Local Drug Delivery for Sympathetic Renal Denervation The

Local Drug Delivery for Sympathetic Renal Denervation: The Mercator Approach Kirk P. Seward, Ph. D President and Chief Technology Officer Mercator Med. Systems, Inc.

Disclosures • President and Chief Technology Officer at Mercator Med. Systems, Inc. • Cash and stock-based compensation 2 | CRT 2012 | Washington, DC | February 7, 2012

The Evolution of Renal Denervation Historical 3 | CRT 2012 | Washington, DC | February 7, 2012 Today

Renal Nerves: an Adventitial Target • Located in the renal artery adventitia • Seminal in the initiation and maintenance of systemic hypertension 1. 0 mm media adventitia renal nerves 4 | CRT 2012 | Washington, DC | February 7, 2012

The Adventitial Delivery Platform 130 -micron diameter needle 2 -4 mm 3 -6 mm The Bullfrog® and Cricket Micro-Infusion Catheters • Use common balloon-inflation techniques (2 atm) • Deploy a microneedle into the adventitia • No perivascular leak in >200 pigs or 44 human cases (19 coronary) • Allows targeted delivery to renal sympathetic nerve sheath • FDA 510(k)-cleared • Catheters available for >2 mm arteries 5 | CRT 2012 | Washington, DC | February 7, 2012

The Adventitial Delivery Platform 130 -micron diameter needle 2 -4 mm 3 -6 mm PAD Anti-restenosis Therapy 6 | CRT 2012 | Washington, DC | February 7, 2012

Adventitial Renal Delivery Creates a Drug. Eluting Reservoir • Injection immediately wraps vessel with drug • 2 x 1. 5 minute injections per artery (20 minutes total procedure time) • No compression or hemorrhage • Bathes target nerves with drug 7 | CRT 2012 | Washington, DC | February 7, 2012

Adventitial Renal Delivery Creates a Drug. Eluting Reservoir (From Atherton, Deep & Mendelsohn, 2011) 20 m m Immediate distribution to 100% of nerves 8 | CRT 2012 | Washington, DC | February 7, 2012

What to Deliver? • Toxins or curares (botox, tetrodotoxin) – Short acting or highly toxic to CNS • Solvents (ETOH) – Not specific to nerves • Anesthetics (lidocaine, bupivicaine) – Only offer transient block • Sympatholytics… 9 | CRT 2012 | Washington, DC | February 7, 2012

Localized Guanethidine Sympathectomy Evidence of guanethidine specificity • Approved in 1960 by FDA for hypertension treatment • Currently used for emergency hypertension control • Enters nerves specifically through amine-uptake pumps • High local concentrations induce neuronal toxicity without collateral damage 10 | CRT 2012 | Washington, DC | February 7, 2012 Control: normal renal adventitial nerve fascicles 24 hours after adventitial guanethidine: injured interstitial nerve fascicles 20 x view of renal perivascular nerve fascicles, H&E stain

Porcine Kidney NE Reduction Neurohormonal Evidence of Denervation 10 mg dose 50 mg dose Reduction in Porcine Kidney Norepinephrine with N=6 vs. 6 controls N=10 vs. 6 controls Adventitial Guanethidine Bilateral Treatment vs. Bilateral P<0. 045 P<0. 024 Vehicle Controls, 0% 28 -49%days after treatment -58% (Error bars: SEM) Kidney NE Drop vs. Controls -20% -40% -60% -80% -100% 11 | CRT 2012 | Washington, DC | February 7, 2012

Preclinical Result at 28 Days in Pigs Vehicle controls 10 mg dose 50 mg dose Normal extrinsic nerves (arrows) Mix of normal nerves (arrows) away from artery and degraded nerves (arrowheads) near artery Mainly degraded nerves (arrowheads) apparent by histopathology Normal artery with minimal perivascular fibrosis 12 | CRT 2012 | Washington, DC | February 7, 2012

Vascular Pathology at 28 and 60 d: Full Endothelium, Minimal Inflammation, Mild Fibrosis 13 | CRT 2012 | Washington, DC | February 7, 2012

Preclinical Result at 28 Days in Pigs 20 x view of renal perivascular nerve fascicles, elastin trichrome stain A B A Vehicle B 10 mg 50 mg A = Normal nerve. Note regular grayish color in the B = Nerve fiber showing endoneurial fibrosis and decreased fiber density nerve to be contrasted with bluish color in treated groups. 14 | CRT 2012 | Washington, DC | February 7, 2012

Preclinical Result at 28 Days in Pigs Neural Degeneration with Guanethidine 15 | CRT 2012 | Washington, DC | February 7, 2012

Porcine Histopathology at 60 d Long-Term Neural Atrophy after 50 mg Guanethidine Atrophied nerve fascicle 16 | CRT 2012 | Washington, DC | February 7, 2012 Normal nerve fascicle

Adventitial Guanethidine for Renal Denervation Summary • Safe delivery with 100% procedural success • Rational pharmacology with favorable PK • Widespread denervation, reduced nerve fiber density and neuronal fibrosis • Dose response seen with NE levels and histopathology endpoints • Straightforward procedure – <30 minutes sheath-in to sheath-out – No pain expected in humans 17 | CRT 2012 | Washington, DC | February 7, 2012

Next Steps • Preparing for clinical trials at U. S. and international sites 18 | CRT 2012 | Washington, DC | February 7, 2012