Samia Thara Sarah Merlen Matthieu Boulenger
HISTORY 1992 Dr Edgar Engleman Dr Samuel Strobber Biotechnology company  called: Activated Cell Therapy Moutain View, Cali...
<ul><li>After several years  :  Activated Cell  Therapy </li></ul><ul><li>Activity shift  : developing therapeutic product...
FUNDING <ul><li>DENDREON came public in 2000 (NASDAQ) :  $10 per share </li></ul><ul><li>Major shareholders: </li></ul><ul...
<ul><li>DENDREON is focused on the  discovery, development  and   commercialization:   </li></ul><ul><ul><li>of novel ther...
<ul><li>CANCER THERAPIES </li></ul><ul><li>Cancer is characterized by  abnormal cells  that   grow and proliferate ,  </li...
Active Cell Immunotherapy « Activates the body 's ability to fight cancer »
RESEARCH ACTIVITY <ul><li>First step  : to find antigens expressed on cancer cells that are  suitable targets  for cancer ...
Second step :  to engineer antigens designed to  stimulate  and  maximize  cell-mediated immunity Aim : to raise the  qual...
FIRST TARGET PROSTATE CANCER  In the mid-90’s
<ul><li>Estimated new cases and death in 2010 (US) :  </li></ul><ul><li>New cases:  217,730 </li></ul><ul><li>Deaths:  32,...
PROSTATE CANCER Diagnosis Symptoms Stages  <ul><li>Average age  when diagnosed:70 years </li></ul><ul><li>Physical examina...
PROVENGE®: Active Cell Immunotherapy applied to Prostate Cancer  <ul><li>3 actors: </li></ul><ul><li>Recombinant antigen: ...
1 PRODUCTION & DELIVERY
LEUKAPHERESIS 3 to 4 hours <ul><li>In a cell collection center </li></ul><ul><li>Antigen Presenting Cells  are removed  </...
2 PRODUCTION & DELIVERY
MANUFACTURING 40 hours APC-PAP-GM-CSF = Sipuleucel-T (PROVENGE®) www.provenge.com <ul><li>Incubation  of Antigen-Presentin...
3 PRODUCTION & DELIVERY
PATIENT INJECTION <ul><li>Injection  of Provenge® = APC-PAP-GMCSF  </li></ul><ul><li>3 days after Leukapheresis </li></ul>
Cost of 1 injection:  $ 31,000 Total cost of the treatment  : $ 93,000 SCHEME OF INJECTIONS
A HUGE LOGISTIC Dendreon website
Provenge’s indication  : treatment of asymptomatic or minimally symptomatic  metastatic castrate resistant (hormone refrac...
PROVENGE MARKET
PROVENGE SALES Total in 2010 : $48 M <ul><li>About  only 500 patients  were treated in 2010 (in 8 months) </li></ul><ul><l...
What’s next for PROVENGE in the USA? <ul><li>Expectations in 2014: </li></ul><ul><li>Market shares =  35% </li></ul><ul><l...
Supply of the recombinant Antigen <ul><li>DENDREON doesn’t produce the antigen itself </li></ul><ul><li>The company utiliz...
MANUFACTURING FACILITIES Los Angeles Mid 2011 <ul><li>New-Jersey  : additional capacity expected in march 2011 </li></ul><...
PROPERTY & EQUIPMENT 76 235 127 427 1730 12 285
INFUSIONS CENTERS Increase of number of Infusion centers by 9 fold  in 2011for DENDREON to be near their patients
OTHER ISSUES FOR 2011 <ul><li>SALES FORCES </li></ul><ul><li>Increase of the sales forces  to approximatly 100 reps to ser...
EMERGING COMPETITORS FOR PROSTATE CANCER Trade name Type of treatment Company Phase PROSTVAC® Viral vector Bavarian Nordic...
PIPELINE Extension of Indication :  Androgen Dependent Prostate Cancer (phase 3 : awaiting data on overall survival) Poten...
Active Cell Imunotherapy New Antigen targets? PIPELINE HER2/neu CA-9 CEA
Active Cell Imunotherapy PIPELINE New Antigen targets? HER2/neu CA-9 CEA
HER2/neu <ul><li>=  Human Epidermal Growth Factor Receptor 2 </li></ul><ul><li>Membrane Glycoprotein involved in cell grow...
BREAST CANCER and HER/neu Total : 207,090 The HER2 protein is  overexpressed in about 30% of all breast cancers (USA) Tota...
One drug already targetting HER2 :  Trastuzumab HERCEPTIN®    Recombinant humanised IgG1 monoclonal antibody BREAST CANCE...
Opportunities in different solid tumors expressing HER2/neu <ul><li>Breast </li></ul><ul><li>Ovarian </li></ul><ul><li>Col...
