Renal Nerve Ablation: Will It Become the treatment Of Choice for Resistant Hypertension? Jie Wang MD PhD Mark Gelfand, MS Howard Levin, MD Disclosure: JW was a consultant and shareholder of Ardian; MG/HL were Co-founders of Ardian

Three Different Diseases, One Common Pathway Heart Failure, Hypertension and Chronic Renal Failure have many different initial causes Irrespective of initial cause, all follow a common pathway on their progression to end-stage disease Physiologic changes caused by the kidney are responsible for this progression including: Abnormal hormone secretion (renin, aldosterone, Norepi) Renal, systemic and pulmonary vasoconstriction Salt and water retention The Common Pathway: Renal Nerve Hyperactivity

Renal Sympathetic Efferent Nerve Activity: Kidney as Recipient of Sympathetic Signals Renal Efferent Nerves Renal Ischemia ↑ Adenosine production BNP resistance ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow

↑ Renin Release  RAAS activation ↑ Sodium Retention Renal Sympathetic Afferent Nerves: Kidney as Origin of Central Sympathetic Drive Vasoconstriction Atherosclerosis Hypertrophy Arrhythmia Oxygen Consumption Heart Failure Renal Afferent Nerves Insulin Resistance ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow

Previous Data Confirm Positive Effects of Renal Nerve Blocking Renal injury/ dysfunction identified as mechanism of increased sympathetic nervous system activity leading to HTN (Campese, 2002) Blocking of renal nerve activity controls HTN in animals with chronic renal insufficiency (Campese, 1995) Surgical renal denervation done to eliminate intractable pain in patients with polycystic kidney disease also eliminates HTN (Valente, 2001) Denervation (by nephrectomy) eliminates HTN in humans on dialysis with severe HTN refractory to multi-drug therapy (Converse,1992) Blocking of renal nerve activity increases diuresis/ naturesis in rats with CHF (Dibona) Blocking of renal nerve activity limits ventricular remodeling in rats post-MI (Tozawa, 2002)

Totally Novel Therapy, Original Plan Intelligent, programmable fully implanted infusion pump with the catheter tip placed in the proximity of the renal nerve Programmable battery operated electronic device similar in size and complexity to a pacemaker Integrated electronic feedbacks to guide therapy Percutaneous refilling of the reservoir once per month

How Does It Work?-Original Thought Catheter is implanted in the periarterial space outside of the renal artery (Gerota’s fascia) This technique is similar to percutaneous drainage of perinephric abscess As needed, a bolus of a nerve blocking drug is infused and temporarily blocks renal nerve activity Drug can be an approved drug such as Marcaine, local anesthetic commonly used for pain management

Our Animal Studies Confirmed The Clinical Utility Of This Concept Obtained data from the 11 dogs with micro-embolization model of Acute HF 8 dogs had Renal Nerve Block (RNB) created by injecting 10 ml of Marcaine (bupivicaine) inside Gerota’s fascia 3 dogs served as controls Urine output (Urine output/every 15 min) significantly increased compared to controls Both naturesis and diuresis were observed confirming physiologic basis for effect Same results found in other 6 dogs with micro- embolization model of chronic CHF

Acute Heart Failure : Urinary output (UOP) in the Treated Kidney (A) and in both Kidneys (Total) (B) after Unilateral Renal Nerve Block (URNB) and Bilateral Renal Nerve Block (BRNB). A significant reduction in UOP was seen after Acute Heart Failure, but UOP was increased significantly after URNB. No additional increase in UOP was seen after BRNB (* p<0.05 vs. Baseline, † p<0.05 vs. AHF).

Congestive Heart Failure : Urinary Output (UOP) in the Treated Kidney and in both Kidneys (Total) after Unilateral Renal Nerve Block (URNB) and Bilateral Renal Nerve Block (BRNB). A significant increase in UOP was seen after URNB compared to the CHF state (* p<0.05 vs. CHF), but BRNB failed to produce a significant increase in UOP compared to URNB alone.

