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ORIGIN AND BACKGROUND

The iovera° System

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Cryotherapy

• Local or general use of low temperatures in medical therapy

• The application of cold to nerve tissues blocks conduction of pain signals from the pain receptor to the brain

– similar to the effect of local anesthetics

• When applied to nerves, it is referred to as cryoneurolysis

– Also known as Cryoanalgesia or Cryoneuromodulation

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The History Of Cryotherapy

460 – 377 BC Hippocrates Analgesic and anti-inflammatory properties

1819 – 1879 James Arnott Palliative tumor treatment

1899 Campbell White First to employ refrigerants for medical use

1950 Allington 1st use liquid nitrogen

1961 Cooper et al. Developed device with liquid nitrogen Reached -190°C

Cooper SM, Dawber RPR. “The history of cryosurgery.” J R Soc Med. 2001 April; 94(4): 196–201

1967 Amoils

Used CO2 or N2O

Reached -70°C

1976 Lloyd et al. Cryoanalgesia superior to other methods of peripheral nerve destruction Not followed by neuritis or neuralgia

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MECHANISM OF ACTION

The iovera° System

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Nerve Anatomy

A nerve is an enclosed, cable-like bundle of axons (the long, slender projections of neurons) in the peripheral nervous system

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Nerve Anatomy

• Endoneurium - layer of connective tissue

surrounding each axon

• Perineurium - layer of connective tissue

surrounding each fascicle (axons are bundled together into

fascicles)

• Epineurium - layer of connective tissue ensheathing the entire

nerve

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Reversible

1st Degree Neuropraxia – Interruption of conduction; Short recovery time +10 to -20°C

2nd Degree Axonotmesis – Loss of continuity of the axon; Wallerian degeneration; Preservation of endo- peri- and epineurium

-20°C to -100°C

iovera° therapy

Non Reversible

3rd/4th Degree Neurotmesis – Loss of continuity; Some loss of continuity of epineurium and perineurium

-140C and colder

Not possible with iovera°

5th Degree Transection (Severe Neurotmesis) – Gross loss of continuity

Not possible with iovera°

Sunderland Nerve Injury Classification

Mechanism research of cryoanalgesia. Zhou L, et al S. Neurol Res 1995; 17:307-311. Nerves and Nerve Injuries. Sunderland S Edinburgh & London: Livingstone, 1968: 180.

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Mechanism of Action

The iovera° System

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TREATMENT A cold zone is created, lowering the temperature to below -20°C.

DEGENERATION Cold zone causes degeneration of the axon and myelin sheath, temporarily blocking nerve signals.

REGENERATION Post-treatment, the axon regenerates at the rate of about 1mm per day.*

REINNERVATION The axon and myelin sheath are fully regenerated and nerve signaling is restored.

*Evans, et al. Br J Anaesth. 1981 53(11):1121-7. Note: Motor nerve depicted; same Mechanism of Action for sensory nerves

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With the iovera° system

Axonotmesis

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Mechanism of Action Video

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Safe and Effective

The iovera° System

• Mechanism of action is well understood – Nerves reliably degenerate and then regenerate

• Decades of safe clinical experience – Used for chronic and post-op pain since the 1970s

– Similar concept as using a cold pack to numb skin

• 2nd degree nerve injury results in Wallerian degeneration of peripheral nerves: – Degeneration of the axons and dedifferentiation of the

myelin sheaths

– Regeneration ensues with proliferation and differentiation of the myelin sheaths, shortly followed by the regeneration of axons

– The newly regenerated axon will mature to its original state

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TECHNOLOGY

The iovera° System

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Traditional Cryo system The iovera° System

Large Handheld

Complicated Simple + Intuitive

Tissue ablative Precise

Invasive procedure Minimally invasive treatment

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Revolutionized cryotherapy platform

The iovera° System

Simple percutaneous treatment, using proven cold therapy, designed to relieve pain

• Immediate, safe, effective

• Non-opioid, non-systemic

• Long-lasting nerve block

• Well-established billing code

• Cleared to treat the pain and symptoms of osteoarthritis

• Can target nerve location via nerve stimulation (90mm tip only)

Family of Smart Tips allow access to peripheral nerves

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Smart Tips

Smart & Sophisticated

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• 3-pronged, 27-gauge needles, 6.9 mm long

• Superficial nerves

─ Branches of the femoral cutaneous and infrapatellar branches of the saphenous nerves around the anterior region of the knee

• 22-gauge needle, 55 mm long

• For deeper nerves

─ Branches of the tibial and common peroneal nerves in the posterior region of the knee

• 20-gauge needle, 90 mm long

• For deep nerves

─ Posterior nerves of the knee

• Trocar tip facilitates easy tissue navigation

• Allows for the attachment of nerve stim for more precise nerve targeting

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Liquid refrigerant expands to gas cooling tissue at tip

forming precise cold

zone

Cold zone forms

Gas exits into handpiece Nothing is injected into the body

Liquid N2O Cartridge

>850psi (6000kPa)

