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Ibc cell therapy clinical development conference (arlington va september 10 11 2012)v.4

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Ibc cell therapy clinical development conference (arlington va september 10 11 2012)v.4

  1. 1. Cell Therapy Clinical Trials: Why They Fail IBC Inaugural Cell Therapy Clinical Development Conference Arlington, VirginiaGregory A. BonfiglioProteus VenturePartnersSeptember 10, 2012
  2. 2. AgendaI. A Brief Review of the RM Market  Where Are We And How Did We Get Here?  The Role of Cell TherapiesI. Cell Therapy: Current Clinical Activity  Ongoing Cell Therapy Clinical TrialsIII. Why Cell Therapies Fail  Overall FDA Clinical Trial Data  Key Failure Modes: Technology Failure; Trial Design; Trial Management; Lack of Funding; Regulatory HurdlesIV. Case Studies  Geron; Dendreon; Osiris; InterCytex CONFIDENTIAL 2
  3. 3. RM Has Entered A New ERA RM Market is Maturing: Key Metrics Rapidly Expanding Market: • $1.6B in 2010 Commercial Products • $20.0B in 2025 • 400 on Market (Mostly Skin, Tools Media, & Devices); • CAGR of 18.34% – 900+ in Development Dramatic Revenue Growth • $130M in 2001 1.2M+ Patients Treated with RM Products. • $1.6B+ in 2010 Worldwide funding for research RM Companies Increasing • 700+ Co’s involved in RM • $2.5B Now • 60+ Public Co’s; • $14B in 10 Years – $8.7B Total Market Cap Clinical Programs • 225+ Private Co’s • Over 4100 Clinical Trials • Over In 650 Late Stage Trials CONFIDENTIAL 3
  4. 4. Global Company DistributionCanada UK 133 firms Europe24 firms (ex. UK) 3% 19% 14% 93 firms Asia 56% 2% 32 firms 5% Middle East 17 firmsUSA386 firms 700+ RM companies worldwide! CONFIDENTIAL 4
  5. 5. The Role of Cell Therapy: 1st RegenerativeMedicine Cell Therapy: Key Metrics Established Technology : • 40+ Years in Clinical Practice 320,000+ Patients Treated • 1st Bone Marrow Transplant: 1968 – Acute Lymphoblastic Commercial Products Leukemia (ALL) • 44 Cell Therapies on Market • 1st Cord Blood Transplant: 1988 – $1B Revenues – Fanconi Anemia Dramatic Revenue Growth Clinical Programs • 22,500+ Clinical Trials (Cell • $410M in 2008 Therapy) • $5.1B+ in 2014 – Vast Majority are HSCs in Oncology • 52.22% CAGR – 2800+ “New” Cell Therapies – 560+ in PIII/Pivitol Trials CONFIDENTIAL 5
  6. 6. The Role of Cord Blood: FastestGrowing Segment of CT Market Cord Blood Key Metrics Market Size: Fastest Growing Segment of Cell • $3.4B (2010) Transplant Market • $14.9B (2015) • 22% of All Cell Transplants in 2010 • CAGR: 27.9% • 40% by 2015 Cord Blood Banks: Total Cord Blood Transplants: 25,000 • 150+ Private Banks in 43 Countries • 44 Public Banks • 1,500 per year (2005) • 26 Countries • 3,000 per year (2010) Total Cord Blood Units Stored • 10,000 per year (2015) • 500,000 Units in Public Banks • 1M+ Units in Private Banks Therapeutic Applications • 60+ in Clinical Practice Clinical Trials • Leukemia; Lymphoma; Blood • Over 650 FDA Clinical Trials Disorders; Hematopoietic – 450+ New Therapies Restoration – 96 Pivotal/PIII Trials CONFIDENTIAL 6
  7. 7. Cell Therapy Market: Expanding Rapidly(50%+ CAGR) Dramatic Cell Therapy Revenue Growth CTI Revenues: $410M (2008) - $5.1B (2014) Cell Therapy Industry: Billion Dollar Global Business With Unlimited Potential; Regenerative Medicine; Chris Mason, David Brindley, Emily J Culme-Seymour & Natasha L Davie CONFIDENTIAL 7
