Innovations In Neuromodulation. Maged Guirguis, MD Director Of Research Pain Management

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1 Innovations In Neuromodulation Maged Guirguis, MD Director Of Research Pain Management 1

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3 Pain Pathway 3

4 Gate Theory In the dorsal horn (where pain signals relay), there is a gate that opens and closes to allow pain signals up to the brain. C and A delta fibers are small pain fibers. When their signals get to the brain, you feel pain A beta fibers are larger fibers that carry non painful signals (vibration, light touch, etc) When A beta fibers are stimulated, they close the gate, and signals from the smaller pain fibers cannot get up to the brain

5 Pathological Cascade Leading to Neuropathic Pain Dorsal horn Increased neuronal discharge from primary sensory neurons Increase EAA release Increased ATP, NO release Increased neural peptide release DRG Activate Activate surrounding surrounding glia glia Release Release proinflammatory proinflammatory cytokines cytokines Ultimately Ultimately stimulates stimulates neurons neurons Increased Increased membrane membrane excitability excitability CSF DR DRG SN Nerve Injury at periphery VR

6 SCS: Mechanisms of Action One of the main ways we believe SCS works is by utilizing this gate theory. SCS stimulates these A-beta fibers in the dorsal horn, so instead of patients feeling pain they feel a tingling/vibration sensation instead.

7 SCS: Mechanisms of Action Releases certain neurotransmitters that cause vasodilation- helpful for angina, PVD and CRPS Increases levels of GABA in patients with allodynia (CRPS), GABA levels are decreased in the CSF Blocks sympathetic outflow. For some CRPS patients, abnormal activity of the SNS is responsible for a lot of their symptoms, and SCS can help significantly with temperature and skin color changes as well as with pain.

8 Cost Effectiveness: FBSS

9 Cost Effectiveness: CRPS Compared to conventional medical management, SCS has an approximately 85% likelihood of being more cost effective for CRPS. Kumar et al. Current Challenges in Spinal Cord Stimulation. Neuromodulation 2014;17:22-35.

10 HIGH FREQUENCY STIMULATION 10

11 HF10 Therapy: Four Key Attributes 11 HF10 therapy is a combination of proprietary attributes

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13 Level I Study Design Study Name SENZA-RCT (registered in ClinicalTrials.gov - NCT ) Objective Provide evidence of safety and efficacy in support of U.S. market approval Design Comparative safety and effectiveness Parallel arms for traditional SCS and HF10 therapy Sample size estimation based on non-inferiority analysis Follows current, best practice guidelines Devices Test: Nevro Senza SCS system delivering HF10 therapy (10 khz stimulation) Control: Boston Scientific Precision Plus system delivering traditional SCS ( Hz)

14 SENZA-RCT Subject Flowchart Participants Assessed for Eligibility 43 Excluded 43 Screen Failures 198 Randomized 101 Assigned to HF10 therapy 97 trialed with SCS system 90 successful SCS trial 7 unsuccessful SCS trial 4 not trialed 2 medical contraindication 1 withdrew consent 1 lost to follow-up 97 Assigned to traditional SCS 92 trialed with SCS system 81 successful SCS trial 11 unsuccessful SCS trial 5 not trialed 4 withdrew consent 1 medical contraindication 90 implanted participants included in the 3 mo primary and 12 mo secondary analyses 81 implanted participants included in the 3 mo primary and 12 mo secondary analyses

15 Superior Responder Rates for Back and Leg Pain at 24 Months Responder Rates (Percentage of Patients Achieving 50% Pain Relief) SENZA-RCT: Patients Achieving 50% Pain Relief at 24 Months 100% 80% 76% 73% 60% 49% 49% n = 156 p-value back < p-value leg = % 20% 0% Back Pain Traditional SCS HF10 therapy Leg Pain

16 VAS (cm) Durable Back Pain Relief to 24 Months Back Pain VAS Score Reduction HF10 therapy Traditional SCS % relief % relief Assessment (mo) P<0.001 HF10 Therapy: Superior Back Pain All Time Points Measured

17 VAS (cm) Durable Leg Pain Relief to 24 Months Leg Pain VAS Score Reduction HF10 therapy Traditional SCS % relief % relief Assessment (mo) P=0.027 HF10 Therapy: Superior Leg Pain All Time Points Measured

18 DRG STIMULATION

19 Why target the DRG? Known mechanisms & processes: DRGs have been physician targets for pain relief for many years Predictable & accessible location in the epidural space within the neural foramen: easy target for neuromodulation by adapting current SCS needle techniques Limited Cerebrospinal Fluid (CSF) around the DRG allows the leads to be closer to the anatomical target & requires less energy to stimulate (compared to conventional SCS) Separation of sensory & motor nerve fibers prevents unintentional stimulation Image from: Gray s Anatomy (2005). Standring, S. (Ed.).

20 Why target the DRG? (cont d) DRGs Spinal Column T12 L1 Patient s Pain Traditional SCS DRG Stim L2 L3 L4 L5 Abdomen/Groin/Back Hip/Groin/Waist/Back Upper Leg & Low Back Lower & Upper Leg/Low Back Leg & Low Back Foot/Lower Leg/Low Back Well mapped & organized to corresponding anatomies allowing for highly focused treatment of pain

21 DRG stimulation & Somatosympathetic Reflexes Baseline Sympathetic Pre-Motor Neuron 1 month Adapted from: Loewy and Spyer, Central Regulation of Autonomic Function,

