The single largest independent vaccine

company in the world.

Thomas BAR

Chloé CHARLES

Elodie LE BIHAN

Jérôme NUTTIN119 mars 2009

19 mars 2009 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.

HistoricalBackground

19 mars 2009 3

1995

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 technology

2002 Parnership with DSM

(Per.C6) 4

ChromaGenics STAR®

(proteine production

technology)

2004

2001Crucell introduces AdVac®

Vivotif®(oral immunization typhoid fever)

MoRu-Viraten® (measles and rubella)

Inflexal® (first trivalent virosomal vaccine for

active immunization against influenza)

(1898)

2006 375 million €4 million €

5

SBL Vaccin (1909)

-Dukoral® cholera& E.coli

oral vaccine

-Vaccine against polio (IPV)

2006

39 million €

6

ManagementCommittee

Jaap Goudsmit

Chief Scientific

Officer

Cees de Jong

Chief Operating

Officer

René Beukema

General Counsel and

Corporate Secretary

René BeukemaGeneral

Counsel and Corporate

Secretary

Björn Sjöstrand

Chief Business

Officer

Leonard Kruimer

Chief Financial

Officer

Ronald Brus

President and Chief

Executive Officer

Ronald Brus

1997: ExecutiveVice

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 2009

Port folio products

• Quinvaxem®

• Hepavax-Gene®

• MoRu-Viraten®

• Epaxal® Junior

PEDIATRIC

• Epaxal®

• Vivotif®

• Dukoral®TRAVEL AND ENDEMIC

•

• Inflexal®RESPIRATORY

819 mars 2009

Technologies

19 mars 2009 9

Technologies

1970

1990 genetherapy

Broaderrange of use, viruses, vaccines

Proteinmarket, antibodyproduction

CRXL + DSM: Percivia®

SAFETY SCALE YIELD

1019 mars 2009

Technologies

PER.C6 technology

Vaccine technology

Protein technology

1119 mars 2009

What 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

. 12

What is PER.C6®?

Recombinant DNA

technology

Single human

retina-derived

cell

Adenovirus 5

DNA

+

can replicate

indefinitely

provides

Human glycosylation

characteristics

produce antibodies

that match

human physiology.

PERC 6® cell line

immortalized

Transfection with Ad 5 E1 genes

Expansion Master Cell

Bank

1319 mars 2009

PERCIVIA CELL LINE Cell Line Generation and culture Compatible with batch, fed batch

Compatible with XD™ Process

batch cultures fed-batch cultures

Viable cellconcentration > 12 X 106 cells/Ml > 25 X 106 cells/mL

billion cell days per liter (bcdl) 100 300

productivities* ~ 2 g/L ~ 8 g/L

In ~ 2 weeks after inoculation:

viable cell concentration =100 – 150 X 106 cells/mL is

achieved

volumetric productivity = 35 – 40 g/L of working volume1419 mars 2009

PER.C6® Advantages Safe

o animal-derived component free and chemically defined

o agreement of the FDA for clinical trial in phase III

Rapid development

o High basic productivities but it can be improved

(The XD™ PROCESS, batch and fed process)

Scalable

o rising volume demands, performed up to a 20,000 L capacity

o compatible with other cell culture technologies on the market

Highly characterized and fully documented

o BMF(Biologics Master File) is maintained with annually filed updates,

according to GLP

Well protected

o Numerous patents (2024)

o customers need access to the BMF AND PER.C6® cells only available

under agreement from the alliance Crucell - DMS

1519 mars 2009

PER.C6® Technology Advantages

Human-like Glycosylation

◦ Natural production of antibodies

◦ that match human physiology

(Better glycosylation than Murine cell lines)

1619 mars 2009

Technologies

PER.C6 technology

Vaccine technology

Protein technology

1719 mars 2009

Vaccine technology

PER.C6 technology

AdVac technology

Recombinant Paramyxovirus

Virosome technology

Hansenula polymorpha

1819 mars 2009

Vaccine technology

1- PER.C6 technology

Human designer cell line for the development and large-scale manufacturing of biopharma products

19

PER.C6

cell

Virus

Virus

reproduction

Inactivated

virus

19 mars 2009

QUINVAXEM ®

Fully liquid pentavalent vaccine for protection against five childhood diseases

First launched in 2006.

WHO’s pre-qualified vaccine

20

Co–developed 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 diseases

21

Novartis Germany,

D, T, wP

Novartis Italy, Hib

Berna Biotech Korea Corp,

HBsAg

2006 2007 2008

Vaccine technology

2- AdVac technology

Used in combination with

PER.C6®, to develop

recombinant vaccines

2219 mars 2009

Vaccine technology3-Recombinant Paramyxovirus

Recombinant measles vectors: high and long-lived immune

responses against inserted antigens

Vaccine technology

4-Virosometechnology

Endocytosis Antigen

presentation

Stimulation of T cellAntigen

proteolysis

24

T cell / B cell

cooperation

B cell direct

activation19 mars 2009

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.

