1. Provenge® (APC-8015, Sipuleucel-T)
Emmanuel Gomez
Jennifer Dao Phan
Gaëlle Datchoua
UEI2 Scientific communication Workshop February 11 & 12, 2010 

2. 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 necesarily those of Dendreon.

3. Product: Sipuleucel-T (Provenge®)
Laboratory: Dendreon
Agent: autologous dendritic cells
Indication: asymptomatic metastatic Androgen Independent Prostate Cancer
Launch on market: expected for mid-2010

4. A short review of advanced prostate cancer
Summary for Prostate Cancer
Diagnosis and follow-up
A medical unmet need?

5. Summary for Prostate Cancer epidemiology
2007 Estimated US Cancer Cases
2007 Estimated US Cancer Deaths 1
Prostate
218,890 (29%)
Lung & Bronchus
89,510 (31%) 2
114,760 (15%)
27,050 (9%) 3
Colon & Rectum
79,130 (10%)
26,000 (9%)
Jemal et al. CA Cancer J Clin. 2009;
Commun Oncol 2007;4:447–452
15%
Metastatic disease
Prostate cancer
Initial diagnosis
85 % localized early disease
60-70%
Localized disease
30-40%
Relapse disease
~ months
Once metastatic androgen-independent prostate
cancer (AIPC) develops, responses to alternative hormonal therapy or chemotherapy are not durable, with a median overall survival of approximately 18 months with docetaxel based chemotherapy.

6. Diagnosis of advanced prostate cancer
Digital Rectal Examination+Biopsy
Gleason’s score
Blood test
PSA doubling time
Residual testosteronemia > 50 ng/mL
Research of metastases

7. Histological grading of Prostate Cancer
The Primary Gleason grade > 50% of the total pattern
1. Small, uniform
glands
2. More stroma
between glands
3. Distincly infiltrate
margins
4. Irregular masses
of neoplastic glands
5. Only occasional
gland formation
Gleason’s grade
The Secondary Gleason grade = 5-50% of the total pattern
Primary grade + secondary grade = Gleason Score
2-4 Well differenciated
5-7 Intermediate
8-10 Poorly differentiated
Gleason’s score

8. Prostatic Specific Antigen doubling time (PSA DT)
PSA = detectable in the blood
PSA ≠ tumoral antigen
PSA level ≠ specific of PCa
PSA DT = correlated with PCa mortality
Adaptated from:J Clin Oncol 23;2005:4975–9

9. Gleason’s Score + PSA DT = predictive for PCa outcome
Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005;294:
Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:

10. Asymptomatic metastatic PCa: a medical unmet need
Early stage Death
Non-Metastatic
Androgen Dependant PCa
Radical prostatectomy
Radiation therapy
1st line hormonal therapy
Castrate Resistant PCa
Metastatic
Androgen Independant PCa
(asymptomatic) (symptomatic)
Chemotherapy
Prednisone+docetaxel
Palliative treatment
Bisphosphonates
2nd line hormonal therapy?
Asymptomatic metastatic PCa : no approved therapies in European guidelines
A gap for brand new treatment strategies?
Adaptated from : Nature Reviews Cancer 2, (May 2002)
Progrès en Urologie (2008), Suppl. 7, S343–S348
Commun Oncol 2007;4:447–452

11. Focus on Provenge® (APC-8015, Sipuleucel-T)
Active Cellular Immunotherapy
Clinical trials and results

13. What is Provenge® and how does it work ?
Sipuleucel-T: autologous Active Cellular Immunotherapy Product
Antigen-specific immunotherapy
Immune system geared to respond to a targeted approach
An antigen delivery cassette engages the immune system and activates Antigen Presenting Cells (APC)
Processed ex-vivo
Provides access to more cells
Cells removed from patient’s immunosuppressive environment

14. Main protagonists Antigen Presenting Cells T-lymphocytes Cancer cells
Prostatic Acid Phosphatase /GM-CSF
IL4 ?

15. Provenge®, the lead A.C.I. candidate of Dendreon
Cancer: immunoevasive environment
ACI platform focused on T-cell activation
Tumor associated antigens  APCs  T-cells activation, proliferation
Challenge: Activate APCs while avoiding the tolerance mechanisms
Isolated autologous APCs  manufacturing facilities  exposed to a fusion recombinant protein = antigen highly expressed in prostate cancers
Loaded with antigens, the APCs are infused back  T-cells activation
Les CD sont les seules cellules présentatrices capables d'activer les lymphocytes T naïfs lors d'une immunisation primaire, et les meilleures pour activer les lymphocytes T mémoire.

