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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
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