Renal Denervation Industry Perspective Sean Salmon President, Coronary & RDN SVP, Medtronic, Inc.

Medtronic Employee with significant equity Sean Salmon Medtronic Employee with significant equity

High Burden of Uncontrolled Hypertension Clear Unmet Need 1 B WW  1.6 B by 2025 1 in 3 adults Leading cause of death WW 50% of treated uncontrolled 25% of treated resistant Direct Cost $500B WW 35% Treated not Controlled 30% Untreated 35% Treated & Controlled Renal Denervation (RDN) = Potentially a Breakthrough Treatment Option

#1 Attributable Cause of Death WW Lopez AD, et al. Lancet. 2006;367:1747-1757.

2-mm Hg decrease in mean SBP Even Small SBP Reductions Important SBP is a Powerful Surrogate Marker and a CV Mortality Equivalent 7% reduction in risk of IHD mortality 2-mm Hg decrease in mean SBP 10% reduction in risk of stroke mortality Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years Lewington S, et al. Lancet. 2002;360:1903-1913.

Renal Nerves and the SNS Efferent Sympathetics Afferent Renal Sympathetics Purpose: To explain sympathetic afferent and efferent signaling between the kidneys and the CNS. Key Points: Efferent signals from the CNS, specifically the hypothalamus, control physiology of the viscera. In the case of the kidneys, these signals promote the renin system and sodium retention, while inhibiting RBF and GFR These components are stimulated in disease states characterized by SNS hyperactivation and contribute to increased BP in hypertension Pharmacologic strategies to inhibit the effects of renal SNS activity include: Beta-blockers (to reduce renin release) Angiotensin-converting enzyme inhibitors (ACEIs) and receptor blockers (ARBs) (to block the actions of angiotensin II and aldosterone which lead to renin release) Diuretics (to counter the renal sympathetic-mediated water and sodium retention) Efferent nerves terminate in blood vessels, the juxtaglomerular apparatus, and renal tubules Renal sensory afferent nerves relay sensory information back to the CNS, and directly affect sympathetic outflow to the kidneys and other organs, such as the heart and peripheral vasculature Source: Schlaich MP, Sobotka PA, Krum H, et al. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension. 2009;54:1195-1201. Renin release  RAAS Na absorption Renal blood flow (TPR) The kidney is a source of central sympathetic activity, sending signals to the CNS Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201. 6

Renal Nerve Anatomy Nerves arise from T10-L2 The nerves arborize around the artery and primarily lie within the adventitia Vessel Lumen Media Adventitia Renal Nerves Key point is that the nerve bundles are larger in the proximal renal artery and branch or arborize as they travel down the artery to the kidney. Confidential 7 7

Novel Catheter-Based Approach to Denervation Standard interventional technique 4-6 two-minute treatments per artery Proprietary RF generator Automated Low power, 8W maximum Built-in safety algorithms RDN, which was subsequently purchased by Medtronic,specifically developed both a catheter and a generator to deliver low-power radiofrequency energy from inside the renal artery in order to render the sympathetic nerves nonfunctional. A proprietary generator that measures various predators to control power and permit or terminate radiofrequency delivery is coupled with the catheter that allows ready frequency emitting electrode to be deployed within the renal artery. Treatment starts distally and proceeds in a circuitous fashion around the artery as the catheter is withdrawn proximally towards the aorta. Radiofrequency is looking for 2 min. at each spot. The pictures above on the left show the catheter tip in the distal renal artery with the radiofrequency energy being applied as evidenced by the semicircular bluelines. In the middle figure the orange colored spots demonstrate the location of a hypothetical series of RF treatments. The fluoroscopic picture on the right shows the distal tip of the catheter with the electrode on the far left applied to the vessel wallin the proper position to deliver radiofrequency energy. Confidential 8

Extensive Pre-Clinical Safety Viable Nerves Ablated Nerves Extensive research in >600 swine with extended follow-up The renal nerves are rendered non-functional via axonal death The renal artery healing is fast, non-stenosing and non-deforming Renal Nerve Viability Naïve Day 7 Day 60 Renal Artery Healing Acute Day 28 Day 60 Treated Segments Rippy MK, et. al. Clin Res Cardiol. 2011. Key outcomes: Minimal damage to vessel wall that heals rapidly No damage to surrounding organs Successful ablation of renal nerve RDN and Medtronic performed an extensive series of preclinical studies to both better understand the anatomy of the sympathetic nerves in the kidney, the optimal conditions for producing renal denervation that would be both safe and effective,and to develop the specific algorithms for the RF generator and the details for constructing the catheter with the electrode to be inserted into the renal artery. These photomicrographs show in the top section sympathetic nerves around the renal artery on the left side as evidenced by the red stain and then nerves that are no longer functional as evidenced by the Greenstein in the middle and right figures. Lower set of this logic pictures show that treatment does not lead to burning, charring, or other serious destruction of tissue in the renal artery but to mild injury and inflammation that rapidly resolves without stenosis or thrombus formation.

