionnelles ne st pas efficaces ou de scurit suffisante.De +, on a: SAFETY, SCALE and YIELD;Puis utilisation pr le march des protines: production de protines et danticorps.50 million de cellules par millilitre.Association DSM, formation de Percivia Development Center in Cambridge Massachussets. But: diminution du cot de production, dc + de gens peuvent en bnficier.

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TechnologiesPER.C6 technologyVaccine technologyProtein technology

1119 mars 200911What is PER.C6?a human designer cell line for manufacturing of biopharmaceuticals in 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.

12Pas seulement une technologie qu ils utilisent directement, mais aussi une technologie leur rapportant par le biais dautres:In areas where we do not aim to develop our own products, we license the technology to the biopharmaceutical industry. Currently over 60 companies and organizations have selected our PER.C6 technology to develop their own products across a wide range of therapeutic areas.

DSM Biologics (a division of DSM Pharmaceutical Products), a leading contract manufacturing organization for the pharmaceutical industry, and Crucell N.V., a biotechnology company developing vaccine and recombinant protein products

DSM Pharmaceutical Products(DPP) is a global supplier of high quality custom contract manufacturing services to the pharmaceutical and biopharmaceutical industries.12

What is PER.C6?Recombinant DNA technologySingle human retina-derived cell

Adenovirus 5 DNA+can replicate indefinitelyprovides Human glycosylationcharacteristicsproduce antibodies that match human physiology.

PERC 6 cell lineimmortalized

Transfection with Ad 5 E1 genesExpansionMaster CellBank1319 mars 2009The E1 gene with precisely known genetic boundariesExpression de E1A.

E1A code des protines transactivatrices de la transcription qui agissent au niveau des promoteurs viraux et promoteurs de gnes cellulaires endognes ainsi que pour des protines dautorgulation. Il active lentre en phase S. Une protine de E1A active galement le gne qui code la protine p53 qui induit les mcanismes dapoptose (p53 est un facteur de transcription qui va activer l'expression du gne de Bax).Expression de E1B. E1B a une fonction anti-apoptotique. E1B sexprime quasi simultanment avec E3 et code la protine p55k qui se lie a p53 et linactive, et pour la protine p19k, un quivalent fonctionnel de Bcl-2 (la protine Bcl2 empche lhomodimrisation de Bax, et lhomodimrisation de Bax permet lactivation de la caspase qui active son tour lendocaspase qui digre lADN). E1B bloque galement lapoptose induite par les produits dE4 (ncessit dun dlai: le virus doit avoir du temps pour synthtiser ses particules virales). E1B19k serait inhibe tardivement par la protine dE3 qui joue un rle dans la destruction de la cellule, la protine p19k tant inhibe, Bax est actif et induit l'apoptose.

13PERCIVIA CELL LINECell Line Generation and cultureCompatible with batch, fed batchCompatible with XD Process

batch culturesfed-batch culturesViable cell concentration> 12 X 106 cells/Ml> 25 X 106 cells/mLbillion cell days per liter (bcdl)100300productivities*~ 2 g/L~ 8 g/L

In ~ 2 weeks after inoculation:viable cell concentration =100 150 X 106 cells/mL is achievedvolumetric productivity = 35 40 g/L of working volume1419 mars 2009Standard cloning without amplification steps requiredConsistent high cell specific productivities >50 pg/cell/day

14PER.C6 AdvantagesSafeanimal-derived component free and chemically definedagreement of the FDA for clinical trial in phase IIIRapid developmentHigh basic productivities but it can be improved (The XD PROCESS, batch and fed process)Scalablerising volume demands, performed up to a 20,000 L capacitycompatible with other cell culture technologies on the marketHighly characterized and fully documented BMF(Biologics Master File) is maintained with annually filed updates, according to GLPWell protectedNumerous patents (2024)customers need access to the BMF AND PER.C6 cells only available under agreement from the alliance Crucell - DMS

1519 mars 2009free of any human- or animal-derived proteinsincluding fertilized chicken eggs and mouse brains

15

PER.C6 Technology AdvantagesHuman-like Glycosylation

Natural production of antibodiesthat match human physiology

(Better glycosylation than Murine cell lines)

1619 mars 2009Non-human protein glycosylation, has been linked to accelerated in vivo protein clearance, leading to reduced therapeutic efficacy in humans.