BLADDER CANCER & HER2/neu Bladder cancer :  70,530 new cases in 2010 (USA)  The 4th most frequent cancer in men  HER2 expr...
PIPELINE Active Cell Imunotherapy New Antigen targets? HER2/neu CA-9 CEA
CA-9 <ul><li>In-licensed  from Bayer Corporation, Business Group Diagnostics </li></ul><ul><li>=  Carbonic Anhydrase IX </...
PIPELINE Active Cell Imunotherapy New Antigen targets? HER2/neu CA-9 CEA
CEA <ul><li>In-licensed  from Bayer Corporation, Business Group Diagnostics </li></ul><ul><li>= CarcinoEmbryonic Antigen  ...
Active Cellular Immunotherapies Market Phase 3 Phase 2 Pre-clinical PIPELINE
DIFFICULTIES FOR ACI PRODUCTS DEVELOPMENT
Active Cellular Immunotherapies Small Molecule Market Phase 3 Phase 2 Pre-clinical
TRPM8 <ul><li>= Transient Receptor Potential Cation Channel subfamily M member 8 </li></ul><ul><li>transmembrane  cation c...
Activation by agonist     induces Ca++ to flow into cells   APOPTOSIS TRPM8: Mechanism of Action <ul><li>The small molec...
AND NOW…CONQUEST OF THE WORLD ?
JUST A BEGINNING
WHO’S NEXT? World age-standardised rates (per 100,000 males) for prostate cancer in 2008
DENDREON’S FIRST TARGET <ul><li>EUROPE  «  Europe is our first ex-US opportunity » </li></ul><ul><li>Market for metastatic...
DIFFERENT STRATEGIES TO EXPAND OUTSIDE THE USA  OR 2 Strategies: Licensing To go alone ?
WHAT ABOUT LICENSING? 1998: license agreement : rights for PROVENGE in Asia and Pacific countries 2003 :  released its rig...
LICENSING? <ul><li>Advantages </li></ul><ul><li>Greater local knowlege  of the Regulatory agencies by the licensee. </li><...
DENDREON’S CHOICE : to go alone in EUROPE <ul><li>Why this choice? </li></ul><ul><li>2 hypothesis: </li></ul><ul><li>Own w...
TRIALS D9902 IMPACT D9901 MONEY Provenge Senior Notes WHAT DO THEY NEED?
TRIALS & REGULATORY
IMPACT TRIAL VS Placebo Dendreon website <ul><li>Randomized </li></ul><ul><li>Double-blind </li></ul><ul><li>Multicenter <...
PRIMARY ENDPOINT Survival median : 4.1 months Dendreon website
IMPACT TRIAL: NEGATIVE POINTS? <ul><li>IMPACT TRIAL </li></ul><ul><ul><li>Primary endpoint : Overall survival </li></ul></...
REIMBURSEMENT CHALLENGE <ul><li>Market access and reimbursement success is key to realizing full product potential in E.U....
WHERE TO HAVE A PLACE? <ul><li>Find a strategic place in EUROPE </li></ul><ul><ul><li>wich must be: </li></ul></ul><ul><ul...
<ul><li>During DENDREON submits an European authorization (late 2011/early 2012) </li></ul><ul><li>Initial manufacturing t...
WITH WICH MONEY? <ul><li>Revenues from Provenge :  $48 millions in 2010 </li></ul><ul><li>January, 14 th  2011 :  Dendreon...
CONCLUSION
Strengths Weaknesses Opportunities Threats <ul><li>ACI : revolutionary therapeutic approach </li></ul><ul><li>ACI : less A...
EXPECTATIONS
HIRING OPPORTUNITIES Regulatory affairs Quality assurance Manufacturing Logistic  coordinators Sales & Marketing R & D
WOULD WE JOIN DENDREON? <ul><li>Cancer treatment is a  « noble » domain </li></ul><ul><li>Working  for  a revolutionary pr...
YES! WOULD WE JOIN DENDREON?
FOR YOUR ATTENTION
BACK UP
Hormone-refractory metastatic prostate cancer  <ul><li>Reference Treatment:  Docetaxel (Taxotere ®)  +  prednisone/prednis...
Clinicaly localized disease Biochemical Reccurence  Castration-Resistant Disease Castration-Resistant Disease Metastatic P...
2006 March 2007 April 2009 Initial clinical results showed immune response April 2010 Building a manufactory facility in N...
CANCER IMMUNOTHERAPIES CAN BE EITHER  : PASSIVE   OR  ACTIVE  <ul><li>immunomodulators, antibodies  or  immune cells </li>...
CA-9 <ul><li>In-licensed  from Bayer Corporation, Business Group Diagnostics </li></ul><ul><li>=  Carbonic Anhydrase IX </...
KIDNEY   CANCER and CA-9   <ul><li>TREATMENTS : </li></ul><ul><li>Surgery,  </li></ul><ul><li>Often resistant to chemother...
