Slide 49 -
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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 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, 11:15 – 11:25 am Patrick W. Serruys, MD PhD
Declares 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
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 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: 31 MyoCell ® , 16 Standard Medical Therapy Treatment Arm ( MyoCell ® 150 - 800 x 10 6 ) 26 ICD Patients Control Arm (Standard Medical Therapy) 14 ICD 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.
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
Dr. Anthony Gershlick, Leicester, UK
Pr. Nicholas Peters, London, UK
Pr. Tomasz Siminiak, Poznan, Poland
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 Holter ICD SCREENING INJECTION 1-M FU ICD -3w 7d 14d 21d -6M -4w 0 1M 3M 6M Holter ICD ICD implant Holter ICD QOL Holter ICD ECG Echo Holter ICD QOL Biopsy Viral ECG QOL Echo MUGA Echo MUGA Holter ICD QOL Echo MUGA 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
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.
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)
< 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) SEISMIC NYHA Heart Failure Class Myoblast Therapy Control Therapy 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 Control Control N=14 N=12 N=13 448 m 441 m 406 m 466 m 6-Minute Walk Test Difference Between
Baseline and 6 Months SEISMIC Minnesota Living With Heart Failure QOL Score NYHA HF LVEF 6MWT Improved
or
No Change Worsened control SEISMIC Response to Treatment NYHA HF / 6MWT / MLFQ / LVEF myoblast MLFQ control myoblast control myoblast control myoblast 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 SEISMIC Serial Echocardiographic Analysis of Dimension in the Myoblast Treated Group (n=26) N=22 N=15 N=15 54.6 51.7 64.4 64.1 6MWT LVEF NYHA HF Improved
or
No Change Worsened control SEISMIC Response to Treatment 6 MWT / NYHA HF / LVEF myoblast control myoblast control myoblast 6MWT LVEF MLHFQ Improved
or
No Change Worsened control SEISMIC Response to Treatment – 6 MWT / QoL / LVEF myoblast control myoblast control myoblast 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 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)
Percutaneous Intramyocardial Transplantation of Autologous Myoblasts: BIOHEART SEISMIC Trial SEISMIC Patient Selection Primary Inclusion Criteria:
Prior MI > 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 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 SEISMIC Study Flow 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 Biopsy Culture Delivery SEISMIC MyoCell™ Production 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 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 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 Apical Basal A B Epi Endo Injections Cell Implant Procedure (From Animal Training) SEISMIC Enrollment By Site SEISMIC 6 Minute Walk Test N=26 N=14 N=21 N=12 N=19 N=13 Treatment change BL – 6 months: 60.3 m + 54.1
Control change BL – 6 months: -0.2 m + 177.1 SEISMIC Dobutamine Stress Echocardiography N=22 N=7 N=15 N=4 N=13 N=6 LVESD LVEDD N=22 N=7 N=15 N=4 N=15 N=6 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 SEISMIC Dobutamine Stress Echocardiography – LVEDD Treatment N=22 N=15 N=15 Control N=7 N=4 N=6 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 SEISMIC MUGA global LV ejection fraction N=26 N=14 N=23 N=13 N=23 N=14 SEISMIC Dobutamine Stress Echocardiography – LVESD Control N=7 N=4 N=6 Treatment N=22 N=15 N=13 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)
< 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 SEISMIC Minnesota Living With Heart Failure QOL Score Control N=14 N=14 N=14 Treatment N=25 N=23 N=24 Seismic A Phase IIa, Multi-Center, Open Label, 6MWT LVEF MLHFQ Improved No Change Worsened Treated Pts.
BL:6-Months Control Pts.
BL:6-Months Treated Pts.
BL:6-Months Control Pts.
BL:6-Months Treated Pts.
BL:6-Months Control Pts.
BL:6-Months Bioheart Clinical Experience MYOHEART
US Phase I
Completed 2007 SEISMIC
EU Phase II-a
Completed 2008 FIM
EU Phase I
Completed 2002 005/006
EU Phase I/II
Completed 2003 BH-TVI*
Single-Site Registry
Discontinued* * 3 patients enrolled. Trial discontinued following acquisition of TransVascular inc. by Medtronic Inc. n = 5 n = 3 n = 15 n = 20 n = 40 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
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
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