Final Results of a Phase II-a, Randomized,

Open-Label Trial to Evaluate Intramyocardial

Autologous Skeletal Myoblast Transplantation

in Congestive Heart Failure Patients:The SEISMIC TrialPatrick W. Serruys, MD PhD

Eric J Duckers, MD PhD on behalf of the BIOHEART

European SEISMIC study investigators

American College of Cardiology Late-Breaking Clinical TrialsApril 1, 2008, 11:15 – 11:25 am

Patrick W. Serruys, MD PhDDeclares no conflicts of interest

relating to this presentation

– Phase II-a, open-label, 2:1 randomized, controlled, multi-center study

– P.I.: Patrick W. Serruys– Sponsor: Bioheart, Inc. Sunrise, Florida, USA

– Blinded analysis by core facilities– Health Decisions – Data Management / Statistics, CRO– Synarc – Echo, MUGA Core-Lab– Spacelabs – Holter Core-Lab– Pivotal – Haematology / Viral Core-Lab

Percutaneous Intramyocardial Transplantation of Autologous Myoblasts:

BIOHEART SEISMIC* Trial

* Safety and Effects of Implanted (Autologous) Skeletal Myoblasts (MyoCell®) using an Injection Catheter = SEISMIC Trial

Overall Objective:To assess the safety and efficacy of MYOCELL® therapy on

myocardial function in CHF patients post MI(s).

Primary Safety Endpoint– Defined Serious Adverse Events (SAEs) at 3 & 6 mos

Bioheart EU Phase II-a Trial – SEISMIC

Secondary Safety Endpoints– Holter monitoring, 12-lead ECG data, frequency

of ventricular arrhythmias– Safety of the use of the MyoCath® injection

catheter by Adverse Event (AE) assessment– Number and mean length of stay for

hospitalizations

Relation between an adverse event and the test article was determined by the Investigator on the basis of his or her clinical

judgment

• fatal or life-threatening events• prolonged or required hospitalization • sustained arrhythmia for > 30 seconds• documented worsening of congestive heart failure• resulting in permanent impairment or surgical

intervention to preclude permanent impairment of a body function

– Medical and scientific judgment by the DSMB committee was exercised when classifying events as serious

Overall Objective:To assess the safety and efficacy of MYOCELL® therapy on myocardial function in CHF patients

post MI(s).

Primary Efficacy Endpoint:– Change in LVEF at 3 & 6 mos. by MUGA

compared with baseline

Secondary Efficacy Endpoints:– QOL assessment, 6-min. walk, NYHA class– Hospitalization, readmissions or the need for

medical treatment outside of hospitalizations– Global and regional contractility by contrast

aided-Dobutamine Stress Echo and Tissue Doppler Imaging

Bioheart EU Phase II-a Trial – SEISMIC

Bioheart EU Phase II-a Trial – SEISMIC

47 Patients Randomized:

ICD Patients: 31MyoCell®, 16 Standard Medical Therapy

Treatment Arm (MyoCell®150-800 x 10

6)

26 ICD Patients

Control Arm(Standard Medical Therapy)

14ICD Patients

Baseline Evaluation

Screening: 62 ICD Patients

15 Screen Fails

5 Withdrawals* 2 Withdrawals**

* All 5 treated patients withdrew due to changes in German biopsy regulations.** Both control patients withdrew after knowledge of randomization allocation.

1. Pr. Patrick Serruys, Rotterdam, the Netherlands (PI)

2. Dr. Jozef Bartunek, Aalst, Belgium

3. Pr. Victor Legrand, Liege, Belgium

4. Dr. Walter Van Mieghem, Genk, Belgium

5. Pr. Christoph Nienaber, Rostock, Germany

6. Pr. Joachim Schofer, Hamburg, Germany

7. Pr. Christoph Hehrlein, Freiburg, Germany

8. Dr. Johannes Waltenberger, Maastricht, the Netherlands

9. Dr. Carlos Macaya, Madrid, Spain

10. Dr. Anthony Gershlick, Leicester, UK

11. Pr. Nicholas Peters, London, UK

12. Pr. Tomasz Siminiak, Poznan, Poland

13. Dr. Peter Smits, Rotterdam, the Netherlands

SEISMIC Trial Investigators

13 investigative sites, 6 European countries

Independent Data Safety & Monitoring Board

– J. Tijssen, Chair – Amsterdam, The Netherlands– G. Steg – Paris, France– F. Verheugt – Nijmegen, The Netherlands– H. Wellens – Maastricht, The Netherlands

