Transcript Celera - Moodle Lille 2

February 9, 2007
CELERA
From a genomic platform
to a product-development company
Cécile DUVAL
Céline DELPLACE
Céline LANTOIN
Pauline SALADIN
Safe Harbor
This is an independent study performed by
students from the Faculté des Sciences
Pharmaceutiques de Lille
The opinions expressed are our own and not
necessarily those of Celera
THE ACTORS
APPLERA
CORPORATION
Celera Genomics
Applied Biosystems
www.celera genomics.com
Financial situation in 2006
(in thousand of
dollars)
Applied
Biosystem
Net revenues
1 911 226
46 207
1 949 390
275 117
- 62 710
212 492
373 921
569 522
943 443
Income/loss
(continuing
operations)
Cash and
cash
equivalent
Celera
Applera
genomic corporation
Plan


Part I : A genomic platform
Part II : Evolution to a product-development
company

Part III : Activities & pipeline

Part IV : Partners network

Part V : Careers in Celera

Part VI: Our vision of Celera in coming years
Part I
A genomic platform
HUMAN GENOME PROJECT
1988
HUGO: Human Genome Organisation
Aim = sequencing the human genome the most rapidly as
possible to avoid patents from private companies
1990
Starting signal of the human genome sequencing is given by
the USA
⇨HGP: Human Genome Project
Co-financing : - NIH National Institutes of Health
- Department of energy(DOE)
Are joined by France, Germany, Japan and China
ec.europa.eu, research, RDT info 27
HUMAN GENOME PROJECT
1992
The U.K. launch into the project
Financing: Foundation Wellcome Trust



USA
60,8 %
UK
28,9 %
Japan
4,9 %
France
2,8 %
Germany
1,5 %
China
0,7 %
Problem of organization
Database complex to stock
Sequencing methods: must be faster and cheaper
www.genoscope.fr
CELERA HISTORY
1998
Creation of Celera Genomics
Foundation: Applera Corporation + Craig Venter
Primary mission


sequencing and assembling the human genome within 2001
budget of 200 to 250 millions $ (-1/10 than HGP’s one)
⇨ database business (one year access = 5millions euros)
⇨ genes which can be useful are patent
HGP reaction: draft of the human genome is announced
for 2000 thanks to an increase of 60.5 millions $ of the
budget
ec.europa.eu, research, RDT info 27
CELERA HISTORY
1999
Recapitalization⇨ creation of 2 subsidiary companies
Applied Biosystems


Headquater:
Foster City, California
Developing and marketing:
-instrument-based systems
-consumables, software, services
Celera Genomics


Headquater:
Rockville,Maryland
Genomics and
proteomics discovery
platforms
⇨ Tools for genome sequencing
www.celera genomics.com
CELERA HISTORY
2000
March
- Drosophila sequence published by Celera
- Common declaration of Bill Clinton and Tony Blair
June
- Celera announces completion of its first draft of the human
genome…but:
 probably used HGP database
 financial obligation (stocks)
 negociation between Celera and HGP failed
(2nd competition: sequencing the human
proteom!)
www.celera genomics.com
CELERA HISTORY
Celera announces completion of its first draft of the human
genome
CELERA HISTORY
2001
february
- publication of Celera’s human genome paper in Science
april
- Celera completes first assembly of the mouse genome
www.celera genomics.com
HGP strategy:
« Clone by clone » or « Hierarchical shotgun
sequencing »






1st step : BAC library
Extraction of human genomic DNA
DNA is cut into pieces (150Mb)
Insertion into BAC vectors
Transformed into E.Coli where they are replicated
clones
www.genoscope.fr
www.bio.davidson.edu
Michael F.Kim, Rich May, Whole genome shotgun, CS262: lecture 8 notes
www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)
HGP strategy:
« Clone by clone » or « Hierarchical shotgun
sequencing »





2nd step : physical map
BAC inserts are isolated and mapped
Search for markers
Determination of the order of each
cloned fragment / genome
Physical map
www.genoscope.fr
www.bio.davidson.edu
Michael F.Kim, Rich May, Whole genome shotgun, CS262: lecture 8 notes
www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)
HGP strategy:
« Clone by clone » or « Hierarchical shotgun
sequencing »

3rd step : Sequencing (shotgun type)

