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Cell Therapy Clinical Trials: Why They Fail IBC Inaugural Cell Therapy Clinical Development Conference Arlington, Virginia
Gregory A. BonfiglioProteus Venture PartnersSeptember 10, 2012
Agenda
I. A Brief Review of the RM Market Where Are We And How Did We Get Here? The Role of Cell Therapies
II. Cell Therapy: Current Clinical Activity Ongoing Cell Therapy Clinical Trials
III. Why Cell Therapies Fail Overall FDA Clinical Trial Data Key Failure Modes: Technology Failure; Trial Design; Trial
Management; Lack of Funding; Regulatory Hurdles
IV. Case Studies Geron; Dendreon; Osiris; InterCytex
CONFIDENTIAL 2
RM Has Entered A New ERA
RM Market is Maturing: Key Metrics
Rapidly Expanding Market:
• $1.6B in 2010
• $20.0B in 2025
• CAGR of 18.34%
Dramatic Revenue Growth
• $130M in 2001
• $1.6B+ in 2010
Worldwide funding for research Increasing
• $2.5B Now
• $14B in 10 Years
Clinical Programs • Over 4100 Clinical Trials• Over In 650 Late Stage Trials
Commercial Products • 400 on Market (Mostly Skin,
Tools Media, & Devices); – 900+ in Development
1.2M+ Patients Treated with RM Products. RM Companies• 700+ Co’s involved in RM • 60+ Public Co’s;
– $8.7B Total Market Cap • 225+ Private Co’s
CONFIDENTIAL 3
Global Company Distribution
5%
Asia32 firms
3%
Canada24 firms
56%
USA386 firms
14%
Europe (ex. UK)93 firms
UK133 firms
19%
2%
Middle East17 firms
700+ RM companies worldwide!
CONFIDENTIAL 4
The Role of Cell Therapy: 1st Regenerative Medicine
Cell Therapy: Key Metrics
Established Technology :
• 40+ Years in Clinical Practice
• 1st Bone Marrow Transplant: 1968
– Acute Lymphoblastic Leukemia (ALL)
• 1st Cord Blood Transplant: 1988
– Fanconi Anemia
Clinical Programs • 22,500+ Clinical Trials (Cell
Therapy)– Vast Majority are HSCs in
Oncology – 2800+ “New” Cell Therapies – 560+ in PIII/Pivitol Trials
320,000+ Patients Treated
Commercial Products • 44 Cell Therapies on Market
– $1B Revenues
Dramatic Revenue Growth
• $410M in 2008
• $5.1B+ in 2014
• 52.22% CAGR
CONFIDENTIAL 5
The Role of Cord Blood: Fastest Growing Segment of CT Market
Cord Blood Key Metrics
Market Size:• $3.4B (2010)
• $14.9B (2015)
• CAGR: 27.9%
Cord Blood Banks:• 150+ Private Banks
• 44 Public Banks
• 26 Countries
Total Cord Blood Units Stored• 500,000 Units in Public Banks
• 1M+ Units in Private Banks
Clinical Trials • Over 650 FDA Clinical Trials
– 450+ New Therapies – 96 Pivotal/PIII Trials
Fastest Growing Segment of Cell Transplant Market
• 22% of All Cell Transplants in 2010
• 40% by 2015
Total Cord Blood Transplants: 25,000 in 43 Countries
• 1,500 per year (2005)
• 3,000 per year (2010)
• 10,000 per year (2015)
Therapeutic Applications