KIDNEY   CANCER and CA-9   <ul><li>Good opportunity for Dendreon’s Active Cell Immunotherapy; </li></ul><ul><li>First pre-...
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  • Transplantation following high dose chemotherapy or radiation
  • http://www.cancer.gov/cancertopics/types/prostate
  • http://www.cancer.gov/cancertopics/types/prostate
  • www.xconomy.com
  • Just after the approval : only patients who participated in the trials where treated  NJ : additional capacity expected in march 2011
  • CMS = CENTERS FOR MEDICARE AND MEDICAID SERVICE Svt les assurances privees suivent les tx de remboursement de medicaid et medicare  plus de patients pourront avoir acces au ttmt
  • Abiratérone inhibe la synthèse des androgènes (inh CP17)
  • entraine l&apos;internalisation du récepteurs HER2, ce qui le rend inactif ; bloque leur dimérisation donc aucune activité kinase n’est possible ; stimule la formation de tétramère de protéine Her2, une conformation non propice à l’activité kinasique. Chacun de ces trois mécanismes empêchent l&apos;activation des récepteurs HER2 et donc la prolifération cellulaire
  • In November 2003, we licensed to Kirin Brewery Co., Ltd. our worldwide patent rights relating to the use of certain HLA-DR antibodies being developed by Kirin for which Kirin agreed to pay us $20 million and released its rights to our active immunotherapy product candidates, including Provenge, in Asia and Pacific Rim countries. This agreement ended our previous collaboration with Kirin. The $20 million is to be paid to us in cash In December 1998 and April 2000, Kirin exercised options under the collaborative license agreement to receive rights to our Provenge prostate program and Mylovenge multiple myeloma program. Kirin was solely responsible for the development and clinical trials of these prostate and multiple myeloma programs in Japan. We received a $1.0 million non-refundable, up-front fee on the exercise of each of these options.  
  • biological product cellular therapy product more than minimally manufactured
  • HR= Hazard Ratio : rapport du risque instantané dans le groupe traité sur le risque dans le groupe contrôle Doit etre inf a 1 pour etre benefique
  • 2/10/2004 AMM taxotere pour cancer prostate en assoc avec prednisone en fr
  • ASENTAR + VITAMINE D? LE VIRER???
  • Qualifying a CMO can be done faster than plant construction Dendreon expects to save 12 to 18 months by outsourcing to support filing.
  • One drug on the market : provenge  ca a comblé un besoin médical pour les patients réfractaires à la chimiotherapie (ou souffrant de trop d’EI)
  • met en évidence le profit généré par l’activité indépendamment des conditions de son financement (les charges financières), des contraintes fiscales (impôts et taxes), et du renouvellement de l’outil d’exploitation (amortissements).
  • Quality assurance : processus extremement complexe qui exige une traçabilité sure RD : recherche de nouveaux Ag d’intérêt. futurs essais cliniques
  • Development of new ACI products New jobs in pharmacoeconomy to evaluate new markets
  • Nb active immunotherapie: réponse durable
  • Ca9 overexpression : 34944
  • Dendreon.Final

    1. 1. Samia Thara Sarah Merlen Matthieu Boulenger
    2. 2. HISTORY 1992 Dr Edgar Engleman Dr Samuel Strobber Biotechnology company called: Activated Cell Therapy Moutain View, California <ul><li>First activity : isolating hematopoietic stem cells from blood for use in patients with cancer who require transplantation. </li></ul>
    3. 3. <ul><li>After several years : Activated Cell Therapy </li></ul><ul><li>Activity shift : developing therapeutic products that fight cancer by manipulating aspects of the immune system </li></ul><ul><li>Today: </li></ul><ul><ul><li>CEO : Mitchell H. Gold </li></ul></ul><ul><ul><li>650 employees (April 2010) </li></ul></ul><ul><ul><li>Main Manufacturing facility in Morris Plain (NJ) </li></ul></ul>Seattle, Washington state « Targeting Cancer, Transforming Lives »  HISTORY
