Cardiovascular Research FoundationCardiovascular Research FoundationColumbia University Medical CenterColumbia University Medical Center

Warren Sherman, M.D.Warren Sherman, M.D. Director, Cell-Based Endovascular TherapiesDirector, Cell-Based Endovascular Therapies

Warren Sherman, M.D.Warren Sherman, M.D. Director, Cell-Based Endovascular TherapiesDirector, Cell-Based Endovascular Therapies

January 17-19, 2007January 17-19, 2007

MYOHEART US Phase I StudyMYOHEART US Phase I StudyInterim AnalysisInterim Analysis

MYOHEART Study FlowMYOHEART Study Flow

Clinical Sites: Columbia Presbyterian, Cleveland Clinic, Mayo Clinic, Minneapolis Heart, St. Joseph’s / ACRI

Core Lab: Gentiae Clinical Research

2 injections(.25 cc)

6 injections(.25 cc)

18 injections(.25 cc)

First Cohort (n=5)25 x 106 cells

30-Day Safety Evaluation

Second Cohort (n=5)75 x 106 cells

30-Day Safety Evaluation

Third Cohort (n=5)225 x 106 cells

30-Day Safety Evaluation

Fourth Cohort (n=5)675 x 106 cells

27 injections(.50 cc)

1.1. To assess the safety and feasibility of MyoCell™ To assess the safety and feasibility of MyoCell™ (autologous myoblasts) following implantation into (autologous myoblasts) following implantation into myocardial tissue of CHF subjects who experienced myocardial tissue of CHF subjects who experienced prior MI (prior MI (>> 12 weeks), 12 weeks),

2.2. To assess the safety and feasibility of the MyoCathTo assess the safety and feasibility of the MyoCath®® transendocardial needle-injection catheter as a transendocardial needle-injection catheter as a system for delivering MyoCell into myocardial tissue, system for delivering MyoCell into myocardial tissue, andand

3.3. To assess the effect on myocardial structure and To assess the effect on myocardial structure and function of MyoCath mediated MyoCell implantation.function of MyoCath mediated MyoCell implantation.

MYOHEART ObjectivesMYOHEART Objectives

SafetySafety:: Incidence and nature of serious Incidence and nature of serious adverse events (SAEs) up to 12 adverse events (SAEs) up to 12 months months (includes events related to (includes events related to vascular, cardiac, vascular, cardiac, arrhythmic or device arrhythmic or device malfunction)malfunction)

Efficacy:Efficacy: Changes from baseline, 1, 3, 6 and 12 Changes from baseline, 1, 3, 6 and 12 month intervals of regional and global month intervals of regional and global LV wall LV wall thickness and functionthickness and function

Independent database managementIndependent database management performed by Gentiae Clinical Research. Responsibilities include core performed by Gentiae Clinical Research. Responsibilities include core laboratory analysis (48-hour Holter, MUGA, PET Scan, Echocardiography and ECG analysis), adverse event laboratory analysis (48-hour Holter, MUGA, PET Scan, Echocardiography and ECG analysis), adverse event

reporting, case report form database, data management and data safety monitoring board.reporting, case report form database, data management and data safety monitoring board.

MYOHEART EndpointsMYOHEART Endpoints

MYOHEART Eligibility CriteriaMYOHEART Eligibility Criteria

INCLUSION CriteriaINCLUSION Criteria

Prior MI involving anterior, lateral, Prior MI involving anterior, lateral, posterior or inferior walls posterior or inferior walls >> 12 weeks 12 weeks old at time of implantold at time of implant

Patients with prior placement of an Patients with prior placement of an ICD ICD >> 30 days prior to implant 30 days prior to implant

NYHA Class II – IIINYHA Class II – III

Age Age >> 30 and 30 and << 80 years old 80 years old

Need for revascularization ruled out by Need for revascularization ruled out by coronary angiogram or noninvasive coronary angiogram or noninvasive stress test within 6 months of stress test within 6 months of screeningscreening

Target region wall thickness of Target region wall thickness of >> 6 mm 6 mm by echocardiographyby echocardiography

LVEF LVEF >> 20% and 20% and << 40% by MUGA at 40% by MUGA at screeningscreening

Ability to walk at least 300 meters Ability to walk at least 300 meters during 6-minute walk testduring 6-minute walk test

EXCLUSION CriteriaEXCLUSION Criteria

MI within 12 weeks of scheduled MI within 12 weeks of scheduled implantimplant

NYHA class I or IVNYHA class I or IV

CABG within 3 months or PCI within 6 CABG within 3 months or PCI within 6 months of implantmonths of implant

Any cardiac valve replacementAny cardiac valve replacement

Heart failure secondary to valvular Heart failure secondary to valvular diseasedisease

Aortic stenosis greater than mild Aortic stenosis greater than mild degreedegree

Severe tortuosity of aorta, iliac or Severe tortuosity of aorta, iliac or femoral arteriesfemoral arteries

Prior angiogenic therapy or myocardial Prior angiogenic therapy or myocardial laser therapylaser therapy