  8. 8. AgendaI. A Brief Review of the RM Market  Where Are We And How Did We Get Here?  The Role of Cell TherapiesI. Cell Therapy: Current Clinical Activity  Ongoing Cell Therapy Clinical TrialsIII. Why Cell Therapies Fail  Overall FDA Clinical Trial Data  Key Failure Modes: Technology Failure; Trial Design; Trial Management; Lack of Funding; Regulatory HurdlesIV. Case Studies  Geron; Dendreon; Osiris; InterCytex CONFIDENTIAL 8
  9. 9. “Cell Therapies” in Clinical Development:19,430+ Ongoing FDA Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 9
  10. 10. “New” Cell Therapies In Clinical Trials 2,800+ FDA Trials Involve “New” Cell Therapies Refining the Data • Remove Oncology Trials o Bone Marrow/Cord Blood/ Mobilized Blood Progenitor Cells • Remove Tissue Engineering Trials • Result: 2,800+ “New” Cell Therapy Trials Open Studies, Without Results: 1,360 Late Stage Trials: 560+ • Phase III: 460+ Trials • Phase IV: 90+ Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 10
  11. 11. FDA Cell Therapy Clinical Trialsby Phase Vast Majority of Cell Therapy Trials Are in “Early Stage” 40% 49% Source: Culme-Seymour EJ, Davie NL, Brindley DA, Edwards-Parton S, Mason C: A decade of cell therapy clinical trials (2000-2010). Regenerative medicine 7,4 (2012);CONFIDENTIAL 11 ClinicalTrials.gov (www.clinicaltrials.gov)
  12. 12. FDA Cell Therapy Clinical Trialsby Cell Origin No Clear Preference for Autologous or Allogeneic Source: Culme-Seymour EJ, Davie NL, Brindley DA, Edwards-Parton S, Mason C: A decade of cell therapy clinical trials (2000-2010). Regenerative medicine 7,4 (2012);CONFIDENTIAL 12 ClinicalTrials.gov (www.clinicaltrials.gov)
  13. 13. FDA Cell Therapy Clinical TrialsMOA: Engraftment vs. Transient Most of the Cell Therapies Are Transient 9% 5% 37% 50% Source: Culme-Seymour EJ, Davie NL, Brindley DA, Edwards-Parton S, Mason C: ACONFIDENTIAL 13 decade of cell therapy clinical trials (2000-2010). Regenerative medicine 7,4 (2012); ClinicalTrials.gov (www.clinicaltrials.gov)
  14. 14. FDA Cell Therapy Clinical Trialsby Cell Type (2010) The Top 5 Cell Types Make Up 88.6% Of All StudiesCONFIDENTIAL 14
  15. 15. FDA Trials Involving MSCs (2010) MSCs in Wide Range of Therapeutic Applications Source: Alan Trounson et al. BMC Medicine 2011 9:52 doi:10.1186/1741- 7015-9-52 CONFIDENTIAL 15
  16. 16. AgendaI. A Brief Review of the RM Market  Where Are We And How Did We Get Here?  The Role of Cell TherapiesI. Cell Therapy: Current Clinical Activity  Ongoing Cell Therapy Clinical TrialsIII. Why Cell Therapies Fail  Overall FDA Clinical Trial Data  Key Failure Modes: Technology Failure; Trial Design; Trial Management; Lack of Funding; Regulatory HurdlesIV. Case Studies  Geron; Dendreon; Osiris; InterCytex CONFIDENTIAL 16
  17. 17. FDA Clinical Trial ProcessCONFIDENTIAL 17
  18. 18. FDA Clinical Trials: Key Metrics(2012) Overall Failure Rate (2012): 84.7% Size Failure Length Purpose (# Pts.) Rate 6-9Phase I 20–100 Months Primarily Safety 53% Up To Short Term 9 MonthsPhase II Several -2 Years Safety; Mainly 77% 100 Effectiveness 100s – Safety, Dosage &Phase III Several 1-4 Years Effectiveness 41% 1000 Source: PARAXEL Biopharmaceutical R&D Statistical Sourcebook (2012/2013); Tufts Center for the Study of Drug Development, http://csdd.tufts.edu (Tufts CSDD)CONFIDENTIAL 18
  19. 19. FDA Approval Rates for All Compounds(1993-2004): 16% Overall Failure Rate (1993-2004): 84% Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs; J A DiMasi1; Clinical Pharmacology & Therapeutics (2010) 87 3, 272–277. doi:10.1038/clpt.2009.295CONFIDENTIAL 19
