Final Results of a Phase II-a, Randomized,

1
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
Trial
Patrick 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 Trials April 1, 2008, 1115 1125 am
2
Patrick W. Serruys, MD PhD Declares no conflicts
of interest relating to this presentation
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Percutaneous Intramyocardial Transplantation of
Autologous Myoblasts BIOHEART SEISMIC Trial

• Phase II-a, open-label, 21 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

Safety and Effects of Implanted (Autologous)
Skeletal Myoblasts (MyoCell) using an Injection
Catheter SEISMIC Trial
4
Bioheart EU Phase II-a Trial SEISMIC

• 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

• fatal or life-threatening events
• prolonged or required hospitalization
• sustained arrhythmia for gt 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

• 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

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SEISMIC Significant Adverse Events

• Study protocol defines SAEs as any adverse events
  meeting one or more of the following
• Fatal
• Life-threatening
• Requiring in-patient hospitalization not
  specifically required by the protocol or is
  elective
• Resulting in permanent impairment or surgical
  intervention to preclude permanent impairment of
  a body function
• Additionally, medical events that may not result
  in death, be life-threatening, or require
  hospitalization may be considered SAEs when they
  jeopardize the patient.
• Medical and scientific judgment by the DSMB
  committee is exercised when classifying events as
  serious
• Relation between an adverse event and the test
  article will be determined by the Investigator on
  the basis of his or her clinical judgment

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Bioheart EU Phase II-a Trial SEISMIC

• 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

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Bioheart EU Phase II-a Trial SEISMIC
Screening
62 ICD Patients
Baseline Evaluation
15 Screen Fails
47 Patients Randomized
,
ICD Patients 31
MyoCell

16
Standard Medical Therapy
5 Withdrawals
2 Withdrawals
Control Arm
Treatment Arm
6
(Standard Medical Therapy)

(
MyoCell
150
-
800 x 10
)
26 ICD Patients
14
ICD Patients
All 5 treated patients withdrew due to
changes in German biopsy regulations. Both
control patients withdrew after knowledge of
randomization allocation.
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SEISMIC Trial Investigators

• Pr. Patrick Serruys, Rotterdam, the Netherlands
  (PI)
• Dr. Jozef Bartunek, Aalst, Belgium
• Pr. Victor Legrand, Liege, Belgium
• Dr. Walter Van Mieghem, Genk, Belgium
• Pr. Christoph Nienaber, Rostock, Germany
• Pr. Joachim Schofer, Hamburg, Germany
• Pr. Christoph Hehrlein, Freiburg, Germany
• Dr. Johannes Waltenberger, Maastricht, the
  Netherlands
• Dr. Carlos Macaya, Madrid, Spain

• 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

13 investigative sites, 6 European countries
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SEISMIC Eligibility Criteria

• 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

• INCLUSION Criteria
• Age gt 18 and lt 75 years old
• NYHA Class II III
• Need for revascularization ruled out within 30
  days of screening
• Optimal pharmacological therapy for gt 60 days
  prior to screening
• Prior MI gt 90 days
• Placement of ICD gt 180 days prior to implant
• Target region wall thickness of gt 5 mm by
  echocardiography
• LVEF gt 20 and lt 45 by MUGA