    4. 4. FUNDING <ul><li>DENDREON came public in 2000 (NASDAQ) : $10 per share </li></ul><ul><li>Major shareholders: </li></ul><ul><ul><li>Mutual Fund : Fidelity Growth Company Fund : 9.50% of shares held </li></ul></ul><ul><ul><li>Individual Investors : David L Urdal (Executive vice president of Dendreon): 0.36% of shares held </li></ul></ul>February 13, 2011: $35.15
    5. 5. <ul><li>DENDREON is focused on the discovery, development and commercialization: </li></ul><ul><ul><li>of novel therapeutics </li></ul></ul><ul><ul><li>that may significantly improve cancer treatment options for patients </li></ul></ul><ul><li>Philosophy of Dendreon : </li></ul><ul><li>produce A ctive C ellular I mmunotherapy products </li></ul>stimulate an immune response against a variety of tumor types ACTIVITY
    6. 6. <ul><li>CANCER THERAPIES </li></ul><ul><li>Cancer is characterized by abnormal cells that grow and proliferate , </li></ul><ul><li>forming masses called tumors </li></ul><ul><li>Cancer therapies must </li></ul><ul><li>eliminate or </li></ul><ul><li>control </li></ul><ul><li>BUT : </li></ul><ul><li>may not have the desired therapeutic effect </li></ul><ul><li>may result in significant detrimental side effects </li></ul>the growth of the cancer New approach to Cancer Treatment: IMMUNOTHERAPIES Chemotherapy Radiation Surgery Hormone treatments
    7. 7. Active Cell Immunotherapy « Activates the body 's ability to fight cancer »
    8. 8. RESEARCH ACTIVITY <ul><li>First step : to find antigens expressed on cancer cells that are suitable targets for cancer therapy </li></ul>Internal antigen discovery program License agreements
    9. 9. Second step : to engineer antigens designed to stimulate and maximize cell-mediated immunity Aim : to raise the quality and the quantity of the immune response = The key to robuste immune response RESEARCH ACTIVITY Creation of the “ Antigen Delivery Cassette™ ”
    10. 10. FIRST TARGET PROSTATE CANCER In the mid-90’s
    11. 11. <ul><li>Estimated new cases and death in 2010 (US) : </li></ul><ul><li>New cases: 217,730 </li></ul><ul><li>Deaths: 32,050 </li></ul><ul><li>The second most common type of cancer among men in the USA </li></ul>ESTIMATED NEW CASES PROSTATE
    12. 12. PROSTATE CANCER Diagnosis Symptoms Stages <ul><li>Average age when diagnosed:70 years </li></ul><ul><li>Physical examination </li></ul><ul><li>Dosing </li></ul><ul><li>Prostate </li></ul><ul><li>Specific </li></ul><ul><li>Antigen </li></ul><ul><li>Biopsy => Gleason score </li></ul><ul><li>Often asymptomatic at the beginning </li></ul><ul><li>Pain </li></ul><ul><li>Difficulty in urinating </li></ul><ul><li>Problems during sexual intercourse </li></ul><ul><li>Erectile dysfunction </li></ul><ul><li>Such as Benign Prostatic Hyperplasia </li></ul><ul><li>Low growth </li></ul><ul><li>Hormono-dependant </li></ul><ul><li>Hormono-independant </li></ul><ul><li>after one to three years and resume growth despite hormone therapy. </li></ul>
    13. 13. PROVENGE®: Active Cell Immunotherapy applied to Prostate Cancer <ul><li>3 actors: </li></ul><ul><li>Recombinant antigen: composed of </li></ul><ul><li>P rostatic A cid P hosphatase ( expressed in more than 95% of prostate cancers cells ) </li></ul><ul><li>GM-CSF : Granulocyte-macrophage colony-stimulating factor </li></ul><ul><li>Antigen Presenting Cell: white blood cells removed from the patient through LEUKAPHERESIS </li></ul><ul><li>T-Cells: actived by the APC-PAP-GM-CSF, attack the tumor cells </li></ul>
    14. 14. 1 PRODUCTION & DELIVERY
    15. 15. LEUKAPHERESIS 3 to 4 hours <ul><li>In a cell collection center </li></ul><ul><li>Antigen Presenting Cells are removed </li></ul><ul><li>Rest of the blood is returned to the patient </li></ul>
    16. 16. 2 PRODUCTION & DELIVERY
    17. 17. MANUFACTURING 40 hours APC-PAP-GM-CSF = Sipuleucel-T (PROVENGE®) www.provenge.com <ul><li>Incubation of Antigen-Presenting-Cell & Prostatic Antigen </li></ul>
    18. 18. 3 PRODUCTION & DELIVERY
    19. 19. PATIENT INJECTION <ul><li>Injection of Provenge® = APC-PAP-GMCSF </li></ul><ul><li>3 days after Leukapheresis </li></ul>
    20. 20. Cost of 1 injection: $ 31,000 Total cost of the treatment : $ 93,000 SCHEME OF INJECTIONS
