Download AIPC - Moodle Lille 2

Emmanuel Gomez
Jennifer Dao Phan
Gaëlle Datchoua
UEI2 Scientific communication Workshop February 11 & 12, 2010
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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.
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Product: Sipuleucel-T (Provenge®)
Laboratory: Dendreon
Agent: autologous dendritic cells
Indication: asymptomatic metastatic Androgen Independent Prostate Cancer
Launch on market: expected for mid-2010
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A short review of advanced prostate cancer
 Summary for Prostate Cancer
 Diagnosis and follow-up
 A medical unmet need?
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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
Lung & Bronchus
114,760 (15%)
Prostate
27,050 (9%)
3
Colon & Rectum
79,130 (10%)
Colon & Rectum
26,000 (9%)
Jemal et al. CA Cancer J Clin. 2009;225-249.
Prostate cancer
Initial diagnosis
85 % localized
early disease
~ 18-36 months
60-70%
Localized disease
30-40%
Relapse disease
15%
Metastatic disease
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Commun Oncol 2007;4:447–452
Diagnosis of advanced prostate cancer
Gleason’s
score
Digital Rectal Examination+Biopsy
PSA doubling time
Blood test
Research of metastases
Residual
testosteronemia >
50 ng/mL
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Histological grading of Prostate Cancer
Gleason’s grade
• The Primary Gleason grade > 50% of the total pattern
•The Secondary Gleason grade = 5-50% of the total pattern
1. Small, uniform
glands
2. More stroma
between glands
3. Distincly infiltrate
margins
4. Irregular masses
of neoplastic glands
• Primary grade + secondary grade = Gleason Score
Gleason’s score
2-4 Well differenciated
5-7 Intermediate
8-10 Poorly differentiated
5. Only occasional
gland formation
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http://www.stjohn.org/InnerPage.aspx?PageID=1446
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
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Adaptated from:J Clin Oncol 23;2005:4975–9
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;294:433-439.
Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597.
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Asymptomatic metastatic PCa: a medical unmet need
Early stage
Death
Non-Metastatic
Androgen Dependant PCa
Radical prostatectomy
Radiation therapy
1st line hormonal therapy
Metastatic
Androgen Independant PCa
(asymptomatic)
2nd line hormonal
therapy?
(symptomatic)
Castrate
Resistant PCa
Chemotherapy
Prednisone+docetaxel
Palliative treatment
Bisphosphonates
Asymptomatic metastatic PCa : no approved therapies in European guidelines
A gap for brand new treatment strategies?
Adaptated from : Nature Reviews Cancer 2, 389-396 (May 2002)
Progrès en Urologie (2008), Suppl. 7, S343–S348
Commun Oncol 2007;4:447–452
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Focus on Provenge® (APC-8015, Sipuleucel-T)
 Active Cellular Immunotherapy
 Clinical trials and results
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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
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Main protagonists
• Antigen Presenting Cells
• T-lymphocytes
• Cancer cells
• Prostatic Acid Phosphatase /GM-CSF
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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
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How do APCs and antigen-specific T cells find each other?
BLC
SLC
ELC
T zone stromal
cell (producing
CCL21)
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
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Antigen Presentation to T Cells
Th1/Th2 pathway
Macrophage/ B cell activation
Cytotoxic effect against
targeted cells
Secondary lymphoid organs
Peripheral tissues
(BARAS, LICHTMAN, Cellular and Molecular Immunology, Saunders ed., 5e ed., 2003)
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How to break the tolerance
Peptide
TCR - CD 3
MHC peptide
Complexe, I or II
CD 4 – CD8
CD 40 L
CD 28
CD 2
LFA - 1
T-Cell
CD 40
B7 (CD80 and CD86)
LFA - 3
ICAM – 1(=CD54)
Antigen Presenting Cells
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 36-44 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
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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.