En clair le fait davoir de smannose en bout de chaine indique limmunit inne que cest pas du soi le soit tant caractris pas cette glycosylation base de groupement SIALYLE Par consquent une limination rapide par lorganisme des Ac murin dont la glycosylation nets pas semblable celle obtenue pour les ac humain

16

TechnologiesPER.C6 technologyVaccine technologyProtein technology

1719 mars 200917Vaccine technology

PER.C6 technologyAdVac technologyRecombinant ParamyxovirusVirosome technology Hansenula polymorpha

1819 mars 2009

18Vaccine technology 1- PER.C6 technologyHuman designer cell line for the development and large-scale manufacturing of biopharma products

19PER.C6 cellVirusVirus reproductionInactivated virus19 mars 200919

QUINVAXEM Fully liquid pentavalent vaccine for protection against five childhood diseasesFirst launched in 2006.

WHOs pre-qualified vaccine

20

20

Codeveloped with Novartis which provides four of the five components

Crucell produce the vaccine at their Korean facilities.

QUINVAXEM Fully liquid pentavalent vaccine for protection against five childhood diseases21

Novartis Germany, D, T, wPNovartis Italy, HibBerna Biotech Korea Corp, HBsAg 2006 2007 2008 21

Vaccine technology

2- AdVac technology

Used in combination with PER.C6, to develop recombinant vaccines2219 mars 2009Gene segment (encoding immunogenic parts of pathogen), into a vector. Vector in patient produces the immunogenic fragmentsTo date, better vector: adenovirusAdVac vectors produced to carry genetic information immunization against life-threathning diseasesTo develop vaccines against hemorhagic fever (Ebola, Lassa, Marburg), malaria, tuberculosis; Aids and Hepatitis C.Scalable RCA-free productionHigh yieldsStrong T cell immune response

22Vaccine technology 3-Recombinant Paramyxovirus

Recombinant measles vectors: high and long-lived immune responses against inserted antigensRecombinant measles vectors carrying RNA encoding for antigenic proteins of other human pathogensHigh and lon-lived immune responses against inserted antigensProduced economicallyStrong humoral and cellular response against measles proteins and the foreign (malaria or HIV) proteins23

Vaccine technology

4-Virosome technology

EndocytosisAntigen presentationStimulation of T cell

Antigen proteolysis

24T cell / B cell cooperationB cell direct activation19 mars 2009Pour les antignes ou pr ADN/ARN qui code pr des prot stimulatrices du SIStimulate antibody and cellular immune responsesNo requires adjuvantsNm and HA: virosome enable to fuse with cells of the immune systemEndocytosis by antigen presenting cellsT cell cytokines stimulate B cell to produce antibodies or direct stimulation of B cell to produce antybodiesLicensedINFLEXAL: contre seasonal influenzaEPAXAL: contre HA24First 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.

Epaxal Low dosage unique aluminum-free hepatitis A vaccine (0.25ml)2519 mars 200925Inflexal V Virosomal adjuvanted 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).

Vaccines antigen composition follows yearly WHO recommendations.

Extensive market experience (more than40 million doses) confirming its safety profile.

2619 mars 200926Vaccine technology

5-Hansenula polymorpha

2719 mars 2009Easy with regard to genetic manipulations and robust in industrial scale fermentationsYeast. Methanol metabolism pathwayDNAHigh copy number and stronger inducible promoter elementHEPAVAX-GENE: contre HB27Hepavax-GeneRecombinant hepatitis B vaccine

Immunogenic component: recombinant hepatitis B surface antigen (HbsAg)

One of the WHOs pre-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 cancer2828Purchased vaccinesVivotif: first oral vaccine against typhoid feverMoRu-Viraten: vaccine against measle and rubellaInflexalEpaxal: vaccine against Hepatitis AHepavax-GeneBy acquisition of Berna BiotechDukoral: oral vaccine against cholera and E.ColiBy acquisition of SBL2919 mars 200929MoRu-Viraten Vaccine for protection against measles and rubella (all age groups)

Marketed since 1986 .

All age groups: children, adolescents and adults. 30Vivotif Unique oral typhoid vaccineLive attenuated typhoid fever vaccine.

