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

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

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

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

Perivascular Renal Denervation (PVRD): Alcohol Provides Excellent Safety Profile Injection sites Expanded view of injection sites Alcohol acts locally ⇒ no collateral damage Micro volume (0.3-0.6 mL) directed to the perivascular space Alcohol bio-activity reduced via dilution by extracellular fluid: self-limited spread

Lateral View

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

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

Chemical Denervation Using Ethanol (EtOH) Depth + Circumferential Treatment -> Greater Denervation Net area covered by PVRD = 50-100 mm2 Fischell et al, EuroIntervention, 2013 RF PVRD Net area covered by RF = 20-30 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

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 0.40 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

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

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

First Human Use

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

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

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, 170-177 (1968)

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.