SEISMIC Steering Committee

– P.W. Serruys, Chair – Rotterdam, The Netherlands– J. Bartunek – Aalst, Belgium– A. Gershlick – Leicester, UK– N. Peters – London, United Kingdom

INCLUSION Criteria

• Age > 18 and < 75 years old

• NYHA Class II – III

• Need for revascularization ruled out within 30 days of screening

• Optimal pharmacological therapy for > 60 days prior to screening

• Prior MI > 90 days

• Placement of ICD > 180 days prior to implant

• Target region wall thickness of > 5 mm by echocardiography

• LVEF > 20% and < 45% by MUGA

EXCLUSION Criteria

• MI within 12 weeks of scheduled implant

• NYHA class I or IV

• CABG within 3 months or PCI within 6 months of cell implant

• Any cardiac valve replacement or significant aortic stenosis

• Heart failure secondary to valvular disease

• Severe tortuosity of aorta, iliac or femoral arteries

• Prior angiogenic therapy or myocardial laser therapy

• End stage renal disease

SEISMIC Eligibility Criteria

SEISMIC Study Flow

3-M FU 6-M FU

HolterICD

SCREENING INJECTION 1-M FUICD

-3w 7d 14d 21d-6M -4w 0 1M 3M 6M

HolterICD

ICDimplant

HolterICDQOL

HolterICDECGEcho

HolterICDQOL

Biopsy

ViralECG QOL

EchoMUGAEcho

MUGA

HolterICDQOLEchoMUGA

QOL comprises Minnesota Living with Heart Failure Questionnaire, NYHA Heart Failure Classification and 6-minute walk test.

-2w -1w

Holter

SEISMIC Baseline Characteristics 6-Month Analysis

(n=40)

Mean Range Mean Range

Age (years) 59 32-72 62 44-75 Years since last MI 8.3 1-21 7.1 1-17

Years ICD in place 1.9 1-5 2.6 1-5

Race: caucasian (%) 100 % 100 %

Prior MI (%) 100 % 100%

Male (%) 92 % 71 %

Prior history of VT (%) 69 % 64 %

Diabetes type II (%) 31 % 14 %

NYHA class III (%) 39 % 21 %

LVEF (%) 30.9 9.2 19-53 32.6 + 11.2 15-55

TREATMENT (n=26) CONTROL (n=14)

SEISMIC Skeletal Myoblasts Harvest and Culture

Biopsy Weight (gr) 9.1 ± 2.8

Cell harvest (x106) 888 ± 319

Cells injected (x106) 592 ± 184

Number of injections 24 + 7

CD56 staining > 50% 100%

Volume of cell transplant (mL)11.8 ± 3.7

Number of cells injected based on infarct size;Non-ionic contrast media may be mixed with cells

Control Tx

Myoblast Tx

Pro

bab

ilit

y F

reed

om

fro

m S

AE /

D

eath

SEISMIC Kaplan Meier Survival Curve for Time to Onset First SAE or Death

d5 VT term by ICDd6, d8, d9 VT term by ATPd11 VT term by ICD

BB/ Amiodarone/ Flecainide arrhythmia control 2 wks with status improvement

27-30 d deterioration CHFdeath

One patient died in the treatment arm (3.8%), no deaths in the control arm.

SEISMIC Serious Adverse Events

MyoCell® Tx Control Tx(n=26) (n=14)no. of pts. no. of no. of pts. no. of

w SAE episodes w SAE episodesCardiovascular-related SAEsArrhythmias

Bradyarrhythmias 1 1 2 2Ventricular fibrillation 1 2 0 0Ventricular tachyacardia 5 8 3 10Idioventricular rhythm 0 0 2 2

Worsening of congestive heart failure 3 3 1 1Hypotension 0 0 1 1Cardiogenic shock 1 1 0 0Pulmonary Edema 1 1 0 0Pericarditis 1 1 0 0Aortic dissection [procedural] 1 1 0 0

Non-cardiovascular SAEs 2 2 2 2

Total Cardiovascular SAEs 18 16All SAEs 20 18No. of subject experiencing SAEs 13/26 (50%) 5/14 (35.7%)

Timing of the episodes of tachyarrhythmia on sequential holter monitoring (no. of patients and no. of episodes in brackets)