    21. 21. A HUGE LOGISTIC Dendreon website
    22. 22. Provenge’s indication : treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer Provenge® PROVENGE MARKET
    23. 23. PROVENGE MARKET
    24. 24. PROVENGE SALES Total in 2010 : $48 M <ul><li>About only 500 patients were treated in 2010 (in 8 months) </li></ul><ul><li>Expectations (2009) : to treat 8% of the Asymptomatic Metastatic AIPC market  7300 patients </li></ul><ul><li>we can expect a large progression </li></ul>
    25. 25. What’s next for PROVENGE in the USA? <ul><li>Expectations in 2014: </li></ul><ul><li>Market shares = 35% </li></ul><ul><li>Patients treated= 38,628 </li></ul><ul><li>BUT can DENDREON provide enough Provenge® to meet demand? </li></ul><ul><li>Enough Recombinant Prostatic Antigen? </li></ul><ul><li>Enough Infusions Centers? </li></ul><ul><li>Enough Manufacturing capacity? </li></ul>2011: A YEAR OF GROWTH
    26. 26. Supply of the recombinant Antigen <ul><li>DENDREON doesn’t produce the antigen itself </li></ul><ul><li>The company utilizes third party suppliers to manufacture and package the recombinant antigene </li></ul><ul><li>First collaboration : </li></ul><ul><li>Since September 2010 , second supplier : </li></ul>
    27. 27. MANUFACTURING FACILITIES Los Angeles Mid 2011 <ul><li>New-Jersey : additional capacity expected in march 2011 </li></ul><ul><li>Atlanta & LA : additional capacity starting in mid-2011 </li></ul>
    28. 28. PROPERTY & EQUIPMENT 76 235 127 427 1730 12 285
    29. 29. INFUSIONS CENTERS Increase of number of Infusion centers by 9 fold in 2011for DENDREON to be near their patients
    30. 30. OTHER ISSUES FOR 2011 <ul><li>SALES FORCES </li></ul><ul><li>Increase of the sales forces to approximatly 100 reps to service 450 centers by the end of 2011 </li></ul>Significant increase in outreach to maximize the additional capacity <ul><li>REIMBURSEMENT </li></ul><ul><li>Will CMS recommend and provide national reimbursement? </li></ul><ul><li>Date of national decision : March, 30,2011 </li></ul><ul><li>But some local Medicare contractors already reimburse PROVENGE® </li></ul>Good clue for a positive decision by CMS JP Morgan – Dencreon MEDCAC All Bark & No Bite; Panel Backs Provenge
    31. 31. EMERGING COMPETITORS FOR PROSTATE CANCER Trade name Type of treatment Company Phase PROSTVAC® Viral vector Bavarian Nordic Phase II completed GVAX GM-CSF gene-transfected cell vaccines BioSante Pharmaceuticals Phase III DCVAX Prostate Cellular vaccine Northwest Biotherapeutics Phase III TROVAX® Viral vector Oxford Biomedical Phase III IPILIMUMAB Monoclonal antibodies BMS Phase III ABIRATERONE Hormonotherapy  Janssen-Cilag Phase III
    32. 32. PIPELINE Extension of Indication : Androgen Dependent Prostate Cancer (phase 3 : awaiting data on overall survival) Potential Raise of the market for PROVENGE® Dendreon website
    33. 33. Active Cell Imunotherapy New Antigen targets? PIPELINE HER2/neu CA-9 CEA
    34. 34. Active Cell Imunotherapy PIPELINE New Antigen targets? HER2/neu CA-9 CEA
    35. 35. HER2/neu <ul><li>= Human Epidermal Growth Factor Receptor 2 </li></ul><ul><li>Membrane Glycoprotein involved in cell growth and differenciation </li></ul><ul><li>Composed of: </li></ul><ul><li>an extracellular domain for binding ligands </li></ul><ul><li>a single transmembrane segment </li></ul><ul><li>an intracellular domain carrying tyrosine-kinase activity </li></ul>
    36. 36. BREAST CANCER and HER/neu Total : 207,090 The HER2 protein is overexpressed in about 30% of all breast cancers (USA) Total : 207,090 www.cancer.gov
    37. 37. One drug already targetting HER2 : Trastuzumab HERCEPTIN®  Recombinant humanised IgG1 monoclonal antibody BREAST CANCER and HER/neu
    38. 38. Opportunities in different solid tumors expressing HER2/neu <ul><li>Breast </li></ul><ul><li>Ovarian </li></ul><ul><li>Colorectal </li></ul><ul><li>Bladder </li></ul>Initiate Phase 2 trial 1Q 2011 Lapuleucel-T NEUVENGE® HER2/neu
    39. 39. 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 cancer : Vs HERCEPTIN? Neuvenge® targeting HER2 in bladder cancer : Vs placebo?
