Next Generation Renal Denervation Devices Mark Wholey M

Next Generation Renal Denervation Devices Mark Wholey M. D. Director Peripheral and Neurovascular Interventions UPMC Shadyside Hospital, Pittsburgh, PA Feb 26, 2013 CRT 2013, Washington DC 2. 2013 Mark Wholey @ CRT 2013 Slide 1

Mark H. Wholey, MD • • Cofounder, Northwind, Setagon Medrad EPI Filter Endotex Consultant, Covidien Abbott Vascular Cordis, Inc.

Role of SNS tone in Hypertension • Renal natriuretic (NA) spillover • Cardiac NA spillover – Renin release and Na retention, proteinuria – RBF, BNP resistance – Renal ischemia, stroke volume, adenosine – – • Hypertrophy Arrhythmias Ischemia Heart Failure Vascular resistance – SMC migration, vasoconstriction and atherosclerosis 2. 2013 • Carotid Body • Other sites Mark Wholey @ CRT 2013 3

Ardian: Interventional Treatment of Hypertension Thomas Zeller, 2011 2. 2013 Mark Wholey @ CRT 2013 Slide 4

The Landmark Trial: Symplicity HTN-1 Reduction in Office BP is significant and sustained over 3 year follow up M. Schlaich TCT 2012 2. 2013 Mark Wholey @ CRT 2013 Slide 5

New Renal Denervation Technologies ENERGY RF, Ultrasound, Cryo Radiation • • • • MDT - Ardian* St. Jude Medical* COV - Maya* BSX - Vessix* Re. Cor Medical* JNJ/Cordis Biosense Cardio. Sonic Sound Interventions Kona Medical Cyber. Heart Sy. Map Medical Cibiem Angiocare IMPLANTS Mechanical, Electrical • • • CVRx* Rox Medical Vascular Dynamics Sympara Verve Medical AGENTS • • NORTHWIND Ablative Solutions Mercator Medsystems Vincristine * Received CE Mark 2. 2013 Mark Wholey @ CRT 2013 Slide 6

Evolution of Key Platforms 3 1 • • • Northwind Mercator Ablative Solutions RADIOFREQUENCY HEATING • • Medtronic (Ardian) St. Jude Medical Covidien (Maya) Boston Scientific (Vessix) FIM: 2008 -11 2. 2013 AGENTS 2011 -12 Mark Wholey @ CRT 2013 -14 Slide 7

Why Next-Generation Platforms ? • Implants may not be the optimal solution • Energy-based interventions have limitations – Untargeted, cumulative damage, can be painful procedure – Refractory patients; unable to treat stented and tortuous anatomy – Circumferential calcification • Next-generation needs – – – 2. 2013 Access: 5 F, radial approach, navigate tortuous anatomy, stability Simple and economical: one size fits all, procedure time ≤ 5 min Safety: no spasm, dissection or late stenosis Efficacy: 100% responder rate and treat all nerves Feedback: Indication for completion Mark Wholey @ CRT 2013 Slide 8

Renal Arterial Nerve Distribution • Most nerves are located 2 -4 mm from the renal artery lumen • More nerves are present in the proximal and inferior regions Owens, TCT 2011 Virmani, TCT 2012 2. 2013 Mark Wholey @ CRT 2013 Slide 9

Northwind Technology Platform • Catheter-based delivery system with microneedles – Access using endovascular methods: 6 -8 F, 0. 014 guide wire-based – Inject small volume of neurotropic agent into renal artery walls • Agents specifically target the sympathetic nervous system – Modulate, block or kill nerves that innervate the kidney 2. 2013 Mark Wholey @ CRT 2013 Slide 10

Northwind Procedural Sequence Advance Catheter into Renal Artery Inflate Balloon and Advance Microneedles Deliver the Agent, and Retract Catheter Agent Binds to Receptors on Axons 2. 2013 Mark Wholey @ CRT 2013 Slide 11

