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

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






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


FDA Cell Therapy Clinical Trials MOA: Engraftment vs. Transient

CONFIDENTIAL 13

50%

37%

5%9%

Most of the Cell Therapies Are Transient


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






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%


Large Molecule Approval Rates Are @3X Higher Than Small Molecules

CONFIDENTIAL 21

Overall Success Rate (1993-2004): 32%


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


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



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



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


Agenda






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 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 Endpoints: o Primary: Time to Disease Progressiono Secondary: Overall Survival

o Results: Failed Primary; Met Secondary •Crohn’s Trial


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


Clinical Trials Involving “Stem Cells” and “Cell Therapy” - 3800+ Ongoing FDA Trials


Cord Blood Therapies in Clinical Development: 600+ Ongoing FDA Trials


Density Of Clinical Trials Worldwide

CONFIDENTIAL 44


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)


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


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



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)


3rd Phase III With Overall Survival (1ary Endpoint) And With Extension Of Population To More Serious Patients

Phase III

CONFIDENTIAL 55


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)


FDA refuses BLAMetastatic

Tumor volume

& activity

Time

Castration

Chemotherapy

Death

LocalTherapy

Non-Metastatic



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)


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 2Control:


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 2Control:


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

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

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