Flow control

valve

Skin warmer

Micro-needles

Closed end tips

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Cold

zone

Gas exits handpiece

Liquid N2O Cartridge >850psi

Flow control valve

Skin warmer

Needles with closed end tips

The iovera˚ Handpiece Treatment delivered by a handheld device

Cycle begins

Cold zone forms

With the press of a button, the iovera˚ device precisely delivers Focused Cold Therapy to target peripheral nerves

• Non-opioid and non-systemic

• Immediate pain relief

• Minimal adverse side effects (consistent with needle insertion)

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Precise Dose Control

2% Agarose Gel Mimicking Tissue

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Visual of 3x6.9mm Smart Tip; other Smart Tips operate with the same cycle phases

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US (FDA)

Indications for Use

The Myoscience iovera° system is used to destroy tissue during surgical procedures by applying freezing cold. It can

also be used to produce lesions in peripheral nervous tissue by the application of cold to the selected site for the blocking of pain. It is also indicated for the relief of pain and symptoms

associated with osteoarthritis of the knee for up to 90 days. The iovera° system is not indicated for treatment of central nervous system tissue.

The iovera° system’s “1x90” Smart Tip configuration (indicating one needle which is 90 mm long) can also facilitate target nerve location by conducting electrical nerve

stimulation from a separate nerve stimulator.

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EFFECTIVENESS AND SAFETY DATA

The iovera° System

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Peripheral Nerve Degeneration

The iovera° System

Pre-clinical results from MYO-0448; Rat motor nerve model

10X 10X

Untreated 1 Week

Hematoxylin and eosin staining of rat tissue

Histological results demonstrate disruption of peripheral nerves as a result of cryoanalgesia. Absence of axon post-treatment is responsible for the disruption in nerve signaling, while the intact structural nerve tissues, the epineurium and the perineurium, ensure that the nerve regenerates along the same path.

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Axon Regeneration

The iovera° Technology

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0

2500

5000

7500

10000

12500

15000

17500

Ax

on

s/m

m^

2

Axon Density Measurements

8 Week

2 Week

4 Week

Untreated Tissue

40x

40x 40x

40x Rat Nerve Immunohistochemistry

Green = Axon Red = Myelin Sheath Blue = Macrophages

Pre-clinical results from MYO-0316; Hsu and Stevenson. J. Neural Transm. 2014 121:15-20.

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Safety: Effect on Adjacent Tissues

• Short intense cooling spares surrounding tissues

• No injury/inflammation observed among hair follicles,

sebaceous glands or sweat glands

Pre-clinical results from MYO-0762 and MYO-0890

Erector Pili muscle

Sebaceous gland

Hair follicle

120 sec Cooling, 11 Days Post-Tx 120 sec Cooling, 12 Days Post-Tx

Sweat gland

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Safety: Effect on Adjacent Tissues

• At 8-32 weeks post-treatment, blood vessels, fat tissue, and surrounding muscles appeared normal1

• Transient injury to muscle fully recovers within 2-3 weeks2

• Negligible fat cell necrosis observed, <0.1%

volume @ 5mm; no fat cell apoptosis2

• Lumens of the small arterioles in proximity to the treatment site remained patent1

1 Hsu M, Stevenson F. Wallerian Degeneration and Recovery of Motor Nerves After Multiple Focused Cold Therapies. Muscle & Nerve (2015) 2 Pre-clinical results from MYO-0762 and MYO-0890

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CLINICAL STUDIES

The iovera° System

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iovera° Osteoarthritis Study

Multicenter, Prospective, Sham-Controlled, Double-Blind • 17 sites across the US,

• n = 180 (randomized 2:1)

• Control Group = 59 subjects treated with a sham tip

• Treatment Group = 121 subjects treated with iovera°

Methods: • Treatment of the ISN only, follow-ups at 30,

60, 90, 120 days.

• Subjects demonstrating effect at 120 and 150 days followed to 150 and 180 days, respectively

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Radnovich, et al. Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial. Osteoarthritis and Cartilage 2017 (25); 1247-1256.

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iovera° Osteoarthritis Study • The iovera° group demonstrated a statistically significant greater

change from baseline in the WOMAC Total score than the sham group at Days 30, 60 and 90

• Patients deemed WOMAC pain responders at Day 120 continued

to experience a statistically significant effect at Day 150

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54% 52%

55%

32%

37% 37%

0%

10%

20%

30%

40%

50%

60%

Day 30 Day 60 Day 90

Pai

n R

ed

uct

ion

WOMAC Total

iovera° sham

p<0.0010 p<0.0359 p<0.0108

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iovera° Osteoarthritis Study

• The results exceeded the minimal

clinically important difference (MCID) for the effect of treatment

• i.e. The treatment was not only statistically significant, but also clinically significant

• Most expected side effects were

mild in severity and resolved within 30 days

• FDA-Cleared for: “the relief of

pain and symptoms associated with osteoarthritis of the knee for up to 90 days”

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Pre-TKA iovera° Retrospective Study

Single site (LSU), Retrospective Review, n = 100

• Control Group = Last 50 patients treated before iovera° introduced

• Treatment Group = First 50 patients treated after iovera° introduced

Methods: iovera° treatment of the ISN and

AFCN 5 days prior to TKA

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Dasa, et al. Percutaneous freezing of sensory nerves prior to total knee arthroplasty. Knee. 2016 Jun;23(3):523-8.

