Download prostate cancer - Moodle Lille 2

Samia Thara
Sarah Merlen
Matthieu Boulenger
1
HISTORY
1992
Dr Edgar
Engleman
Dr Samuel
Strobber
Biotechnology company called:
Activated Cell Therapy
Moutain View, California
•First activity : isolating hematopoietic stem cells from blood for use in patients
with cancer who require transplantation.
2
HISTORY
After several years : Activated Cell Therapy
• Activity shift : developing therapeutic products that
fight cancer by manipulating aspects of the immune
system
Seattle, Washington
state
« Targeting Cancer, Transforming Lives »
• Today:
o CEO : Mitchell H. Gold
o 650 employees (April 2010)
o Main Manufacturing facility in Morris Plain (NJ)
3
FUNDING
•DENDREON came public in 2000 (NASDAQ) : $10 per share
•Major shareholders:
o Mutual Fund : Fidelity Growth Company Fund: 9.50% of shares held
o Individual Investors : David L Urdal (Executive vice president of Dendreon):
0.36% of shares held
February 13, 2011: $35.15
4
ACTIVITY

DENDREON is focused on the discovery, development and commercialization:
•
of novel therapeutics
•
that may significantly improve cancer treatment options for patients
Philosophy of Dendreon :
produce Active Cellular Immunotherapy products
stimulate an immune response against a variety of tumor types
5
CANCER THERAPIES
• Cancer is characterized by abnormal cells that grow and proliferate,
• forming masses called tumors
• Cancer therapies must
eliminate or the growth of the cancer
control
Chemotherapy
Hormone
treatments
Surgery
Radiation
•BUT :
may not have the desired therapeutic effect
may result in significant detrimental side effects
New approach to Cancer Treatment:
IMMUNOTHERAPIES
6
Active Cell
« Activates
the body 's ability to fight cancer »
Immunotherapy
7
RESEARCH ACTIVITY
•First step : to find antigens expressed on cancer cells that are suitable targets for
cancer therapy
Internal antigen
discovery
program
License
agreements
8
RESEARCH ACTIVITY
Second step: to engineer antigens designed to stimulate and maximize cellmediated immunity
Creation of the “Antigen Delivery Cassette™”
= The key to robuste immune response
Aim : to raise the quality and the quantity of the immune response
9
FIRST TARGET
In the mid-90’s
PROSTATE
CANCER
10
PROSTATE
ESTIMATED NEW
CASES
•Estimated new cases and deaths in 2010 (US) :
New cases: 217,730
Deaths: 32,050
The second most common type of cancer among men in the
11
PROSTATE CANCER
Diagnosis
•Average age when
diagnosed:70 years
Symptoms
•Often asymptomatic
at the beginning
•Physical examination •Pain
Stages
•Low growth
•Hormonodependant
• Dosing
Prostate
Specific
Antigen
•Difficulty in urinating
•Biopsy => Gleason
score
•Erectile dysfunction
•Hormonoindependant
•
Such as Benign
Prostatic Hyperplasia
after one to three years and resume
growth despite hormone therapy.
•Problems during
sexual intercourse
12
PROVENGE®: Active Cell
Immunotherapy applied to Prostate
Cancer
3 actors:
Recombinant antigen: composed of
Prostatic Acid Phosphatase (expressed in more than
95% of prostate cancers cells)
GM-CSF : Granulocyte-macrophage colony-stimulating
factor
Antigen Presenting Cell: white blood cells removed
from the patient through LEUKAPHERESIS
T-Cells: actived by the APC-PAP-GM-CSF, attack the tumor
cells
13
PRODUCTION &
DELIVERY
1
14
LEUKAPHERESIS
•In a cell collection center
3 to 4 hours
•Antigen Presenting Cells are removed
•Rest of the blood is returned to the patient
15
PRODUCTION &
DELIVERY
2
16
MANUFACTURING
• Incubation of Antigen-Presenting-Cell & Prostatic Antigen
40 hours
APC-PAP-GM-CSF
=
Sipuleucel-T
(PROVENGE®)
17
PRODUCTION &
DELIVERY
3
18
PATIENT INJECTION
• Injection of Provenge® = APC-PAP-GMCSF
• 3 days after Leukapheresis
19
SCHEME OF INJECTIONS
Cost of 1 injection: $ 31,000
Total cost of the treatment : $
20
A HUGE LOGISTIC
21
PROVENGE
MARKET
Provenge®
Provenge’s indication : treatment of asymptomatic or minimally symptomatic
metastatic castrate resistant (hormone refractory) prostate cancer
22
PROVENGE
MARKET
23
PROVENGE SALES
Total in 2010 : $48 M
• About only 500 patients were treated in 2010 (in 8 months)
• Expectations (2009) : to treat 8% of the Asymptomatic Metastatic AIPC market7300
patients
24
What’s next for PROVENGE in
the USA?
