Dendreon.Final

Samia Thara Sarah Merlen Matthieu Boulenger

HISTORY 1992 Dr Edgar Engleman Dr Samuel Strobber Biotechnology company called: Activated Cell Therapy Moutain View, California First activity : isolating hematopoietic stem cells from blood for use in patients with cancer who require transplantation.

After several years : Activated Cell Therapy Activity shift : developing therapeutic products that fight cancer by manipulating aspects of the immune system Today: CEO : Mitchell H. Gold 650 employees (April 2010) Main Manufacturing facility in Morris Plain (NJ) Seattle, Washington state « Targeting Cancer, Transforming Lives » HISTORY

FUNDING DENDREON came public in 2000 (NASDAQ) : $10 per share Major shareholders: Mutual Fund : Fidelity Growth Company Fund : 9.50% of shares held Individual Investors : David L Urdal (Executive vice president of Dendreon): 0.36% of shares held February 13, 2011: $35.15

DENDREON is focused on the discovery, development and commercialization: of novel therapeutics that may significantly improve cancer treatment options for patients Philosophy of Dendreon : produce A ctive C ellular I mmunotherapy products stimulate an immune response against a variety of tumor types ACTIVITY

CANCER THERAPIES Cancer is characterized by abnormal cells that grow and proliferate , forming masses called tumors Cancer therapies must eliminate or control BUT : may not have the desired therapeutic effect may result in significant detrimental side effects the growth of the cancer New approach to Cancer Treatment: IMMUNOTHERAPIES Chemotherapy Radiation Surgery Hormone treatments

Active Cell Immunotherapy « Activates the body 's ability to fight cancer »

RESEARCH ACTIVITY First step : to find antigens expressed on cancer cells that are suitable targets for cancer therapy Internal antigen discovery program License agreements

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™ ”

FIRST TARGET PROSTATE CANCER In the mid-90’s

Estimated new cases and death in 2010 (US) : New cases: 217,730 Deaths: 32,050 The second most common type of cancer among men in the USA ESTIMATED NEW CASES PROSTATE

PROSTATE CANCER Diagnosis Symptoms Stages Average age when diagnosed:70 years Physical examination Dosing Prostate Specific Antigen Biopsy => Gleason score Often asymptomatic at the beginning Pain Difficulty in urinating Problems during sexual intercourse Erectile dysfunction Such as Benign Prostatic Hyperplasia Low growth Hormono-dependant Hormono-independant after one to three years and resume growth despite hormone therapy.

PROVENGE®: Active Cell Immunotherapy applied to Prostate Cancer 3 actors: Recombinant antigen: composed of P rostatic A cid P hosphatase ( expressed in more than 95% of prostate cancers cells ) GM-CSF : Granulocyte-macrophage colony-stimulating factor Antigen Presenting Cell: white blood cells removed from the patient through LEUKAPHERESIS T-Cells: actived by the APC-PAP-GM-CSF, attack the tumor cells

LEUKAPHERESIS 3 to 4 hours In a cell collection center Antigen Presenting Cells are removed Rest of the blood is returned to the patient

MANUFACTURING 40 hours APC-PAP-GM-CSF = Sipuleucel-T (PROVENGE®) www.provenge.com Incubation of Antigen-Presenting-Cell & Prostatic Antigen

PATIENT INJECTION Injection of Provenge® = APC-PAP-GMCSF 3 days after Leukapheresis

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 refractory) prostate cancer Provenge® PROVENGE MARKET

PROVENGE SALES Total in 2010 : $48 M About only 500 patients were treated in 2010 (in 8 months) Expectations (2009) : to treat 8% of the Asymptomatic Metastatic AIPC market  7300 patients we can expect a large progression

What’s next for PROVENGE in the USA? Expectations in 2014: Market shares = 35% Patients treated= 38,628 BUT can DENDREON provide enough Provenge® to meet demand? Enough Recombinant Prostatic Antigen? Enough Infusions Centers? Enough Manufacturing capacity? 2011: A YEAR OF GROWTH

Supply of the recombinant Antigen DENDREON doesn’t produce the antigen itself The company utilizes third party suppliers to manufacture and package the recombinant antigene First collaboration : Since September 2010 , second supplier :

MANUFACTURING FACILITIES Los Angeles Mid 2011 New-Jersey : additional capacity expected in march 2011 Atlanta & LA : additional capacity starting in mid-2011