Renal Denervation ≠ Cardiac Ablation

Electrode Size & Orientation Important Symplicity electrode, 8W Larger electrode, >8W Intima/Media Intima/Media Adventitia Adventitia Other tissue Other tissue

Impact of Irrigation on Lesion Size

Surrounding Structures 5 mm 5 mm

SYMPLICITY HTN-1 Initial Cohort – Reported in the Lancet, 2009: Catheter-based Renal Sympathetic Denervation for Resistant Hypertension Durability of Blood Pressure Reduction Out to 24 Months Symplicity HTN-1 Investigators* Lancet. 2009;373:1275-1281 Hypertension. 2011;57:911-917. Initial Cohort – Reported in the Lancet, 2009: First-in-man, non-randomized study conducted in Europe and Australia Cohort of 45 patients with resistant HTN All patients received bilateral renal denervation with the Symplicity Renal Denervation System Primary endpoint: change in office BP at 6 months post-procedure Expanded Cohort – SYMPLICITY HTN-1: Expanded cohort of patients (n=153) from 19 sites (US, Europe, and Australia) 24 and 36-month follow-up of safety and effectiveness Confidential 15

Change in Office Blood Pressure Through 36 Mo* P<0.01 for ∆ from BL for all time points *Data is reported only on the patients available at each timepoint, not full cohort Confidential

SBP Change at Baseline, 1, 12, 24, and 36 Months % Patients placeholder (N=150) (N=143) (N=132) (N=105) (N=34) Confidential

Vascular Safety Out to 36 months Procedural Safety: Complications: 1 renal artery dissection during catheter delivery treated with a stent; RDN not performed 3 access site complications – no sequelae Safety during Follow-up: One progression of a pre-existing stenosis unrelated to RF treatment (stented without further sequelae) One new moderate stenosis which was not hemodynamically relevant, required no treatment Ask Bryan – can this be included Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917. Confidential 18 18

SYMPLICITY HTN-2 Lancet. 2010;376:1903-1909. Purpose: To demonstrate the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with uncontrolled hypertension in a prospective, randomized, controlled, clinical trial Patients: 106 patients randomized 1:1 to treatment with renal denervation vs. control Clinical Sites: 24 centers in Europe, Australia, & New Zealand (67% were designated hypertension centers of excellence) Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909. Confidential 19

Symplicity HTN-2 OBP at 6 Months ∆ from Baseline (mmHg) 33/11 mmHg difference between RDN and Control (p<0.0001) 1Symplicity HTN-1 Investigators. Hypertension. 2011; 57(5): 911-7 2Symplicity HTN-2 Investigators. Lancet 2010; 376:1903-1909. Not approved for clinical use in the US or Japan 20

Change in OBP Through 18 Months* Crossover Group (mm Hg) (mm Hg) SBP DBP SBP DBP 6 month N=49 12 months N=47 18 months N=43 6 months N=35 12 months N=33 18 months N=31 P-values < 0.01 at each time point compared to pre procedure values for each group *Post Procedure follow up

Renal Function Over Time Renal function parameters were not obtained beyond 12 months follow up *eGFR mL/min/1.73m2 Confidential

Global Clinical Program Enrollment Complete / In Follow Up SYMPLICITY HTN-1 Series of non-randomized pilot studies, N = 153 3 yr SYMPLICITY HTN-2 Randomized Controlled Trial (1:1), N = 106 >1 yr 2 yr Enrolling/Planning SYMPLCITY HTN-3 Randomized Controlled Trial (2:1), N = 530 Enrolling HTN - Japan Randomized Controlled Trial (1:1), N = 100 Enrolling Global Registry Prospective, Registry, N = 5,000 Enrolling HTN - India Non-Randomized Controlled Trial, N = 40 Planning ~750 subjects in randomized studies 1,200+ subjects at time of PMA submission Confidential 23

Symplicity HTN-3 Study Design Flow Treatment Control Primary Endpoint 6M 12- 60 M Home BP & Med Confirmation Patient and Research staff assessing BP and performing follow-ups are blinded to treatment status No changes in medications for 6M Office SBP ≥ 160 mmHg Full doses of ≥ 3 meds No HTN med changes in past 2 wks No plan to change meds for 6 M Initial Screening 2 weeks 24 hr ABPM SBP ≥ 135 Documented compliance on meds Confirmatory Screening If eligible anatomy, randomize “on the table” Renal Angiogram 1M 3M Sham 2:1 Confidential

Office, Home and Ambulatory BP

Trial Execution Considerations Burdensome for Participating Sites Low screening randomization yield Dedicated blinded and unblinded research coordinators Patient Referral Challenges Primary Care vs. Specialist Stability of Drug Regimen Patient Enrollment Challenges Confirming stage 2/3 rHTN Diet, lifestyle and drug-drug interactions Drug regiments (doses & classes) Patient adherence and intolerance Secondary causes eGFR, recent hospitalization for HTN crisis, anatomical…

Reimbursement

Symplicity is HIGHLY Cost Effective Cost/QALY Comparison c/e Threshold $50k

Age Distribution

Combined SYMPLICITY HTN-1 & HTN-2 1 Month 6 Months 12 Months BP change (mmHg) Actual values to be added N=104 N=39 N=158 N=70 N=129 N=51 Data on file, Medtronic Confidential

Utility Beyond Severe rHTN?