Provenge (Sipuleucel T)


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Provenge (Sipuleucel T)

  1. 1. Jennifer Dao Phan Gaëlle Datchoua Emmanuel Gomez UEI2 Scientific communication Workshop February 11 & 12, 2010 
  2. 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. 3. Product: Sipuleucel-T (Provenge®) Laboratory: Dendreon Indication: asymptomatic metastatic Androgen Independent Prostate Cancer Agent: autologous dendritic cells Launch on market: expected for mid-2010
  4. 4. A short review of advanced prostate cancer Summary for Prostate Cancer Diagnosis and follow-up A medical unmet need?
  5. 5. Summary for Prostate Cancer epidemiology Jemal et al. CA Cancer J Clin. 2009;225-249. 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 ~ 18-36 months
  6. 6. Diagnosis of advanced prostate cancer Gleason’s score PSA doubling time Residual testosteronemia > 50 ng/mL Digital Rectal Examination+Biopsy Blood test Research of metastases
  7. 7. Histological grading of Prostate Cancer The Primary Gleason grade > 50% of the total pattern The Secondary Gleason grade = 5-50% of the total pattern Primary grade + secondary grade = Gleason Score 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 2-4 Well differenciated 5-7 Intermediate 8-10 Poorly differentiated Gleason’s score
  8. 8. 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 Adaptated from:J Clin Oncol 23;2005:4975–9
  9. 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
  10. 10. Asymptomatic metastatic PCa : no approved therapies in European guidelines A 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
  11. 11. Focus on Provenge® (APC-8015, Sipuleucel-T) Active Cellular Immunotherapy Clinical trials and results
  12. 12. What is Provenge® and how does it work ? Sipuleucel-T: autologous A ctive C ellular I mmunotherapy 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
  13. 13. Main protagonists Antigen Presenting Cells T-lymphocytes Cancer cells Prostatic Acid Phosphatase /GM-CSF
  14. 14. 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
  15. 15. 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 SLC ELC T zone stromal cell (producing CCL21)
  16. 16. Antigen Presentation to T Cells (BARAS, LICHTMAN, Cellular and Molecular Immunology, Saunders ed., 5e ed., 2003) Secondary lymphoid organs Peripheral tissues Th1/Th2 pathway Macrophage/ B cell activation Cytotoxic effect against targeted cells
  17. 17. 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
  18. 18. 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
  19. 19. 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.
  20. 20. 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 Cassette TM triggers the stimulation of T-cell immunity. « Significant survival benefit » APC activation correlates with survival
  21. 21. 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
  22. 22. Clinical Trials and Publications
  23. 23. Clinical development program of Sipuleucel-T
  24. 24. Randomized Placebo Controlled Trial Overall Survival D9901
  25. 25. APC Activation Correlates with Survival D9901 and D9902
  26. 26. 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
  27. 27. T-cell Mediated Immune Response Week 0 to Week 8, Study D9901
  28. 28. 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) pg/nL
  29. 29. Randomized Phase 3 IMPACT Trial (9902B) (Immunotherapy Prostate AdenoCarcinoma Treatment) Primary endpoint: Overall survival Secondary endpoint: Time to objective disease progression
  30. 30. Consistency Across Phase 3 Studies *Unadjusted Cox model & log rank **Cox model adjusted for PSA and LDH
  31. 31. Keep an eye on … Group Sipuleucel-T n / N (%) Placebo n / 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 --- ---
  32. 32. PROTECT (P11): PROVENGE Treatment and Early Cancer Treatment. Ongoing Phase 3 trial with enrollment completed
  33. 33. 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 .
  34. 34. 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 .
  35. 35. Challenges for Provenge® Supply chain Regulatory Affairs
  36. 36. Sipuleucel-T (Provenge ® ) production and delivery PROVENGE® (sipuleucel-T) Cellular, Tissue, and Gene Therapies Advisory Committee Meeting March 29, 2007 The Mattson Jack Group, Cancer Metric Database 2009 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? Day 1 Leukapheresis Apheresis Center Day 2-3 Manufacturing Dendreon’s facility Day 3-4 Infusion Doctor’s Office
  37. 37. 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
  38. 38. 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.
  39. 39. Exemple of a workstation to manufacture Provenge
  40. 40. Exemple of a workstation to manufacture Provenge
  41. 41. 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
  42. 42. Manufacturing sites location SDI, PCa Patient Population 2006
  43. 43. Product Follow-Up
  44. 44. Regulatory aspects
  45. 45. 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
  46. 46. 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
  47. 47. FDA Decision on Provenge: Who’s who, who’s connected ?
  48. 48. 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.
  49. 49. Regulatory framework in Europe (2)
  50. 50. 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
  51. 51. 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
  52. 52. Dendreon Company overview Dendreon’s pipeline Projection sales of Provenge (US/EU)
  53. 53. Targeting cancer, transforming lives™
  54. 54. 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) .
  55. 55. Dendreon website 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
  56. 56. Dendreon’s pipeline (2)
  57. 57. Sales and income 2009 THOMSON REUTERS When and How will they make Money ? Millions US$
  58. 58. Financial analysis (stock price)
  59. 59. 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
  60. 60. US sales projection (2011-2019)
  61. 61. EU sales projection (2011-2019)
  62. 62. 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
  63. 63. What’s next for Dendreon ? Best option for Dendreon in Europe Any idea?…
  64. 64. 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
  65. 65. Any idea?… Big pharma specialized in vaccines-like: Biotechnology which better knows personalized treatment and its regulatory pressure Biotech specialized in cellular therapies
  66. 66. Thanks for your attention! Any question?