5e année Industrie - projet de groupe "Business model: Dendreon"

1. Samia Thara
Sarah Merlen
Matthieu Boulenger
1

2. HISTORY
1992
Biotechnology company called:
Activated Cell Therapy
Moutain View, California
Dr Edgar Dr Samuel
Engleman Strobber
•First activity : isolating hematopoietic stem cells from blood for use in patients with cancer
who require transplantation.
2

3. 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

4. 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

5. 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

6. 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

7. Active Cell Immunotherapy
« Activates the body 's ability to fight cancer »
7

8. RESEARCH ACTIVITY
•First step : to find antigens expressed on cancer cells that are suitable targets for cancer therapy
Internal antigen License
discovery program agreements
8

9. RESEARCH ACTIVITY
Second step: to engineer antigens designed to stimulate and maximize cell-mediated 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

10. FIRST TARGET
In the mid-90’s
PROSTATE CANCER
10

11. ESTIMATED NEW CASES
PROSTATE
•Estimated new cases and deaths in 2010 (US) :
New cases: 217,730
Deaths: 32,050
11
The second most common type of cancer among men in the USA

12. PROSTATE CANCER
Diagnosis Symptoms Stages
•Average age when •Often asymptomatic •Low growth
diagnosed:70 years at the beginning
•Physical examination •Pain •Hormono-
dependant
• Dosing •Difficulty in urinating
Prostate
Specific •Problems during
Antigen sexual intercourse
•Biopsy => Gleason •Erectile dysfunction •Hormono-
score independant
• Such as Benign after one to three years and resume
growth despite hormone therapy.
Prostatic Hyperplasia
12

13. 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

14. PRODUCTION & DELIVERY
1
14

15. 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

16. PRODUCTION & DELIVERY
2 16

17. MANUFACTURING
• Incubation of Antigen-Presenting-Cell & Prostatic Antigen
40 hours
APC-PAP-GM-CSF
=
Sipuleucel-T (PROVENGE®)
17

18. PRODUCTION & DELIVERY
3 18

19. PATIENT INJECTION
• Injection of Provenge® = APC-PAP-GMCSF
• 3 days after Leukapheresis
19

20. SCHEME OF INJECTIONS
Cost of 1 injection: $ 31,000
Total cost of the treatment : $ 93,000
20

21. A HUGE LOGISTIC
21

22. 22

23. PROVENGE MARKET
Provenge®
Provenge’s indication : treatment of asymptomatic or minimally symptomatic metastatic
castrate resistant (hormone refractory) prostate cancer 23

24. PROVENGE MARKET
24

25. 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
we can expect a large progression
25

26. 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
26

27. 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 :
27

28. MANUFACTURING FACILITIES
Los Angeles
Mid 2011
• New-Jersey : additional capacity expected in march 2011
• Atlanta & LA: additional capacity starting in mid-2011
28

29. PROPERTY & EQUIPMENT
127 427
76 235
12 285
1730
29

30. INFUSIONS CENTERS
Increase of number of Infusion centers by 9 fold in 2011 for DENDREON to be
near their patients 30

31. 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
31

32. EMERGING COMPETITORS FOR
PROSTATE CANCER
Trade name Type of treatment Company Phase
PROSTVAC® Viral vector Bavarian Nordic Phase II completed
GVAX GM-CSF gene- BioSante Phase III
transfected cell Pharmaceuticals
vaccines
DCVAX Prostate Cellular vaccine Northwest Phase III
Biotherapeutics
TROVAX® Viral vector Oxford Biomedical Phase III
IPILIMUMAB Monoclonal antibodies BMS Phase III
ABIRATERONE Hormonotherapy Janssen-Cilag Phase III
32

33. PIPELINE
Extension of Indication: Androgen Dependent Prostate Cancer
(phase 3 : awaiting data on overall survival)
Potential Raise of the market for PROVENGE® 33

34. PIPELINE
Active Cell Imunotherapy New Antigen targets?
HER2/neu CEA
CA-9
34

35. PIPELINE
Active Cell Imunotherapy New Antigen targets?
HER2/neu CEA
CA-9
35

36. 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
36

37. BREAST CANCER and HER2/neu
Total : 207,090 (USA)
Total : 207,090
The HER2 protein is overexpressed in about 30% of all breast
cancers
37

