This document describes a novel transcatheter device to treat hypertrophic obstructive cardiomyopathy (HOCM) using non-thermal irreversible electroporation (NTIRE). HOCM is a common genetic heart condition that can cause sudden death. Current treatments have limitations. The proposed device uses NTIRE, which damages cell membranes without heat, to ablate thickened heart muscle in seconds via a minimally invasive approach. Preclinical studies show NTIRE safely and effectively ablates cardiac tissue. The team aims to develop an endovascular NTIRE device for HOCM and pursue FDA approval based on existing use in cancer. They expect the addressable market to be large with an opportunity to develop additional cardiac applications

1. Novel Transcatheter
Device to Treat
Hypertrophic Obstructive
Cardiomyopathy
Elad Maor MD PHD
Zachi Berger PhD MBA
Sheba Medical Center, Israel
2016

2. The clinical need:
Hypertrophic Obstructive
Cardiomyopathy
 Dynamic left ventricular outflow tract obstruction
 The most common cardiac genetic disorder
 Prevalence 1:500 adults (600,000 in the US)
 A major cause of sudden death and heart failure in young
people

3. HCM Can Cause
Outflow Track Obstruction
 Characterized by a thickened but nondilated left ventricle
 Cause increased intraventricular pressures that may be
detrimental to LV function
 Increased myocardial wall stress and oxygen demand
 In histopathology specimens of HCM, cardiac muscle cells
(myocytes) in both ventricular septum and left ventricle (LV)
free wall show increased transverse diameter and bizarre
shapes
 Clinical diagnosis of HCM is usually made with two-
dimensional echocardiography
A 14 years old boy with sudden death and
septal thickness of 65 mm. Ao - aorta, LVFW
– left ventricular free wall, VS – ventricular
septum

4. Clinical Course and
Medical Treatment 1
 HCM can lead to sudden cardiac death or progressive heart failure with
exertional dyspnea and functional limitation
 Current medical treatments: Myectomy Surgery, Alcohol Ablation,
Anticoagulation Drugs
 Surgical septal reduction therapy - Myectomy - is the gold standard as the
results for, are unmatched for early, long term benefit
 However, Myectomy has generally been confined to selected major centers
having substantial experience with this procedure and is not suitable for all
patients

5. Clinical Course and
Medical Treatment 2, 3
 Percutaneous alcohol septal ablation, is alternative to Myectomy only in
selected patients and is a sub-optimal solution
 The use of Beta Blockers, Calcium Channel Blockers and anticoagulation in
patients who develop atrial fibrillation with a lot of side effects
 There is clinical need for novel minimally invasive
non-surgical approach

6. Our Device and Method:
Non Thermal Irreversible
Electroporation - NTIRE
 Our novel transcatheter endovascular device and method will be
able to attenuate left ventricular obstruction and heart failure in
patients with HCM, without the need for open heart surgery
 Our approach is based on a novel non thermal ablation approach
that can damage only cellular components within seconds and with
no damage to the extra cellular components

7. Irreversible Electroporation (IRE) is
an emerging ablation approach

8. Medical Use of Irreversible
Electroporation
 It can induce significant ablation of biological tissue, and is
currently under evaluation in clinical trials for the treatment
of solid tumors utilizing 1,500V
 Irreversible electroporation with voltages of up to 3,000V is
CE and FDA approved for solid tumors. It is being used
clinically all over the world
 There are currently more than 90 clinical trials running but
not in Cardiology

9. Summary of NTIRE Preclinical
Studies
 Non-thermal Irreversible Electroporation (NTIRE) is an
emerging cell ablation approach
 NTIRE induces cell death by creating pores in cell membranes
 In contrast to all other available ablation modalities, it induces
ablation within microseconds and with no heat generation
 Due to its non-thermal nature, NTIRE does not damage extra
cellular components
 Our preliminary in vivo results show that endovascular NTIRE
has the potential to ablate hypertrophic myocardium, without
the need for open heart surgery
 Our results demonstrate the efficacy and safety of in-vivo non
thermal ablation of cellular components in the beating heart

10. Preliminary Animal Model
In vivo IRE is achieved using two needle
electrodes inserted into the anterior
myocardium of SD rat through the 4th
inter-costal space
Ablation effect due to different NTIRE protocols
on vascular smooth muscle cells (VSMC). The
figure summarizes and compares NTIRE
ablation efficiency of eight different
electroporation protocols. Ablation effect is
shown as the percentage of vascular smooth
muscle cells in the treated carotid artery
compared with the right carotid artery of the
same animal. The reduction in five of the groups
was statistically significant (P<0.001, bars)
marked with an asterisk)

