1. Next Generation Renal Denervation The Promise of Chemical Renal Denervation
Innovation Session CRT Meeting
Washington, D.C.
February 22, 2014
Tim A. Fischell, M.D., FACC, FSCAI
Director Cardiovascular Research Borgess Heart Institute Professor of Medicine
Michigan State University

2. CRT 2015 – Disclosure Slide Tim A. Fischell, M.D.
Ablative Solutions, Inc. Founder, Co-Inventor, Stockholder, CEO
Abbott Vascular:
Advisory Board Member, Grant Support
Boston Scientific:
Grant Support

3. Conclusions from Report
Post Symplicity HTN-3 Analysis Reveals Design Flaws and “Inadequate Denervation”*
Conclusions from Report
Renal denervation will work if sufficient ablation/denervation is performed
50% of patients did not receive the minimum of least 8 total ablations
Adequate treatments (9-10 burns/artery) with RF requires vessel length of at least 4 -5 cm
* Cardiology news: Renal denervation proceeds as U.S. trial’s flaws emerge, Jun 23, 2014

4. Targeted (Adventitial) Chemical Neurolysis
PeriVascular Renal Denervation (PVRD™)
Unique Mechanism
PVRD: Distinctive Features
Controlled perivascular targeting to access deep nerve locations
Efficient, simultaneous delivery of neurolytic agent via micro-needles
Circumferential, axial, deep coverage achieved with single injection
Self-limited spread; adventitial space
No obstruction of blood flow
No significant intimal/medial injury. ~ No anatomical limitations.
Essentially painless
No capital equipment
Renal
nerves
Micro -Needles
Renal Artery

5. Perivascular Renal Denervation (PVRD): Alcohol Provides Excellent Safety Profile
Injection sites
Expanded view of injection sites
Alcohol acts locally ⇒ no collateral damage
Micro volume ( mL) directed to the perivascular space
Alcohol bio-activity reduced via dilution by extracellular fluid: self-limited spread

6. Lateral View

7. Angiographic and Neuro-Chemical 90-Day Follow-Up After EtOH (0
Angiographic and Neuro-Chemical 90-Day Follow-Up After EtOH (0.3 ml) PVRD
Angiography
Neurochemistry*
Pre-Rx Rx
90-Day Post-Rx
* Control= 10 animals
* Rx= 1 kidney, 6 measurements

8. RF (Symplicity) vs. Peregrine Porcine Model at 3 Months
RF Symplicity Modest Arc and Depth Nerve Injury + Medial Necrosis
Alcohol (0.6 ml) Injection Circumferential Nerve Injury Without Medial Injury
Ablation CSA – 4.3 mm2
Ablation CSA – 58.7 mm2
Media Necrotic
Media Healthy
Ablation CSA 11.4 mm2
Ablation CSA – 46.3 mm2
Morphometry performed by Virmani, et al. CV Path

9. Chemical Denervation Using Ethanol (EtOH)
Depth + Circumferential Treatment -> Greater Denervation
Net area covered by PVRD = mm2
Fischell et al, EuroIntervention, 2013 RF
PVRD
Net area covered by RF = mm2
EuroPCR, 2013
Conclusion: PVRD coverage is ~ 3-4 times the area covered by RF treatment
PVRD offers inherent Rx efficacy advantages over RF-based treatments

10. EtOH-Mediated, Dose-Dependent Renal Tissue Norepinephrine Reduction
P<0.0001, all active vs. all controls
P = 0.01, all active vs. HTS control
Renal Tissue Norepinephrine (ng/g)
HTS= Hypertonic saline
EtOH= Ethanol
Error bars = SD
Naive Control
(n=7)
HTS Control mL (n=3)
EtOH
0.15 mL (n=6)
EtOH
0.30 mL (n=4)
EtOH
0.60 mL (n=3)
Dose-dependent norepinephrine reduction ~2 weeks post-EtOH treatment

11. Safety, procedural feasibility Numerous favorable outcomes
Clinical Trial Status
Enrollment Underway
Study Complete
First-Human-Use
Safety, procedural feasibility
(n= 18)
Expect to use data for
CE Mark,
US IDE submission
CE Mark Study
Single-arm treatment study
Pre/post arterial imaging ABPM as criterion
(n= 20)
Enrollment underway
Met primary endpoints
Numerous favorable outcomes

12. Artery:6 mos Post Treatment
First Human Use
Artery: Pretreatment
Artery:6 mos Post Treatment
Artery: Post-Treatment
Peregrine Introduction
Guide Tube Engagement
Needle Engagement 12

13. First Human Use

14. Target Artery: Pretreatment Artery: 6 mo Post-Treatment
Advantage of Peregrine: Treatment of Challenging Anatomy (Short Stem Artery)
Target Artery: Pretreatment
Artery: 6 mo Post-Treatment
Artery: 10 min Post-Treatment
Artery: Short Length (9.8 mm)
Guide Tube Engagement
Needles Injecting

15. Sustained OBP Lowering Despite Significant Reduction in Medication Group 1: Two Patients
HTN Medications
Baseline: 4
Month 3: 2
Month 6: 2
HTN Medications
Baseline: 3
Month 3: 1
Month 6: 1
SYMPLICITY I Trial average BP meds 5.2 (baseline) increased to 5.6 at follow-up

16. First-Human-Use Study No/Minimal Procedural Pain Using Modest Sedation
Results
Sedation (diagnostic catherization conditions)
Pain (reported by patient)
Most needed to be roused to report pain score
Discomfort lasted ≤ 1 min post alcohol injection
Possible Explanations for Lack of Pain
Alcohol (5-10%) behaves as a local anesthetic1
Arterial pain receptors reside in the media2, whereas alcohol is being delivered in the adventitia
By Comparison: Energy-Mediated Ablation
Severe pain, high doses of opiate used for sedation
1 Tlton A, Injectable Neuromuscular Blockade in the Treatment of Spasticity and Movement Disorders, J Child Neural 18: S50 (2003)
2 Schenk et al, Dual Innervation of Arteries and Arterioles, Zeitschrift für Zellforschung 91, (1968)

17. Summary and Conclusions
Renal denervation remains a promising and potentially disruptive technology for the treatment of hypertension, CHF and possibly other conditions.
The failure of Symplicity HTN 3 may be primarily related to a failure to consistently and adequately denervate, and not a failure of “renal denervation.”
Chemical renal denervation (PVRD) with very low doses of alcohol is a promising means of creating complete (deep and circumferential) and predictable renal sympathetic dener- vation, with essentially no anatomical limitations, pain or vessel wall injury.
This technology may prove to have significant advantages over “energy-based” denervation.