38. BREAST CANCER and HER2/neu
One drug already targetting HER2 : Trastuzumab HERCEPTIN®
 Recombinant humanised IgG1 monoclonal antibody
38

39. HER2/neu
Opportunities in different solid tumors expressing HER2/neu
• Breast
• Ovarian
• Colorectal
• Bladder
Initiate Phase 2 trial 1Q 2011
Lapuleucel-T NEUVENGE®
39

40. 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 Neuvenge® targeting HER2 in
cancer : Vs HERCEPTIN? bladder cancer : Vs placebo?
40

41. PIPELINE
Active Cell Imunotherapy New Antigen targets?
HER2/neu CEA
CA-9
41

42. 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
42

43. PIPELINE
Active Cell Imunotherapy New Antigen targets?
HER2/neu CEA
CA-9
43

44. 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
44

45. DIFFICULTIES FOR ACI
PRODUCTS DEVELOPMENT
Long
studies
Manufacturing Huge
Antigens logistic
ACI
Exclusion
Ethic : vs
of HIV,
placebo?
HepB- C
45

46. Small Molecule Active Cellular Immunotherapies
Pre-clinical
Phase 2
Phase 3
Market
46

47. 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 Attractive target
• 80% of lung cancers
Synthesis of small molecule agonists
47

48. 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
48

49. AND NOW…CONQUEST OF THE
WORLD ?
49

50. JUST A BEGINNING
50

51. WHO’S NEXT?
World age-standardised rates (per 100,000 males) for prostate
51
cancer in 2008

52. 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 »
52

53. DIFFERENT STRATEGIES TO
EXPAND OUTSIDE THE USA
2 Strategies:
Licensing
OR
To go alone ?
53

54. WHAT ABOUT LICENSING?
1998: license agreement : rights for
PROVENGE in Asia and Pacific countries
2003 : released its
rights for
PROVENGE
54

55. 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
55

56. DENDREON’S CHOICE : to go
alone in EUROPE
Why this choice?
•2 hypothesis: They want 100% of worldwide rights
Own will of DENDREON
They don’t want to share their revenues
Corporate image of growth
Choice by default: they didn’t find any partners?
No certitude to get an european
•Too risky? approval
Reimbursement?
Provenge « is not just a pill
in a bottle » 56

57. WHAT DO THEY NEED?
TRIALS MONEY
IMPACT D9901 D9902 Provenge Senior Notes

58. 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?
58

59. IMPACT TRIAL
•Randomized •512 men •Primary endpoint :
•Double-blind •With asymptomatic Overall survival
•Multicenter •Or minimally •Secondary endpoint:
symptomatic MPC •Time to objective
disease progression
VS Placebo
59
Dendreon website

60. PRIMARY ENDPOINT
Survival median : 4.1 months
60
Dendreon website

61. 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
61

62. 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
62

63. 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
63

64. WHERE TO HAVE A PLACE?
• During DENDREON submits an European authorization (late 2011/early 2012)
Initial manufacturing through a Contract Manufacturing
Organization (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!!
64

65. 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
65

66. CONCLUSION
66

67. Strengths Weaknesses
- ACI : revolutionary therapeutic approach - Huge logistic :
 Expensive
- ACI : less AEs than chemotherapy  Restrictions for Clinical trials
- One drug on the market at least : Provenge - Provenge sales too low compared to
 revenues expectations
- Huge logistic : difficult to copy for generics - Increase of debts (senior notes)
- No profit yet
SWOT
Opportunities Threats
- Expansion
-Decision for reimbursment of Provenge
 In the USA
expected in March
 In Europe : similarity with US
market
- Emerging competitors
-Provenge : new indication in development
- At the mercy of the EMA for the approval of
Provenge (clinical trial vs. Taxotere?)
- ACI : repeatible with new Antigens
 other cancers targeted
67

68. 68

69. EXPECTATIONS
69

70. HIRING OPPORTUNITIES
Quality assurance
Manufacturing
Logistic
coordinators
Regulatory affairs
Sales &
Marketing
R&D
70

71. 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 fully-integrated
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
71

72. WOULD WE JOIN DENDREON?
YES!
72

73. FOR YOUR ATTENTION 73