22 DRG stimulation addresses limits of conventional SCS Unstable Stimulation Unspecific Stimulation High Energy Usage Limited Cerebrospinal Fluid (CSF) around the DRG allows the leads to be closer to the anatomical target: significantly less postural effects and lower lead migration rates (compared to conventional SCS) Separation of sensory & motor nerve fibers prevents unintentional stimulation Well mapped & organized to corresponding anatomies allowing for highly focused treatment of pain Limited Cerebrospinal Fluid (CSF) around the DRG allows the leads to be closer to the anatomical target: less energy needed to stimulate sensory fibers (compared to conventional SCS)

23 ACCURATE Study A Prospective, Randomized, Multi-Center, Controlled Clinical Trial to Assess the Safety and Efficacy of the Axium Neurostimulator System in the Treatment of Chronic Intractable Pain Levy R and Deer T. NANS

24 ACCURATE: OBJECTIVE AND STUDY DESIGN Objective: To assess the safety and efficacy of DRG stimulation compared to a commercially available SCS device Multicenter, prospective, randomized, controlled trial Designed in conjunction with FDA input and considerations Non-inferiority study design w/subsequent superiority testing Subject devices programmed and optimized by appropriate medical and technical personnel Independent committee assessed adverse events Independent medical monitor assessed patient inclusion/exclusion criteria 24

25 Accurate: consort N = 152 Subjects Randomized (1:1) DRG (n =76) Control (n = 76) 152 subjects enrolled Randomized 1:1 ratio DRG vs. Trial Implant > 50% VAS reduction 1 Month Visit 3 Month Visit (Primary Endpoints) 6 Month Visit 9 Month Visit Trial Implant Control (commercially available SCS device) 22 Investigational sites 3 month Primary Endpoint Subject population Chronic, intractable pain of the lower limbs Complex Regional Pain Syndrome (CRPS) or Peripheral Causalgia 12 Month Visit 25

26 Primary Endpoint Success (MITT) Accurate Primary Endpoint: MITT 100% 90% 80% 70% 60% 50% 81.2% 55.7% 74.2% 53.0% Superiority Achieved P-value for non-inferiority at 3 months < % 30% 20% 10% P-value for superiority at 3 months % 3 months 12 months DRG (n=69 at 3 months, n=66 at 12 months) Control (n=70 at 3 months, n=66 at 12 months) 26

27 Implant Only Success (IO) Accurate Primary Endpoint: Implant Only 100% 90% 93.3% 86.0% Superiority Achieved 80% 70% 60% 50% 72.2% 70.0% P-value for non-inferiority at 3 months < % 30% 20% 10% P-value for superiority at 3 months % 3 months 12 months DRG (n=60 at 3 months, n=57 at 12 months) Control (n=54 at 3 months, n=50 at 12 months) 27

28 Accurate Primary Endpoint: Non- Inferiority and Superiority Superiority Non-Inferiority ITT % MITT % P = ; Superiority Implant Only % P = ; Superiority P = ; Superiority DRG group demonstrated superiority at 3 months in all analyses 28

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30 DRG Cases: 30

31 DRG Cases: 31

32 DRG Cases: 32

33 BURST STIMULATION CAUTION: Investigational device and is not available for sale in the U.S. 33

34 Spinal Cord Stimulation Waveforms Traditional Tonic Relatively low energy Recharge every 1-2 weeks Burst Stimulation* Parameters within traditional ranges Low-moderate energy Average recharge similar to tonic Device provides both tonic & burst 1 Same projected device life as traditional tonic 1 High Frequency Stimulation Parameters outside the traditional ranges Highest energy, daily recharge Device only provides tonic stimulation at programmable frequencies (up to 10,000hz) 2 Reduced projected device life compared to traditional tonic *CAUTION: Investigational device and is not available for sale in the U.S.

35 SUNBURST IDE study Study Design Overview Subjects randomized to Burst or tonic stimulation modes in a crossover study design Patient Indication Intractable pain of the trunk and/or limbs Primary Efficacy Endpoint Secondary Efficacy Endpoint Change in average daily pain (VAS) between Tonic and Burst Presence of paresthesia Quality of Life Status First patient enrollment January 2014 Enrollment completed Q Submission 2H 2015 PMA Submission 2H 2015 *CAUTION: Investigational device and is not available for sale in the U.S. 35

36 Consort SUNBURST Consented (N=173) Completed Tonic Evaluation (N = 121) Randomized (N = 100) 52 Did not meet Inclusion/Exclusion 9 Failed Tonic Trial 12 Exited for Other Reasons Burst / Tonic (N = 55) Tonic / Burst (N = 45) Completed 24 Week Visit (N = 85) CAUTION: Investigational device and is not available for sale in the U.S.

37 Conclusion: SUNBURST Study Preliminary report: NANS 2015 Provided pain relief superior to tonic for overall, trunk, and limb pain Resulted in reduced or eliminated paresthesia in 91% of patients Even though all patients had successful trials with tonic stimulation, Burst was preferred by a majority of patients (69%) *CAUTION: Investigational device and is not available for 3 sale in the U.S. 7

38 Growing evidence for Burst therapy Significantly improved pain outcomes More than 70% of patients preferred Burst over tonic SCS with better pain relief cited as the primary reason Almost 95% of tonic responders experienced a greater reduction in NRS score during Burst stimulation Provided pain relief superior to tonic for overall, trunk, and limb pain 6 Demonstrated ability to rescue prior failures 62.5% of non-responders responded to Burst Preferred by patients while preserving patient choice (Upgradable IPG platform) 69% of patient preferred Burst (p<0.001) 9 However, 21% of patients still preferred Tonic stimulation and only SJM can provide both options in a single solution 9 Improved workflow- simplified programming Burst was ½ the office visits, 1/10 the time CAUTION: Investigational device and is not available for sale in the U.S.

39 EXCITEMENT IN 2017? Foldable leads for less invasive implants Navigation for radiation reduction and improved visibility Ultra miniaturized stimulation technology

40 THANK YOU! 40