16. How do APCs and antigen-specific T cells find each other?
BLC
SLC
ELC
T zone stromal cell (producing CCL21)
very little is known about the EXIT process
Antigen-bearing DCs and T cells find each other by:
migrating to a common microenvironment within secondary lymphoid organs
DCs stop in T zone while T cells migrate rapidly through the zone surveying the DCs for MHC-peptide complexes

17. Antigen Presentation to T Cells
Th1/Th2 pathway
Macrophage/ B cell activation
Cytotoxic effect against targeted cells
Cross presentation
Secondary lymphoid organs
Peripheral tissues
(BARAS, LICHTMAN, Cellular and Molecular Immunology, Saunders ed., 5e ed., 2003)

18. How to break the tolerance
CD 4 – CD8
LFA - 3
ICAM – 1(=CD54)
CD 40
B7 (CD80 and CD86)
LFA - 1
CD 2
CD 40 L
-S–S -
CD 28
T-Cell
Antigen Presenting Cells
MHC peptide
Complexe, I or II
-S– S -
TCR - CD 3
Peptide

19. Flow Chart Leukapheresis: for each patient, for each dose
Culture Lab: fraction containing APCs is isolated
2 subsequent centrifugation steps
Cells are cultured with the Antigen Delivery Cassette PA2024
Recombinant PAP fused with GM-CSF
Prostatic Acid Phosphatase: expressed in 95% of all prostate cancers
After hours in culture, cell product is ready: Sipuleucel-T
Immunologically active peptide fragments are displayed on the dendrites
Co-stimulatory molecules (CD54+, CD80+ …) are upregulated
No free GM-CSF is present in the infused product
Transported back to the patient for infusion

20. Patient management Three leukapheresis procedures
Performed at a local blood bank or at the hospital
Standard 1,5 -2,0 volume leukapheresis is collected
4 hours
Baseline, week 2 and week 4
First dose primes the immune system
Cultured product arrives at the infusion center 2 days after WBC collection.
30-60 minutes to infuse
Infusion-related reactions:
primarily fevers and rigors
Typically readily manageable
Generally resolved within 1 or 2 days.

21. APCs and fusion protein
Antigen presenting cells:
Phenotype: HLA DR +, CD3 -, CD 14-, CD16 - and CD 20 -
Ability to elicit primary and secondary immune responses when co-cultured with human lymphocytes in culture.
PA2024: the Antigen Delivery CassetteTM triggers the stimulation of T-cell immunity.
« Significant survival benefit »
APC activation correlates with survival

22. Quality control of final product
The activation of APC is measured by CD54 (ICAM-1) upregulation
IL2 secretion dependant on CD54 and CD80/CD86 expression by APCs.
Th1 – microglia upregulted the surface expression of MHC class II, CD40, and CD54 molecules.
CD54 Upregulation across clinical trials (Fluorescence Intensity)
S= sipuleucel-T, P= placebo
Molecules de costim pour fonction
- Swain, S. L., M. Croft, C. Dubey, L. Haynes, P. Rogers, X. Zhang, L. M. Bradley From naive to memory T cells. Immunol. Rev. 150:143
- The Journal of Immunology, 2000, 164: Functional Maturation of Adult Mouse Resting Microglia into an APC Is Promoted by Granulocyte-Macrophage Colony-Stimulating Factor and Interaction with Th1 Cells Francesca Aloisi et al

23. Clinical Trials and Publications
Sipuleucel-T
Clinical Trials and Publications

24. Clinical development program of Sipuleucel-T
Phase I & II
AIPC
Study P07-2 (ProACT)
Study P09-1
(OpenACT)
ADPC
Study P07-1 (NeoACt)
Phase III Completed
Study I
(Protocol D9901)
Study II & III
(Protocol D9902A&B)
Phase III Ongoing
Study P-11 (PROTECT)