• 60+ in Clinical Practice
• Leukemia; Lymphoma; Blood Disorders; Hematopoietic Restoration
CONFIDENTIAL 6
Cell Therapy Market: Expanding Rapidly (50%+ CAGR)
CONFIDENTIAL 7
Cell Therapy Industry: Billion Dollar Global Business With Unlimited Potential; Regenerative Medicine; Chris Mason, David Brindley, Emily J Culme-Seymour & Natasha L Davie
Dramatic Cell Therapy Revenue Growth
CTI Revenues: $410M (2008) - $5.1B (2014)
Agenda
I. A Brief Review of the RM Market Where Are We And How Did We Get Here? The Role of Cell Therapies
II. Cell Therapy: Current Clinical Activity Ongoing Cell Therapy Clinical Trials
III. Why Cell Therapies Fail Overall FDA Clinical Trial Data Key Failure Modes: Technology Failure; Trial Design; Trial
Management; Lack of Funding; Regulatory Hurdles
IV. Case Studies Geron; Dendreon; Osiris; InterCytex
CONFIDENTIAL 8
“Cell Therapies” in Clinical Development: 19,430+ Ongoing FDA Trials
CONFIDENTIAL 9Source: ClinicalTrials.gov (www.clinicaltrials.gov)
“New” Cell Therapies In Clinical Trials
CONFIDENTIAL 10
Refining the Data
• Remove Oncology Trialso 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
2,800+ FDA Trials Involve “New” Cell Therapies
Source: ClinicalTrials.gov (www.clinicaltrials.gov)
FDA Cell Therapy Clinical Trials by Phase
CONFIDENTIAL 11
40%
49%
Vast Majority of Cell Therapy Trials Are in “Early Stage”
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); ClinicalTrials.gov (www.clinicaltrials.gov)
FDA Cell Therapy Clinical Trials by Cell Origin
CONFIDENTIAL 12
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); ClinicalTrials.gov (www.clinicaltrials.gov)
FDA Cell Therapy Clinical Trials MOA: Engraftment vs. Transient
CONFIDENTIAL 13
50%
37%
5%9%
Most of the Cell Therapies Are Transient
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); ClinicalTrials.gov (www.clinicaltrials.gov)
FDA Cell Therapy Clinical Trials by Cell Type (2010)
CONFIDENTIAL 14
The Top 5 Cell Types Make Up 88.6% Of All Studies
FDA Trials Involving MSCs (2010)
CONFIDENTIAL 15
Source: Alan Trounson et al. BMC Medicine 2011 9:52 doi:10.1186/1741-7015-9-52
MSCs in Wide Range of Therapeutic Applications
Agenda
I. A Brief Review of the RM Market Where Are We And How Did We Get Here? The Role of Cell Therapies
II. Cell Therapy: Current Clinical Activity Ongoing Cell Therapy Clinical Trials
III. Why Cell Therapies Fail Overall FDA Clinical Trial Data Key Failure Modes: Technology Failure; Trial Design; Trial
Management; Lack of Funding; Regulatory Hurdles
IV. Case Studies Geron; Dendreon; Osiris; InterCytex
CONFIDENTIAL 16
FDA Clinical Trial Process
CONFIDENTIAL 17
FDA Clinical Trials: Key Metrics (2012)
Size (# Pts.)
