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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 The iovera° System • When applied to nerves, it is referred to as ORIGIN AND BACKGROUND cryoneurolysis – Also known as Cryoanalgesia or Cryoneuromodulation

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The History Of Cryotherapy

1800 1900

1950 Allington 460 – 377 BC 1st use Hippocrates 1961 liquid Cooper et al. Analgesic and anti- nitrogen inflammatory Developed 1967 properties device with liquid Amoils nitrogen Used CO or N O 1976 Reached -190°C 2 2 1819 – 1879 Reached -70°C Lloyd et al. James Arnott Cryoanalgesia

Palliative tumor superior to other The iovera° System treatment methods of 1899 peripheral nerve Campbell White destruction First to employ Not followed by MECHANISM OF ACTION refrigerants for neuritis or medical use neuralgia

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

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Nerve Anatomy Nerve Anatomy

• Endoneurium - layer A nerve is an of connective tissue enclosed, cable-like surrounding each bundle of • - layer of (the long, slender connective tissue surrounding each projections of fascicle (axons are neurons) in the bundled together into peripheral nervous fascicles) system • - layer of connective tissue ensheathing the entire nerve

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Sunderland Nerve Injury The iovera° System Classification Mechanism of Action Reversible 1st Degree Neuropraxia – Interruption of conduction; Short recovery time +10 to -20°C

nd 2 Degree -20°C – Loss of continuity of the axon; ; to -100°C Preservation of endo- peri- and epineurium iovera° therapy Non Reversible 3rd/4th Degree -140C and – Loss of continuity; Some loss of continuity of epineurium colder and perineurium Not possible with iovera° 5th Degree TREATMENT DEGENERATION REGENERATION REINNERVATION Not possible A cold zone is Cold zone causes Post-treatment, the The axon and Transection (Severe Neurotmesis) – Gross loss of continuity with iovera° created, lowering degeneration of the axon and axon regenerates at sheath are fully the temperature myelin sheath, temporarily the rate of about regenerated and nerve to below -20°C. blocking nerve signals. 1mm per day.* signaling is restored. 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. *Evans, et al. Br J Anaesth. 1981 53(11):1121-7. MKT-0007 Rev F 7 MKT-0007 Rev F Note: Motor nerve depicted; same Mechanism of Action for sensory nerves 8

Axonotmesis The iovera° System With the iovera° system Safe and Effective

• 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 Mechanism of Action Video

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Traditional Cryo system The iovera° System

The iovera° System Large Handheld TECHNOLOGY Complicated Simple + Intuitive Tissue ablative Precise

Invasive procedure Minimally invasive treatment

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The iovera° System Smart & Sophisticated Revolutionized cryotherapy platform Smart Tips Simple percutaneous treatment, using proven cold therapy, designed to relieve pain

• Immediate, safe, effective • 3-pronged, 27-gauge needles, 6.9 mm long • 22-gauge needle, 55 mm long • Non-opioid, non-systemic • Superficial nerves • For deeper nerves • Long-lasting nerve block ─ Branches of the femoral cutaneous and ─ Branches of the tibial and common infrapatellar branches of the saphenous peroneal nerves in the posterior region of • Well-established billing code nerves around the anterior region of the the knee • Cleared to treat the pain and symptoms of osteoarthritis knee • Can target nerve location via nerve stimulation (90mm tip only) • 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 Family of Smart Tips allow access to peripheral nerves more precise nerve targeting

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Liquid N2O Cartridge Liquid The iovera˚ Handpiece >850psi refrigerant expands to Treatment delivered by a handheld device (6000kPa) gas cooling tissue at tip forming precise cold With the press of a button, zone Liquid N2O the iovera˚ device precisely Cartridge delivers Focused Cold >850psi Therapy to target peripheral Flow Gas exits into nerves control handpiece valve Nothing is Closed Cycle begins injected into end tips Flow control valve the body • Non-opioid and non- Gas exits systemic handpiece • Skin warmer Immediate pain relief • Minimal adverse side Skin warmer effects (consistent with Micro-needles Needles with needle insertion)

closed end tips Cold zone Cold zone Cold zone forms forms

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Precise Dose Control Indications for Use US (FDA)

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.

2% Agarose Gel Mimicking 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.

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

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The iovera° System Peripheral Nerve Degeneration

Untreated 1 Week

The iovera° System

EFFECTIVENESS AND SAFETY DATA Hematoxylin and eosin staining of rat tissue 10X 10X

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.

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

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The iovera° Technology Safety: Effect on Adjacent Tissues Axon Regeneration • Short intense cooling spares surrounding tissues Untreated 2 Week Tissue Axon Density Measurements • No injury/inflammation observed among hair follicles, sebaceous glands or sweat glands 17500 15000

12500 40x 40x 10000 4 Week 8 Week 7500

5000 Sebaceous gland Axons/mm^2 2500 Hair follicle Sweat gland 0

Erector Pili muscle 40x 40x Rat Nerve Immunohistochemistry 120 sec Cooling, 11 Days Post-Tx 120 sec Cooling, 12 Days Post-Tx Green = Axon Red = Myelin Sheath Blue = Macrophages

