1. Eberhard Grube MD, FACC, FSCAI
CRT 2013
Externally Delivered Ultrasound for Renal Denervation: The Kona Surround Sound System
Eberhard Grube MD, FACC, FSCAI
On behalf of the KONA investigators
Todd Brinton MD, Stanford University, USA
Robert Whitbourn MD, St. Vincent’s Melbourne, Australia
Petr Neužil MD, Nemocnice Na Homolce, Prague, Czech Republic
Zdeněk Starek MD, St. Anne’s Hospital, Brno, Czech Republic
Murray Esler MD, Baker Heart and Diabetes Institute, Melbourne, Australia
Michael Gertner MD, Kona Medical, Bellevue, WA, USA

2. Eberhard Grube, MD
Consulting: Medtronic CoreValve, Boston Scientific Corporation, Cordis Corporation, Johnson and Johnson and Abbott Vascular
Honoraria: Boston Scientific Corporation and Biosensors International
Stocks, Stock Options, other ownership interest: Medtronic CoreValve and Biosensors International
Off-Label: Off-label use of stents and valve prosthesis

3. Ultrasound for Renal Denervation
Inherent advantages for renal denervation
Nerves are inhibited at intensities where necrosis does not occur
Nerves are sensitive to mechanical effects of ultrasound as well as heat
Broader energy field
Externally-delivered ultrasound energy
Addresses variable anatomy
Can be non-invasive

4. Why External? Average nerve distance = 3.2mm from endothelium
anterior
superior
Arteries from 10 cadavers
Distance from vessel to nerve can be over 1 cm and is not uniform
Efficient ablation must account for this variability
Parent RA
Branch
posterior
Distance of nerves to vessel is not the same
Patient anatomy is varied
Efficiency of delivery
MG --- might put this earlier in the presentation
Average nerve distance = 3.2mm from endothelium
Analysis performed by Renu Virmani MD-CV Path Institute

5. Surround SoundTM Ablative Field
Shape of ultrasound energy field designed to provide coverage of renal nerves
Safely ablates nerves without impacting artery or surrounding tissues

6. Surround SoundTM System
External ultrasound transducer tracks target and delivers therapeutic ultrasound energy
Wave I & II: Low profile intravascular catheter for targeting and tracking
Wave III: Fully non-invasive system utilizing ultrasound for targeting / tracking

7. Clinical Paradigm
1. Transducer positioned posterior and catheter placed
2. Ultrasound energy delivered to renal nerves
3. Energy field ablates renal nerves without impacting artery
INVESTIGATIONAL DEVICE NOT APPROVED FOR SALE

8. Therapy Development
Significant preclinical research completed: safety, dose ranging, optimization
>100 animals treated over course of development (porcine model)
70 human CT scans used in simulations to develop energy transfer / dosing models
Additional preclinical and human safety (from Therus Corp)
Human pilot studies demonstrated ability to target and track intended treatment area

9. Clinical Trial Strategy
Wave I
FIM
Whitbourn -St. Vincent’s
First-in-Man Dose
Wave I
Expanded
Neuzil-Na Homolce; Starek-St. Anne’s
Expanded Dose Experience
Wave II
Multi-Center OUS
Dose optimization
Wave III
Multi-Center OUS
Non-invasive therapy

10. Wave I FIM: Study Design
Single Center:
Robert Whitbourn-St. Vincent’s Hospital
Norepinephrine analysis
Murray Esler, Baker IDI Heart & Diabetes Inst.
Primary Endpoint:
Adverse events
Clinical Events
Renal angiogram at 6 weeks, MRA at 6 months
Secondary Endpoint:
Systolic and Diastolic Blood Pressure
Norepinephrine (NE) spillover
Safety is the primary endpoint of this study. Safety will be assessed by incidence and evaluation of any serious adverse effects associated with the investigational procedure through the 24-week evaluation of bilateral treatment. Clinical utility is the secondary endpoint of this study. Clinical utility will be evaluated by assessing pre and post therapy systolic and diastolic blood pressure and norepinephrine (NE) spillover.

