Renal Denervation

Renal Denervation
Does the Failure of Simplicity Mark the
End of the Therapy?
Evolving Concept in the Restoration of
Sympathetic Balance
Mark Wholey M.D. 2014
Mt.Sinai; CCVVC
DISCLOSURES for this presentation
!  Northwind Inc.
Attache Device Group llc.
Setagon ,Nano med stent
Role of SNS Tone in Hypertension
3
HTN-3 was intended to
revolutionize treatment of
Hypertension. 75 million pts.
!  This did not happen, Renal nerve
deactivation is not dead but
arguably badly damaged
—  Intended to Reduce the over Axon
sympathetic activity between the kidneys and
brain .
!  Emerging Options for
Sympathetic Overactivity
— 
— 
— 
— 
Heart Failure
Atrial Arrhythmia,
Sleep apnea,COPD
Insulin Resistance
Potential Issues with Symplicity
HTN-3
6.8.14
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The Landmark Trial: Symplicity HTN-1
Reduction in Office BP is significant and sustained over 3 years
M. Schlaich TCT 2012 CONFIDENTIAL - Northwind Medical, Inc.
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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-Terumo
•  Verve Medical
IMPLANTS
Mechanical,
Electrical
•  CVRx*
•  Rox Medical
•  Vascular Dynamics
•  Sympara
AGENTS
•  NORTHWIND
•  Ablative Solutions
•  Mercator
Medsystems
•  Vincristine
* Received CE Mark
CONFIDENTIAL - Northwind Medical, Inc.
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6.8.14
Northwind Medical, Inc. - CONFIDENTIAL
Simplicity HTN-3 met Safety end
point but not Efficacy
Question is did it meet Safety, because of under dosage, operator
inexperience,device design,ablation no greater than 2mm,
unipolar electrode, only 40%denervation achieved,or different
patient groups
Is Denervation beginning to unwind ?
Critical that Industry continue development if Renal DN
Is to survive. This was only 1 trial, 1 device and a selected group 20
Bhatt 2014
The Pivotal Trial: Symplicity HTN-3*
* D. Bha2 et al, NEJM (2014) 5.21.14
Northwind Medical, Inc. - CONFIDENTIAL
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Symplicity HTN-3 Study Limitations
!  Procedural variability
!  Device limitations and operator experience
!  No real-time indicator of treatment efficacy. Neural mapping
would solve that problem
!  Medication changes or adherence
!  Regimen, dosing and wash-out period prior to treatment
!  Only 40% denervation achieved with unipolar electrode cath
!  Patient demographics
!  Patient selection: age and ethnicity
!  Trial design and execution
5.21.14
Limitations of Energy-Based Denervation
!  Non-Targeted therapy requires catheter manipulation
–  Potential to cause tissue damage: acute thrombosis
–  Long-term effects not known: renal artery stenosis
–  Not certain of energy penetration depth Media vs Adventitia
!  No currently available data on treating
–  Diseased (atherosclerotic) arteries, fibromuscular dysplasia and
aneurysms
–  Re-intervention of ablated arteries
–  Stented arteries
!  Unfavorable Anatomy
–  Unable to treat small (<4 mm) vessels
–  Hostile aorta or supplemental renal arteries
–  Acute take-off, short/no common renal artery trunk
–  Not certain of penetration energy depth
CONFIDENTIAL - Northwind Medical, Inc.
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RF-Based Denervation has Limited Penetration
Nephrology Dial Transplant (2014)
!  RF ablation induces a 2 mm domeshape damage zone
!  Nerve bundles in the peri-adventitial
regions were unaffected
6.8.14
Northwind Medical, Inc. - CONFIDENTIAL
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Energy-based Denervation:
Histology
Radiofrequency ablation of renal arteries causes significant
wall damage; Effects may persist up to 6 months
30 days
60 days
damage
zones
180 days
180 days
H. Sievert (2009)
10.18.2013
TZeller @ TCT2013
Energy-based Denervation: OCT
Findings
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Significant intraluminal thrombus formation is seen after renal nerve
ablation
10.18.2013
TZeller @ TCT2013
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Renal Arterial Nerve Distribution
•  Most nerves are located 2-4 mm from
the renal artery lumen
•  More nerves are present in the proximal
regions
NERVE DISTRIBUTION, %
35%
30%
25%
20%
Owens, TCT 2011
15%
10%
5%
0%
DISTANCE FROM LUMEN, mm
6.8.14
Virmani, TCT 2012
Northwind Medical, Inc. - CONFIDENTIAL
Energy-based Denervation: Late
Stenosis
10.18.2013
TZeller @ TCT2013
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RF Ablation Inadvisable in Stented
Arteries*
Artery
Ablation zone
!  Possible interaction of radio frequency energy with an implanted stent
makes it inadvisable to perform an ablation procedure within or in its close
proximity.
!  Optimal renal nerve ablation within a segment of stented artery was not
possible since the Symplicity Catheter System safety controls terminated
the procedure before the full ablation time was reached, preventing
undesirable local heating and resulting in reduces but non-optimal renal
norepinephrine concentration.