Epaxal®Low dosage unique aluminum-free hepatitis A vaccine (0.25ml)

2519 mars 2009

Inflexal®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).

Vaccine’s antigen composition follows yearly WHO

recommendations.

Extensive market experience (more than 40 million doses)

confirming its safety profile.

2619 mars 2009

Vaccine technology

5-Hansenula polymorpha

2719 mars 2009

Hepavax-Gene®

Recombinant hepatitis B vaccine

Immunogenic component: recombinant hepatitis B surface antigen (HbsAg)

One of the WHO’s 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 cancer

28

Purchased vaccines

Vivotif®: first oral vaccine against typhoid fever

MoRu-Viraten®: vaccine against measle and rubella

Inflexal®

Epaxal®: vaccine against Hepatitis A

Hepavax-Gene®

Dukoral®: oral vaccine against cholera and E.Coli

2919 mars 2009

MoRu-Viraten®

Vaccine for protection against measles and rubella (all age groups)

Marketed since 1986 .

All age groups: children, adolescents and adults.

30

Vivotif®Unique oral typhoid vaccine

Live 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.

DUKORAL®

Internationally 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.

WHO’s pre-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%.

31

Oral 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

DUKORAL®

Internationally licensed oral vaccine against cholera (and ETEC)

32

Partner/licensee Starting date Technology Disease targetDevelopment

stage

Harvard School of

MedicineDec. 2003

AdVac +

Ad5HVR48HIV Pre-clinical

National Institutes

of Health (NIH)Mar. 2002-2004

PER.C6 and

AdVac

Ebola, Lassa,

Marburg, MalariaPhase 1

Novartis Dec. 2004 PER.C6 Alphavirus Pre-clinical

Aeras Global TB

Vaccine

Foundation

Mar. 2004PER.C6 and

AdVacTuberculosis Phase 1

Pfizer animal

healthMar. 2007 PER.C6 Veterinary Pre-clinical

Sanofi pasteur Dec. 2003 PER.C6 Influenza Phase 2

Singvax Mar. 2005 PER.C6Japanese

EncephalitisPre-clinical

Wyeth

PharmaceuticalsJul. 2007 AdVac Non-disclosed Pre-clinical

Vaccin licensees and partners(total=14)

3319 mars 2009

Technologies

PER.C6 technology

Vaccine technology

Protein technology

3419 mars 2009

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 lines

Expression of the

gene

Number of

clones

3519 mars 2009

STAR® technologyKey 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

36

Partner/licensee Starting date TechnologyDevelopment

stage

Abbott Jan. 2007 STAR Pre-clinical

Genentech Feb. 2004 STAR Pre-clinical

Genzyme

CorporationDec. 2005 STAR Pre-clinical

LFB

BiotechnologiesJul. 2007 PER.C6 Pre-clinical

Merck & Co., Inc. May 2003 PER.C6 Pre-clinical

NovartisSep. 2006

Aug. 2004

STAR

PER.C6Pre-clinical

Centocor Mar 2009 STAR Pre-clinical

MAbstract® technology

MAbstract® technology can be used to

rapidly select monoclonal specificities

◦ identification of neutralizing antibodies

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”

37

MAbstract® technology

Antibody genes

Human donor

lymphocytes

Bacteriophages

Extraction

Insertion

Targetan entire pathogen or

an isolated antigen

Libraries of phages

expressing antibodies

Exposition

Isolation of the relevant

phages/antibodies

Fully Humain

Antibody

Preclinical testing

Selection

Optimisation

Antibody ready

for PER.C6®

clone

generation3819 mars 2009

Protein products

Prolastin

Protein indicated for hereditary deficiency of alpha-1 proteinase

inhibitor.

Cofact (prothrombin complex )

Marketing and distribution agreement with Sanquin.

Flu monoclonal antibody CR6261

Potential therapy against seasonal and pandemic flu

Rabies monoclonal antibody CL184

combination of two human monoclonal antibodies

using Crucell's MAbstract® and PER.C6® technology

39

Pipeline

19 mars 2009 40

Pipeline

4119 mars 2009

Key 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).

Pipeline

4219 mars 2009

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)

4319 mars 2009

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

44

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 sanofi pasteur.

Antibody cocktail entered a Phase II clinical trial in the US in March 2008.

Study completed, positive preliminary results.