  20. 20. Approval Rates Vary Substantially ByTherapeutic Application CNS Approval Rate: 8.2% vs. Anti-Infective: 23.9% Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs; J A DiMasi1; Clinical Pharmacology & Therapeutics (2010) 87 3, 272–277. doi:10.1038/clpt.2009.295CONFIDENTIAL 20
  21. 21. Large Molecule Approval Rates Are @3XHigher Than Small Molecules Overall Success Rate (1993-2004): 32% Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs; J A DiMasi1; Clinical Pharmacology & Therapeutics (2010) 87 3, 272–277. doi:10.1038/clpt.2009.295CONFIDENTIAL 21
  22. 22. Key Reasons for Late Stage Failures:Efficacy; Safety; Finances Failures in Phase II Failures in Phase III Reinventing Clinical Trials; Malorye Allison; Nature Biotechnology 30,41–49(2012); doi:10.1038/nbt.2083CONFIDENTIAL 22
  23. 23. Why Cell Therapies Fail Cell Therapy Trials: Key Failure Modes Technology Failures 1. Efficacy  FDA Trials: 50%+ Efficacy Related Failures  Cell Therapies Efficacy Rates Should Be Better o Significant Pre-Clinical Data Developed in Academic Settings o Often Have Patient Data o Expect “Large Molecule” Approval Rates: 34% 2. Safety  FDA Trials: 30-40% Safety Related Failures  Cell Therapies Do Not Present the Same Risk Profile o Limited Risk of Systemic Toxicity o But GvHD; Tumorgenicity; Arrhythmias (Cardio) Are Safety Failure ModesCONFIDENTIAL 23
  24. 24. Why Cell Therapies Fail Cell Therapy Trials: Key Failure Modes Clinical Trial Design 1. Poorly Chosen Endpoints  Primary & Secondary o E.g.: Disease Progression vs. Overall Survival  Difficult To Measure Clinical Benefit Objectively 2. Inappropriate Patient Population  Broad Patient Base vs. Targeted Application 2. Discontinuity b/w Research & Commercial Processes • Lose “Magic” When Manufacturing Process Is Optimized for Commercial Production 2. Control Group Issues  Failure to Anticipate Benefit in Clinical Setting  Bias CONFIDENTIAL 24
  25. 25. Why Cell Therapies Fail Cell Therapy Trials: Key Failure Modes Clinical Trial Management 1. Lack of Clinical Operations Experience  Most CT Trials Conducted by Start Ups or Academics  Limited Pharma Involvement 2. Patient Enrollment  Inappropriate Inclusion/Exclusion Criteria  Inadequate Supply of Patients  80% of Clinical Trials Fail to Meet Their Enrollment Goals 3. Data Management  Poor Data Capture/Entry 3. Bias  Investigator Bias; Reporting BiasCONFIDENTIAL 25
  26. 26. Why Cell Therapies Fail Cell Therapy Trials: Key Failure Modes Funding 1. Very Challenging Funding Environment 2. Limited Capital Available 3. Inadequate Resources To Correct For Errors, or Re-Design Trials Regulatory Hurdles 1. Regulatory Framework Evolving 2. Some Key Parameters Unclear  e.g. Data Necessary to Establish Safety 3. Regulatory Agencies Climbing Learning Curve CONFIDENTIAL 26
  27. 27. AgendaI. A Brief Review of the RM Market  Where Are We And How Did We Get Here?  The Role of Cell TherapiesI. Cell Therapy: Current Clinical Activity  Ongoing Cell Therapy Clinical TrialsIII. Why Cell Therapies Fail  Overall FDA Clinical Trial Data  Key Failure Modes: Technology Failure; Trial Design; Trial Management; Lack of Funding; Regulatory HurdlesIV. Case Studies  Geron; Dendreon; Osiris; InterCytex CONFIDENTIAL 27