Proposed Two Step Approach To Prove Clinical Utility in Humans Acute study of renal nerve block using CT guided technique to demonstrate either: Diuresis and neurohormonal effects in patients with HF and fluid overload Lowering of blood pressure and neurohormonal effects in patients with hypertension

Acute Human Feasibility Study in 5-10 Patients Class III-IV CHF patients refractory to diuretics or patients with BP > 140/90 on medication Injection of drug to block RN using CT guided technique Comparison of urine volume, urine and serum electrolytes, hemodynamic and neurohormonal effects from 6 hours pre- to 12 hours post- injection

Intervention Performed In 5 Patient Successful test of RN blocking technique Performed under CAT Scan Guidance Needle placed at the hilum of the kidney Single injection of Marcaine resulted as predicted in: Nerve block for 12 hours Reduction in blood pressure

Proposed Two Step Approach To Prove Clinical Utility in Humans Chronic (1-3 month) study of renal nerve block using minimally invasively implanted port to demonstrate either: Diuresis and neurohormonal effects in patients with HF and fluid overload Lowering of blood pressure and neurohormonal effects in patients with hypertension

What the Therapy/Device Should be? Device Based Therapy Interventional/Trans-catheter Similar to Current Medical Practice

Renal Nerve Anatomy Allows a Catheter-Based Approach Standard interventional technique 4-6 two-minute treatments per artery Proprietary RF Generator Automated Low-power Built-in safety algorithms In the United States: Caution: Investigational Device. Limited by U.S. law to investigational use. 16 16

Symplicity Catheter System Simple, 40-minute catheter-based procedure Simultaneously ↓ the renal contribution to systemic sympathetic activation and the efferent effects of sympathetic activation of the kidney Selectively disable the renal sympathetic afferent and efferent nerves without impairing sympathetic signaling to other organs An anticipated durable clinical benefit Ramped low power radiofrequency energy delivery (5-8W) Blood flow minimizes surface/endothelial injury Focal ablations spaced along vessel allows for rapid healing CE Mark In the United States: Caution: Investigational Device. Limited by U.S. law to investigational use.

Multiple Discrete Treatments Maximize Nerve Coverage Without Applying Circumferential Energy in a Single Segment

Study Aims Krum et al. Lancet. 2009;373(9671):1275-1281.

Inclusion/Exclusion Criteria Key Inclusion Criteria Office SBP ≥160 mmHg despite 3+ anti-hypertensive medications (including diuretic), or confirmed intolerance to medications eGFR (MDRD formula) of ≥ 45 mL/min/1.73m2 Key Exclusion Criteria Known secondary cause of hypertension Type I diabetes mellitus Currently taking clonidine, moxonidine, or rilmenidine Renovascular abnormalities: significant renal artery stenosis, prior renal stenting or angioplasty, dual renal arteries Krum et al. Lancet. 2009;373(9671):1275-1281.

Baseline Patient Characteristics Treated Patients (N=45) Age (years) 58 ± 9 Gender (% female) 44 Race (% non-Caucasian) 4 Diabetes Mellitus II (%) 31 CAD (%) 22 Heart Rate (bpm) 72 ± 11 eGFR (mL/min/1.73m2) 81 ± 23 BP (mmHg) 177/101 ± 20/15 Krum et al. Lancet. 2009;373(9671):1275-1281.

Results: Procedure Characteristics & Safety Procedure time: median 38 (IQR 34-48) minutes Treatment delivered without complication in 43/45: 1 renal artery dissection during catheter delivery (before RF energy application) 1 femoral pseudoaneurysm, manually reduced without further sequelae

Vascular and Renal Safety No chronic vascular complications 18 patients with angiograms at 14-30 days post-procedure 38 of 38 patients with CTA/MRA 6 months post-procedure No chronic renal (∆ eGFR) complications 3 Month: 0.4 mL/min/1.73m2 (95% CI: -4.2 to 4.9; N=31; p=0.87) 12 Month: -3.1 mL/min/1.73m2 (95% CI: -9.0 to 2.8; N=28; p=0.31) No orthostatic or electrolyte disturbances

Change in Blood Pressure (mmHg) Blood Pressure Response Change in Blood Pressure (mmHg) 89% Responder Rate Repeated measures ANOVA: P<0.001 for SBP & DBP P<0.00001 vs. baseline for each SBP & DBP

The Potential Market Developed Countries: Drug-Resistant Hypertension China: Hypertension Patient, 160 millions Optimized Drug Therapies: 6.1%, 3.23 millions

Conclusions

Staged Clinical Evaluation First-in-Man  Series of Pilot studies  Symplicity HTN-2  EU/AU Randomized Clinical Trial Symplicity HTN-1 USA Symplicity HTN-3 US Randomized Clinical Trial (upcoming) EU/AU Other Areas of Research: Insulin Resistance, HF/Cardiorenal, Sleep Apnea, More 28 28