    40. 40. PIPELINE Active Cell Imunotherapy New Antigen targets? HER2/neu CA-9 CEA
    41. 41. CA-9 <ul><li>In-licensed from Bayer Corporation, Business Group Diagnostics </li></ul><ul><li>= Carbonic Anhydrase IX </li></ul><ul><li>Transmembrane protein involved in cell proliferation </li></ul><ul><li>the only tumor-associated carbonic anhydrase isoenzyme known </li></ul><ul><li>Tumors over-expressing CA-9 : </li></ul><ul><li>Colon </li></ul><ul><li>Cervical </li></ul><ul><li>Kidney </li></ul>CA-9 is overexpressed in 75% of Renal cell Carcinoma phase 1 in Renal Cell Carcinoma planned in 2011
    42. 42. PIPELINE Active Cell Imunotherapy New Antigen targets? HER2/neu CA-9 CEA
    43. 43. CEA <ul><li>In-licensed from Bayer Corporation, Business Group Diagnostics </li></ul><ul><li>= CarcinoEmbryonic Antigen : glycoprotein involved in cell adhesion </li></ul><ul><li>Not usually present in healthy adults, although levels are raised in heavy smokers </li></ul><ul><li>Cancers expressing CEA : </li></ul><ul><li>Breast (65%) </li></ul><ul><li>Lung (70%) </li></ul><ul><li>Colon </li></ul>Phase 1 expected in 2012
    44. 44. Active Cellular Immunotherapies Market Phase 3 Phase 2 Pre-clinical PIPELINE
    45. 45. DIFFICULTIES FOR ACI PRODUCTS DEVELOPMENT
    46. 46. Active Cellular Immunotherapies Small Molecule Market Phase 3 Phase 2 Pre-clinical
    47. 47. TRPM8 <ul><li>= Transient Receptor Potential Cation Channel subfamily M member 8 </li></ul><ul><li>transmembrane cation channel identified through Dendreon’s internal antigen discovery program </li></ul>Patent on the gene in 2001 <ul><li>Over-expressed in : </li></ul><ul><li>100% of prostate cancers </li></ul><ul><li>71% of breast cancers </li></ul><ul><li>93% of colon cancers </li></ul><ul><li>80% of lung cancers </li></ul>Synthesis of small molecule agonists Attractive target
    48. 48. Activation by agonist  induces Ca++ to flow into cells  APOPTOSIS TRPM8: Mechanism of Action <ul><li>The small molecule agonist is orally available </li></ul>Clinical phase 1 trial ongoing
    49. 49. AND NOW…CONQUEST OF THE WORLD ?
    50. 50. JUST A BEGINNING
    51. 51. WHO’S NEXT? World age-standardised rates (per 100,000 males) for prostate cancer in 2008
    52. 52. DENDREON’S FIRST TARGET <ul><li>EUROPE «  Europe is our first ex-US opportunity » </li></ul><ul><li>Market for metastatic AIPC patients = 1.5 X to 2 X US </li></ul><ul><li>Overall market characteristics similar to US </li></ul><ul><ul><li>Both urologists & oncologists are involved in treatment </li></ul></ul><ul><ul><li>Treatment paradigms similar </li></ul></ul><ul><ul><li>Significant therapeutic unmet need remains </li></ul></ul><ul><li>DENDREON CEO Mitch Gold : </li></ul>«    Low rates of PSA testing in Europe meant that many men arrived in their physicians office with metastatic disease » JP Morgan Conference call – January 2011
    53. 53. DIFFERENT STRATEGIES TO EXPAND OUTSIDE THE USA OR 2 Strategies: Licensing To go alone ?
    54. 54. WHAT ABOUT LICENSING? 1998: license agreement : rights for PROVENGE in Asia and Pacific countries 2003 : released its rights for PROVENGE
    55. 55. LICENSING? <ul><li>Advantages </li></ul><ul><li>Greater local knowlege of the Regulatory agencies by the licensee. </li></ul><ul><li>Better manufacturing capacity of the licensee </li></ul><ul><li>No administrative expenses and no cost of good solds for Dendreon (PROVENGE® commercialization needs much money) </li></ul><ul><li>Disadvantage </li></ul><ul><li>DENDREON will depend on the skills, abilities and ressources of the licensee as a source of revenue  dependence </li></ul>
    56. 56. DENDREON’S CHOICE : to go alone in EUROPE <ul><li>Why this choice? </li></ul><ul><li>2 hypothesis: </li></ul><ul><li>Own will of DENDREON </li></ul>They want 100% of worldwide rights They don’t want to share their revenues <ul><li>Choice by default : they didn’t find any partners? </li></ul><ul><li>Too risky? </li></ul>No certitude to get an european approval Reimbursement? Provenge « is not just a pill in a bottle » Corporate image of growth
    57. 57. TRIALS D9902 IMPACT D9901 MONEY Provenge Senior Notes WHAT DO THEY NEED?