Northwind Agents: Mechanism of Action • Diffuse longitudinally and circumferentially • Target axons and induce neuronal apoptosis 2. 2013 Mark Wholey @ CRT 2013 Slide 12

NW 2013: Molecular Mechanism of Action • NW 2013 targets receptors on the axonal surface Agent at neuron receptor – Binds to the ion pump – Blocks the ion-pump, causing cytosolic Ca+ flux – Triggers the Caspase cascade – Results in neuronal apoptosis • Dose-dependent efficacy – Neuro-blockade (low-mid) – Neurotoxic (high) Neuron Apoptosis 2. 2013 Mark Wholey @ CRT 2013 13

Bench and Preclinical Studies • Screened many FDA approved agents – Primary neuron screens – Identified by enhanced neurotoxicity at FDAapproved doses • Verified mechanism of action in rat sciatic nerve model Healthy – Clinical signs of neuralgia and neuropathology; prolonged efficacy – Neurodegenerative, atrophy and loss of perineurium – Neurotropic, no permanent injury to surrounding tissue • Completed feasibility studies in the porcine model 2. 2013 Mark Wholey @ CRT 2013 NW 2013 (Day 30) Slide 14

Preclinical Study in the Porcine Model • Safety and efficacy of administering NW 2013 into renal artery wall – – Surgical access Direct injection of NW 2013 into the wall • Feasibility of renal nerve degeneration – Low and high concentration, saline controls – Acute (14 day) and chronic (90 day) time points • Endpoints – Biomarkers: Renal tissue norepinephrine – Histology: Vascular architecture and neuronal pathology 2. 2013 Mark Wholey @ CRT 2013 Slide 16

NW 2013 selectively affects nerves (H&E stain) Normal NW 2013 Low, 14 days RF, 6 months Rippy, MK et al. 2011 2. 2013 Neuron Apoptosis with intact peri neural space w holey @ CRT 2013 Slide 17

Porcine Histopathology at 14 -days NW 2013 is effective in causing neuronal degeneration Nerve fascicle with severe perineural inflammation Lymph node Re na l. A rte ry Nerve bundle H&E No Tyrosine Hydroxylase (TH) stain indicating functional loss of nerve fascicle Focal Neuro. Filament Protein (NFP) staining showing structural axonal damage NFP 2. 2013 TH Mark Wholey @ CRT 2013 Slide 19

Porcine Histopathology at 90 -days Effect on NW 2013 on neuronal function is sustained Fascicle with moderate perineural inflammation (black arrows) with fibrosis H&E NFP TH Weak to strong Neurofilament protein (NFP) staining of nerve fascicles 2. 2013 No Tyrosine Hydroxylase (TH) staining indicating continued functional loss of nerve fascicles Mark Wholey @ CRT 2013 Slide 20

Porcine Study: Angiogram at 90 -days SAFETY • Vascular architecture and vessel integrity is preserved • No renal stenosis • No organ damage • No puncture site • No emboli 2. 2013 Mark Wholey @ CRT 2013 Slide 21

Clinical Efficacy: Kidney NE Levels at 90 -days Kidney Tissue NE Levels at 90 days • • 2. 2013 76% reduction in renal tissue norepinephrine levels at low dose Good dose response with 91% reduction at high dose 120% 100% 80% 60% 40% 20% 0% Control NW 2013 -L Mark Wholey @ CRT 2013 NW 2013 -H Slide 22

Other Targets and Disease States • Carotid Body – Baroreceptors • Cardiac Nerves – Atrial Fibrillation • Pulmonary Nerves – Chronic pulmonary obstructive disease • Other – Sleep Apnea – Diabetes 2. 2013 Mark Wholey @ CRT 2013 23

Conclusions • Renal denervation through targeted, local delivery of neurotropic agents is safe, simple and feasible. • Neurotropic agents, like NW 2013, have the advantage to modulate nerve activity through dosing. • Dose-finding studies are in progress; First-In-Human (FIH) study planned in 2013. 2. 2013 Mark Wholey @ CRT 2013 Slide 24