Length PurposeFailure
Rate
Phase I 20–1006-9
MonthsPrimarily Safety 53%
Phase IIUp To Several
100
9 Months -2 Years
Short Term Safety; Mainly Effectiveness
77%
Phase III100s –
Several 1000
1-4 YearsSafety, Dosage & Effectiveness
41%
CONFIDENTIAL
Overall Failure Rate (2012): 84.7%
18
Source: PARAXEL Biopharmaceutical R&D Statistical Sourcebook (2012/2013); Tufts Center for the Study of Drug Development, http://csdd.tufts.edu (Tufts CSDD)
FDA Approval Rates for All Compounds (1993-2004): 16%
CONFIDENTIAL 19
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.2009.295
Approval Rates Vary Substantially By Therapeutic Application
CONFIDENTIAL 20
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.2009.295
Large Molecule Approval Rates Are @3X Higher Than Small Molecules
CONFIDENTIAL 21
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.2009.295
Key Reasons for Late Stage Failures: Efficacy; Safety; Finances
Failures in Phase II
CONFIDENTIAL 22
Reinventing Clinical Trials; Malorye Allison; Nature Biotechnology 30,41–49(2012); doi:10.1038/nbt.2083
Failures in Phase III
Why Cell Therapies Fail
CONFIDENTIAL 23
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 Toxicityo But GvHD; Tumorgenicity; Arrhythmias (Cardio) Are Safety
Failure Modes
Cell Therapy Trials: Key Failure Modes
Why Cell Therapies Fail
CONFIDENTIAL 24
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
3. Discontinuity b/w Research & Commercial Processes• Lose “Magic” When Manufacturing Process Is Optimized
for Commercial Production
4. Control Group Issues Failure to Anticipate Benefit in Clinical Setting Bias
Cell Therapy Trials: Key Failure Modes
Why Cell Therapies Fail
CONFIDENTIAL 25
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
4. Bias Investigator Bias; Reporting Bias
Cell Therapy Trials: Key Failure Modes
Why Cell Therapies Fail
CONFIDENTIAL 26
Funding
1. Very Challenging Funding Environment2. Limited Capital Available 3. Inadequate Resources To Correct For Errors, or Re-
Design Trials
Regulatory Hurdles
1. Regulatory Framework Evolving2. Some Key Parameters Unclear
e.g. Data Necessary to Establish Safety 3. Regulatory Agencies Climbing Learning Curve
Cell Therapy Trials: Key Failure Modes
Agenda
I. A Brief Review of the RM Market Where Are We And How Did We Get Here? The Role of Cell Therapies
II. Cell Therapy: Current Clinical Activity Ongoing Cell Therapy Clinical Trials
III. Why Cell Therapies Fail Overall FDA Clinical Trial Data Key Failure Modes: Technology Failure; Trial Design; Trial
Management; Lack of Funding; Regulatory Hurdles
IV. Case Studies Geron; Dendreon; Osiris; InterCytex
CONFIDENTIAL 27
Geron’s hESC Spinal Cord Trial
CONFIDENTIAL 28
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 testsMENLO 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 company's research and clinical-stage assets.".
Geron’s hESC Spinal Cord Trial
Geron Finances
•Went Public in 1996o Raised Over $500M
• 52 Week Market Range: 70% Drop (2011) o Stock Price: $6.12 -- $1.82 o Market Cap: $790M -- $239M
• Cash Position: $142Mo Monthly Burn: $6.5M
• Spent Over $200M on hESC Programs
hESC Clinical Program
•Halted SPI Trial After 4 Patients Treated
•Also Halted Programs in Diabetes, Cardio, Cartilage & Immunotherapy
• Relationship With CIRMoTerminated $25M Funding Agreement oReturned $6.4M to CIRM
CONFIDENTIAL 29
Reasons for Failure: Regulatory Hurdles & Finances
APC takes up the
antigen
Recombinant PAP-
GM-CSF antigen combines with
resting APC
The mature antigen-loaded APCs are the active component of
sipuleucel-T
Antigen is processed and displayed on surface of the
APCINFUSE
PATIENT
T-cells proliferate and attack