*RJ Melder, EuroPCR 2013
10.18.2013
TZeller @ TCT2013
Effects of RF Energy-based Ablation
Baseline: Main and upper pole accessory renal !  Treatment
!  6 ablations per artery, left and
right
!  2 ablations in upper pole renal
!  No complications
!  5 months: recurrent
hypertension
!  80% ostial, 70% mid segment
stenoses in main right renal
!  50% stenosis, mid right upper
pole renal
!  Successfully stented
After 5 Months
10.18.2013
Kaltenbach et al, JACC, 2012
!  No significant stenosis in left
renal artery
TZeller @ TCT2013
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New Renal Denervation Platforms
!  Implants may not be the optimal solution
!  Energy-based interventions have limitations
!  Next generation therapy needs
—  Simple and economical: one size fits all, procedure time ≤ 5min
—  Treat all patients and anatomies
—  Improved access: 5F, radial approach, navigate tortuous anatomy
—  Safe: no spasm, dissection or late stenosis
—  Efficacious: 100% responder rate and treat all nerves
—  In-situ feedback: Indicator for treatment completion
—  Personalized: Dose-titratable
CONFIDENTIAL - Northwind Medical, Inc.
Northwind Technology Platform
!  Catheter-based delivery system with microneedles
–  Access using endovascular methods: 6-8F, 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
–  Selected NW2013 after careful screening; FDA approved
CONFIDENTIAL - Northwind Medical, Inc.
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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)
5.21.14
Northwind Medical, Inc. - CONFIDENTIAL
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Northwind Procedure: Preclinical Study
Advance catheter to
position; Inflate Balloon
Advance needles;
Inject the agent
Retract needles; Deflate
balloon; Remove catheter
!  Minimal damage to renal artery
!  No dissections, perforations
!  Vascular integrity maintained
!  Nerve-specific degenerative
changes
!  No renal artery stenosis
!  Permanent degenerative changes
CONFIDENTIAL - Northwind Medical, Inc.
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CASE No. 1
!  Patient 001:
–  Male, 72 y/o, non smoker
!  Past Medical History:
–  Hypertensive since 1999 with medication, BP is 170/95 mm Hg
–  History of coronary angiography 04/10/2009; no significant
stenosis. Ejection Fraction 63%
!  Medications:
–  Prestance 10/10 mg (Amlodipine besilate/Perindopril arginine)
–  Indapamine 1.5 mg
–  HCTZ (hydrochlorothiazide) 12.5 mg
CONFIDENTIAL - Northwind Medical, Inc.
CASE No. 1 CTA Scan
72 y/o male long standing Hx HTN
CONFIDENTIAL - Northwind Medical, Inc
Case 1: Left Kidney Pre-Treatment
7 French Renal Double Curve
Sheath Used for Access Left Renal
Initial Left Renal Angiogram
CONFIDENTIAL - Northwind Medical, Inc
Case No 1. Left Kidney Distal
Balloon Catheter Advanced to Distal
Angiogram Assessing Branch Vessels
Segment of Left Renal Artery
and Site for Distal Treatment
CONFIDENTIAL - Northwind Medical, Inc
Case No 1. Left Kidney Distal
Angiogram Confirming Total
Balloon Inflated Distally
Occlusion with Balloon
CONFIDENTIAL - Northwind Medical, Inc
Case No 1. Left Kidney Distal
Balloon Catheter Deflated, Pulled
Proximal, Contrast Injection
Angiogram After Distal Treatment
-No Evidence of Dissection,
Perforation, or Significant Spasm
CONFIDENTIAL - Northwind Medical, Inc
Case No 1. Left Kidney Proximal
Proximal Segment Treated
Final Angiogram
CONFIDENTIAL - Northwind Medical, Inc
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Office Blood Pressure Changes
Systolic Office Blood Pressure, mm Hg 250 200 150 100 50 0 Baseline 5.21.14
Discharge 1-­‐Month 3 Month Northwind Medical, Inc. - CONFIDENTIAL
CVRx: Carotid Baroreceptor
Stimulation
!  Continuously modulates the
autonomic nervous system
!  Inhibits Sympathetic
activity
!  Enhances Parasympathetic
activity
!  Heart: ↓ HR
!  Vessels: ↑ Vasodilation, ↓
Stiffness
!  Kidneys: ↑ Natriuresis, ↓
Renin secretion
MWholey: 5.30.12
NORTHWIND MEDICAL: CONFIDENTIAL
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Other Nerve Targets and Disease States
! 
Cardiac Nerves
! 
! 
Carotid Body
! 
! 
5.21.14
Chronic Kidney Disease
Pulmonary Nerves
! 
! 
! 
Congestive heart failure
Renal Nerves
! 
! 
Atrial fibrillation
Pulmonary hypertension
Chronic pulmonary obstructive disease
Other Indications
! 
! 
Metabolic syndrome
Sleep apnea
! 
Diabetes
Northwind Medical, Inc. - CONFIDENTIAL
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CONCLUSIONS
!  Renal denervation has had a serious setback.
However it was only one device, one trial
CONFIDENTIAL - Northwind Medical, Inc.