  28. 28. Geron’s hESC Spinal Cord Trial November 14,2011 Geron Halting Stem Cell Research, Laying Off Staff, Stem Cell Pioneer Exits Field Geron exiting such research, laying off staff, to focus on cancer drug tests MENLO PARK, Calif. (AP) -- Money troubles have forced the first company doing a government- approved test of embryonic stem cell therapy to discontinue further stem cell programs and lay off much of its staff. >>>>>>> In a statement, the company said the decision to narrow its focus "was made after a strategic review of the costs, ... timelines and clinical, manufacturing and regulatory complexities associated with the companys research and clinical-stage assets.". CONFIDENTIAL 28
  29. 29. Geron’s hESC Spinal Cord Trial Reasons for Failure: Regulatory Hurdles & Finances Geron Finances hESC Clinical Program •Went Public in 1996 •Halted SPI Trial After 4 Patients o Raised Over $500M Treated • 52 Week Market Range: 70% •Also Halted Programs in Drop (2011) Diabetes, Cardio, Cartilage & o Stock Price: $6.12 -- $1.82 Immunotherapy o Market Cap: $790M -- $239M • Cash Position: $142M • Relationship With CIRM o Monthly Burn: $6.5M oTerminated $25M Funding Agreement • Spent Over $200M on hESC oReturned $6.4M to CIRM Programs CONFIDENTIAL 29
  30. 30. Dendreon’s Provenge: AutologousDendritic Cell Immunotherapy Recombinant APC takes Antigen is The mature antigen- PAP- up the processed and loaded APCs are the GM-CSF antigen displayed on active component of antigen surface of the sipuleucel-T combines with APC resting APC INFUSE Inactive Active PATIENT T-cell T-cell T-cells Sipuleucel-T proliferate and activates T- attack cells in the prostate cancer body cells CONFIDENTIAL 30 Source: David Urdal (2011)
  31. 31. Dendreon’s Provenge: Autologous Dendritic Cellsfor Late Stage Prostate Cancer Death Chemotherapy Castration 1 st targetedTumor patientsvolume Local & Therapyactivity Asymptomatic Symptomatic Non-Metastatic Metastatic Androgen Dependent Castrate Resistant Time CONFIDENTIAL 31 Source: David Urdal (2011)
  32. 32. Dendreon’s Provenge: Phase III ClinicalTrial Design & Results Reasons for Failure: Poorly Chosen Endpoints Phase III Trial – 3 Arms FDA Action •1st & 2nd Arms: •1st & 2nd Arms: Refused o Patient Population: Asymptomatic, Metastatic to Grant Approval on Prostate Cancer Patients Secondary Endpoints o Endpoints: o Primary: Time to Disease Progression o Secondary: Overall Survival o Results: Failed Primary; Met Secondary •3rd Arm: Granted •3rd Arm: Approval on Primary Endpoint in o Patient Population: Asymptomatic, Metastatic Prostate Cancer Patients o Overall Survival o Endpoints: o Primary: Overall Survival o Secondary: Time to Disease Progression o Results: Met Primary; Failed Secondary CONFIDENTIAL 32
  33. 33. Intercytex Cyzact: Autologous FibroblastsFor Venous Leg Ulcers CONFIDENTIAL 33 Source: Paul Kemp (2010))
  34. 34. Intercytex Cyzact: Autologous FibroblastsFor Venous Leg Ulcer Reason for Failure: Patient Population; Control Issues Cyzact Phase III Trial FDA Action •Initial Patient Population: Patients With •Refused to Grant Severe Venous Leg Ulcer Approval •Primary Endpoint: Complete Healing At 12 Weeks •Insufficient Showing of •Supplemental Patient Population: Patients Efficacy Against SoC on With Moderate Venous Leg Ulcers Secondary Endpoints from •Control: Traditional Bandage (SoC) 1st & 2nd Arms •Results: Failed To Meet Primary Endpoint o Failed to Properly Account for Efficacy of Traditional Bandage in a Clinical Setting o Expanded Patient Population Diluted Efficacy CONFIDENTIAL 34
  35. 35. Osiris Prochymal: MSCs For GvHD (andCrohn’s) CONFIDENTIAL 35
