Results of the Burst Trial

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Results of the Burst Trial: A Prospective, Randomized, Controlled Trial Assessing Burst Stimulation for the Treatment of Chronic Pain Timothy R. Deer, MD Peter S. Staats, MD Representing the Burst investigators

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Disclosures • Timothy Deer is a consultant for Axonics, Bioness, St Jude Medical, Saluda, Medtronic, Nevro, Nuvectra, Flowonix, Vertos, and Jazz – Minority Stock options: Axonics, Bioness, Nevro, Vertos, Saluda – Previous stock options: Spinal Modulation – Funded research by St Jude Medical, Nevro, Jazz, and Saluda

• Peter Staats is a consultant for St Jude, Medtronic Nevro, Boston Scientific – Board of Director and minority ownership: ElectroCore Medical – Research funded by Medtronic, St Jude Medical, Boston Scientific, Saluda, Grunenthal, Nevro, and Bioness 12/23/2015

Caution: The Burst waveform is investigational and not available in the U.S.

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Burst Investigators and Steering Committee Principal Investigators Kasra Amirdelfan, MD Allen Burton, MD Vu Dang, MD Bart Edmiston, MD Alain Fabi, MD Steven Falowski, MD Timothy Houden, MD Rafael Justiz, MD Christopher Kim, MD Camden Kneeland, MD Carroll Mcleod, MD Gregory Phillips, MD Julie Pilitsis, MD

Phillip Smith, DO Alexander Taghva, MD Edward Tavel, MD Jacob Vella, MD Derron Wilson, MD Thomas Yearwood, MD Steering Committee: Timothy Deer, MD Richard North, MD Konstantin Slavin, MD Peter Staats, MD

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Background

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Current Neuromodulation Dynamics • Increasing stigma and negative outcomes from long-term opioid use in chronic pain – Diversion – Abuse – Overdose • Growing evidence for improved outcomes and healthcare economics with earlier intervention – Kumar’s last work – NACC • Significant opportunities for growth of Patient access: – SCS innovation – Novel stimulation modes and new anatomical targets provide differentiation from our previous therapies

Burst Stimulation Mimics Natural Neuronal Signaling • Burst firing is a naturally occurring signaling modality in human physiology and is interpreted differently by the nervous system1,2,3. • Thalamic cells can fire in tonic and burst modes1. • Thalamic burst firing considered a more potent activator of the cortex2,3.

1. 2. 3.

Jahnsen H, Llinás R. : Voltage-dependent Burst-to-tonic switching of thalamic cell activity: an in vitro study. Arch Ital Biol. 1984 Mar;122(1):73-82. Harvey A. Swadlow1 & Alexander G. Gusev : The impact of 'Bursting' thalamic impulses at a neocortical synapse. Nature Neuroscience 4, 402 - 408 (2001). Sherman SM : A wake-up call from the thalamus. Nature neuroscience, 2001

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Burst Stimulation Current Hypothesis: Burst stimulation may exert its main effect through an ability to modulate both lateral & medial pathways4

Lateral Pathway

Medial Pathway

(Ongoing Burst sub-study using PET and EEG to identify pathways during stimulation) 4. De Ridder D, et al. World Neurosurgery 2013.

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Artistic representation of the neuron/synapse 9

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Burst Trial Design

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Objectives • Demonstrate the safety and effectiveness of a neurostimulation system that delivers both Burst and tonic stimulation • Demonstrate non-inferiority of overall pain with Burst versus tonic stimulation

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Trial Design • Multi-center, prospective • Randomized (1:1) • Crossover design (each subject was their own control) • 76 subjects required to perform primary endpoint analysis • Each patient had a device that could deliver both tonic and Burst stimulation

Randomization

Burst (12 weeks)

Tonic (12 weeks)

Tonic (12 weeks)

Burst (12 weeks)

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Inclusion/Exclusion Key Inclusion Criteria: • Successful SCS tonic trial (>50% pain relief) system evaluation • Chronic, intractable pain of trunk and/or limb • Average 7-day VAS of 60 mm or higher prior to SCS tonic trial • Stable pain medications

Key Exclusion Criteria: • More than mild depression symptoms (BDI>24) • History of substance abuse 14

Endpoints Primary Endpoint: • Non-inferiority of Burst: Difference in overall VAS (mm) between Burst and Tonic (within subject controls)

Secondary Endpoint • Superiority of Overall VAS • Superiority of Trunk VAS • Superiority of Limb VAS • Paresthesia coverage • Preference

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Consort

Consented (N=173) 52 Did not meet Inclusion/Exclusion

Completed Tonic Evaluation (N = 121) 9 Failed Tonic Trial 12 Exited for Other Reasons

Randomized (N = 100)

Burst / Tonic (N = 55)

Tonic / Burst (N = 45)

Completed 24 Week Visit (N = 85)

Subjects • • • •

Age 59.1 (± 13.5) years 12.8 (± 10.9) years of pain 60% Female Conditions: – –

42% FBSS 37% Radiculopathies

• Overall baseline VAS = 75.1 mm • Mental Health: – –

Mean BDI 10.1.(±6.0) with 75% having no depression Not clinically meaningful catastrophizing Mean PCS 20.2 (±11.8) 17

Results

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Primary Endpoint: Pain Intensity Superiority

Overall VAS

p = 0.035; Superiority

Trunk VAS

p = 0.024; Superiority

Limb VAS

p = 0.044; Superiority

-10

-6

-8

Inferior

Non-inferiority

-4

-2

0

2

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Mean Difference of Burst VAS - Tonic VAS (mm)

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Preferred Therapy Type: Percentage of Patients A significantly higher proportion of patients preferred Burst (p<0.001).

100% 90% 80% 70% 60%

69.4%

50% 40% 30% 20%

21.2% 9.4%

10% 0% Burst (n=59)

Tonic (n=18)

No Preference (n=8)

Paresthesia Reduction: SUNBurst™ Burst Compared With Tonic Secondary Endpoint

100%

100% of subjects reported paresthesia during tonic stimulation

91%

90% 80%

70%

65% Eliminated

91% of subjects reported a decrease in paresthesia during Burst relative to tonic

60% 50% 40% 30% 20% 10%

26% Reduced

9%

Eliminated or reduced

No reduction

0%

65% of subjects had no paresthesia while using Burst

Reasons for Preference Preferred Burst (n=59)

Preferred Tonic (n=18) 33.7%

Better Pain Relief

10.3%

37.5%

Lack of Paresthesia

1.4%

1.5%

Preferred Paresthesia

10.3%

3.8% 1.4%

Other 0%

5%

10%

15%

20%

25%

Percentage of Patients

30%

35%

40%

Adverse Events • No unanticipated adverse events were reported • Similar adverse event profile to other SCS studies • Rates similar for both stimulation modes

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Adverse Events Number of events

% Subjects

Unanticipated

0

0%

Serious Events Related to the Device or Procedures

2

1.1%

Procedure-Related

4

2.3%

Device- or Stimulation-Related

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16.2%

Description

Key Takeaways • Burst Stimulation provided superior pain relief vs. tonic for overall, trunk, and limb pain • Burst stimulation was preferred by the majority of patients (69%) • Burst stimulation eliminated or reduced paresthesia in 91% of subjects • There are patients who prefer paresthesia • Each patient experienced both stimulation modes (tonic and Burst) and chose their preferred mode

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Thank you

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