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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 cocultured 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
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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
- Swain, S. L., M. Croft, C. Dubey, L. Haynes, P. Rogers, X. Zhang, L. M. Bradley. 1996. From naive to memory T cells. Immunol. Rev. 150:143
- The Journal of Immunology, 2000, 164: 1705-1712. 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
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Clinical Trials and Publications
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Clinical development program of Sipuleucel-T
Phase I & II
Phase III
Completed
Phase III
Ongoing
AIPC
Study P07-2
(ProACT)
Study P09-1
(OpenACT)
ADPC
AIPC
Study I
(Protocol D9901)
Study II & III
ADPC
Study P-11
(PROTECT)
(Protocol D9902A&B)
Study P07-1
(NeoACt)
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Randomized Placebo Controlled Trial Overall Survival
D9901
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APC Activation Correlates with Survival
D9901 and D9902
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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
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T-cell Mediated Immune Response
Week 0 to Week 8, Study D9901
Median Stimulation Index ratio
18
16
p=0.003
14
12
10
8
6
4
2
0
Sipuleucel-T (Mean=16,9)
Placebo (Mean=1,9)
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pg/nL
Cytokine Signature of Activated T cells observed in
Sipuleucel-T after first priming dose
•
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)
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Randomized Phase 3 IMPACT Trial (9902B)
(Immunotherapy Prostate AdenoCarcinoma Treatment)
Primary endpoint: Overall survival
Secondary endpoint: Time to objective disease progression
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Consistency Across Phase 3 Studies
*Unadjusted Cox model & log rank
**Cox model adjusted for PSA and LDH
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Keep an eye on …
Sipuleucel-T
n / N (%)
Placebo
n / N (%)
Odds Ratio
(95% CI)
p-value
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
Group
All Subjects
AIPC (Proposed Indication)
All CVA’s
17 / 345 (4.9%)
3 / 172 (1.7%)
2.92 (0.84, 10)
0.092
Deaths attributed
to CVAs
7 / 345 (2.0%)
2 / 172 (1.2%)
1.76 (0.36, 8.6)
0.724
1 / 116 (0.9%)
3 / 59 (5.1%)
0.16 (0.016, 1.596)
0.112
0
0
---
---
ADPC (P-11)
All CVA’s
Deaths attributed
to CVAs
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PROTECT (P11): PROVENGE Treatment and Early Cancer Treatment.
Ongoing Phase 3 trial with enrollment completed
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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
.
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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
.
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Challenges for Provenge®
 Supply chain
 Regulatory Affairs
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Sipuleucel-T (Provenge®) production and delivery
Apheresis Center
Dendreon’s facility
Doctor’s Office
Day 1
Leukapheresis
Day 2-3
Manufacturing
Day 3-4
Infusion
COMPLETE COURSE OF THERAPY:
3 CYCLES
100 000 patients in USA with metastatic AIPC in 2010
100 000 X 3 = 300 000 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
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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
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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.
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Exemple of a workstation to manufacture Provenge
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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
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Manufacturing sites location
SDI, PCa Patient Population 2006
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Product Follow-Up
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Regulatory aspects
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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 threedimensional matrix and use for immunization – Jan 1997
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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
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FDA Decision on Provenge: Who’s who, who’s connected ?
www.caretolive.com/research
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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.
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Regulatory framework in Europe (2)
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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
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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
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Dendreon
 Company overview
 Dendreon’s pipeline
 Projection sales of Provenge (US/EU)
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Targeting cancer, transforming lives™
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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) .
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Dendreon’s pipeline (1)
Sipuleucel- T
(PROVENGE)
Lapuleucel-T
(NEUVENGE)
Mature autologous
DCs obtained via
leukapheresis
procedure
Targets the HER2/neu
Ag.
Same process as
sipuleucel-T.
Preclinical
Program:
CA-9 and CEA
Dendreon website
Treatment of
metastatic androgenindependent prostate
cancer (AIPC).
Phase 3
The treatment of
breast, ovarian and
colorectal solid
tumors
Phase 2
carbonic anhydrase
IX (CA9).
CA9 colon and
cervical cancer.
carcinoembryonic
antigen (CEA).
CEA lung &
breast cancer.
Preclinic
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Dendreon’s pipeline (2)
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Sales and income
Millions US$
When and How will they make Money?
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2009 THOMSON REUTERS
Financial analysis (stock price)
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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
61
US sales projection (2011-2019)
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EU sales projection (2011-2019)
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Strengths
Weaknesses
• First ACI product to demonstrate improvement
in overall survival for cancer
• Mechanism unknown
• Engages both the adaptative and innate immune system
•Manufacturing process necessary to ensure the safety standards
•Patient quality of life
(no pre/post medications, short duration of therapy)
•Lack of financial resources
•No product out of the market
• Autologous: few ethical question, regulatory aspect easier
•Safety analysis about CVA ? About autoimmune diseases ?
•Less toxic vs. chemo
•Exclusive patent rights
•Lack of study Sipuleucel vs. Docetaxel
Opportunities
Sipuleucel-T
• 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
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What’s next for Dendreon ?
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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
66
Any idea?…
-
Big pharma specialized in vaccines-like:
-
Biotechnology which better knows personalized treatment and its
regulatory pressure
-
Firms specialized in cellular therapies
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Thanks for your attention!
Any question?
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