Active infectious diseaseActive infectious disease

Pregnant femalesPregnant females

3 MFup 6MFup 12 MFup

- Holter -ICD

SCREENING INJECTION 1 MFupICD

-3w 1d 3d 7d-1M -4w 0 1M 3M 12M6M

HolterICD

ICDimplant

HolterICDQOL

HolterICDECGEcho

HolterICDQOL

Biopsy

Viral / CP

- ECG

QOLEchoMUGA

HolterICDQOLEchoMUGAPET

HolterICDQOLEchoMUGA

EchoMUGA

PET

MYOHEART Study FlowMYOHEART Study Flow

Cohort 1 Cohort 2 Cohort 3 Cohort 4 ALL TOTAL (25x106) (75x106) (225x 106) (675x106) Subjects 5 5 5 5 20

Age (yr) Mean (SD) 51.4 (8.6) 63.4 (10.9) 61.0 (9.5) 57.0 (8.0) 58.3 (9.8) Median (Min, Max) 48.0 (44, 65) 59.0 (53, 77) 60.0 (47, 73) 57.0 (49, 65) 58.0 (44, 77)

Sex, Male (%) 5/5 (100) 5/5 (100) 5/5 (100) 5/5 (100) 20/20 (100)

Race (%) Caucasian 3/5 (60.0) 5/5 (100) 4/5 (80.0) 4/5 (80.0) 16/20 (80.0) Black 0/5 (0) 0/5 (0) 0/5 (0) 1/5 (20.0) 1/20 (5.0) Asian 1/5 (20.0) 0/5 (0) 0/5 (0) 0/5 (0) 1/20 (5.0) Hispanic 1/5 (20.0) 0/5 (0) 1/5 (20.0) 0/5 (0) 2/20 (10.0)

Medical History Diabetes 3/5 (60.0) 1/5 (20.0) 1/5 (20.0) 3/5 (60.0) 8/20 (40.0) Stroke 0/5 (0) 0/5 (0) 0/5 (0) 1/5 (20.0) 1/20 (5.0) Arrhythmia 3/5 (60.0) 1/5 (20.0) 4/5 (80.0) 2/5 (40.0) 10/20 (50.0)

NYHA Class Class II 4/5 (80.0) 3/5 (60.0) 1/5 (20.0) 3/5 (60.0) 11/20 (55.0) Class III 1/5 (20.0) 2/5 (40.0) 4/5 (80.0) 2/5 (40.0) 9/20 (45.0)

LVEF – MUGA (%) 5 5 5 2 17 Mean (SD) 22.4 (2.0) 27.0 (8.1) 22.4 (2.1) 24.5 (6.3) 24.0 (5.0) Median (Min, Max) 23.0 (20, 25) 28.0 (14, 36) 22.0 (22, 28) 24.5 (20, 29) 23.0 (14, 36)

MYOHEART Baseline ProfileMYOHEART Baseline Profile

MYOHEART Cell Product and DeliveryMYOHEART Cell Product and Delivery

Cohort I Cohort II Cohort III Cohort IV (N = 5) (N = 5) (N = 5) (N = 5) Pts Events Pts Events Pts Events Pts Events

Overall 2/5 5 1/5 3 3/5 4 2/5 4

Death 0 0 1/5 1 0 0 1/5 1

Cardiac disorders 2/5 2 1/5 2 1/5 1 2/5 3

Progressive HF 0 0 0 0 0 0 1/5 1 NSVT 1/5 1 0 0 0 0 1/5 1 Ventricular arrhythmia 0 0 1/5 2 1/5 1 1/5 1 Atrial arrhythmia 1/5 1 0 0 0 0 0 0

Incision site Hemorrhage 1/5 1 0 0 0 0 0 0

Skeletal & Tissue Disorders 1/5 2 0 0 0 0 0 0

Arthralgia 1/5 1 0 0 0 0 0 0 Osteoarthritis 1/5 1 0 0 0 0 0 0

Nervous System Disorders 0 0 0 0 1/5 1 0 0

Dizziness 0 0 0 0 1/5 1 0 0

Respiratory, Thoracic Disorders 0 0 0 0 1/5 2 0 0

Pleural effusion 0 0 0 0 1/5 2 0 0

MYOHEART Clinical OutcomesMYOHEART Clinical Outcomes

6 patients experienced arrhythmias6 patients experienced arrhythmiasAdjudicated by Investigator as Not Related to TherapyAdjudicated by Investigator as Not Related to Therapy

Patient 506:Patient 506: intermittent VT 278 days post-procedure resolved with single ICD intermittent VT 278 days post-procedure resolved with single ICD firing. Full resolution.firing. Full resolution.

Patient 902: Patient 902: atrial fibrillation with single ICD firing. Firing deemed inappropriate, atrial fibrillation with single ICD firing. Firing deemed inappropriate, anti- atrial fibrillation medication provided with full resolution.anti- atrial fibrillation medication provided with full resolution.