    58. 58. TRIALS & REGULATORY
    59. 59. IMPACT TRIAL VS Placebo Dendreon website <ul><li>Randomized </li></ul><ul><li>Double-blind </li></ul><ul><li>Multicenter </li></ul><ul><li>512 men </li></ul><ul><li>With asymptomatic </li></ul><ul><li>Or minimally symptomatic MPC </li></ul><ul><li>Primary endpoint : </li></ul><ul><li>Overall survival </li></ul><ul><li>Secondary endpoint: </li></ul><ul><li>Time to objective disease progression </li></ul>
    60. 60. PRIMARY ENDPOINT Survival median : 4.1 months Dendreon website
    61. 61. IMPACT TRIAL: NEGATIVE POINTS? <ul><li>IMPACT TRIAL </li></ul><ul><ul><li>Primary endpoint : Overall survival </li></ul></ul><ul><ul><ul><li>trials done versus placebo : ethic problems , same efficiency </li></ul></ul></ul><ul><ul><ul><li>versus taxotere? </li></ul></ul></ul><ul><ul><ul><li>patients having metastases: what medicine did they take before? (docetaxel approval for prostate cancer by FDA: 19/05/2004) </li></ul></ul></ul><ul><ul><ul><li>ethnic population isn’t the same and ethny change impact of the </li></ul></ul></ul><ul><ul><ul><li>disease </li></ul></ul></ul><ul><ul><li>Secondary endpoint : Time to objective disease survival </li></ul></ul><ul><ul><ul><li>FDA agreed to allow Dendreon to amend the design of the IMPACT study </li></ul></ul></ul>
    62. 62. REIMBURSEMENT CHALLENGE <ul><li>Market access and reimbursement success is key to realizing full product potential in E.U. </li></ul><ul><li>Key factors influencing reimbursment: </li></ul><ul><ul><li>overall survival is the « gold standart » for payers </li></ul></ul><ul><li> IMPACT: 4 months survival benefits against placebo… </li></ul><ul><ul><li>total cost of care is taken into account </li></ul></ul><ul><li>$93,000/ complete cost treatement for Provenge VS $18,000/ 6 cycles </li></ul><ul><li>of treatment for taxotere </li></ul><ul><li> lack of required premedication and supportive care costs compared to </li></ul><ul><li>Taxotere </li></ul>
    63. 63. WHERE TO HAVE A PLACE? <ul><li>Find a strategic place in EUROPE </li></ul><ul><ul><li>wich must be: </li></ul></ul><ul><ul><ul><ul><ul><li>Near airport and road network </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>In a reasonable distance from each European capital </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Able to cover the majority of the market </li></ul></ul></ul></ul></ul><ul><li>DENDREON’s decision to build its manufacturing site: GERMANY </li></ul><ul><ul><ul><ul><ul><li>50% of patients live in less than 8 hours to this site in car or flight </li></ul></ul></ul></ul></ul>JP Morgan Conference call – January 2011
    64. 64. <ul><li>During DENDREON submits an European authorization (late 2011/early 2012) </li></ul><ul><li>Initial manufacturing through a Contract Manufacturing </li></ul><ul><li>Organization (CMO): </li></ul><ul><ul><ul><ul><ul><li>Qualifying a CMO can be done faster than plant construction </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Dendreon expects to save 12 to 18 months by outsourcing to support filing. </li></ul></ul></ul></ul></ul><ul><li>Concurrently DENDREON will build its first manufacturing site: </li></ul><ul><ul><ul><ul><ul><li>Initiate built out in 2011 </li></ul></ul></ul></ul></ul>Huge expenses!! WHERE TO HAVE A PLACE?
    65. 65. WITH WICH MONEY? <ul><li>Revenues from Provenge : $48 millions in 2010 </li></ul><ul><li>January, 14 th 2011 : Dendreon announced the pricing of a publing offering of $540 million convertible senior notes </li></ul><ul><li>Raise the equity : in the beginning of 2010 : public offering of 15 Million shares </li></ul>
    66. 66. CONCLUSION
    67. 67. Strengths Weaknesses Opportunities Threats <ul><li>ACI : revolutionary therapeutic approach </li></ul><ul><li>ACI : less AEs than chemotherapy </li></ul><ul><li>One drug on the market at least : Provenge </li></ul><ul><li> revenues </li></ul><ul><li>Huge logistic : difficult to copy for generics </li></ul><ul><li>Huge logistic : </li></ul><ul><ul><ul><li>Expensive </li></ul></ul></ul><ul><ul><ul><li>Restrictions for Clinical trials </li></ul></ul></ul><ul><li>Provenge sales too low compared to expectations </li></ul><ul><li>Increase of debts (senior notes) </li></ul><ul><li>No profit yet </li></ul><ul><li>Expansion </li></ul><ul><ul><ul><li>In the USA </li></ul></ul></ul><ul><ul><ul><li>In Europe : similarity with US market </li></ul></ul></ul><ul><li>Provenge : new indication in development </li></ul><ul><li>ACI : repeatible with new Antigens </li></ul><ul><li> other cancers targeted </li></ul><ul><li>Decision for reimbursment of Provenge expected in March </li></ul><ul><li>Emerging competitors </li></ul><ul><li>At the mercy of the EMA for the approval of Provenge (clinical trial vs. Taxotere?) </li></ul>
    68. 68. EXPECTATIONS
    69. 69. HIRING OPPORTUNITIES Regulatory affairs Quality assurance Manufacturing Logistic coordinators Sales & Marketing R & D
    70. 70. WOULD WE JOIN DENDREON? <ul><li>Cancer treatment is a « noble » domain </li></ul><ul><li>Working for a revolutionary process as ACI must be exciting </li></ul>Development of domains corresponding to our professional expectations Transition from a total R&D to a fully-integrated commercial company <ul><li>Regulatory Challenge in Europe </li></ul><ul><li>New jobs in Regulatory Affairs </li></ul><ul><li>Development of new ACI products </li></ul><ul><li>Evaluation of new markets </li></ul>
    71. 71. YES! WOULD WE JOIN DENDREON?