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 SALES FORCES Increase of the sales forces to approximatly 100 reps to service 450 centers by the end of 2011 Significant increase in outreach to maximize the additional capacity REIMBURSEMENT Will CMS recommend and provide national reimbursement? Date of national decision : March, 30,2011 But some local Medicare contractors already reimburse PROVENGE® Good clue for a positive decision by CMS JP Morgan – Dencreon MEDCAC All Bark & No Bite; Panel Backs Provenge

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

PIPELINE Extension of Indication : Androgen Dependent Prostate Cancer (phase 3 : awaiting data on overall survival) Potential Raise of the market for PROVENGE® Dendreon website

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 = Human Epidermal Growth Factor Receptor 2 Membrane Glycoprotein involved in cell growth and differenciation Composed of: an extracellular domain for binding ligands a single transmembrane segment an intracellular domain carrying tyrosine-kinase activity

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

One drug already targetting HER2 : Trastuzumab HERCEPTIN®  Recombinant humanised IgG1 monoclonal antibody BREAST CANCER and HER/neu

Opportunities in different solid tumors expressing HER2/neu Breast Ovarian Colorectal Bladder Initiate Phase 2 trial 1Q 2011 Lapuleucel-T NEUVENGE® HER2/neu

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?

PIPELINE Active Cell Imunotherapy New Antigen targets? HER2/neu CA-9 CEA

CA-9 In-licensed from Bayer Corporation, Business Group Diagnostics = Carbonic Anhydrase IX Transmembrane protein involved in cell proliferation the only tumor-associated carbonic anhydrase isoenzyme known Tumors over-expressing CA-9 : Colon Cervical Kidney CA-9 is overexpressed in 75% of Renal cell Carcinoma phase 1 in Renal Cell Carcinoma planned in 2011

CEA In-licensed from Bayer Corporation, Business Group Diagnostics = CarcinoEmbryonic Antigen : glycoprotein involved in cell adhesion Not usually present in healthy adults, although levels are raised in heavy smokers Cancers expressing CEA : Breast (65%) Lung (70%) Colon Phase 1 expected in 2012

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 = Transient Receptor Potential Cation Channel subfamily M member 8 transmembrane cation channel identified through Dendreon’s internal antigen discovery program Patent on the gene in 2001 Over-expressed in : 100% of prostate cancers 71% of breast cancers 93% of colon cancers 80% of lung cancers Synthesis of small molecule agonists Attractive target

Activation by agonist  induces Ca++ to flow into cells  APOPTOSIS TRPM8: Mechanism of Action The small molecule agonist is orally available Clinical phase 1 trial ongoing

AND NOW…CONQUEST OF THE WORLD ?

WHO’S NEXT? World age-standardised rates (per 100,000 males) for prostate cancer in 2008

DENDREON’S FIRST TARGET EUROPE « Europe is our first ex-US opportunity » Market for metastatic AIPC patients = 1.5 X to 2 X US Overall market characteristics similar to US Both urologists & oncologists are involved in treatment Treatment paradigms similar Significant therapeutic unmet need remains DENDREON CEO Mitch Gold : « 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

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 rights for PROVENGE

LICENSING? Advantages Greater local knowlege of the Regulatory agencies by the licensee. Better manufacturing capacity of the licensee No administrative expenses and no cost of good solds for Dendreon (PROVENGE® commercialization needs much money) Disadvantage DENDREON will depend on the skills, abilities and ressources of the licensee as a source of revenue  dependence

DENDREON’S CHOICE : to go alone in EUROPE Why this choice? 2 hypothesis: Own will of DENDREON They want 100% of worldwide rights They don’t want to share their revenues Choice by default : they didn’t find any partners? Too risky? No certitude to get an european approval Reimbursement? Provenge « is not just a pill in a bottle » Corporate image of growth

TRIALS D9902 IMPACT D9901 MONEY Provenge Senior Notes WHAT DO THEY NEED?