  36. 36. Osiris Prochymal: MSCs For GvHD &Crohn’s Reasons for Failure: Clinical Trial Design Prochymal Trials Regulatory Action •GvHD Trial: •GvHD: FDA Refused to o Patient Population: Asymptomatic, Metastatic Grant Approval (2010) Prostate Cancer Patients o Inadequate Showing o Endpoints: of Efficacy o Primary: Time to Disease Progression o Secondary: Overall Survival •Health Canada Approves o Results: Failed Primary; Met Secondary Prochymal for Pediatric GvHD (May 2012) •Crohn’s Trial o Patient Population: Asymptomatic, Metastatic Prostate •Crohn’s: Trial Suspended Cancer Patients in 2009 o Endpoints: o Resumed Enrollment o Primary: Overall Survival o Secondary: Time to Disease Progression in May 2010 o Issue: Significant “Placebo Effect” – Patient Reporting CONFIDENTIAL 36
  37. 37. The Final Word CONFIDENTIAL 37 CONFIDENTIAL 37
  38. 38. APPENDIXCONFIDENTIAL 38
  39. 39. Proteus: An Investment and AdvisoryFirm Focused on RM Proteus, Inc. Proteus Proteus Proteus Management, LLC Insights, LLC Advisors, LLC (Fund Management) (Consulting Services) (Investment Banking Services)CONFIDENTIAL 39
  40. 40. Cell Therapy Products Involve VariousTechnology Combinations Technology Requirements: Examples CNS Myocardial Cell Orthopaedic Islet Cell Replacement Replacement Replacement Replacement Cells Embryonic Cardiac progenitor cells Chondrocytes Islet cells stem cells Bone marrow cells Bone marrow cells Progenitors Cell harvester Implantation & Device +/- Catheter +/- Catheter & concentrator encapsulation Immunotherapy? Drug / Biologic (for allo cells) Immunotherapy? Immunotherapy? Biomaterials 3D Scaffolds? 3D Scaffolds 3D Scaffolds Scott Bruder, BD; MSC Conference (2011) CONFIDENTIAL 40
  41. 41. Stem Cells in Clinical Development:4100+ Ongoing FDA Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 41
  42. 42. Clinical Trials Involving “Stem Cells” and“Cell Therapy” - 3800+ Ongoing FDA Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 42
  43. 43. Cord Blood Therapies in Clinical Development:600+ Ongoing FDA Trials Source: ClinicalTrials.gov (www.clinicaltrials.gov) CONFIDENTIAL 43
  44. 44. Density Of Clinical Trials Worldwide Reinventing Clinical Trials; Malorye Allison; Nature Biotechnology 30,41–49(2012); doi:10.1038/nbt.2083 CONFIDENTIAL 44
  45. 45. Phase II & III Failures (2007–2010):“Unsustainably High” Phase II Failures in 2008–2010: 82% Phase III Failures in 2007–2010: @ 50% John Arrowsmith: Nature Reviews Drug Discovery 10, 328-329 (May 2011); doi:10.1038/nrd3439; Nature Reviews Drug Discovery 10, 87 (February 2011) | doi:10.1038/nrd3375CONFIDENTIAL 45
  46. 46. FDA Drug Approvals Per Year (1996-2010) Reinventing Clinical Trials; Malorye Allison; Nature Biotechnology 30,41–49(2012); doi:10.1038/nbt.2083 CONFIDENTIAL 46
  47. 47. FDA Clinical Trials Involving “Cell Therapy”s a r Tl ac nl C l i i i Year CONFIDENTIAL 47 www.ClinicalTrials.gov (excludes cancer studies); Scott Bruder, BD
  48. 48. FDA Clinical Trials Involving “Stem Cells”s a r Tl ac nl Cl i i i Year www.ClinicalTrials.gov (excludes cancer studies); CONFIDENTIAL 48 Scott Bruder, BD
  49. 49. Key Failure Modes: Lack ofFunding Probability: Probability: Probability:Probability 66% 70% 40%of success Steps Basic & Discovery Preclinical Preclinical Clinical Clinical Clinical Market Research Research Development Phase I Phase II Phase III 1-3 years 1.4-1.8 year 2.5-3.8 years Outcome Proof of Concept. Therapeutic IND Safety Efficacy Product Candidate ReleaseInvestment PI PII PIII $75=100MM Amount $5-10MM $10-15MM $20-25MM $50-75MM Actors Grants to Universities Venture IPO & Partnering & Research Deals Investments • Average Time to Market: 10-15 Years Institutes, • Average Costs: $1.3B+ Key • Failure Rate: @ 90% • Less than 30% of approved drugs recoup M etrics: development costs CONFIDENTIAL 49