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SEISMIC Study Flow
Holter
Holter
Holter
Holter
Holter
Holter
ICD
ICD
ICD
ICD
ICD
ICD
ECG
ECG
QOL
QOL
QOL
QOL
ICD
Echo
Echo
Viral
Echo
MUGA
MUGA
implant
Echo
MUGA
Biopsy
Holter
-3w
7d
14d
21d
-6M
-4w
1M
3M
6M
-2w
-1w
0
ICD
3-M FU
6-M FU
1-M FU
SCREENING
INJECTION
QOL comprises Minnesota Living with Heart Failure
Questionnaire, NYHA Heart Failure Classification
and 6-minute walk test.
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SEISMIC Baseline Characteristics 6-Month Analysis
(n40)
TREATMENT (n26) CONTROL (n14)
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
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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 gt
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
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SEISMIC Kaplan Meier Survival Curve for Time to
Onset First SAE or Death
One patient died in the treatment arm (3.8), no
deaths in the control arm.
14
SEISMIC Serious Adverse Events
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) lt 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)
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SEISMIC NYHA Heart Failure Class
Myoblast Therapy
BL
1 mo
3 mo
6 mo
N26
N23
N22
N20
Control Therapy
N14
N9
N12
N13
16
SEISMIC MUGA Global LV Ejection Fraction
32.6
32.5
30.9
31.2
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SEISMIC
Difference Between Baseline and 6 Months
6-Minute Walk Test
Control
Control
448 m
441 m
-0.2 m 177.1
N14
N12
N13
Treatment
406 m
466 m
60.3 m 54.1
N26
N21
N19
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SEISMIC Minnesota Living With Heart Failure QOL
Score
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SEISMIC Response to Treatment NYHA HF / 6MWT /
MLFQ / LVEF
myoblast
myoblast
myoblast
myoblast
control
control
control
control
Improved or No Change
58 94 31 84 57 67 50 56
42 6 69 16 43 33 50 44
Worsened
NYHA HF
LVEF
6MWT
MLFQ
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Percutaneous Intramyocardial Transplantation of
Autologous Myoblasts BIOHEART SEISMIC Trial

• 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.

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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).

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(No Transcript)
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SEISMIC Serial Echocardiographic Analysis
ofDimension in the Myoblast Treated Group (n26)
54.6
51.7
64.4
64.1
N22
N15
N15
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SEISMIC Response to Treatment 6 MWT / NYHA HF /
LVEF
myoblast
myoblast
myoblast
control
control
control
Improved or No Change
31 84 58 94 50 56
69 16 42 6 50 44
Worsened
6MWT
LVEF
NYHA HF
25
SEISMIC Response to Treatment 6 MWT / QoL /
LVEF
myoblast
myoblast
myoblast
control
control
control
Improved or No Change
31 84 57 67 50 56
69 16 43 33 50 44
Worsened
6MWT
LVEF
MLHFQ
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Percutaneous Intramyocardial Transplantation of
Autologous Myoblasts BIOHEART SEISMIC Trial

• 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.

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Percutaneous Intramyocardial Transplantation of
Autologous Myoblasts BIOHEART SEISMIC Trial

• However, these clinical benefits could not be
  substantiated by echocardiography and MUGA LVEF
• Placebo effect ?
• Appropriate surrogate end point markers ?
• (regional wall motion by MRI/ TTE, PV loop
  analysis)
• Technical issues
• Is this the correct target population for cell
  therapy per se? arrhythmia prone, irreversible
  CMP
• Validity of efficacy end points
• Placebo effect is a confounding factor, therefore
  double blind, placebo-control with sham
  treatment, adequately powered studies are
  warranted (Causmic II, Marvel)

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SEISMIC Patient Selection

• Primary Inclusion Criteria
• Prior MI gt 90 days with region of myocardial
  dysfunction involving the anterior, lateral,
  posterior or inferior walls
• Placement of ICD 6 months prior to study entry
• LVEF at screening of 20 45 (by MUGA scan)
• New York Heart Association (NYHA) Class II or III
• Patients on optimal pharmacological therapy for
  at least 2 months prior to study entry
• Need or feasibility for re-vascularization has
  been ruled out within 30 days of screening
• Minimum myocardial wall thickness of 5mm
• Age 18 and 75 years old

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SEISMIC Patient Selection

• Primary Exclusion Criteria
• CABG within 180 days OR PCI within 90 days prior
  to scheduled MyoCell implantation
• Aortic valve replacement
• Exposure to any investigational drug or procedure
  within 1 month prior to study entry or enrolled
  in any concurrent study that could confound the
  data
• ICDs implanted less than 180 days or reprogrammed
  less than 90 days prior to cellular implantation
• Patients fitted with Bi-V pacers
• Patients unable to take anti-arrhythmic
  medications
• Evidence of left ventricular mural thrombus

30
SEISMIC Study Flow
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SEISMIC Committees

• Independent Data Safety Monitoring Board
• J. Tijssen, Chair Amsterdam, The Netherlands
• G. Steg Paris, France
• F. Verheugt Nijmegen, The Netherlands
• H. Wellens, EP Maastricht, The Netherlands
• SEISMIC Steering Committee
• P.W. Serruys, Chair Rotterdam, The Netherlands
• J. Bartunek Aalst, Belgium
• A. Gershlick Leicester, UK
• N. Peters, EP London, United Kingdom