IMPACT TRIAL VS Placebo Dendreon website Randomized Double-blind Multicenter 512 men With asymptomatic Or minimally symptomatic MPC Primary endpoint : Overall survival Secondary endpoint: Time to objective disease progression

PRIMARY ENDPOINT Survival median : 4.1 months Dendreon website

IMPACT TRIAL: NEGATIVE POINTS? IMPACT TRIAL Primary endpoint : Overall survival trials done versus placebo : ethic problems , same efficiency versus taxotere? patients having metastases: what medicine did they take before? (docetaxel approval for prostate cancer by FDA: 19/05/2004) ethnic population isn’t the same and ethny change impact of the disease Secondary endpoint : Time to objective disease survival FDA agreed to allow Dendreon to amend the design of the IMPACT study

REIMBURSEMENT CHALLENGE Market access and reimbursement success is key to realizing full product potential in E.U. Key factors influencing reimbursment: overall survival is the « gold standart » for payers IMPACT: 4 months survival benefits against placebo… total cost of care is taken into account $93,000/ complete cost treatement for Provenge VS $18,000/ 6 cycles of treatment for taxotere lack of required premedication and supportive care costs compared to Taxotere

WHERE TO HAVE A PLACE? Find a strategic place in EUROPE wich must be: Near airport and road network In a reasonable distance from each European capital Able to cover the majority of the market DENDREON’s decision to build its manufacturing site: GERMANY 50% of patients live in less than 8 hours to this site in car or flight JP Morgan Conference call – January 2011

During DENDREON submits an European authorization (late 2011/early 2012) Initial manufacturing through a Contract Manufacturing Organization (CMO): Qualifying a CMO can be done faster than plant construction Dendreon expects to save 12 to 18 months by outsourcing to support filing. Concurrently DENDREON will build its first manufacturing site: Initiate built out in 2011 Huge expenses!! WHERE TO HAVE A PLACE?

WITH WICH MONEY? Revenues from Provenge : $48 millions in 2010 January, 14 th 2011 : Dendreon announced the pricing of a publing offering of $540 million convertible senior notes Raise the equity : in the beginning of 2010 : public offering of 15 Million shares

Strengths Weaknesses Opportunities Threats ACI : revolutionary therapeutic approach ACI : less AEs than chemotherapy One drug on the market at least : Provenge  revenues Huge logistic : difficult to copy for generics Huge logistic : Expensive Restrictions for Clinical trials Provenge sales too low compared to expectations Increase of debts (senior notes) No profit yet Expansion In the USA In Europe : similarity with US market Provenge : new indication in development ACI : repeatible with new Antigens  other cancers targeted Decision for reimbursment of Provenge expected in March Emerging competitors At the mercy of the EMA for the approval of Provenge (clinical trial vs. Taxotere?)

HIRING OPPORTUNITIES Regulatory affairs Quality assurance Manufacturing Logistic coordinators Sales & Marketing R & D

WOULD WE JOIN DENDREON? Cancer treatment is a « noble » domain Working for a revolutionary process as ACI must be exciting Development of domains corresponding to our professional expectations Transition from a total R&D to a fully-integrated commercial company Regulatory Challenge in Europe New jobs in Regulatory Affairs Development of new ACI products Evaluation of new markets

Hormone-refractory metastatic prostate cancer Reference Treatment: Docetaxel (Taxotere ®) + prednisone/prednisolone Cost-effectiveness evaluation, Sanofi-Aventis,2005: Median survival (from Kaplan Meyer) Taxotere+prednisone: 18.9 months Vs mitoxantrone+prednisone : 16.5 months Total per patient cost: Taxotere+prednisone: £15.767(including first-line chemotherapy and for further therapy) Adverses events : Fatigue Nausea, vomiting,diarrhea Alopecia Sensory neuropathy 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

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

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®

CANCER IMMUNOTHERAPIES CAN BE EITHER : PASSIVE OR ACTIVE immunomodulators, antibodies or immune cells to initiate an anti-tumor action not targeted to a specific antigen Use in : breast cancer, melanoma, renal cell carcinoma, leukemia... Stimulates the patient's immune system using the body's own immune cells generates a T-cell response against tumor-associated antigens a type of therapeutic cancer vaccine Ex: adoptive T-cell therapy

CA-9 In-licensed from Bayer Corporation, Business Group Diagnostics = Carbonic Anhydrase IX Transmembrane protein involved in cell proliferation the only tumor-associated carbonic anhydrase isoenzyme known Tumors over-expressing CA-9 : Colon Cervical Kidney CA-9 is overexpressed in 75% of Renal cell Carcinoma phase 1/2 in Renal Cell Carcinoma planned in 2011

KIDNEY CANCER and CA-9 TREATMENTS : Surgery, Often resistant to chemotherapy and radiotherapy Well responder to immunotherapy Total : 46,592

KIDNEY CANCER and CA-9 Good opportunity for Dendreon’s Active Cell Immunotherapy; First pre-clinical results presented at the American Association of Immnology:  Candidate product targeted at CA-9 significantly prolonged survival in animal tumor models phase 1/2 in Renal Cell Carcinoma planned in 2011

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