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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
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