  50. 50. Key Failure Modes: Lack of Funding Coming Out (?) of the Worst Financial Crisis in 75+ Years CONFIDENTIAL 50
  51. 51. CT Business Models: Autologous v. Allogeneic Autologous Model Allogeneic Model Patients Own Cells/Tissue Universal Cells in a Bottle • Personalized Medicine • Big Pharma “Drug Model” • Provenge: Autologous Treatment for Advantages: Advantages: Prostate Cancer Using Dendritic Cells • Easier Regulatory Path • Scalable (GTP) - Centralized Processing COGS • Low • No Immune Response • $93K per Treatment Challenges: Challenges: - $350K+ Projected Revenues Regulatory • More Difficult • Difficult to Scale Path • High COGS• $725M Market Cap ($5.0B in 2011) • Immune Response Service vs. Product CONFIDENTIAL 51
  52. 52. Dendreon’s Provenge: Manufacturing &Treatment Protocol Day 1 Day 2-3 Day 3-4 Leukapheresis Provenge is manufactured Patient is infused Patient Patient Provenge Provenge Apheresis Center Dendreon Doctor’s Office Three Treatments (On Weeks 0, 2, 4) CONFIDENTIAL 52 Source: David Urdal (2011)
  53. 53. Provenge: Two Phase III Arms Failed To Meet The Primary Endpoint But Showed Improvement In Overall Survival Phase III Targeted Endpoints (Provenge vs Placebo) Patients 127 asymptomatic, 1ary: Time to D9901 D9902A metastatic androgen disease independent prostate progression No statistical significant delay in time to cancer patients 2ary: overall disease progression survival Death Chemotherapy Castration Targeted Endpoints phases PatientsTumor 3 98 asymptomatic, 1ary: Time to Local D9901volume Therapy and metastatic androgen disease & D9902Aactivity independent prostate progression cancer patients 2ary: overall Asymptomatic Symptomati c survival Non-Metastatic Metastatic Androgen Castrate Resistant Dependent Time CONFIDENTIAL 53
  54. 54. Provenge: FDA Refused To Approve BLA BasedOn Secondary Endpoint (Overall Survival) Phase III D9901 D9902A(1ary endpoint time to (1ary endpoint time to disease progression) disease progression) Submission of the overall survival data for a FDA’s answer in May 2007 BLA • “the lack of pre-specified primary method for survival analysis rendered it impossible to estimate the Type I error (statistical persuasiveness) for this survival difference” • “under-representation of the African American population should be addressed” • “Request of additional clinical data to support the overall survival efficacy claim” CONFIDENTIAL 54
  55. 55. 3rd Phase III With Overall Survival (1ary Endpoint) AndWith Extension Of Population To More Serious Patients Chemotherapy Phase III Castration Death phases D9901 D9902A 3 D9901(1ary endpoint time to (1ary endpoint time to Tumor and Local disease progression) disease progression) volume Therapy D9902A & activity IMPAC T Asymptomatic Symptomati FDA refuses BLA c Non-Metastatic Metastatic Phase III Androgen Castrate Resistant Dependent IMPACT Time (1ary endpoint overall survival) Targeted Endpoints Patients 512 Asymptomatic and 1ary: Overall minimally metastatic survival androgen independent 2ary: Time to prostate cancer patients disease progression CONFIDENTIAL 55