BAC fragments are fragmented randomly into
smaller pieces

Each smaller piece is cloned into a plasmid and
sequenced on both strands

These sequences are aligned so that identical
sequences are overlapping

These contiguous pieces are assembled into finished
sequence
www.genoscope.fr
www.bio.davidson.edu
Michael F.Kim, Rich May, Whole genome shotgun, CS262: lecture 8 notes
www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)
Celera strategy :
« Whole genome shotgun »

One step :

Extraction of human genomic DNA



DNA is cut into smaller pieces (2-10Mb /
150Mb)
Smaller pieces are cloned randomly into a
plasmid and sequenced on both strands ⇨
some fragments are « lost »
These fragments are aligned and
assembled into finished sequence, based
on overlapping sequences
⇨ Elimination of BAC step and physical map
Celera strategy :
the limits…
 repetitive sequences
www.ncbi.nlm.nih.gov
Celera strategy :
the limits…
 overlap detection
Notion of « coverage »
= average number of reads representing a given
nucleotide in the reconstructed sequence
Ex: « 10X coverage » = each base in the final
sequence was present, on average, in 10 reads
www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)
Celera strategy :
the limits…
 Matter of linking: some « gaps »
can still remain
The goal is to select « good » overlapping pairs and lay
them out into larger contigs: « contiguous regions »
⇓
We have to order these contigs
⇓
Michael F.Kim, Rich May, Whole genome shotgun, CS262: lecture 8 notes
www.snv.jussieu.fr (Gilles Furelaud, Yann Esnault, Genoscope)
Which method is better ?
HGP
Less likely to make mistakes
Celera
Chromosomal location for each
BAC is known
More prone to errors
Incorrect assembly of finished
sequence
Repetitive sequences
Less complex
More complex
Sequencing organization is easier
Fewer random pieces to assemble
« physical gaps » ⇨ ↗ coverage or
make use of map…
Slower (physical map)
Faster (no map and rapid access
More expensive ($ 2.7 billion)
Less expensive ($ 300 million)
to a draft)
Part II
Evolution to a product-development
company
o Why ?
o How?
o Targeted Medicine
o The New Business Model
Why ?
Database business model : Technological platform
• Limited markets
• Fast but poor near-term profit
• Free access to genome sequences
Why ?
Net revenues
Million Dollars
5,44
1800
1600
1400
1200
1000
800
600
400
200
0
3,12
1,03
0,45
Celera Genomics
Applied Biosystems
1998
1999
2000
2001
Year
Annual Report 2002
Why ?
Cash
Million Dollars
1200
1000
800
600
Applied Biosystems
Celera Genomics
400
200
0
1999
2000
2001
Year
Annual Report 2002
Why ?
Database business model : Technological platform
• Limited markets
• Fast but poor near-term profit
• Free access to genome sequences
1. Celera Diagnostics
2. Axys Pharmaceuticals
New business model : Product-development company
• Bigger markets
• More important revenues
• Easier access to alliances
How ?
1. Celera Diagnostics
Presentation
• Creation : april 2001
• 50/50 joint-venture between Celera
Genomics and Applied Biosystems
• Director : Kathy Ordonez
• Strategic Alliance with Abbott
Laboratories (development and
distribution)
How ?
1. Celera Diagnostics
Activities
• Industrial-scale study variations : SNPs
(Database : 150000 specimens, 30000 SNPs)
• Genotyping, gene expression
• New genetic markers
• Genetic tests, In Vitro Diagnostic products
• Therapeutic targets (targeted medicine)
Diseases
• Auto-immune diseases
• Cardiovascular diseases
• Alzheimer’s disease
• Infectious diseases
• Cancers
How ?
2. Axys Pharmaceuticals
Presentation
• Acquisition : november 2001
• Drug discovery and development company
Activities
• Programs and expertise in medicinal chemistry, in biology,
screening and structure-based design (protease inhibitors)
• Pipeline of preclinical small molecules
• Chronic diseases
• Chemical libraries and facilities
Most of the drugs in development in Celera’s pipeline
are from Axys’ program at the acquisition
Targeted Medicine
Targeted medicine = Pharmacogenomics
Molecular diagnostic tests
Genomic
SNPs
DISEASE
Therapeutic targets
Targeted medicine : Why?
Consequences on therapeutics
• Improving current response rates1:
- Alzheimer’s Disease : 30%
-Osteoporosis : 48%
-HCV : 47%
-Rheumatoid arthritis : 50%
-Cancer : 25%
• Recent Targeted Medicine Example:
Gleevec for CML : 60%2
1
• Avoiding adverse drug reactions3:
- 2 million ADRs / 2.8 billion
prescriptions (>100,000 deaths)
- cost : ~$1.3 billion
• Reuse of drugs in eligible population
Spear, Heath-Chiozzi and Huff, Trends in Mol Med 7, 201 (2001).
N Engl J Med, 348 (11),1048 (2003).
3 Lazarou et al., JAMA, 279, 15 (1998).
2
Targeted medicine = Pharmacogenomics
Consequences on development
Development
cost
Development
cost
Time
Time
• Stratified population => smaller and more
consistent clinical trial population =>improvement
• Sooner marketing
LESS COSTS
www.celera.com
New business model
History
January 2002 : Dr. J. Craig Venter
steps down as President of Celera
Genomics
April 2002 : Kathy Ordoñez appointed President of
Celera Genomics
New mission : « To build a valuable portfolio
of preclinical and clinical therapeutics »
December 2002 : announcement of Celera Genomics’ new strategy
New business model
Celera Genomics
Genome
sequence
s
+
Products
Knowledge
Cash
Celera Diagnostics
R&D
Axys Pharmaceuticals
Partners
Cash
Applied Biosystems
Small molecules
Antibodies
Out licensing
Thèse Zoé Verhasselt
Part III
Activities & pipeline


