A Non-vascular Treatment for Resistant Hypertension RICHARD R. HEUSER, MD, FACC, FACP, FESC, FSCAI Chief of Cardiology, St. Luke’s Medical Center, Phoenix, Arizona Professor of Medicine Univ. of Arizona, College of Medicine, Phoenix, Arizona

Richard R. Heuser, MD Consulting: Abbott Vascular and ev3, Inc. Honoraria: Abiomed, Inc., Bard Peripheral Vascular, Inc., Medtronic, Inc. and Spectranetics Corporation Stocks, Stock Options, other ownership interest: QuantumCor, Inc., PQBypass and CSI.

This paper was presented on behalf of Verve Medical and the following individuals: Terry Buelna, President, CTO Winton Berci, Chief Business Officer Brad Hubbard, DVM, Managing Director, Gateway Medical Innovation Center Renu Virmani, MD, FACC, President and Medical Director, CVPath Institute

Presenter Disclosure Information Name: RICHARD R. HEUSER M.D. Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. QuantumCor, Major Stock Holder/Medical Director; Radius Medical, Avinger and Claret Medical, Major Stock Holder; PQ ByPass, Founder and Major Stock Holder; CSI, Stockholder; Spectranetics, Abbott, Medtronic, Bard, Abiomed, Honorarium; Medtronic, Abbott, AngioScore, Speaker; Acist Medical Systems Grant; and Verve Medical, Inc., Major Stockholder Patents -- RF, Snares, Wires, Balloon Catheters, Covered Stents, Devices for Arterial Venous Connection, Devices for LV and RV Closure

Renal Nerve Actions RAAS- Renin-Angiotensin-Aldosterone System

Renal Nerves

Ardian Tx by Renal RF Catheter 4 to 8 Ablations per Kidney Verve Medical Inc. CONFIDENTIAL

Verve Medical Inc. CONFIDENTIAL Renal Artery Devices Mercator Maya/ Covidien ReCor Vessix / BSX Ardian/Medtronic Verve Medical Inc. CONFIDENTIAL

Market Size $30 Billion - $40 Billion Hypertension Market Prevalence: 1 Billion Patients 25 % uncontrolled HTN 5% penetration Patients: 12.5 Million ASP: $2,400-$3,200 Market Size $30 Billion - $40 Billion Source – St Jude Medical

Vascular Exclusion Vessels with renal artery aneurysms Vessels with area of visible disease Anatomical abnormalities Acute angle of the take off of the renal artery Short or no common renal artery trunk Renal artery branches < 4mm

Renal Arterial Supply 55% 1 hilar artery CONFIDENTIAL ----- Meeting Notes (10/3/12 08:19) ----- Sampaio, F :Renal Anatomy Applied to Urology, Endourology & Interventional Radiology 1993 CONFIDENTIAL

Renal Denervation for HTN Numerous articles show renal denervation or the interruption of renal AFFERENT nerve activity attenuates systemic sympathetic tone, lowering blood pressure Suzanne Oparil, Prof Department of Medicine, Cardiovascular Dx Kidney International 1986 Sep;30(3) 437-52 The sympathetic nervous system in clinical and experimental hypertension University of Alabama Birmhamg

Neuroanatomy “ In contrast to the widespread distribution of EFFERENT Sympathetic nerve fibers in the kidney, the majority of the AFFERENT Renal Sensory nerves are located in the renal pelvic area” Kopp UC, University of Iowa. Neural Control of Renal Function 2011

Verve Medical Inc. CONFIDENTIAL Verve’s Approach ACCESS METHOD THERAPY BENEFITS Verve Ureter – Natural body Orifice Catheter – Standard technique for Urologist RF Heat LESS-invasive No arterial intervention/Tx Standard Technique Not restricted by anatomical variances of artery Potential Office procedure Verve Medical Inc. CONFIDENTIAL

Pre-Clinical Results

Procedural Fluoroscopy ----- Meeting Notes (10/3/12 08:19) ----- retrograde pyelogram - 3 bands CONFIDENTIAL

Pathology

A) Image shows relation to the surrounding renal pelvis tissue A) Image shows relation to the surrounding renal pelvis tissue. H&E B) High power showing ureteral epithelial loss and thermal injury of wall. H&E. C) High power showing adjacent vein thermal injury. Movat. D) High power showing severe nerve injury with necrosis of endineural cells and perineural thermal injury . A B C D

Materials and Methods 8 female swine underwent renal denervation via ureteral access 3 were euthanized after treatment 5 survived for 7 days Renal cortical norepinephrine levels measured Histopathology in the treated zone confirmed nerve damage

Reduction in Porcine Norepinephrine

Reduction in Porcine Norepinephrine Mean Reduction = 70.8%

Reduction in Porcine Norepinephrine

Reduction in Porcine Norepinephrine

Results Pyelography, ureterography and arterial angiography performed and unremarkable Histopathology confirmed nerve ablation Tissue norepinephrine levels dropped 70%and remains reduced at 30 days

Device design protocol being finalized for first human treatment Chronic Swine Studies >12 animals treated 7 – 30 day survival Transurethral approach Histopathology and norepinephrine levels consistently reduced Device design protocol being finalized for first human treatment

Who Is Going To Do These procedures? Primary Care (Internist) Nephrologist Cardiologist Urologist, Interventional Radiologist, Interventional Nephrologist or perhaps Interventional Cardiologist

Verve Hypertension Market US Prevalence: 75 Million Patients 25 % uncontrolled HTN (18.8M) 30% Cannot Undergo Vascular Denervation Patients: 5.6 Million ASP: $2,500 Market Size $14 Billion

CONCLUSION Pre-Clinical Results Acute and Chronic Animal Studies Catheter introduction requires little skill Safe Technique, no damage to surrounding tissue Animals returned to normal diet and uresis next day Norepinephrine reduced 70% First-in-man in 2013