Only oral vaccine against Salmonella enterica serovar Typhi (S. typhi).

Adults and children over the age of five.

Licensed in over 30 countries.

30DUKORALInternationally licensed oral vaccine against cholera (and ETEC)First licensed in 1991 and licensed in over 60 countries.

Recommended since 2001 by the WHO for immunisation against cholera (V.cholerae serogroup O1) in endemic areas.

WHOs pre-qualified vaccines.

Adults and children from two years of age.

Over10 million doses of Dukoral have been supplied with very few adverse events reported.

Protective efficacy against cholera of approximately 85%.

3131Oral vaccine

The most efficient way of eliciting an intestinal IgA response

Killed bacterial cells and cholera toxine B subunit

Create an anti-bacterial response and an anti-toxin response

Synergistic action of Ig A antibodies

DUKORALInternationally licensed oral vaccine against cholera (and ETEC)

3232Partner/licenseeStarting dateTechnologyDisease targetDevelopment stageHarvard School of MedicineDec. 2003AdVac + Ad5HVR48HIVPre-clinicalNational Institutes of Health (NIH)Mar. 2002-2004PER.C6 and AdVacEbola, Lassa, Marburg, MalariaPhase 1NovartisDec. 2004PER.C6AlphavirusPre-clinicalAeras Global TB Vaccine FoundationMar. 2004PER.C6 and AdVacTuberculosisPhase 1Pfizer animal healthMar. 2007PER.C6VeterinaryPre-clinicalSanofi pasteurDec. 2003PER.C6InfluenzaPhase 2SingvaxMar. 2005PER.C6Japanese EncephalitisPre-clinicalWyeth PharmaceuticalsJul. 2007AdVacNon-disclosedPre-clinicalVaccin licensees and partners (total=14)3319 mars 200933

TechnologiesPER.C6 technologyVaccine technologyProtein technology

3419 mars 200934

STAR technologySTAR-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

Introduction of STAR-elementsmammalian cell linesExpression of the geneNumber of clones3519 mars 2009Background: To maintain the identity and function, of a cell, it is important to maintains its gene expression profileEpigenetic genes play a pivotal role in maintaining the gene expression profile of a cell.

35STAR technologyKey features and advantagesUseful for the production of recombinant human antibodies and proteinsIdentify stable high producing mammalian cell linesEstablished 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) lineLicensing36Partner/licenseeStarting dateTechnologyDevelopment stageAbbottJan. 2007STARPre-clinicalGenentechFeb. 2004STARPre-clinicalGenzyme CorporationDec. 2005STARPre-clinicalLFB BiotechnologiesJul. 2007PER.C6Pre-clinicalMerck & Co., Inc.May 2003PER.C6Pre-clinicalNovartisSep. 2006Aug. 2004STARPER.C6Pre-clinicalCentocorMar 2009STARPre-clinicalAcquired through the purchase of ChromaGenics B.V

36MAbstract technologyMAbstract technology can be used to

rapidly select monoclonal specificities identification of neutralizing antibodies

identify unique targets on proteins, viruses, bacterialarge antibody phage display libraries

Exclusive license to research, develop and commercialize antibodies with MedImmune (AstraZeneca)

MAbstract technology uses the phage-display technology

3737MAbstract technology

Antibody genes Human donor lymphocytes Bacteriophages

ExtractionInsertionTargetan entire pathogen or an isolated antigenLibraries of phages expressing antibodiesExpositionIsolation of the relevant phages/antibodiesFully Humain AntibodyPreclinical testingSelection OptimisationAntibody ready for PER.C6 clone generation

3819 mars 200938

Protein products

ProlastinProtein indicated for hereditary deficiency of alpha-1 proteinase inhibitor. Cofact (prothrombin complex )Marketing and distribution agreement with Sanquin.Flu monoclonal antibody CR6261Potential therapy against seasonal and pandemic fluRabies monoclonal antibody CL184 combination of two human monoclonal antibodies using Crucell's MAbstract and PER.C6 technology

39Cofact with Sanquin, the Dutch Blood Supply Foundation. Prothrombin complex concentrates (PCCs) are pharmaceutical products made out of blood plasma containing vitamin K-dependent clotting factors as factor II, VII, IX and X. PCCs are used primarily for substitution therapy in cases of acquired disorders of haemostasis. Cofact provides the right INR in 15 minutes.