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Pre-TKA iovera° Retrospective Study

Results for the iovera° group:

• Required 45% less opioids during the first 12 weeks after surgery based on prescription requests

• Demonstrated a significantly lower proportion of patients with a LOS of ≥2days compared with the control group (6% vs. 67%, p<0.0001)

• Reported a statistically significant reduction in symptoms at the six- and 12-week follow-up compared with the control group

• Reported within-group significant reductions in pain intensity and pain interference at two- and six-week follow-up, respectively

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Dasa, et al. Percutaneous freezing of sensory nerves prior to total knee arthroplasty. Knee. 2016 Jun;23(3):523-8.

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Pre-TKA Feasibility Study Results:

• Subjects who received cryoneurolysis at single surgeon sites with highly standardized practices (perioperative treatment, surgical technique and in-patient pain management) demonstrated:

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Results from study MYO-1070, manuscript draft currently under review by investigators

– A statistically significant difference in cumulative opioid use with respect to the sham group at 4 weeks post-TKA (p=0.0258)

– A similar trend in cumulative opioid consumption at 6 weeks (p=0.0520) and 12 weeks (p=0.0565) post-TKA

– Over the 12 week follow-up period, a 36% reduction in average opioids consumed compared to the sham group

• No significant differences in adverse event report rates or hospital readmit rates between the control and treatment groups for the entire study population

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TREATMENT: KNEE PAIN

The iovera° System

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Patient Assessment

Patient Preparation

• Measure baseline pain levels (VAS, etc.)

• Identify activities limited by pain

– Deep knee bends, stairs, rising from chair

– Will be used post treatment to verify treatment success

• Identify locations on knee that are painful upon palpation or movement

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Knee pain in anterior inferior

portion of the knee:

consider treating the ISN

Knee pain in anterior superior

portion of the knee:

consider treating the AFCN

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AFCN: Anterior Femoral Cutaneous Nerve

Treatment Marking

Anterior, superior knee pain 1. Find and mark the center of the patella

2. Draw a line to the inguinal crease in the thigh; measure the line and calculate 1/3

3. Starting at the center of the patella (1), measure the 1/3 calculation, and mark on the line (2)

4. Draw a dotted line on each side of the patella

5. Draw a solid line between the dotted lines (4), at the 1/3 mark (3)

This is your treatment line

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Not to scale

1

3

2

4 4

5

Med

ial

Late

ral

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ISN: Infrapatellar Branch of the Saphenous Nerve

Treatment Marking

Anterior, inferior knee pain 1. Find and mark the lower pole of the

patella

2. Draw a line 5 cm medial

3. Find and mark the bottom of the tibial tubercle

4. Draw a line 5 cm medial

5. Draw a straight vertical line between

the horizontal lines (2 and 4) on the medial side of the knee

This is your treatment line

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Not to scale

1

3

2

4

5

Med

ial

Late

ral

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Treatment

• Administer anesthetic – E.g. Lidocaine or Marcaine

– Along identified treatment line

• Insert Smart Tip

• Perform treatment cycle

• Move to adjacent site on treatment line (overlapping one needle)

• May also use ultrasound guidance

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Treatment Technique

Treatment

AFCN

Treat from A to B along the treatment line

– Use dotted lines as boundaries

– Apply pressure during treatment

• If relief is not achieved:

– Continue treating towards the inside (medially) of the thigh

– In some cases, the nerve may be at a depth unreachable by the Smart Tip

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Not to scale

A B

Med

ial

Late

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Treatment Technique

Treatment

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Not to scale

Med

ial

Late

ral

A

B

ISN

Treat from A to B along the treatment line

• If relief is not achieved:

– Continue treating inferior to the treatment line (not exceeding 1cm past B)

– Exercise caution; other nerves may reside in area

• If relief is still not achieved:

– Treat superior to the treatment line until relief is achieved (not exceeding the mid-

line patella)

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Safe and Effective

The iovera° System

• Mechanism of action is well understood – Nerves reliably degenerate and then regenerate

• Decades of safe clinical experience – Used for chronic and post-op pain since the 1970s

– Similar concept as using a cold pack to numb skin

• 2nd degree nerve injury results in Wallerian degeneration of peripheral nerves: – Degeneration of the axons and dedifferentiation of the

myelin sheaths

– Regeneration ensues with proliferation and differentiation of the myelin sheaths, shortly followed by the regeneration of axons

– The newly regenerated axon will mature to its original state

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