11. Arterial Wall Ablation with
In-Vivo IRE

12. In-Vivo IRE Safety Studies
(Sheba 2012)

13. In-Vivo Myocardial Ablation

14. Cellular Environment Rich in
Collagen (Masson Trichrome Stain)

15. Elastic Stain Shows Sparing of
Blood Vessels Structure

16. Device Prototype Concept

17. Endovascular NTIRE Prototype:
Disposable Flexible Nitinol Cage
Real picture of the prototype in its
inflated state. The four legs are 2
cm in length. (Assembled by Jim
Mitchell, Angiodynamics Inc.,
Queensbury , NY - subcontractor)
Electric field distribution (∆V = 600 Volts) -.
Color-Scale is in units of V/cm. This potential
difference electric field is relatively uniform and
high enough throughout the vessel wall

18. Scientific and Medical
Recognition
 Peer Reviewed Journal Articles:
 Maor E, Ivorra A, Leor J, Rubinsky B. The Effect of Irreversible Electroporation on Blood Vessels. Technol
Cancer Res Treat. 2007 Aug; 6(4): 307-312. Cited in PubMed; PMID: 17668938.
 Maor E, Ivorra A, Leor J, Rubinsky B. Irreversible Electroporation Attenuates Neointimal Formation after
Angioplasty. IEEE transactions on bio-medical engineering. IEEE Trans Biomed Eng. 2008 Sep;55(9):2268-
74. Cited in PubMed; PMID: 18713696
 Maor E, Ivorra A, Rubinsky B. Non Thermal Irreversible Electroporation - Novel Technology For Vascular
Smooth Muscle Cells Ablation. PLoS One. 2009;4(3):e4757. Epub 2009 Mar 9. Cited in PubMed; PMID:
19270746.
 Granot Y, Ivorra A, Maor E, Rubinsky B. In vivo imaging of irreversible electroporation by means of electrical
impedance tomography. Phys Med Biol. 2009 Aug 21;54(16):4927-43. Epub 2009 Jul 30. PMID: 19641242
 Maor E, Rubinsky B. Endovascular Nonthermal Irreversible Electroporation: A Finite Element Analysis.
Journal of Biomechanical Engineering 2010;132(3): 031008. Cited in PubMed; PMID: 20459196.
 Maor E, Ivorra A, Mitchell JJ, Rubinsky B. Vascular smooth muscle cells ablation with endovascular
nonthermal irreversible electroporation. J Vasc Interv Radiol. 2010. 21(11):1708-15.
 Phillips M, Maor E, Rubinsky B. Nonthermal irreversible electroporation for tissue decellularization. J
Biomech Eng. 2010. 132(9):091003.
 Peer Reviewed Book Chapter
 Maor E, Nagler A, Leor J (November 2008). Umbilical Cord Blood Cells for Cardiac Repair. In Ioannis
Dimarakis (Ed.), Handbook of Cardiac Stem Cell Therapy (chapter 4). London, United Kingdom. Imperial
College Press. ISBN: 9781848162563

19. Summary of Results
 NTIRE damages cell membrane only
 NTIRE has a non thermal nature
 Treatment duration of less than 10 sec !
 Efficient and precise
 Sparing of extra cellular components

20. IP
 PCT/IL2014/050219
 MYOCARDIAL ABLATION BY IRREVERSIBLE
ELECTROPORATION
 BY TEL HASHOMER MEDICAL RESEARCH
INFRASTRUCTURE AND SERVICES LTD
 INVENTOR – ELAD MAOR
 PRIORITY DATE 05/06/2013

21. Regulation
 FDA - PMA based on utilizing IRE in cancer treatment

22. Market potential
 Business model – selling disposables
 Prevalence of HCM within the general population is ~0.5%
 2.5 Million individual worldwide with HCM
 10% will benefit intervention
 Estimated price target 5K-10K USD
 1-2 B USD potential market

23. Future Clinical Applications
 Septal ablation for HOCM
 Tissue scaffolding
 Cardiac arrhythmias
 Endovascular drug delivery

24. 2 years Development Plan
Activity Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8
1 Design of possible endovascular prototypes X X
2
Finish element simulation of the heat transfer
problem
X X
3 Assembly of the selected endovascular prototype X X
4 In Vivo experiments – Safety X X
5 In Vivo experiments – Efficacy X X
6 Analysis of histopathology specimens X

25. The Team
 Elad Maor, MD – Inventor and Consultant
 Zachi Berger, Ph.D. MBA – CEO/Founder
 Clinical development – Sheba Medical Center

26. Summary
 Large market with limited medical solutions
 Novel minimally invasive procedure
 IP in PCT stage
 Regulation will be based on other procedures
 Short development time
 Leading team and Medical Center

27. Thank you
Contact: Zachi Berger +972-547-250-960
zachiganbar@gmail.com