Expectations in 2014:
•Market shares = 35%
•Patients treated= 38,628
BUT can DENDREON provide enough
Provenge® to meet demand?
•Enough Recombinant Prostatic Antigen?
•Enough Infusions Centers?
•Enough Manufacturing capacity?
2011: A YEAR OF GROWTH
25
Supply of the
recombinant Antigen
• DENDREON
doesn’t
produce the antigen itself
• The company utilizes third party suppliers to
manufacture and package the recombinant
antigene
• First collaboration :
• Since September 2010 , second supplier
:
26
MANUFACTURING
FACILITIES
Los Angeles
Mid 2011
• New-Jersey : additional capacity expected in march 2011
• Atlanta & LA: additional capacity starting in mid-2011
27
PROPERTY & EQUIPMENT
127 427
76 235
12 285
1730
28
INFUSIONS CENTERS
Increase of number of Infusion centers by 9 fold in 2011 for
DENDREON to be near their patients
29
OTHER ISSUES FOR 2011
SALES FORCES
• Increase of the sales forces to approximatly 100 reps to service 450 centers by the
end of 2011
Significant increase in outreach to maximize the additional
capacity
REIMBURSEMENT
• Will CMS recommend and provide national reimbursement?
•Date of national decision : March, 30,2011
•But some local Medicare contractors already reimburse PROVENGE®
Good clue for a positive decision by CMS
30
EMERGING COMPETITORS
FOR PROSTATE CANCER
Trade name
Type of treatment
Company
Phase
PROSTVAC®
Viral vector
Bavarian Nordic
Phase II completed
GVAX
GM-CSF genetransfected cell
vaccines
BioSante
Pharmaceuticals
Phase III
DCVAX Prostate
Cellular vaccine
Northwest
Biotherapeutics
Phase III
TROVAX®
Viral vector
Oxford Biomedical
Phase III
IPILIMUMAB
Monoclonal antibodies BMS
Phase III
ABIRATERONE
Hormonotherapy
Phase III
Janssen-Cilag
31
PIPELINE
Extension of Indication:
Androgen Dependent Prostate Cancer
(phase 3 : awaiting data on overall survival)
Potential Raise of the market for
32
PIPELINE
Active Cell
Imunotherapy
New Antigen
targets?
CEA
HER2/neu
CA-9
33
PIPELINE
Active Cell
Imunotherapy
New Antigen
targets?
CEA
HER2/neu
CA-9
34
HER2/neu
= Human Epidermal Growth Factor Receptor 2
Membrane Glycoprotein involved in cell growth and
differenciation
Composed of:
• an extracellular domain for binding ligands
• a single transmembrane segment
• an intracellular domain carrying tyrosine-kinase activity
35
BREAST CANCER and
HER2/neu
Total : 207,090
Total : 207,090
(USA)
The HER2 protein is overexpressed in about 30% of all
breast cancers
36
BREAST CANCER and
HER2/neu
One drug already targetting HER2 : Trastuzumab HERCEPTIN®
 Recombinant humanised IgG1 monoclonal antibody
37
HER2/neu
Opportunities in different solid tumors expressing
HER2/neu
• Breast
• Ovarian
• Colorectal
• Bladder
Initiate Phase 2 trial 1Q 2011
Lapuleucel-T NEUVENGE®
38
BLADDER CANCER & HER2/neu
Bladder cancer : 70,530 new cases in 2010 (USA)
The 4th most frequent cancer in men
HER2 expression in bladder cancer : very variable between the different
studies (from 9 to 81%)
WHY TO CONDUCT A CLINICAL TRIAL IN BLADDER CANCER AND NOT IN
BREAST CANCER?