25. Randomized Placebo Controlled Trial Overall Survival D9901

26. APC Activation Correlates with Survival D9901 and D9902

27. The Innate Immune System also engaged
NK lytic activity observed in Sipuleucel-T for each of 3 subjects at Week 2 (Dose2)
NK effector cell activity measured by the killing of K562 target cells in vitro
Sipuleuce-T contains APCs and other mononuclear cells sucha as:
T-Cells, NK Cells and B-Cells
It engages both the adaptive and innate arms of the immune system

28. T-cell Mediated Immune Response Week 0 to Week 8, Study D9901
Median Stimulation Index ratio
PBMC + Ag: restimulation in vitro: culture 48h centri recup surnageant ELISA

29. Cytokine Signature of Activated T cells observed in Sipuleucel-T after first priming dose
pg/nL
Sipuleucel-T Dose 1, Week 0; Dose 2, Week 2; Dose 3, Week 4
First dose primes the immune system
Activated T-cells present in Dose 2 and 3 (Week 2 and Week 4)

30. Randomized Phase 3 IMPACT Trial (9902B) (Immunotherapy Prostate AdenoCarcinoma Treatment)
Primary endpoint: Overall survival
Secondary endpoint: Time to objective disease progression

31. Consistency Across Phase 3 Studies
*Unadjusted Cox model & log rank
**Cox model adjusted for PSA and LDH

32. Keep an eye on … Group Sipuleucel-T n / N (%) Placebo Odds Ratio
(95% CI)
p-value
All Subjects
All CVA’s
18 /461 (3.9%)
6/231 (2.6%)
1.52 (0.596, 3.892)
0.510
Deaths attributed to CVAs
7 / 461 (1.5%)
2 / 231 (0.9%)
1.76 (0.364, 8.566)
0.725
AIPC (Proposed Indication)
17 / 345 (4.9%)
3 / 172 (1.7%)
2.92 (0.84, 10)
0.092
7 / 345 (2.0%)
2 / 172 (1.2%)
1.76 (0.36, 8.6)
0.724
ADPC (P-11)
1 / 116 (0.9%)
3 / 59 (5.1%)
0.16 (0.016, 1.596)
0.112
---
Sans oublier les multiplications exvivo de virus ou la survenue de maladies autoimmune.

33. PROTECT (P11): PROVENGE Treatment and Early Cancer Treatment
PROTECT (P11): PROVENGE Treatment and Early Cancer Treatment. Ongoing Phase 3 trial with enrollment completed

34. Open Trials (Phase II) - AIPC
P09-1 (OpenACT - Open-Label Active Cellular ImmunoTherapy)
An open-label study of Sipuleucel-T in men with metastatic castrate resistant prostate cancer (CRPC)
Objective: To provide sipuleucel-T to men with metastatic CRPC while marketing approval is being pursued, obtain safety data, evaluate the magnitude of immune responses to treatment with sipuleucel-T, and to further characterize the cellular components of sipuleucel-T.
P07-2 (ProACT – Treatment of PROstate cancer with ACI)
A randomized, multicenter, single blind study in men with metastatic androgen independent prostate cancer to evaluate Sipuleucel-T manufactured with different concentrations of PA2024 antigen.
Objective: To compare the cumulative CD54 upregulation ratio between each of the cohorts, evaluate the magnitude of the immune response in each of the cohorts, and evaluate the overall survival in each of the cohorts .

35. Open Trials (Phase II & IIIB) – ADPC
P07-1 (NeoACT- NEOadjuvant Active Cellular ImmunoTherapy)
An open-label, Phase 2 trial of immunotherapy with Sipuleucel-T as Neoadjuvant treatment in men with localized prostate cancer
Objective: To assess the safety of and immune response induced by sipuleucel-T in men with localized prostate cancer.
P11 (PROTECT – PROvenge Treatment and Early Cancer Treatment)
Phase IIIB trial for patients with hormone sensitive prostate cancer
Objective: To determine if Provenge is effective for treatment of early stage, non-metastatic prostate cancer .