    72. 72. FOR YOUR ATTENTION
    73. 73. BACK UP
    74. 74. Hormone-refractory metastatic prostate cancer <ul><li>Reference Treatment: Docetaxel (Taxotere ®) + prednisone/prednisolone </li></ul><ul><li>Cost-effectiveness evaluation, Sanofi-Aventis,2005: </li></ul><ul><li>Median survival (from Kaplan Meyer) </li></ul><ul><li>Taxotere+prednisone: 18.9 months </li></ul><ul><li>Vs mitoxantrone+prednisone : 16.5 months </li></ul><ul><li>Total per patient cost: </li></ul><ul><li>Taxotere+prednisone: £15.767(including first-line chemotherapy and for further therapy) </li></ul><ul><li>Adverses events : </li></ul><ul><li>Fatigue </li></ul><ul><li>Nausea, vomiting,diarrhea </li></ul><ul><li>Alopecia </li></ul><ul><li>Sensory neuropathy </li></ul>R Collins,1* E Fenwick,2 R Trowman,1 R Perard,2 G Norman,1 K Light,1 A Birtle,3 S Palmer2 and R Riemsma1
    75. 75. Clinicaly localized disease Biochemical Reccurence Castration-Resistant Disease Castration-Resistant Disease Metastatic Primary Therapy (Surgery,Radiation therapy…) Hormonal Therapy (chemical castration) Secondary Hormonal Therapy Docetaxel+ chemotherapy immunotherapy TREATMENTS
    76. 76. 2006 March 2007 April 2009 Initial clinical results showed immune response April 2010 Building a manufactory facility in New Jersey to accommodate production for a phase III trial FDA accepted Dendreon’s BLA filling for Provenge® FDA voted 17-0 that Provenge is reasonably safe and that the trial data showed substantial evidence that it is effective Dendreon received a letter from the FDA demanding more results and information before approval Dendreon announced that the results for the Phase III trial of Provenge were positive FDA approved Provenge for use in the treatment of advanced prostate cancer. DISCOVERY OF PROVENGE®
    77. 77. CANCER IMMUNOTHERAPIES CAN BE EITHER : PASSIVE OR ACTIVE <ul><li>immunomodulators, antibodies or immune cells </li></ul><ul><li>to initiate an anti-tumor action </li></ul><ul><li>not targeted to a specific antigen </li></ul><ul><li>Use in : breast cancer, melanoma, renal cell carcinoma, leukemia... </li></ul><ul><li>Stimulates the patient's immune system </li></ul><ul><li>using the body's own immune cells </li></ul><ul><li>generates a T-cell response against </li></ul><ul><li>tumor-associated antigens </li></ul><ul><li>a type of therapeutic cancer vaccine </li></ul><ul><li>Ex: adoptive T-cell therapy </li></ul>
    78. 78. CA-9 <ul><li>In-licensed from Bayer Corporation, Business Group Diagnostics </li></ul><ul><li>= Carbonic Anhydrase IX </li></ul><ul><li>Transmembrane protein involved in cell proliferation </li></ul><ul><li>the only tumor-associated carbonic anhydrase isoenzyme known </li></ul><ul><li>Tumors over-expressing CA-9 : </li></ul><ul><li>Colon </li></ul><ul><li>Cervical </li></ul><ul><li>Kidney </li></ul>CA-9 is overexpressed in 75% of Renal cell Carcinoma phase 1/2 in Renal Cell Carcinoma planned in 2011
    79. 79. KIDNEY CANCER and CA-9 <ul><li>TREATMENTS : </li></ul><ul><li>Surgery, </li></ul><ul><li>Often resistant to chemotherapy and radiotherapy </li></ul><ul><li>Well responder to immunotherapy </li></ul>Total : 46,592
    80. 80. KIDNEY CANCER and CA-9 <ul><li>Good opportunity for Dendreon’s Active Cell Immunotherapy; </li></ul><ul><li>First pre-clinical results presented at the American Association of Immnology: </li></ul><ul><li> Candidate product targeted at CA-9 significantly prolonged survival in animal tumor models </li></ul>phase 1/2 in Renal Cell Carcinoma planned in 2011

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