prostate cancer cells
Sipuleucel-T activates T-cells in the
body
ActiveT-cell
Inactive T-cell
Dendreon’s Provenge: Autologous Dendritic Cell Immunotherapy
CONFIDENTIAL 30 Source: David Urdal (2011)
Metastatic
Tumor volume
& activity
Time
Castration
ChemotherapyDeath
LocalTherapy
Non-Metastatic
SymptomaticAsymptomatic
Androgen Dependent Castrate Resistant
Dendreon’s Provenge: Autologous Dendritic Cells for Late Stage Prostate Cancer
1st targeted patients
CONFIDENTIAL 31 Source: David Urdal (2011)
Dendreon’s Provenge: Phase III Clinical Trial Design & Results
Phase III Trial – 3 Arms•1st & 2nd Arms:
o Patient Population: Asymptomatic, Metastatic Prostate Cancer Patients
o Endpoints: o Primary: Time to Disease Progressiono Secondary: Overall Survival
o Results: Failed Primary; Met Secondary •3rd Arm:
o Patient Population: Asymptomatic, Metastatic Prostate Cancer Patients
o Endpoints: o Primary: Overall Survival o Secondary: Time to Disease Progression
o Results: Met Primary; Failed Secondary
FDA Action
•1st & 2nd Arms: Refused to Grant Approval on Secondary Endpoints
•3rd Arm: Granted Approval on Primary Endpoint in
o Overall Survival
CONFIDENTIAL 32
Reasons for Failure: Poorly Chosen Endpoints
CONFIDENTIAL 33
Intercytex Cyzact: Autologous Fibroblasts For Venous Leg Ulcers
Source: Paul Kemp (2010))
Intercytex Cyzact: Autologous Fibroblasts For Venous Leg Ulcer
Cyzact Phase III Trial
•Initial Patient Population: Patients With Severe Venous Leg Ulcer
•Primary Endpoint: Complete Healing At 12 Weeks
•Supplemental Patient Population: Patients With Moderate Venous Leg Ulcers
•Control: Traditional Bandage (SoC)
•Results: Failed To Meet Primary Endpointo Failed to Properly Account for Efficacy of
Traditional Bandage in a Clinical Settingo Expanded Patient Population Diluted Efficacy
FDA Action
•Refused to Grant Approval
•Insufficient Showing of Efficacy Against SoC on Secondary Endpoints from 1st & 2nd Arms
CONFIDENTIAL 34
Reason for Failure: Patient Population; Control Issues
Osiris Prochymal: MSCs For GvHD (and Crohn’s)
CONFIDENTIAL 35
Osiris Prochymal: MSCs For GvHD & Crohn’s
Prochymal Trials•GvHD Trial:
o Patient Population: Asymptomatic, Metastatic Prostate Cancer Patients
o Endpoints: o Primary: Time to Disease Progressiono Secondary: Overall Survival
o Results: Failed Primary; Met Secondary •Crohn’s Trial
o Patient Population: Asymptomatic, Metastatic Prostate Cancer Patients
o Endpoints: o Primary: Overall Survival o Secondary: Time to Disease Progression
o Issue: Significant “Placebo Effect” – Patient Reporting
Regulatory Action
•GvHD: FDA Refused to Grant Approval (2010)
o Inadequate Showing of Efficacy
•Health Canada Approves Prochymal for Pediatric GvHD (May 2012)
•Crohn’s: Trial Suspended in 2009
o Resumed Enrollment in May 2010
CONFIDENTIAL 36
Reasons for Failure: Clinical Trial Design
CONFIDENTIAL 37
The Final Word
CONFIDENTIAL 37
CONFIDENTIAL 38
APPENDIX
CONFIDENTIAL 39
Proteus: An Investment and Advisory Firm Focused on RM
Proteus, Inc.
Proteus Management, LLC
(Fund Management)
Proteus Insights, LLC
(Consulting Services)
Proteus Advisors, LLC
(Investment Banking Services)
Cell Therapy Products Involve Various Technology Combinations
Biomaterials 3D Scaffolds
Drug / Biologic Immunotherapy?
Device Cell harvester & concentrator
Implantation &encapsulation
OrthopaedicReplacement
CNSReplacement
Islet Cell Replacement
Myocardial Cell Replacement
Cells Embryonic stem cells
Islet cellsProgenitors
ChondrocytesBone marrow cells
+/- Catheter
Immunotherapy?(for allo cells)
Immunotherapy?
Cardiac progenitor cells Bone marrow cells
+/- Catheter
3D Scaffolds
Technology Requirements: Examples
3D Scaffolds?