Celera genomics
Celera diagnostic
Celera genomics
o Chemical molecules acquired with Axys
o Proteomic and genomic research
Pipeline in 2005
Axys
Chemicals program
Therapeutic
domain
development
Histone deacetylase
inhibitors
oncology
Phase 1
FVII inhibitors
coagulation
Candidate
selection
Tryptase inhibitors
Asthma and
hypersensibility
Lead
optimization
Cathepsin K
inhibitors
osteoporosis
Phase 1
Cathepsin S
inhibitors
Inflammation and
autoimmune
diseases
Phase 1
Cancer - proteomic
oncology
Target
evaluation
PTPN22-based
target
Autoimmune
diseases
Lead
optimization
An exemple of a small
molecule acquired with Axys
Histone desacetylase inhibitors
(HDACi)
HDACi: histone desacetylase inhibitors
Lysine
Targets of HDAC: histones
HAT
HDAC
Lysine: NH3+
Transcriptional repression
Cancer
Lysine: NH-CO-CH3
Transcriptional activation
HDAC inhibitors
Chromatin Remodeling and Leukemia: New Therapeutic Paradigms By Robert L. Redner, JianxiangWang, and Johnson M. Liu
Apoptosis
Anticancer activities of histone deacetylase inhibitors Jessica E. Bolden, Melissa J. Peart and Ricky
W. Johnstone
Some competitors
Companies:
-Merck
-Schering AG
-Methylgene
-Novartis
-Etc…
Results from proteomic and
genomic research


Generalities
Some examples
Clinical genomic and proteomic
Differences between sequence of genes
Differences of gene expression: RNA
Differences of proteins
Celera genomics: structural genomic
Sequence of gene
Sequence of RNA
Sequence of protein
Structure of protein
Find the function of the protein
Discover new ligands
New markers of cancer
o Differentially expressed
proteins found in multiple
cancers provide clues to
disease development
Target selection
Collaboration with Medarex
to discover fully human
antibodies for the potential
treatment of multiple
indications cancer
New markers of autoimmune
disease
o Identification of SNP in a
cytoplasmic tyrosine
phosphatase gene
(PTPN22) associated with
certain autoimmune
conditions
Lead optimization of chemicals that target the protein
coding by this SNP.
Celera diagnostic