HER2 Cancer market : HERCEPTIN®  No indication in the bladder cancer
Neuvenge® targeting HER2 in
breast cancer : Vs
HERCEPTIN?
Neuvenge® targeting HER2 in
bladder cancer : Vs placebo?
39
PIPELINE
Active Cell
Imunotherapy
New Antigen
targets?
CEA
HER2/neu
CA-9
40
CA-9
•In-licensed from Bayer Corporation, Business Group Diagnostics
= Carbonic Anhydrase IX
•Transmembrane protein involved in cell proliferation
the only
tumor-associated carbonic anhydrase isoenzyme known
Tumors over-expressing CA-9:
•Colon
•Cervical
•Kidney
CA-9 is overexpressed in 75% of
Renal cell Carcinoma
phase 1 in Renal Cell Carcinoma planned
in 2011
41
PIPELINE
Active Cell
Imunotherapy
New Antigen
targets?
CEA
HER2/neu
CA-9
42
CEA
• In-licensed from Bayer Corporation, Business Group Diagnostics
=CarcinoEmbryonic
Antigen : glycoprotein involved in cell adhesion
• Not usually present in healthy adults, although levels are raised in heavy
smokers
Cancers expressing CEA :
• Breast (65%)
• Lung (70%)
Phase 1 expected in
2012
• Colon
43
DIFFICULTIES FOR ACI
PRODUCTS DEVELOPMENT
Long
studies
Manufacturi
ng
Antigens
Exclusion
of HIV,
HepB- C
ACI
Huge
logistic
Ethic : vs
placebo?
44
Small Molecule
Active Cellular Immunotherapies
Market
Phase 3
Phase 2
Pre-clinical
45
TRPM8
=Transient Receptor Potential Cation Channel subfamily M member 8
• transmembrane cation channel identified through Dendreon’s internal antigen
discovery program
Patent on the gene in 2001
Over-expressed in :
• 100% of prostate cancers
• 71% of breast cancers
• 93% of colon cancers
• 80% of lung cancers
Attractive target
Synthesis of small molecule agonists
46
TRPM8: Mechanism of
Action
Activation by agonist 
induces Ca++ to flow into cells APOPTOSIS
•This small molecule agonist is orally available
Clinical phase 1 trial ongoing
47
AND NOW…CONQUEST OF
THE WORLD ?
48
JUST A BEGINNING
49
WHO’S NEXT?
World age-standardised rates (per 100,000 males) for
prostate cancer in 2008
50
DENDREON’S FIRST
TARGET
EUROPE « Europe is our first ex-US opportunity »
•Market for metastatic AIPC patients = 1.5X to 2X US
•Overall market characteristics similar to US
 Both urologists & oncologists are involved in treatment
 Treatment paradigms similar
 Significant therapeutic unmet need remains
•DENDREON CEO Mitch Gold :
« Low rates of PSA testing in Europe meant that
many men arrived in their physicians office with
metastatic disease »
51
DIFFERENT STRATEGIES TO
EXPAND OUTSIDE THE USA
2 Strategies:
Licensing
OR
To go alone ?
52
WHAT ABOUT LICENSING?
1998: license agreement : rights for
PROVENGE in Asia and Pacific
countries
2003 : released
its rights for
PROVENGE
53
LICENSING?
Advantages
• Greater local knowlege of the Regulatory agencies by the
licensee.
• Better manufacturing capacity of the licensee
• No administrative expenses and no cost of good solds for Dendreon
(PROVENGE® commercialization needs much money)
Disadvantage
•DENDREON will depend on the skills, abilities and ressources of the
licensee as a source of revenue  dependence
54
DENDREON’S CHOICE : to go
alone in EUROPE
Why this choice?
•2 hypothesis:
Own will of DENDREON
They want 100% of worldwide
rights
They don’t want to share their revenues
Corporate image of growth
Choice by default: they didn’t find any partners?
•Too risky?
No certitude to get an
european approval
Reimbursement?
Provenge « is not just a
pill in a bottle »
55
WHAT DO THEY NEED?