CONFIDENTIALScott Bruder, BD; MSC Conference (2011)
40
Stem Cells in Clinical Development: 4100+ Ongoing FDA Trials
CONFIDENTIAL 41Source: ClinicalTrials.gov (www.clinicaltrials.gov)
Clinical Trials Involving “Stem Cells” and “Cell Therapy” - 3800+ Ongoing FDA Trials
CONFIDENTIAL 42Source: ClinicalTrials.gov (www.clinicaltrials.gov)
Cord Blood Therapies in Clinical Development: 600+ Ongoing FDA Trials
CONFIDENTIAL 43Source: ClinicalTrials.gov (www.clinicaltrials.gov)
Density Of Clinical Trials Worldwide
CONFIDENTIAL 44
Reinventing Clinical Trials; Malorye Allison; Nature Biotechnology 30,41–49(2012); doi:10.1038/nbt.2083
Phase II & III Failures (2007–2010):“Unsustainably High”
CONFIDENTIAL 45
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/nrd3375
Phase III Failures in 2007–2010: @50%
Phase II Failures in 2008–2010: 82%
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
FDA Clinical Trials Involving “Cell Therapy”
www.ClinicalTrials.gov (excludes cancer studies); Scott Bruder, BD
Cli
nic
al T
rial
s
Year
CONFIDENTIAL 47
FDA Clinical Trials Involving “Stem Cells”C
lin
ical
Tri
als
Year
www.ClinicalTrials.gov (excludes cancer studies); Scott Bruder, BD
CONFIDENTIAL 48
Basic & DiscoveryResearch
Preclinical Research
Venture InvestmentsGrants to Universities & Research Institutes,
IPO & Partnering Deals
TherapeuticCandidate
Product Release
Proof of Concept.
PI$10-15MM
Probability: 66%
Probability: 70%
Probability: 40%
Preclinical Development
Clinical Phase I
Clinical Phase II
Clinical Phase III
Market
1-3 years 1.4-1.8 year 2.5-3.8 years
PII$20-25MM
PIII$50-75MM
IND Safety Efficacy
Key Failure Modes: Lack of Funding
Probabilityof success
Steps
Outcome
InvestmentAmount
Actors
$5-10MM $75=100MM
CONFIDENTIAL 49
Key Metrics:
• Average Time to Market: 10-15 Years
• Average Costs: $1.3B+
• Failure Rate: @90%
• Less than 30% of approved drugs recoup development costs
Key Failure Modes: Lack of Funding
Coming Out (?) of the Worst Financial Crisis in 75+ Years
CONFIDENTIAL 50
CT Business Models: Autologous v. Allogeneic
Autologous Model
Patients Own Cells/Tissue
• Personalized Medicine
Advantages:
• Easier Regulatory Path (GTP)
• No Immune Response
Challenges:
• Difficult to Scale
• High COGS
Allogeneic Model
Universal Cells in a Bottle
• Big Pharma “Drug Model”
Advantages:
• Scalable
• Low COGS
Challenges:
• More Difficult Regulatory Path
• Immune Response
CONFIDENTIAL 51
Service vs. Product
• Provenge: Autologous Treatment for Prostate Cancer Using Dendritic Cells
- Centralized Processing
• $93K per Treatment
- $350K+ Projected Revenues
• $725M Market Cap ($5.0B in 2011)
Day 1Leukapheresis
Day 2-3Provenge is manufactured
Day 3-4Patient is infused
Apheresis Center Dendreon Doctor’s Office
Three Treatments
(On Weeks 0, 2, 4)
Patient Patient
Provenge
Provenge
CONFIDENTIAL 52
Dendreon’s Provenge: Manufacturing & Treatment Protocol
Source: David Urdal (2011)
Targeted Patients Endpoints
127 asymptomatic, metastatic androgen independent prostate cancer patients
1ary: Time to disease progression 2ary: overall survival
Provenge: Two Phase III Arms Failed To Meet The Primary Endpoint But Showed Improvement In Overall Survival
D9901
Phase III (Provenge vs Placebo)
D9902A
CONFIDENTIAL 53
Targeted Patients Endpoints
98 asymptomatic, metastatic androgen independent prostate cancer patients
1ary: Time to disease progression 2ary: overall survival
Metastatic
Tumor volume
& activity
Time
Castration
ChemotherapyDeath
LocalTherapy
Non-Metastatic
SymptomaticAsymptomatic