Diagnostic tools
Diseases markers
Genetic and Infectious diseases

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

Cystic fibrosis: mutation identification
HCV: genotyping, viral load, and progression (HCV
liver fibrosis GenotypR™)
HIV: genotyping (Viroseq™) and viral load of HIV 1
Etc…
Viroseq™
Adaptation of the treatment
Plasma samples
Identification of mutations
HIV
Production of a consensus
sequence
RNA
retrotranscription
comparison with a reference
strain
DNA
PCR
ATTGACTGAAACT
DNA copies
Sequencing
In 7 fragments
TAACAGACTTTGA
Viral load of HIV and HCV
Real time PCR system: m2000™
Myocardal infarction
predict genetic risk independant of other standards
risk factors such as level lipids, smoking etc…
Identification of SNPs associated with
myocardial infarction:
2 trials CARE and WOSCOPS
Association of polymorphisms in IgA Fc
Receptor gene with Myocardial Infarction
CARE: Cholesterol And Recurrent Events
551 genes / 1000 SNPs
2523 men
67 SNPs are associated with myocardial infarction
WOSCOPS: West of Scotland Coronary Prevention Study
24 of the 67 SNPs
1562 men
Only the SNP on Ig A Fc receptor gene (FCAR) is linked
with coronary heart disease
Association of polymorphisms in IgA Fc
Receptor gene with Myocardial Infarction
SNP: Asp92Asn
1.46
1.49
1.68
1.75
Asp92Asn Polymorphism in the Myeloid IgA Fc Receptor Is Associated With Myocardial Infarction in Two Disparate Populations : CARE
and WOSCOPS Olga A. Iakoubova, Carmen H. Tong, Anand P. Chokkalingam, Charles M. Rowland, Todd G. Kirchgessner, Judy Z. Louie, Lynn
M. Ploughman, Marc S. Sabatine, Hannia Campos, Joseph J. Catanese, Diane U. Leong, Bradford A. Young, David Lew, Zenta Tsuchihashi, May
M. Luke, Christopher J. Packard, Kim E. Zerba, Peter M. Shaw, James Shepherd, James J. Devlin, Frank M. Sacks
The atherosclerosis process
MOLECULAR, CELLULAR AND FUNCTIONAL IMAGING OF ATHEROTHROMBOSIS Robin P.
Choudhury*,Valentin Fuster‡ and Zahi A. Fayad‡
Hypothesis
The SNP is located near the Ig A
binding domain.
The SNP may influence Ig A binding and
the inflammatory cascade.
CARE study
Targeted medicine
Part IV
Partners network
Partnerships strategy
DIAGNOSTICS
COLLABORATIONS
THERAPEUTICS
COLLABORATIONS
Laboratory Corporation
of America
Abbott
Laboratories
Genentech
Celera
Seattle Genetics
General Electric
Merck
Bristol-Myers
Squibb
Medarex
University of California,
San Francisco
STRATEGIC ALLIANCE
Abbott Laboratories
Specialty
Laboratories
Trend to increase
Partners number
14
12
10
8
6
4
2
0
2001
2002
2003
2004
2005
Partners number evolution since 2001
2006
Motivations for entering into an collaboration
Biotech

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
Genetic target = little value
Challenge : turn the flood of data into profitable
commercial products
Cost of generating a new drug : $450M to $800M
High Risks
Lack of expertise
Motivations for entering into an collaboration
Pharmaceuticals Companies
Threats to their « blockbuster business model »
 Difficulties to develop innovative new
technologies
 Cost of drug increases
Pharma-Biotech alliances are 30%
more likely to gain FDA approval than
a drug developed independently.
Source: Drug-Development; Pharma-Biotech Alliances Present
Lower Risk Opportunities, DRUG WEEK ; January 9, 2004
The purpose of the collaboration

Licensing of intellectual property rights :
 license
A
L
L
I
A
N
C
E
exclusive or non exclusive
 limited : clauses
 reciprocity



Co-development
Co-marketing
Shared manufacturing & product supply
The most common compensations

Up-front fees

Milestone payment

Royalties

Payment for R&D costs
Partnerships
Therapeutic Collaborations
Diagnostic Collaborations
2 examples
 Merck
 Specialty Laboratories
Strategic Alliance : with Abbott Laboratories
Therapeutics collaborations
Company
 Cancer
Abbott
Genentech
Seattle
Genetics
Medarex
Purpose
Antibodies,
small molecules
Antibodies,
antibody fragment,
proteins, small
molecules
Antibodies,
antibody-drugconjugates
Antibodies
Specifics
Protein antigens
identified &
validated by C,
screened by A.
A. has six
targets under
investigation.
G. funds and
manages preclinical, clinical,
manufacturing &
sales.
Co-funding of
pre-clinical &
clinical
development,
jointly decide
sales.
M. & C. jointly
select targets. M.
develops
antibodies using
its proprietary
system. They plan
to develop &
commercialize
independently.
Value for
Celera
Milestones &
royalties
Milestones &
royalties
Milestones &
royalties
Milestones &
royalties
Recent deals

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
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
April 2006
Sale of small drug
candidates (HDAC inh.)
To Pharmacyclics
Up-front cash
payment : $2 million
Future milestones :
$144 million