Adjudicated by Investigator as Possibly Related to TherapyAdjudicated by Investigator as Possibly Related to Therapy

Patient 701:Patient 701: 2 ICD firings at 2 ICD firings at days 52 and 72days 52 and 72 post procedure. Second event of post procedure. Second event of sustained VT not resolved and patient expired.sustained VT not resolved and patient expired.

Patient 911:Patient 911: runs of NSVT through runs of NSVT through first weekfirst week post-procedure. No ICD firing. post-procedure. No ICD firing. Amiodarone provided, full resolution.Amiodarone provided, full resolution.

Patient 912: Patient 912: runs of NSVT through runs of NSVT through first two weeks first two weeks post-procedure. Amiodarone post-procedure. Amiodarone provided, full resolution. No ICD firing.provided, full resolution. No ICD firing.

Patient 914: Patient 914: multiple ICD firings multiple ICD firings 7 days7 days post implant. Patient hospitalized, post implant. Patient hospitalized, provided with Amiodarone, arrhythmias resolved. Patient expired approximately 5 provided with Amiodarone, arrhythmias resolved. Patient expired approximately 5 months post-procedure due to progressive heart failure.months post-procedure due to progressive heart failure.

MYOHEART: MYOHEART: ArrhythmiaArrhythmia

10

15

20

25

30

35

Cohort 1 Cohort 2 Cohort 3 Cohort 4

Baseline 3-Month 6-Month 12-MonthN=17 N=14 N=14 N=10

p = n/s

20

22

24

26

28

30

All Total

Baseline 3-Month 6-Month 12-Month

ME

AN

(%

)

ME

AN

(%

)

N=17 N=14 N=14 N=10

N/A N/A

24.0

26.926.1 26.4

MYOHEART MUGAMYOHEART MUGA

300

325

350

375

400

425

450

475

500

525

Cohort 1 Cohort 2 Cohort 3 Cohort 4

Baseline 3-Month

N=5 N=4 N=5 N=1

p = n/s

0

3

6

9

12

15

18

21

24

6%10%

22% 20%

Cohort 1 Cohort 2 Cohort 3 Cohort 4N=5 N=4 N=5 N=1

Absolute Improvement (m) Relative Improvement (%)

MYOHEART: MYOHEART: 6 minute walk6 minute walk

0

10

20

30

40

50

60

70

Cohort 1 Cohort 2 Cohort 3 Cohort 4

Baseline 3-Month 6-Month 12-Month

N=18 N=16 N=12 N=7

p = n/s

0

10

20

30

40

50

60

70

All Total

Baseline 3-Month 6-Month 12-Month

ML

HF

Q

Sc

ore

ML

HF

Q

Sc

ore

N=18 N=16 N=12 N=7

N/A N/A

54.8

42.0 43.1

29.3

21 QOL Questions: Each Question Relates to Degree HF Limits the Patient Physically and Emotionally.Range 0 (no impact) – 5 (highest impact). Lower is Better.

MYOHEART: MYOHEART: QOLQOL

What have we learned?What have we learned?

Safety strongly suggested in this small Safety strongly suggested in this small studystudy

Clinical efficacy suggested re. QOL, Clinical efficacy suggested re. QOL, exercise capacityexercise capacity

Learning curves inherent in an early Learning curves inherent in an early phase trial:phase trial:• Optimization of cell processingOptimization of cell processing• Modifications Injection techniqueModifications Injection technique

Subject # 19: Benefit of cell labelingSubject # 19: Benefit of cell labeling

What have we learned?What have we learned?

In combination with results from other non-In combination with results from other non-randomized and randomized (MAGIC, SEISMIC) randomized and randomized (MAGIC, SEISMIC) we have sufficient justification to proceed to a we have sufficient justification to proceed to a pivotal, clinical end-point trial:pivotal, clinical end-point trial:• Randomized, double-blinded, placebo-controlled Randomized, double-blinded, placebo-controlled

studystudy• Unique design features:Unique design features:

Serial injections: 2 sessions, 4 weeks apartSerial injections: 2 sessions, 4 weeks apart Cross-over: Cross-over:

– First dose – placebo controlledFirst dose – placebo controlled– Second dose – both groups treatedSecond dose – both groups treated

ContributorsContributors

InvestigatorsInvestigators• Steve EllisSteve Ellis• Tim HenryTim Henry• Nic ChronosNic Chronos• David HolmesDavid Holmes

BioheartBioheart• Richard SpencerRichard Spencer• Howard LeonhardtHoward Leonhardt• Doug OwensDoug Owens

Cardiovascular Research FoundationCardiovascular Research FoundationColumbia University Medical CenterColumbia University Medical Center

Warren Sherman, M.D.Warren Sherman, M.D. Director, Cell-Based Endovascular TherapiesDirector, Cell-Based Endovascular Therapies

Warren Sherman, M.D.Warren Sherman, M.D. Director, Cell-Based Endovascular TherapiesDirector, Cell-Based Endovascular Therapies

January 17-19, 2007January 17-19, 2007

MYOHEART US Phase I StudyMYOHEART US Phase I StudyInterim AnalysisInterim Analysis