39

Pipeline19 mars 200940

40

Pipeline4119 mars 200941Key developments

Seasonal flu vaccine being developed with sanofi pasteur 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).

Pipeline4219 mars 200942Tuberculosis

The worlds 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)4319 mars 200943TuberculosisCollaboration 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

4444Rabies

Using MAbstract and PER.C6 technology, discovery of a human monoclonal antibody cocktail for the post-exposure treatment of rabies

Exclusive collaboration agreement with sanofi pasteur.

Antibody cocktail entered a Phase II clinical trial in the US in March 2008. Study completed, positive preliminary results.

4545

Financial overview19 mars 200946

46Revenues47472008 : Net profit 14.6 mln19 mars 20094848

4949

Technology and ResearchDevelopment5050

5151

Sales and marketing5252Liabilities & cash(In millions )5353Research & Developement54Courbe tendance 54Shares19 mars 200955

55

Crucell shares

Total number of shares: 65,833,242 Capitalisation: 1,58 bilions

Crucells ordinary shares are listed on: NYSE Euronext since 2000 Nasdaq since 2000 Swiss Exchange 2005

56A Van fond de specul holandaisAviva fond de specul UK

56

Shares65,499,442 ordinary shares outstanding

RiskGrades (Nasdaq)5757

Source: WSJShares

Crucell and Wyeth in discussion on a combination of the two companiesDiscussions on a Combination of Crucell and Wyeth Discontinued5858

207 jan 2009

11,57 jan 200959ING We value Crucell at 11.5 per share, using a risk- adjusted NPV.Wyeth propose 20$ per share59

2015About 1.35bn $ deal value - implying a price of 15 per share-(1.8 bn $ for 20)(With limited comparable deal metrics applicable from other vaccine M&A deals)

60With limited comparable deal metrics applicable from other vaccine M&Adeals (bearing in mind that Crucell is still loss-making but has a substantial level of revenues), placing a closely argued takeout value on the business is difficult.

6061

161161Strategic Partners

December 2002, Crucell formed an alliance with DSM to licence PER.C6. December 2003, agreement to develop & commercialize novel influenza vaccine products based on PER.C6

March 2006, KFDA (korea) awarded licensure to QuinvaxemSeptember 2007, option for the exclusive use of Crucells PER.C6 technology and AdVac vaccine technology in two infectious disease areas. ( TB & HIV)

62The combination of the PER.C6 human cell line and DSM's manufacturing services provides companies with a turn-key biologic manufacturing solution reducing cost, risk and time to market. Furthering this commitment to the PER.C6 cell line, Crucell and DSM have established a joint PER.C6 R&D Center in Cambridge, Massachusetts62Who can be interested in buying Crucell?CompagnyEver had with crucessIntersest MoneyDSMPer.C6 magnufacturing Per.C6NosanofiPer.C6 licence, pipeline vaccines for influenza and rabbie. Per.C6, completes pipeline with HepA & paediatric vaccinesSTARYesnovartisPer.C6 licence, Quinvaxem paediatric vaccine Per.C6, competes in influenza vaccines, STAR YesMerckexclusive licence Per.C6 (gene therapy), Influenza vaccines, STARYes63 When i look at the price, i coughChris Viehbacher 63 Who can interest Crucell?Mymetics, switzerland: malaria vaccines phase I/II, Virosome Biologicals B.V.14,763,361 shares (0,01$ per share)Medicago (Canada): recombinant vaccine antigens in the cells of non-transgenic plants (H5N1). 21,112,440 shares (0,30$ per share)

6464In September 2007, Merck & Co., Inc. Exercised an option for the exclusive use of Crucells PER.C6 technology and an option for access to Crucells AdVac vaccine technology in two infectious disease areas.6519 mars 200965

SWOT analysis: Strengths

6th fast-growing vaccines market5 core technologies and Distinctive TechnologyProprietary of PER.C6, the cell line technology Broad Product Portfolio Strategic alliances to co-develop and commercializeLarge-scale manufacturingProfit increasement

6619 mars 2009

6th fast-growing vaccines market5 core technologies and Distinctive TechnologyProprietary of PER.C6, the cell line technology Broad Product Portfolio Strategic alliances to co-develop and commercializeLarge-scale manufacturingProfit increasement