45

Financial overview

19 mars 2009 46

Revenues

47

79%

12,90%

8,10%

sales

licenses

services

0

50

100

150

200

250

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

revenues (in millions)

51%

23%

17%

9%

paediatric vaccines

travel & endemic vaccines

respiratory vaccines

others

2008 : Net profit €14.6 mln

19 mars 2009 48

-160

-140

-120

-100

-80

-60

-40

-20

0

20

40

60

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

profit (in millions)

0

200

400

600

800

1000

1200

1999 2000 2001 2002 2003 2004 2005 2006 2007

Numbers of employees

0

50

100

150

200

250

2003 2004 2005 2006 2007

Property plan and equipment

(in millions)

49

Technology and Research

Development50

51

Sales and marketing

52

Liabilities & cash

0

20

40

60

80

100

120

140

160

180

2002 2003 2004 2005 2006 2007 2008

Long-term

liabilities

cash end of

period

(In millions €)

53

0

20

40

60

80

100

120

140

160

180

200

0

10

20

30

40

50

60

70

80

2000 2001 2002 2003 2004 2005 2006 2007

R&D Spending (in millions €)

R&D spending per Employee (in thousands €)

Linéaire (R&D spending per Employee (in thousands €))

Research & Developement

54

Shares

19 mars 2009 55

Crucell shares

Total number of shares: 65,833,242

Capitalisation: 1,58 bilions €

Crucell’s ordinary shares are listed on: NYSE Euronext since 2000

Nasdaq since 2000

Swiss Exchange 2005

56

Shares65,499,442 ordinary shares outstanding

RiskGrades

(Nasdaq)

57

Source: WSJ

Shares

Crucell and Wyeth in discussion on a

combination of the two companies

Discussions on a Combination of

Crucell and Wyeth Discontinued

58

20€

7 jan 2009

11,5€

7 jan 2009

59

20€

15€

About 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)

60

61

16€

11€

Strategic 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

Quinvaxem

September 2007, option for the exclusive use of Crucell’s

PER.C6 technology and AdVac vaccine technology in two

infectious disease areas. ( TB & HIV)

62

Who can be interested in buying

Crucell?

Compagny Ever had with crucess Intersest Money

DSM Per.C6 magnufacturing Per.C6 No

sanofiPer.C6 licence, pipeline

vaccines for influenza and

rabbie.

Per.C6, completes pipeline with HepA

& paediatric vaccinesSTARYes

novartisPer.C6 licence, Quinvaxem

paediatric vaccine

Per.C6, competes in influenza vaccines,

STAR Yes

Merck exclusive licencePer.C6 (gene therapy), Influenza

vaccines, STARYes

63

« When i look

at the price, i cough »

Chris Viehbacher

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)

64

SWOT analysis: Strengths

6th fast-growing vaccines market

5 core technologies and Distinctive Technology

Proprietary of PER.C6, the cell line technology

Broad Product Portfolio

Strategic alliances to co-develop and commercialize

Large-scale manufacturing

Profit increasement

6619 mars 2009

6th fast-growing vaccines market

5 core technologies and Distinctive Technology

Proprietary of PER.C6, the cell line technology

Broad Product Portfolio

Strategic alliances to co-develop and commercialize

Large-scale manufacturing

Profit increasement

SWOT analysis: Weaknesses

Clinical development generally not in Crucell’s hands.

Involved in various legal proceedings

affect the customers perception of the company

Over-dependence on lead product

6719 mars 2009

SWOT analysis: Opportunities

Rapid expansion of antibody and vaccine worldwide market

License Agreements STAR®

production technology effective for production of antibodies and

proteins on mammalian cell lines(especially the CHO )

Performance of Quinvaxem

Long-term pact with Talecris Biotherapeutics

Commercialisation of Prolastin (alpha-1 proteinase inhibitor).

annual market treatment estimated to be over $250 million.

International expansion

Growing blood factor market

68

“Market 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)

2006 2007 2008

Doses in mln units

Essentially in European countries, but also in Asia and North America

SWOT analysis: Threats

Intellectual Property Risks (Patent dispute)

Crucell’s competitive position depends on its ability

to obtain patents

Intense Competition especially in paediatric

vaccines

Impact of the Financial Crisis

Industry Consolidation

Heightened M&A activity in the pharmaceutical sector

69

In the future...February 26, 2009

Crucell antibody CR6261 a potentially therapy against

seasonal and pandemic flu

Isolated from the immune repertoire of a healthy and

vaccinated individual

CR6261 antibody attacks a Highly Conserved

part of the of the hemaglutinin HA

Neutralizes the virus by blocking conformational

rearrangements associated with membrane fusion

flu vaccine market of $2.2 billion

estimated to double by 2016

19 mars 2009 70

WHAT DO WE THINK

ABOUT CRUCELL ?

19 mars 2009 71

Thank you for your attention.

Any questions?

19 mars 2009 72

19 mars 2009 73

Bibliography

www.crucell.com

www.percivia.com

www.pubmed.com

www.nature.com

Sanofi/merck/DSM/novartis/wyeth

www.nasdaq.com

www.euronext.com

ING, Medtrack,

Globalmarketdirect

lifescienceanalytics

19 mars 2009 80