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

2. Medtronic Employee with significant equity
Sean Salmon
Medtronic Employee with significant equity

3. 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

4. #1 Attributable Cause of Death WW
Lopez AD, et al. Lancet. 2006;367:

5. 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:

6. 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:
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: 6

7. 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

8. 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

9. 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 Day 60
Treated Segments
Rippy MK, et. al. Clin Res Cardiol
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.

11. Renal Denervation ≠ Cardiac Ablation

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

13. Impact of Irrigation on Lesion Size

14. Surrounding Structures
5 mm
5 mm

15. 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:
Hypertension. 2011;57:
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

16. 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

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

18. 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:
Confidential 18 18

19. SYMPLICITY HTN-2
Lancet. 2010;376:
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:
Confidential 19

20. 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 ; 57(5): 911-7
2Symplicity HTN-2 Investigators. Lancet 2010; 376:
Not approved for clinical use in the US or Japan 20

21. 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

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

23. 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
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24. Symplicity HTN-3 Study Design Flow
Treatment
Control
Primary Endpoint 6M 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

25. Office, Home and Ambulatory BP

26. 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…

28. Reimbursement

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

30. Age Distribution

31. 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

32. Utility Beyond Severe rHTN?