June 2006
Sale of its Cathepsin
S inhibitor program
To Schering SA
Up-front cash
payment : $5 million
Future milestones :
$360 million
Diagnostics collaborations
Merck
Since November 1996 : Cathepsin K inhibitors
Celera received clinical milestone payment (July 2004)

Since October 2003 : Breast cancer
Celera : Access to IP of Merck (tissue samples)
Merck : Access to selected research data from Celera

Since July 2004 : Alzheimer’s Disease
Merck : right for therapeutic applications
Celera : right for diagnostic applications, milestones/royalties

Diagnostics collaborations
Specialty Laboratories





Since June 2006
Celera granted SL a non-exclusive license to risk
markers for cirrhosis
SL can develop & commercialize a genetic test that
predicts risk of progression to liver cirrhosis (HCV)
HCV Liver Fibrosis GenotypR™ commercialized
(October 2006)
SL pays an upfront license fee & royalties
A Strategic Alliance with
Abbott Laboratories
Strategic alliance





Active relation
License + co-development & co-marketing
Development of intellectual property
jointly
To share resources & capacities, different
but complementary
Common objective
Alliance with Abbott Laboratories







Since June 2002
Long-term complementary strategic alliance
Objective : « bridge between gene-based research
and new products beneficial to human health »
250 scientists & engineers devoted to the
program
Joint Review Board manages the alliance
Interest for Abbott : intellectual property, licenses
Interest for Celera : resources
Roles of each partner
Celera
Abbott
Novel genetic
 Products
markers discovery development
for disease
 Marketing
 Validation
 Sales
 Distribution

Share profits & expenditures related to research,
development, manufacture and commercialization
Products sold throughout the Alliance
Cystic fibrosis
Analyte Specific Reagents (ASRs) & IVD product


m2000 Real-Time Molecular Diagnostics
$900 million market


ASRs for monitoring viral load & genotyping the
HCV virus
ViroSeq™ for HIV-Genotyping
Thrombosis panel (January 2006)
ASRs for detection of mutations in Factors V & II, MTHFR

Sales increase
Alliance Sales
$79,5M
$61,7M
FY 2006 :
Royalty to
Celera ~ 14%
$11M
Source: 2006 Annual Stockholders Meeting; Applera Corporation
Molecular Diagnostic Market
Abbott/Celera
Second quarter of
fiscal 2007 : $105M
14%
Other
5%
BD
4%
6% Digene
7% Bayer
Revenue by
company
20%
44%
Roche
Source : JP Morgan 25th Annual
Healthcare Conference, January 2007
Gen-Probe/
Chiron
Total = $2.1B
Summary
Strength
• Strategic alliance
• Genomic & proteomic expertise
• Targeted medicine
Weaknesses
Threats
• Failure of pipeline development
• Competition
• Early stage of development
Celera
Opportunities
• To strengthen the partners network
• To focus on selling diagnostics
• Financially dependant
Careers in Celera
Who are they looking for?

Manufacturing & engineering employees
Legal employees
Regulatory Affairs employees
Purchasing employees
Quality Assurance/Quality control employees

College Programs




« Celera seeks talented & motivated recent graduates
to launch their careers »
www.celera.com
Where?
Rockville, Maryland (US)
~ 300 employees
Alameda, California (US)
Celera’s values






Solid plan
Financial strength
Skilled management
Financial rewards
Supportive environment : « Celera family »
Benefits package :





Medical, Dental & Vision insurance
Basic Life Insurance
Company Holidays
Paid Time Off : a minimum of 3 weeks
Adoption Assistance Program …
Our vision about Celera in
coming years…
« Kathy Ordonez : The fortune-teller »
Reported Revenues in 2011
Jp Morgan january 2007
Net revenues
Million Dollars
7,50
6,08
5,27
3,59
2,36
2000
1500
1000
Celera Genomics group
Applied Biosystems group
500
0
2002
2003
2004
2005
2006
Year
Annual Report 2006
Cash
Million Dollars
900
800
700
600
500
400
300
200
100
0
Celera Genomics group
2002
2003
2004
2005
2006
Year
Annual Report 2006
Stockholders are not blind…
Bonus
Tryptase inhibitors
Inhibitors of mast cell tryptase beta as therapeutics for the treatment of asthma and inflammatory disorders
J.A. Cairns Respiratory and Rheumatoid Arthritis Disease Group, Aventis Pharmaceuticals, Route 202/206,
Bridgewater, NJ 08807, USA
Cathepsin K inhibitors: osteoporosis
Real time PCR