MONEY
TRIALS
IMPACT
D9901
D9902
Provenge
Senior
Notes
TRIALS & REGULATORY
• Advanced Therapy Medicinal Product (ATMP) Annex IV of
directive 2003/63/CE
 Cellular Therapy
 Via Centralised Procedure
Same dossier as for a medicinal product with technical
adaptations
• DENDREON wants to rely on its IMPACT trial, conducted in the US
BUT: Will it be acceptable in EU?
57
IMPACT TRIAL
•Randomized
•Double-blind
•Multicenter
VS
Placebo
•512 men
•With asymptomatic
•Or minimally
symptomatic MPC
•Primary endpoint :
Overall survival
•Secondary endpoint:
•Time to objective
disease progression
58
Dendreon website
PRIMARY ENDPOINT
Survival median : 4.1 months
59
Dendreon website
IMPACT TRIAL:
NEGATIVE POINTS?
IMPACT TRIAL
 Primary endpoint: Overall survival



trials done versus placebo: ethic problems, same efficiency
versus taxotere?
patients having metastases: what medicine did they take before?
(docetaxel approval for prostate cancer by FDA: 19/05/2004)
ethnic population isn’t the same and ethny changes impact of the
disease
 Secondary endpoint: Time to objective disease
survival
 FDA agreed to allow Dendreon to amend the design of the IMPACT
study
60
REIMBURSEMENT
CHALLENGE
Market access and reimbursement success is key to realizing full product
potential in E.U.
Key factors influencing reimbursment:
•
overall survival is the « gold standart » for payers
IMPACT: 4 months survival benefits against placebo…
• total cost of care is taken into account
$93,000/ complete cost treatement for Provenge VS $18,000/ 6 cycles
of treatment for taxotere
lack of required premedication and supportive care costs compared to
Taxotere
61
WHERE TO HAVE A PLACE?
• Find a strategic place in EUROPE
wich must be:
 Near airport and road network
 In a reasonable distance from each European capital
 Able to cover the majority of the market
• DENDREON’s decision to build its manufacturing site: GERMANY
 50% of patients live in less than 8 hours to this site in car or
flight
62
WHERE TO HAVE A PLACE?
• During DENDREON submits an European authorization (late 2011/early 2012)
Initial manufacturing through a Contract
Organization
Manufacturing
(CMO):
 Qualifying a CMO can be done faster than plant construction
 Dendreon expects to save 12 to 18 months by outsourcing to support
filing.
• Concurrently DENDREON will build its first manufacturing site:

Initiate built out in 2011
Huge expenses!!
63
WITH WICH
MONEY?
 Revenues from Provenge : $48 millions in 2010
 January, 14th 2011: Dendreon announced the pricing of a publing
offering of $540 million convertible senior notes
 Raise the equity : in the beginning of 2010 : public offering of 15
Million shares
64
CONCLUSION
65
Strengths
Weaknesses
- ACI : revolutionary therapeutic
approach
- ACI : less AEs than chemotherapy
- Provenge sales too low compared
to expectations
- One drug on the market at least :
Provenge
 revenues
- Increase of debts (senior notes)
- Huge logistic : difficult to copy for
generics
Opportunities
- Huge logistic :
 Expensive
 Restrictions for Clinical
trials
- No profit yet
SWOT
- Expansion
 In the USA
 In Europe : similarity with
US market
-Provenge : new indication in
development
- ACI : repeatible with new Antigens
 other cancers targeted
Threat
s
-Decision for reimbursment of
Provenge expected in March
- Emerging competitors
- At the mercy of the EMA for the
approval of Provenge (clinical trial
vs. Taxotere?)
66
EXPECTATIONS
67
HIRING
OPPORTUNITIES
Quality assurance
Manufacturing
Logistic
coordinators
Regulatory
affairs
R&D
Sales &
Marketing
68
WOULD WE JOIN
DENDREON?
Cancer treatment is a «
noble » domain
Working for a revolutionary process as ACI must be exciting
Transition from a total R&D to a fullyintegrated commercial company
Development of domains corresponding to our
professional expectations
Regulatory Challenge in Europe
Development of new ACI products
New jobs in Regulatory Affairs
Evaluation of new markets
69
WOULD WE JOIN
DENDREON?
YES!
70
FOR YOUR ATTENTION
71