36. Challenges for Provenge®
Supply chain
Regulatory Affairs

37. Provenge® supply chain

38. Sipuleucel-T (Provenge®) production and delivery
Day 1 Leukapheresis
Apheresis Center
Day 2-3
Manufacturing
Dendreon’s facility
Day 3-4
Infusion
Doctor’s Office
COMPLETE COURSE OF THERAPY:
3 CYCLES
Sipuleucel-T is manufactured
APCs are seperated from other white blood cells using proprietary technology. APCs are combined with Dendreon’s Antigen Delivery Cassette for approximatively 40 hours
patients in USA with metastatic AIPC in 2010
X 3 = doses to prepare and to deliver on time
How will Dendreon make it?
PROVENGE® (sipuleucel-T)
Cellular, Tissue, and Gene Therapies Advisory Committee Meeting March 29, 2007
The Mattson Jack Group, Cancer Metric Database 2009

39. Advance Planning System (APS)
APS facilitates the management of Provenge’ supply chain:
Enables automated scheduling of patients’ appointments
Provides electronic notification to apheresis centers and physicians
Notifies logistics firms of expected shipping and delivery times

40. Track patients sample through process using barcode
Apheresis center: cells are barcoded with specific information
Dendreon facility: the patient’s specific barcod is scanned to:
- verify that the cells are arrived
- notify the manufacturing team
As they travelled through the manufacturing plant the barcod is scanned and verified
Each patient’s cells are assigned and delivered to a specific workstation.

41. Exemple of a workstation to manufacture Provenge

42. Transportation Courier logistics provided by world class third party
Specialize in time delivery of materials
Performing this type of transportation for years
Make use of commercial airlines

43. Manufacturing sites location
SDI, PCa Patient Population 2006

44. Product Follow-Up

45. Sipuleucel-T
Regulatory aspects

46. Patents
Methods for inducing a natural killer (NK) cell-mediated immune response and for increasing NK cell activity
Oct 2008
Immunotherapeutic compositions and methods for the treatment of moderately to well differentiated cancers – Apr 2004
Composition and method for inducing an immune response against tumour-related antigens – Oct 1998
Isolated Nucleic Acid Molecule Encoding Cancer Associated Antigen, The Antigen Itself, And Uses Thereof
Apr 1998
Immunostimulatory composition and method – Jul 1997
Method for in vitro proliferation of dendritic cells, composition containing the cells entrapped in a three-dimensional matrix and use for immunization – Jan 1997

47. Regulatory Strategy in US
Basis of licensure – Improvement in overall survival
Pivotal study IMPACT
Special Protocol Assessment
FDA agreement that positive results sufficient to amend the BLA
Supportive studies D9901 and D9902A
Highly favorable benefit to risk profile
Submit BLA amendment mid-november 2009
FDA decision by may 2010

48. FDA Decision on Provenge: Who’s who, who’s connected ?
In March,an FDA advisory committee voted 13-4 that Provenge was effective and 17-0 that Provenge was safe.
It was later discovered that two of the Doctors on the panel that voted against the effectiveness of the treatment - and who also subsequently lobbied heavily for the FDA to deny Provenge approval - were found to have previously undisclosed financial interests in companies in direct competition to Dendreon

49. Regulatory framework in Europe (1)
First of all, need to define the product:
biological product
cellular therapy product
more than minimally manufactured
Advanced Therapy Medicinal Product (ATMP)
(Annex IV of directive 2003/63)
Somatic cell therapy medicinal product means a biological medicinal product which has the following characteristics:
(a) contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor; (directive 2009/120)
(b) is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues.

50. Regulatory framework in Europe (2)

51. Regulation 1394/2007: Consequences
For products within the scope:
No marketing without prior authorisation
Assessment of the Quality, Safety & Efficacy
Post-authorisation vigilance; specific obligation for safety and for efficacy
 Pharmacovigilance plan, Efficacy follow-up plan
Authorisation via the centralized procedure mandatory
Same dossier as for a medicinal product (CTD) with technical adaptations
CAT: Committee for Advanced Therapies
New Committee within the EMA
pooling of Community expertise
multidisciplinary nature: biotechnology, medical devices, risk management, ethics, …
representation of Civil Society and Research Community
Tasks: dossier assessment, classification, scientific advice, guidelines, certification
Technical Guidances available: Human cell-based medicinal products: CHMP/410869/06

52. Best option for Dendreon in Europe
Licensing Provenge (already planned)
Centralized procedure for marketing authorization
Several platforms in Europe for industrial process.
Potential parternships based in France
Sound regulatory department to support the project in EU
Quality management for those specific products

53. Dendreon Company overview Dendreon’s pipeline
Projection sales of Provenge (US/EU)

54. Targeting cancer, transforming lives™

55. Dendreon Corporation Created in 1992 NASDAQ : DNDN
Headquarters: Seattle, WA
Facilities:
Morris Plains, NJ
Atlanta, GA
Los Angeles, CA
~ 232 people
R&D and marketing of innovative therapeutics that harness the immune system to fight cancer (Active Cellular Immunotherapy) .