66SWOT analysis: Weaknesses

Clinical development generally not in Crucells hands.Involved in various legal proceedings affect the customers perception of the companyOver-dependence on lead product

6719 mars 2009Litigations The companys business is involved in various legal proceedings, law suits and disputes. 67

SWOT analysis: Opportunities Rapid expansion of antibody and vaccine worldwide marketLicense Agreements STAR production technology effective for production of antibodies and proteins on mammalian cell lines(especially the CHO )Performance of QuinvaxemLong-term pact with Talecris Biotherapeutics Commercialisation of Prolastin (alpha-1 proteinase inhibitor). annual market treatment estimated to be over $250 million. International expansionGrowing blood factor market

68Market for growth factors in the United States is expected to rise by about US$14.1 billion during the period 2008 to 2012"We are very excited to have received additional Quinvaxem contracts bringing the total value of the contracts awarded to date to $0.5 billion.Ronald Brus, Crucell's Chief Executive Officer. (September 23, 2008)

20062007 2008Doses in mln unitsEssentially in European countries, but also in Asia and North AmericaCommercialisation of Prolastin (alpha-1 proteinase inhibitor). the annual market size for Alpha 1 treatment is estimated to be over $250 million.

CHO = Chinese hamster ovary

Growth of the blood factor markethttp://www.bio-medicine.org/medicine-news-1/Global-Growth-Factors--28Blood-and-Tissue-29-Market-to-Reach--2452-1-Billion-by-2012--According-to-New-Report-by-Global-Industry-Analysts-29225-1/

About ProlastinProlastin is a concentrated form of alpha1-antitrypsin (AAT) that is derived from human plasma-the fluid part of the blood. Given as prescribed, Prolastin raises the levels of AAT in the blood and lungs. Raising the AAT level may help reduce the damage to the lungs caused by destructive enzymes. Because Prolastin "augments" or replaces missing AAT, it is referred to as "augmentation" or "replacement" therapy. It's important to know that Prolastin is not a cure for AAT deficiency. However, it may help to slow the loss in lung function caused by the disease. Also, Prolastin is approved only for chronic, or ongoing, replacement therapy in people with emphysema caused by genetic AAT deficiency

68SWOT analysis: Threats

Intellectual Property Risks (Patent dispute)Crucells competitive position depends on its ability to obtain patents Intense Competition especially in paediatric vaccines Impact of the Financial CrisisIndustry Consolidation Heightened M&A activity in the pharmaceutical sector69( difficulties of raising additional cash) could delay the development of new drugs, impacting the companys ability to develop new drugs in long-term. 69

In the future...February 26, 2009Crucell antibody CR6261 a potentially therapy against seasonal and pandemic fluIsolated from the immune repertoire of a healthy and vaccinated individualCR6261 antibody attacks a Highly Conserved part of the of the hemaglutinin HA Neutralizes the virus by blocking conformationalrearrangements associated with membrane fusion

flu vaccine market of $2.2 billion estimated to double by 2016

19 mars 200970Every year, in the United States200,000 people are hospitalized 36,000 people die from fluflu vaccine market of $2.2 billion estimated to double by 2016

influenza virus subtypes different viral surface protein known as hemagglutinin by mutation on the variable structure

hemaglutinin protein key for the virus to start replication once it has infected an individual

70WHAT DO WE THINK ABOUT CRUCELL ?19 mars 20097171Thank you for your attention.

Any questions?19 mars 2009727219 mars 200973

73Bacterial diseases:CholeraDiphtheriaHaemophilus influenzae typeb InfectionsMeningococcal InfectionsPertussisPneumococcal InfectionsTetanusTuberculosisTyphoid FeverViral diseases: Hepatitis AHepatitis BInfluenzaJapanese Encephalitis MeaslesMumpsPoliomyelitisRabiesRubellaVaricellaYellow Feverand smallpox, eradicated in 1980 (vaccine produced as a measure in response to the threat of bioterrorism)

