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

2. Disclosures
President and Chief Technology Officer at Mercator MedSystems, Inc.
Cash and stock-based compensation
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3. The Evolution of Renal Denervation
Historical
Today
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4. 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
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5. 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
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6. The Adventitial Delivery Platform
130-micron diameter needle
2-4 mm
3-6 mm
PAD Anti-restenosis Therapy
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7. 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
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8. Adventitial Renal Delivery Creates a Drug-Eluting Reservoir
(From Atherton, Deep & Mendelsohn, 2011)
20 mm
Immediate distribution to
100% of nerves
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9. 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…
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10. 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
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11. Porcine Kidney NE Reduction Neurohormonal Evidence of Denervation
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12. 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
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13. Vascular Pathology at 28 and 60d: Full Endothelium, Minimal Inflammation, Mild Fibrosis
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14. 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
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15. Preclinical Result at 28 Days in Pigs Neural Degeneration with Guanethidine
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16. Atrophied nerve fascicle
Porcine Histopathology at 60d Long-Term Neural Atrophy after 50 mg Guanethidine
Atrophied nerve fascicle
Normal nerve fascicle
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17. 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
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18. Next Steps
Preparing for clinical trials at U.S. and international sites
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