1. Next Generation Renal Denervation Devices
11/7/11
Next Generation Renal Denervation Devices
Mark Wholey M.D. Director Peripheral and Neurovascular Interventions
UPMC Shadyside Hospital, Pittsburgh, PA
Feb 26, 2013
CRT2013, Washington DC
Mark CRT2013
CONFIDENTIAL - NORTHWIND MEDICAL INC.

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

3. Role of SNS tone in Hypertension
Renal natriuretic (NA) spillover
 Renin release and Na retention, proteinuria
 RBF, BNP resistance
Renal ischemia,  stroke volume, adenosine
Cardiac NA spillover
Hypertrophy
Arrhythmias
Ischemia
Heart Failure
Vascular resistance
SMC migration, vasoconstriction and atherosclerosis
Carotid Body
Other sites
Mark CRT2013

4. Ardian: Interventional Treatment of Hypertension
Thomas Zeller, 2011
Mark CRT2013

5. The Landmark Trial: Symplicity HTN-1
Reduction in Office BP is significant and sustained over 3 year follow up
M. Schlaich TCT 2012
Mark CRT2013 5

6. New Renal Denervation Technologies
ENERGY
RF, Ultrasound, Cryo Radiation
MDT - Ardian*
St. Jude Medical*
COV - Maya*
BSX - Vessix*
ReCor Medical*
JNJ/Cordis Biosense
CardioSonic
Sound Interventions
Kona Medical
CyberHeart
SyMap Medical
Cibiem
Angiocare
IMPLANTS
Mechanical, Electrical
CVRx*
Rox Medical
Vascular Dynamics
Sympara
Verve Medical
AGENTS
NORTHWIND
Ablative Solutions
Mercator Medsystems
Vincristine
* Received CE Mark
Mark CRT2013

7. Evolution of Key Platforms
9/1/11
Evolution of Key Platforms
AGENTS
Northwind
Mercator
Ablative Solutions 3
ULTRASOUND HEATING
Recor Medical
Sound Interventions
Kona Medical
Cardiosonics 2
RADIOFREQUENCY HEATING
Medtronic (Ardian)
St. Jude Medical
Covidien (Maya)
Boston Scientific (Vessix) 1
FIM:
Mark CRT2013

8. Why Next-Generation Platforms ?
11/7/11
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
Access: 5F, radial approach, navigate tortuous anatomy, stability
Simple and economical: one size fits all, procedure time ≤ 5min
Safety: no spasm, dissection or late stenosis
Efficacy: 100% responder rate and treat all nerves
Feedback: Indication for completion
Mark CRT2013
CONFIDENTIAL - NORTHWIND MEDICAL INC.

9. Renal Arterial Nerve Distribution
9/1/11
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
Mark CRT2013

10. Northwind Technology Platform
Catheter-based delivery system with microneedles
Access using endovascular methods: 6-8F, 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
Mark CRT2013

11. Northwind Procedural Sequence
9/1/11
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
Label the slide A, B, C, D
Mark CRT2013

12. Northwind Agents: Mechanism of Action
Diffuse longitudinally and circumferentially
Target axons and induce neuronal apoptosis
Mark CRT2013

13. NW2013: Molecular Mechanism of Action
9/1/11
NW2013: Molecular Mechanism of Action
NW2013 targets receptors on the axonal surface
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)
Agent at neuron receptor
Targeting the achilles heel of the nerve- the axon. The cable is shut down… prolonged bathing in agent causes them to go into apoptosis.
Hitting the ion-pump. This is the receptor target for NW triggers caspase activation- triggers apoptosis.
Neuron Apoptosis
Mark CRT2013

14. Bench and Preclinical Studies
Screened many FDA approved agents
Primary neuron screens
Identified by enhanced neurotoxicity at FDA- approved doses
Verified mechanism of action in rat sciatic nerve model
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
Healthy
NW2013 (Day 30)
Mark CRT2013
CONFIDENTIAL - NORTHWIND MEDICAL INC.

15. Preclinical Study in the Porcine Model
Safety and efficacy of administering NW2013 into renal artery wall
Surgical access
Direct injection of NW2013 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
Mark CRT2013

16. NW 2013 selectively affects nerves (H&E stain)
11/7/11
NW 2013 selectively affects nerves (H&E stain)
Normal
NW 2013 Low, 14 days
RF, 6 months
Rippy, MK et al. 2011
Neuron Apoptosis with intact peri neural space w
CRT2013
CONFIDENTIAL - NORTHWIND MEDICAL INC.

17. Porcine Histopathology at 14-days
9/1/11
Porcine Histopathology at 14-days
NW2013 is effective in causing neuronal degeneration
NFP TH
Lymph node
Renal Artery
Nerve bundle
H&E
Focal NeuroFilament Protein (NFP) staining showing structural axonal damage
Nerve fascicle with severe perineural inflammation
No Tyrosine Hydroxylase (TH) stain indicating functional loss of nerve fascicle
Explain TH-
Mark CRT2013

18. Porcine Histopathology at 90-days
Effect on NW2013 on neuronal function is sustained
NFP TH
H&E
Fascicle with moderate perineural inflammation (black arrows) with fibrosis
Weak to strong Neurofilament protein (NFP) staining of nerve fascicles
No Tyrosine Hydroxylase (TH) staining indicating continued functional loss of nerve fascicles
Mark CRT2013

19. 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
Mark CRT2013

20. Clinical Efficacy: Kidney NE Levels at 90-days
11/7/11
Clinical Efficacy: Kidney NE Levels at 90-days
76% reduction in renal tissue norepinephrine levels at low dose
Good dose response with 91% reduction at high dose
Mark CRT2013
CONFIDENTIAL - NORTHWIND MEDICAL INC.

21. Other Targets and Disease States
Carotid Body
Baroreceptors
Cardiac Nerves
Atrial Fibrillation
Pulmonary Nerves
Chronic pulmonary obstructive disease
Other
Sleep Apnea
Diabetes
Mark CRT2013

22. Conclusions
Renal denervation through targeted, local delivery of neurotropic agents is safe, simple and feasible.
Neurotropic agents, like NW2013, have the advantage to modulate nerve activity through dosing.
Dose-finding studies are in progress; First-In-Human (FIH) study planned in 2013.
Mark CRT2013