56. Dendreon’s pipeline (1)
Sipuleucel- T (PROVENGE)
Mature autologous DCs obtained via leukapheresis procedure
Treatment of metastatic androgen- independent prostate cancer (AIPC).
Phase 3
Lapuleucel-T (NEUVENGE)
Targets the HER2/neu Ag.
Same process as sipuleucel-T.
The treatment of breast, ovarian and colorectal solid tumors
Phase 2
Preclinical Program:
CA-9 and CEA
carbonic anhydrase IX (CA9).
carcinoembryonic antigen (CEA).
CA9 colon and cervical cancer.
CEA lung & breast cancer.
Preclinic
Dendreon website

57. Dendreon’s pipeline (2)

58. Financial analysis of Dendreon

59. When and How will they make Money?
Sales and income
Millions US$
When and How will they make Money?
2009 THOMSON REUTERS

60. Financial analysis (stock price)

61. Wholesale price of Provenge®
Manufacturing costs
manufacturing facilities
leukapheresis providers
physician infusion centers
Transportation
R&D and marketing
It is difficult to forecast its price because it is the first active imunotherapy in advanced prostate cancer

62. US sales projection (2011-2019)

63. EU sales projection (2011-2019)

64. Sipuleucel-T Strengths Weaknesses Opportunities Threats
First ACI product to demonstrate improvement
in overall survival for cancer
Engages both the adaptative and innate immune system
Patient quality of life
(no pre/post medications, short duration of therapy)
Autologous: few ethical question, regulatory aspect easier
Less toxic vs. chemo
Exclusive patent rights
Lack of study Sipuleucel vs. Docetaxel
Sipuleucel-T
Weaknesses
Mechanism unknown
Manufacturing process necessary to ensure the safety standards
Lack of financial resources
No product out of the market
Safety analysis about CVA ? About autoimmune diseases ?
Opportunities
Potential to create new paradigm in treatment of cancer
ACI for Renal Cell Cancer, Bladder cancer…
Future innovation & technological advances
Patients request
No competition from generics expected for yrs
Niche products with high potential market penetration
Threats
FDA denial
Leader opinion denial
Limit of large scale transposition ?
Export outside USA regulatory questions …
Unfavorable results from R&D & clinical trials

65. What’s next for Dendreon ?

66. Best option for Dendreon in Europe
Licensing Provenge (already planned)
Centralized procedure for marketing authorization
Several platforms in Europe for industrial process.
Potential parternships based in France
Sound regulatory department to support the project in EU
Quality management for those specific products

67. Any idea?… Big pharma specialized in vaccines-like:
Biotechnology which better knows personalized treatment and its regulatory pressure
Firms specialized in cellular therapies
Genzyme: possede une branche hémato transf….work bcp sur des cellules souches.

69. Thanks for your attention!
Any question?

70. Type of « vaccine » in clinical study
Trade name
What’s that?
Company
Type of drug
Phase
Provenge
Autologous (reimplanted) dendritic cells complexed with the Prostatic Acid Phosphatase (PAP) antigen and GM-CSF
Dendreon
Cell therapy
Phase 3
DCVax Prostate
Whole cells derived from two prostate cancer lines modified to secrete GM-CSF and irradiated to arrest growth.
Northwest Biotherapeutics
Cellular vaccine
GVax
. Patients dendritic cells boosted with Prostate Membrane Specific Antigen (PMSA)
Cell Genesis
Trovax
Designed to induce an immune response against the tumor-associated antigen 5T4 using a viral vector, Modified Vaccinia Ankara (MVA). The 5T4 tumor antigen is expressed at high levels in the majority of epithelial-derived cancers such as colorectal, renal, prostate, lung and breast.
Oxford Biomedical
Viral vector
Phase 2
PROSTVAC
Vaccinia-PSA-TRICOM and Fowl pox-PSA-TRICOM
Bavarian Nordic