11. Wave I FIM: Inclusion/ Exclusion Criteria
Key Inclusion Criteria:
Systolic blood pressure of 160 mmHg or greater
Refractory, hypertension
> three anit-hypertensive medications
eGFR ≥ 60 ml/min
Key Exclusion Criteria:
Renal stenosis greater than 50%
Accessory renal artery ≥ 3 mm present

12. Wave I FIM – Timeline Treatment #1 (Unilateral) Treatment #2
(Contralateral)
6 Wk follow-up
(Angiogram)
24 Wk follow-up
(MRA)
12 Wk follow-up
52 Wk follow-up
Baseline 1
Baseline 2
Baseline: BP, ultrasound, MRA , kidney function
Norepinephrine assessment pre- and post-treatment

13. Wave I Expanded: Study Design
Multi-Center:
Robert Whitbourn-St. Vincent’s Hospital
Petr Neužil-Na Homolce
Zdeněk Starek-St. Anne’s Hospital
Primary Endpoint:
Adverse events
Clinical Events
MRA at 6 months
Secondary Endpoint:
Systolic and Diastolic Blood Pressure
Safety is the primary endpoint of this study. Safety will be assessed by incidence and evaluation of any serious adverse effects associated with the investigational procedure through the 24-week evaluation of bilateral treatment. Clinical utility is the secondary endpoint of this study. Clinical utility will be evaluated by assessing pre and post therapy systolic and diastolic blood pressure and norepinephrine (NE) spillover.

14. Wave I FIM + Expanded: Baseline Patient Characteristics (n=24)
Demographics
Age (years)
63 [46-88]
Gender (% female)
42%
Race (% non-Caucasian) 0%
Co-morbidities
Diabetes Mellitus II (%)
16%
Hyperlipidemia
50%
Blood Pressure
Baseline Systolic BP
183 ± 20
Baseline Diastolic BP
101 ± 17

15. Safety Results (N = 24) Serious Adverse Events # (subjects)
Death, Heart Attack, Stroke, Organ Damage
0 (0)
Hypotension
Phlebitis with Bilateral PE’s
Febrile Post Procedure
Intra-procedure Hypotension with Asystole*
Angina Pectoris
Nausea & Vomiting
1 (1)
1(1)
Same Subject
*Secondary to Contrast Anaphylaxis Prior to Initiation of Therapy

16. Changes in Office-Based Measurements of Systolic and Diastolic BP

17. Subgroup: Changes in Office-Based Measurements of Systolic and Diastolic BP, Patients with 6 mo follow-up (N=5)

18. Wave I FIM Norepinephrine Spillover Results
Data available for 9 patients, 17 blood vessels
>35% reduction in 11/17 arteries
2 arteries showed almost 100% reduction
Esler, et al. Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension 1988;11:3-20.

19. Renal Vascular Safety Results Angiogram at 6 Weeks (N=8)
Adverse Events (Renal Vascular) at 6 Weeks
# (subjects)
Spasm
0 (0)
Stenosis
Aneurysm
Pseudoaneurysm
Dissection

20. Renal Vascular Safety Results MRI at 6 Months (N=5)
Adverse Events (Renal Vascular) at 6 Months
# (subjects)
Stenosis
0 (0)
Aneurysm
Pseudoaneurysm

21. Case Study Patient 07 60 year old, male 179 cm, 83 kg; BMI = 26
4 Anti-hypertensive medications
Blood Pressure
Baseline / 133 mmHg
Post Treatment:
3 weeks / 124 mmHg
6 weeks / 94 mmHg
24 weeks / 93 mmHg

22. Case Study: Angiogram
Baseline
Post treatment
6 weeks

23. Case Study: Norepinephrine Spillover
Significant bilateral reduction following treatment:
54% reduction on right side
79% reduction left side
Reduction in NE
Spillover (%)

24. Renal Vascular Safety Results Optical Coherence Tomography
Pre-RSD
Post-RSD
Right Renal
Artery
Left Renal
Artery 24
Investigation and Images Courtesy of Dr. Petr Neuzil, Na Homolce Hospital, Prague, Czech Republic

25. MRA Vessel and Surrounding TissuesID
Baseline
6 mo Follow-up

26. Wave I vs Wave II Therapy
External applied extravascular spatial pattern
Intra-vascular targeting Catheter
Therapy time: 12.6 min/side
Wave II:
External applied modified extravascular spatial pattern
Intra-vascular targeting catheter
Reduced therapy time: 2.8 min/side

27. Conclusions
Renal denervation utilizing external focused ultrasound demonstrates optimal vascular safety
Efficacy of external focused ultrasound demonstrates significant blood pressure reductions in patients with refractory hypertension
Wave II modified spatial dose pattern will significantly reduce procedure time.
Non-invasive targeting system completing pre-clinical studies. Plan to begin WAVE III in 2013.