Local Drug Delivery for Sympathetic Renal Denervation: The Mercator Approach Kirk P. Seward, PhD President and Chief Technology Officer Mercator MedSystems, Inc.

Disclosures President and Chief Technology Officer at Mercator MedSystems, Inc. Cash and stock-based compensation | CRT2012 | Washington, DC | February 7, 2012

The Evolution of Renal Denervation Historical Today | CRT2012 | Washington, DC | February 7, 2012

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 | CRT2012 | 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 | CRT2012 | Washington, DC | February 7, 2012

The Adventitial Delivery Platform 130-micron diameter needle 2-4 mm 3-6 mm PAD Anti-restenosis Therapy | CRT2012 | 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 | CRT2012 | Washington, DC | February 7, 2012

Adventitial Renal Delivery Creates a Drug-Eluting Reservoir (From Atherton, Deep & Mendelsohn, 2011) 20 mm Immediate distribution to 100% of nerves | CRT2012 | 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… | CRT2012 | 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 Control: normal renal adventitial nerve fascicles 24 hours after adventitial guanethidine: injured interstitial nerve fascicles 20x view of renal perivascular nerve fascicles, H&E stain | CRT2012 | Washington, DC | February 7, 2012

Porcine Kidney NE Reduction Neurohormonal Evidence of Denervation | CRT2012 | 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 Normal artery with minimal perivascular fibrosis | CRT2012 | Washington, DC | February 7, 2012

Vascular Pathology at 28 and 60d: Full Endothelium, Minimal Inflammation, Mild Fibrosis | CRT2012 | Washington, DC | February 7, 2012 13

Preclinical Result at 28 Days in Pigs 20x view of renal perivascular nerve fascicles, elastin trichrome stain B A A B Vehicle 10 mg 50 mg A = Normal nerve. Note regular grayish color in the nerve to be contrasted with bluish color in treated groups. B = Nerve fiber showing endoneurial fibrosis and decreased fiber density | CRT2012 | Washington, DC | February 7, 2012

Preclinical Result at 28 Days in Pigs Neural Degeneration with Guanethidine | CRT2012 | Washington, DC | February 7, 2012 15

Atrophied nerve fascicle Porcine Histopathology at 60d Long-Term Neural Atrophy after 50 mg Guanethidine Atrophied nerve fascicle Normal nerve fascicle | CRT2012 | Washington, DC | February 7, 2012 16

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 | CRT2012 | Washington, DC | February 7, 2012

Next Steps Preparing for clinical trials at U.S. and international sites | CRT2012 | Washington, DC | February 7, 2012