MyoCell Tx Control Tx

periproc 1/26 (3.8 %, 1 eps) < 1 wk 2/26 (7.7 %, 3 eps) 1/14 (7.1 %, 1 eps)1-4 wks 2/26 (7.7 %, 3 eps) 3/14 (21.4 %, 10 eps)1-6 mo 2/26 (7.7 %, 3 eps) 1/14 (7.1 %, 1 eps)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

NYHA Class I

NYHA Class II

NYHA Class III

NYHA Class IV

SEISMIC NYHA Heart Failure Class

Myoblast Therapy

Control Therapy

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

NYHA Class I

NYHA Class II

NYHA Class III

NYHA Class IV

N=26 N=23 N=22 N=20

N=14 N=9 N=12 N=13

BL 1 mo 3 mo 6 mo

BL 1 mo 3 mo 6 mo

SEISMIC MUGA Global LV Ejection Fraction

Treatment

N=26 N=23 N=23

Control

N=14 N=13 N=14

30.9 % 31.2 %

32.6 % 32.5 %

SEISMIC

+60.3 m + 54.1

-0.2 m ± 177.1

Treatment

N=26 N=21 N=19

ControlControl

N=14 N=12 N=13

448 m 441 m

406 m 466 m

6-Minute Walk Test Difference BetweenBaseline and 6 Months

SEISMIC Minnesota Living With Heart Failure QOL

Score

Baseline 3-month 6-monthN=26 N=14 N=21 N=12 N=19 N=13

58%58% 94%94% 31%31% 84%84% 57%57% 67%67% 50%50% 56%56%

42%42% 6%6% 69%69% 16%16% 43%43% 33%33% 50%50% 44%44%

NYHA HFNYHA HF LVEFLVEF6MWT6MWT

ImprovedImproved oror

No ChangeNo Change

WorsenedWorsened

cont

rol

cont

rol

SEISMIC Response to Treatment

NYHA HF / 6MWT / MLFQ / LVEF

myo

blas

t

myo

blas

t

MLFQMLFQ

cont

rol

cont

rol

myo

blas

t

myo

blas

tco

ntro

l

cont

rol

myo

blas

t

myo

blas

t

cont

rol

cont

rol

myo

blas

t

myo

blas

t

– The SEISMIC trial is a phase II-a, open-label, placebo-controlled, randomized, multi-center study.

– Primary Safety Endpoint: In this heart failure population previously fitted with an ICD, myoblast cell therapy was not associated with an increased incidence of arrhythmia, as documented by holter tape and ICD recordings, and appeared to be safe.

– Primary Efficacy Endpoint: The MUGA global LVEF remained unchanged, without overall sign of deterioration.

Percutaneous Intramyocardial Transplantation of Autologous Myoblasts:

BIOHEART SEISMIC Trial

– Secondary Efficacy Endpoint: 6-minute walk test showed an improvement not seen in the control group, which was corroborated by a change in NYHA classification, while further deterioration in these parameters was observed in the control group.

– However, none of these changes were statistically significant, and may be the result of a placebo effect in the absence of a true blind placebo- control group with sham treatment.

– Further investigation in double-blind (sham treatment), placebo-controlled studies to evaluate autologous myoblasts in patients with CHF is warranted (MARVEL, CAUSMIC II).

Percutaneous Intramyocardial Transplantation of Autologous Myoblasts:

BIOHEART SEISMIC Trial

31%31% 84%84% 58%58% 94%94% 50%50% 56%56%

69%69% 16%16% 42%42% 6%6% 50%50% 44%44%

6MWT6MWT LVEFLVEFNYHA HFNYHA HF

ImprovedImproved oror

No ChangeNo Change

WorsenedWorsened

cont

rol

cont

rol

SEISMIC Response to Treatment 6 MWT / NYHA HF / LVEF

myo

blas

t

myo

blas

t

cont

rol

cont

rol

myo

blas

t

myo

blas

t

cont

rol

cont

rol

myo

blas

t

myo

blas

t

Secondary efficacy end point: 6 min walking test shows an improvement not seen in the control group, corroborated by a change in the NYHA classification in the cell-treated group, while a further deterioration was seen in the control group.

However, none of these changes were statistically significant, and may be the result of a placebo effect in the absence of a true blind placebo control group with sham treatment.

Percutaneous Intramyocardial Transplantation of Autologous Myoblasts:

BIOHEART SEISMIC Trial

SEISMIC Serial echocardiographic analysis of

dimension in the myoblast treated group (n=26)

N=22 N=15 N=13

N=22 N=15 N=15

LVESD

LVEDD