Androgen Dependent Castrate Resistant
phases 3 D9901
and D9902A
No statistical significant delay in time to disease progression
Provenge: FDA Refused To Approve BLA Based On Secondary Endpoint (Overall Survival)
D9901
Phase III
D9902A
CONFIDENTIAL 54
FDA’s answer in May 2007
• “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”
Submission of the overall survival data for a BLA
(1ary endpoint time to disease progression)
(1ary endpoint time to disease progression)
3rd Phase III With Overall Survival (1ary Endpoint) And With Extension Of Population To More Serious Patients
Phase III
CONFIDENTIAL 55
Targeted Patients Endpoints
512 Asymptomatic and minimally metastatic androgen independent prostate cancer patients
1ary: Overall survival2ary: Time to disease progression
Phase III
IMPACT
(1ary endpoint overall survival)
D9901 D9902A(1ary endpoint time to disease progression)
(1ary endpoint time to disease progression)
FDA refuses BLAMetastatic
Tumor volume
& activity
Time
Castration
Chemotherapy
Death
LocalTherapy
Non-Metastatic
SymptomaticAsymptomatic
Androgen Dependent Castrate Resistant
phases 3 D9901
and D9902A
IMPACT
FDA Approved BLA For Provenge Based On IMPACT Trial Results
Phase III
CONFIDENTIAL 56
Phase III
IMPACT
(1ary endpoint overall survival)
D9901 D9902A(1ary endpoint time to disease progression)
(1ary endpoint time to disease progression)
FDA refuses BLA
Submission of IMPACT data (showing 4.1 month overall survival improvement) for a
BLA
FDA’s answer in April 2010
• Approval of BLA: IMPACT results met 1ary endpoint of overall survival and exhibits safety profile
Provenge: Primary Reasons For Failure of the 1st & 2nd Arms of the Phase III Trial
CONFIDENTIAL 57
• 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 Populationo Patient Population in the Trial Must Be Sufficiently Large To Represent The
US Patient Population Adequately
• Poor Choice Of Patient Population (Included Extreme Patients)
Source: Joyce Frey (2011)
Targeted Patients Endpoint
• 396 patients with venous leg ulcer with at least 3 months duration
• With a four layer compression bandaging, venous leg ulcer of the patient would decrease in size less than 30% in one month
1ary: complete healing at 12 weeks
Cyzact : 1st Stage: Intercytex Enrolled Very Ill Patients
Phase III
CONFIDENTIAL 58
Arm 1Cyzact with compression bandaging
Arm 2Control:
compression bandaging
Intercytex action
• Intercytex enrolling extreme cases of venous leg ulcer patients
Cyzact 2nd Stage: Intercytex Enrolled Moderate Patients, To Increase The Rate Of Healing
Phase III
CONFIDENTIAL 59
Data Safety Monitoring Board said
• “continue the trial and enrol more patients: 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)
Arm 1Cyzact with compression bandaging
Arm 2Control:
compression bandaging
Result: Cyzact Failed To Meet Primary Endpoint
Phase III
CONFIDENTIAL 60
FDA’s answer in 2008
• Failed to meet primary endpoint: no statistical difference between Cyzact (Arm 1) and Control (Arm 2)
No statistical difference
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
Arm 1Cyzact with compression bandaging
Arm 2Control:
compression bandaging
No further work on Cyzact planned
Cyzact: Primary Reasons For Phase III Failure
CONFIDENTIAL 61
• Did Not Adequately Select Patient Populationo Intercytex Selected Both Extreme And Non Extreme Patients Instead Of
Only Focusing On Extreme Patients
• Rushed To Enroll Patients To Obtain Phase III Resultso 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