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SEISMIC MyoCell Production
Biopsy
Culture
Delivery
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MyoCell Specifications

• Skeletal myoblasts suspended in organ transport
  media
• 30 ml bag is sterilized prior to filling with
  cells and handled aseptically thereafter
• Concentration 25
  million cells / .50 cc
• Temperature controlled delivery
• Cell viability 4-days from harvest

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MyoCath Specifications

• Sheath Compatibility 8f
• Usable Catheter Length 115 cm
• Core Needle Diameter 25 gauge
• Core Needle dead space 0.5cc
• Adjustable Needle Length 3mm 6mm
• Syringe Compatibility 1cc Luer Lock
• Curve Size Medium and Large

35
SEISMIC Injection Guide

• Non-ionic contrast media may be mixed with the
  cells
• Confirm accuracy of injections under fluoroscopy
  
• Contrast media approved for use Visipaque,
  Optiray
• Create grid pattern with 1 cm spacing

36
Cell Implant Procedure(From Animal Training)
A
B
Basal
Apical
Endo
Injections
Epi
37
SEISMIC Enrollment By Site
38
SEISMIC 6 Minute Walk Test
Treatment change BL 6 months 60.3 m
54.1 Control change BL 6 months -0.2 m 177.1
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SEISMIC Dobutamine Stress Echocardiography
LVESD
N22
N7
N15
N4
N13
N6
LVEDD
N22
N7
N15
N4
N15
N6
40
SEISMIC Serial echocardiographic analysis
ofdimension in the myoblast treated group (n26)
LVESD
N22
N15
N13
LVEDD
N22
N15
N15
41
SEISMIC Dobutamine Stress Echocardiography
LVEDD
42
SEISMIC change of NYHA heart failure class
distribution
0 - 1 mo
0 - 3 mo
0 - 6 mo
0 - 1 mo
0 - 3 mo
0 - 6 mo
N
N
N
N
N
N
Myoblast therapy
Control therapy
43
SEISMIC MUGA global LV ejection fraction
N26
N14
N23
N13
N23
N14
44
SEISMIC Dobutamine Stress Echocardiography
LVESD
45
SEISMIC Serious Adverse Events
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) lt 1 wk 2/26
(7.7 , 3 eps) 1/16 (6.3 , 1 eps) 1-4 wks 2/26
(7.7 , 3 eps) 3/16 (18.8 , 10 eps) 1-6 mo 2/26
(7.7 , 3 eps) 1/16 (6.3 , 1 eps)
Relation between all adverse event and study
therapy (no of episodes) MyoCell
Tx Control Tx Possible 3/10 (30.0
) Probable 7/10 (70.0 ) Definite 0/10 ( 0.0 )
Peri-procedural arrhythmia were not adjudicated
as (S)AE
46
SEISMIC Minnesota Living With Heart Failure QOL
Score
47
Seismic
A Phase IIa, Multi-Center, Open Label,
LVEF
MLHFQ
6MWT
Treated Pts. BL6-Months
Control Pts. BL6-Months
Treated Pts. BL6-Months
Control Pts. BL6-Months
Treated Pts. BL6-Months
Control Pts. BL6-Months
23 84 57 67 50 30
8 0 0 0 0 26
69 16 43 33 50 44
Improved
No Change
Worsened
48
Bioheart Clinical Experience
FIM EU Phase I Completed 2002
n 5
005/006 EU Phase I/II Completed 2003
BH-TVI Single-Site Registry Discontinued
n 3
n 15
MYOHEART US Phase I Completed 2007
SEISMIC EU Phase II-a Completed 2008
n 20
n 40
3 patients enrolled. Trial discontinued
following acquisition of TransVascular inc. by
Medtronic Inc.
49
Bioheart EU Phase II-a Trial SEISMIC

• 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

• fatal or life-threatening events
• prolonged or required hospitalization
• sustained arrhythmia for gt 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

• 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