Emmanuel GomezJennifer Dao PhanGaëlle Datchoua

UEI2 Scientific communication Workshop February 11 & 12, 2010 1

Safe Harbor

This is an independent study performed by students from This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques de Lille.the Faculté des Sciences Pharmaceutiques de Lille.

The opinions expressed are our own and not necesarily The opinions expressed are our own and not necesarily those of Dendreon.those of Dendreon.

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Product: Sipuleucel-T (Provenge®)

Laboratory: Dendreon

Indication: asymptomatic metastatic Androgen Independent Prostate Cancer

Agent: autologous dendritic cells

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

Jemal et al. CA Cancer J Clin. 2009;225-249.

Commun Oncol 2007;4:447–452

15%Metastatic disease

15%Metastatic disease

Prostate cancerInitial diagnosisProstate cancerInitial diagnosis

85 % localized early disease

85 % localized early disease

60-70%Localized disease

60-70%Localized disease

30-40%Relapse disease

30-40%Relapse disease

~ 18-36 months

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Diagnosis of advanced prostate cancer

Digital Rectal Examination+Biopsy

Gleason’s score

PSA doubling time

Residual testosteronemia > 50 ng/mL

Blood test

Research of metastases 6

http://www.stjohn.org/InnerPage.aspx?PageID=1446

Histological grading of Prostate Cancer

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 Primary Gleason grade > 50% of the total pattern

•The Secondary Gleason grade = 5-50% of the total pattern

2-4 Well differenciated

5-7 Intermediate

8-10 Poorly differentiated

Gleason’s score

• Primary grade + secondary grade = Gleason Score

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Prostatic Specific Antigen doubling time (PSA DT) • PSA = detectable in the blood• PSA ≠ tumoral antigen• PSA level ≠ specific of PCa• PSA DT = corralated with PCa mortality

8Adaptated from:J Clin Oncol 23;2005:4975–9

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.

Gleason’s Score + PSA DT = predictive for PCa outcome

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Asymptomatic metastatic PCa : no approved therapies in European guidelinesA gap for brand new treatment strategies?

Asymptomatic metastatic PCa: a medical unmet need

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

15Animation available on Dendreon website

How do APCs and antigen-specific T cells find each other?

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

BLC

SLCELC

T zone stromal cell (producing CCL21)

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Antigen Presentation to T Cells

17(BARAS, LICHTMAN, Cellular and Molecular Immunology, Saunders ed., 5e ed., 2003)

Secondary lymphoid organs Peripheral tissues

Th1/Th2 pathwayMacrophage/ B cell activation

Cytotoxic effect against targeted cells

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 peptideComplexe, I or II

-S–

S -

TCR - CD 3

Peptide

How to break the tolerance

Flow Chart

• Leukapheresis: for each patient, for each dose

• Culture Lab: fraction containing APCs is isolated2 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 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

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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

Randomized Placebo Controlled Trial Overall Survival D9901

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APC Activation Correlates with SurvivalD9901 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 ResponseWeek 0 to Week 8, Study D9901

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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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pg/n

L

Randomized Phase 3 IMPACT Trial (9902B)(Immunotherapy Prostate AdenoCarcinoma Treatment)

Primary endpoint: Overall survivalSecondary 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

Keep an eye on …

GroupSipuleucel-T

n / N (%)Placebon / N (%)

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)

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

ADPC (P-11)

All CVA’s 1 / 116 (0.9%) 3 / 59 (5.1%) 0.16 (0.016, 1.596) 0.112

Deaths attributed to CVAs

0 0 --- ---

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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

PROVENGE® (sipuleucel-T)Cellular, Tissue, and Gene Therapies Advisory Committee Meeting March 29, 2007The Mattson Jack Group, Cancer Metric Database 2009

COMPLETE COURSE OF THERAPY:3 CYCLES

Day 1 Leukapheresis

Apheresis Center

Day 2-3Manufacturing

Dendreon’s facility

Day 3-4Infusion

Doctor’s Office

100 000 patients in USA with metastatic AIPC in 2010100 000 X 3 = 300 000 doses to prepare and to deliver on time

How will Dendreon make it?

Advance Planning System (APS)

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• 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

Transportation

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• 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

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 three-dimensional 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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www.caretolive.com/research

FDA Decision on Provenge: Who’s who, who’s connected ?

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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)

50Pr JH Trouvin

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

51Pr JH Trouvin

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 website

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’s pipeline (1)

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Dendreon’s pipeline (2)

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Sales and income

2009 THOMSON REUTERS59

Millions US$

When and How will they make Money?

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

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US sales projection (2011-2019)

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EU sales projection (2011-2019)

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Strengths• First active immunotherapy 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

Weaknesses• Mechanism unknown

•Manufacturing process necessary to ensure the safety standards

•Lack of study Sipuleucel vs. Docetaxel

•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

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What’s next for Dendreon ?

Best option for Dendreon in Europe Any idea?…

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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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Any idea?…

- Big pharma specialized in vaccines-like:

- Biotechnology which better knows personalized treatment and its regulatory pressure

- Biotech specialized in cellular therapies

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Thanks for your attention!

Any question?

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