7419 mars 200974Paris, France, September 25, 2008 Sanofi Pasteur announced today that Sanofi Pasteur Holding has successfully completed the acquisition of Acambis plc for 285 millionAcambis portfolio: smallpox vaccine, ChimeriVax technology platform* against Japanese encephalitis, dengue and West Nile; Early-stage programme targeting potentially significant markets in the fields of C. difficile, influenza and genital herpes.pipeline: Clostridium difficile bacteria, ACAM-529 universal vaccine against influenza,7519 mars 200975

Meningococcal Polysaccaride VaccineConjugated Meningococcal C VaccineInfluenza Vaccines (5 vaccins, change: age, state)Encepur Travel ick-borne encephalitis (TBE)Rabipur/ RabAvert (PCEC rabies vaccine)yellow fever Oral typhoid vaccineInactivated Hepatitis A vaccineDukoral vaccine for cholera

Pediatricdiphtheriahaemophilus influenzae type BMeningitisPertussispoliotick-borne encephalitistetanus

Adult tetanos DiphtheriaDT DTP7619 mars 200976

Transgene et roche concluent a un accord de partenariat

ATTENUVAX (Measles Virus VaccineCOMVAX [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) VaccineMERUVAX II (Rubella Virus Vaccine Live) PedvaxHIB [HaemophilusB Conjugate Meningococcal Protein.ProQuad (Measles, Mumps, Rubella and Varicella Virus Vaccine Live)RECOMBIVAX HB [Hepatitis B Vaccine Recombinant) VAQTA (Hepatitis A Vaccine, InactivatedZOSTAVAX (Zoster Vaccine Live)

7719 mars 200977PartnersSANOFI wants an international expansion and diversification to advance

SANOFI PARIS (Reuters) - Certificate loss acquisitions in 2009 to dynamise his growth- Chris Viechbacher (laboratory general director) will buy small and medium biotechnologies societies?

A future partnership? Sanofi-Aventis- Le mode de fonctionnement de base doit tre de laisser travailler nos partenaires ,- Mieux vaut des partenariats comme celui que nous avons avec Regeneron, qui nousdonne accs une partie des anticorps quils mettent au point. - Quand je vois le prix, je tousse ! ,

7819 mars 2009Confront des pertes de brevets, Sanofi-Aventis devra s'engager dans des acquisitions en 2009 pour redynamiser sa croissance, estiment des analystes qui parient sur des oprations cibles de taille moyenne.Sanofi "devait grandir" en se servant de sa trsorerie de quatre milliards d'euros par an. Chris Viehbacher "Sanofi devrait raliser une ou plusieurs acquisitions cibles de taille moyenne afin de redynamiser la croissance de son top line (chiffre d'affaires), en augmentant ainsi la part des segments de croissance dans le total du groupe".Sous couvert d'anonymat, un autre analyste pense que "Chris Viehbacher va faire chez Sanofi ce qu'il a fait chez GSK : acheter des petites et moyennes socits de biotechnologie". il faut changer compltement de culture, sintresser la science des autres, tre pluscurieux quant au reste du monde, aux biotechnologies, Priorit la rechercheexterne. Le mode de fonctionnement de base doit tre de laisser travailler nos partenaires ,Marc Cluzel, le responsable de la recherche, va donc devoir multiplier les contacts avec les laboratoires extrieurs, les entreprisesde biotechnologies, pour chercher les meilleurs projets.Mieux vaut des partenariats comme celui que nous avons avec Regeneron, qui nousdonne accs une partie des anticorps quils mettent au point. Quand je vois le prix, je tousse ! , Gedeon Richter Plc.

78Pb ac WYETH

Names who would likely be interested in CRXL include:

- MERCK: Could bolster its vaccine division to expand beyond the succesful launch of cervical cancer vaccine Gardasil as the company waits on the FDA to expand label to include older women and males

- NOVARTIS and SANOFI-AVENTIS Represent existing strategic partners with CRXL who are based in Europe and would likely consider making a bid

- GlaxoSmithKline: Is also developping a cervical cancer vaccine (Cervarix) to compete with Gardasil and CRXL would expand upon their pipeline and marketed vaccines.

7919 mars 200979Bibliographywww.crucell.comwww.percivia.comwww.pubmed.comwww.nature.comSanofi/merck/DSM/novartis/wyethwww.nasdaq.comwww.euronext.comING, Medtrack, Globalmarketdirectlifescienceanalytics

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