  56. 56. FDA Approved BLA For Provenge Based On IMPACT Trial Results Phase III D9901 D9902A(1ary endpoint time to (1ary endpoint time to disease progression) disease progression) FDA refuses BLA Phase III IMPACT (1ary endpoint overall survival) FDA’s answer in April 2010 Submission of IMPACT data (showing 4.1 • Approval of BLA: IMPACT results met 1ary month overall survival improvement) for a endpoint of overall survival and exhibits BLA safety profile CONFIDENTIAL 56
  57. 57. Provenge: Primary Reasons For Failure of the1st & 2nd Arms of the Phase III Trial • Failed To Meet Primary Endpoint (Time To Disease Progression) • Submitted Retrospective Analysis (On Overall Survival Improvement Which Was The 2ary Endpoint And Not The 1ary Endpoint) o FDA Generally Does Not Accept This Retrospective Analysis • Did Not Adequately Select Primary Endpoint And Did Not Explore Endpoint In Early Clinical Trials (E.G. Phase 2 Trial) o FDA Of Prefers Primary Clinical Endpoint Over Seceondary Endpoint • Did Not Target A Representative US Patient Population o Patient Population in the Trial Must Be Sufficiently Large To Represent The US Patient Population Adequately • Poor Choice Of Patient Population (Included Extreme Patients) CONFIDENTIAL 57 Source: Joyce Frey (2011)
  58. 58. Cyzact : 1st Stage: Intercytex Enrolled VeryIll Patients Phase III Targeted Endpoint Arm 1 Arm 2 Patients Cyzact with Control: • 396 patients with 1ary: complete compression compression venous leg ulcer healing at 12 bandaging bandaging with at least 3 weeks months duration • With a four layer compression bandaging, venous leg ulcer of the patient would decrease in size less than 30% in one month Intercytex action • Intercytex enrolling extreme cases of venous leg ulcer patients CONFIDENTIAL 58
  59. 59. Cyzact 2nd Stage: Intercytex Enrolled ModeratePatients, To Increase The Rate Of Healing Phase III Arm 1 Arm 2 Data Safety Monitoring Board said Cyzact with Control: compression compression • “continue the trial and enrol more patients: bandaging bandaging the control arm is achieving a higher rate of healing than expected” Intercytex action • Under the pressure of investors, Intercytex rushed to quickly enroll patients but Intercytex enrolled different type of patients (i.e. not only extreme patients but also easy to heal patients) CONFIDENTIAL 59
  60. 60. Result: Cyzact Failed To Meet PrimaryEndpoint Phase III Arm 1 Arm 2 FDA’s answer in 2008 Cyzact with Control: compression compression • Failed to meet primary endpoint: no bandaging bandaging statistical difference between Cyzact (Arm 1) and Control (Arm 2) No statistical difference No further work on Cyzact planned Intercytex thoughts • Should have enrolled only extreme patients (i.e. patient with venous leg ulcers that had decreased in size by less than 10% in one month instead of 30%) and this would have enabled to show difference between Cyzact arm and control arm CONFIDENTIAL 60
  61. 61. Cyzact: Primary Reasons For Phase IIIFailure • Did Not Adequately Select Patient Population o Intercytex Selected Both Extreme And Non Extreme Patients Instead Of Only Focusing On Extreme Patients • Rushed To Enroll Patients To Obtain Phase III Results o The Company Enrolled Diverse Type Of Patients Who Were Reacting Differently With The Control • Underestimated The Control Efficacy In A Clinical Trial Setting o The Control With The Compression Bandaging Showed Better Efficacy Results In The Clinical Trial Setting Than In The Usual Setting CONFIDENTIAL 61

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