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

• At 8-32 weeks post-treatment, blood vessels, fat

tissue, and surrounding muscles appeared normal 1 • Transient injury to muscle fully recovers within 2- 3 weeks2 • Negligible fat cell necrosis observed, <0.1% volume @ 5mm; no fat cell apoptosis2 The iovera° System • Lumens of the small arterioles in proximity to the treatment site remained patent1 CLINICAL STUDIES

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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iovera° Osteoarthritis Study iovera° Osteoarthritis Study • The iovera° group demonstrated a statistically significant greater Multicenter, Prospective, Sham- change from baseline in the WOMAC Total score than the sham Controlled, Double-Blind group at Days 30, 60 and 90 • 17 sites across the US, • Patients deemed WOMAC pain responders at Day 120 continued • n = 180 (randomized 2:1) to experience a statistically significant effect at Day 150

• Control Group = 59 subjects treated with a sham tip WOMAC Total • Treatment Group = 121 subjects treated with 60%

iovera° p<0.0010 p<0.0359 p<0.0108 50% 54% 55% 52%

Methods: 40% 37% 37% 30% • Treatment of the ISN only, follow-ups at 30, 32% 60, 90, 120 days.

Pain Reduction Pain 20% • Subjects demonstrating effect at 120 and 150 days followed to 150 and 180 days, 10% respectively 0% Day 30 Day 60 Day 90 Radnovich, et al. Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham- iovera° sham controlled trial. Osteoarthritis and Cartilage 2017 (25); 1247-1256. Radnovich, et al. Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, 26 randomized, double-blind, sham-controlled trial. Osteoarthritis Cartilage 25:1247-1256. 2017 MKT-0007 Rev F 25 MKT-0007 Rev F

iovera° Osteoarthritis Study Pre-TKA iovera° Retrospective Study • The results exceeded the minimal clinically important difference (MCID) for the effect of Single site (LSU), Retrospective treatment Review, n = 100 • i.e. The treatment was not only statistically significant, but also • Control Group = Last 50 patients treated clinically significant before iovera° introduced • Treatment Group = First 50 patients treated • Most expected side effects were after iovera° introduced

mild in severity and resolved within 30 days Methods: iovera° treatment of the ISN and • FDA-Cleared for: “the relief of AFCN 5 days prior to TKA pain and symptoms associated with osteoarthritis of the knee for up to 90 days”

Dasa, et al. Percutaneous freezing of sensory nerves prior to total knee arthroplasty. Knee. 2016 Jun;23(3):523-8. 28 MKT-0007 Rev F MKT-0007 Rev F

Pre-TKA iovera° Retrospective Study Pre-TKA Feasibility Study Results: Results for the iovera° group: • Subjects who received cryoneurolysis at single surgeon sites with highly • Required 45% less opioids during the standardized practices (perioperative treatment, surgical technique and in- first 12 weeks after surgery based on patient pain management) demonstrated: prescription requests

– A statistically significant difference in • Demonstrated a significantly lower cumulative opioid use with respect to the proportion of patients with a LOS of sham group at 4 weeks post-TKA ≥2days compared with the control (p=0.0258) group (6% vs. 67%, p<0.0001)

– A similar trend in cumulative opioid • Reported a statistically significant consumption at 6 weeks (p=0.0520) and reduction in symptoms at the six- and 12 weeks (p=0.0565) post-TKA 12-week follow-up compared with the control group – Over the 12 week follow-up period, a 36%

reduction in average opioids consumed compared to the sham group • Reported within-group significant reductions in pain intensity and pain interference at two- and six-week • No significant differences in adverse event report rates or hospital follow-up, respectively readmit rates between the control and treatment groups for the entire study population

Dasa, et al. Percutaneous freezing of sensory nerves prior to total knee arthroplasty. Knee. 2016 Results from study MYO-1070, manuscript draft currently under review by investigators Jun;23(3):523-8. MKT-0007 Rev F 29 MKT-0007 Rev F 30

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Patient Preparation Patient Assessment

• 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 The iovera° System Knee pain in anterior inferior Knee pain in anterior superior TREATMENT: KNEE PAIN portion of the knee: portion of the knee: consider treating the ISN consider treating the AFCN

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Treatment Marking Treatment Marking AFCN: Anterior Femoral Cutaneous Nerve ISN: Infrapatellar Branch of the Saphenous Nerve

Anterior, superior knee pain Anterior, inferior knee pain 1. Find and mark the center of the patella 2 1. Find and mark the lower pole of the 2. Draw a line to the inguinal crease in the patella thigh; measure the line and calculate 1/3 5 2. Draw a line 5 cm medial 3. Starting at the center of the patella (1), measure the 1/3 calculation, and mark on 3 3. Find and mark the bottom of the tibial the line (2) tubercle 2 1 4. Draw a dotted line on each side of the 4 4 4. Draw a line 5 cm medial patella 5. Draw a straight vertical line between 5 5. Draw a solid line between the dotted lines the horizontal lines (2 and 4) on the 3

(4), at the 1/3 mark (3) medial side of the knee 4

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Medial Medial Lateral This is your treatment line Lateral Not to scale This is your treatment line Not to scale

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Treatment Treatment Treatment Technique

• Administer anesthetic AFCN – E.g. Lidocaine or Marcaine Treat from A to B along the treatment – Along identified treatment line line – Use dotted lines as boundaries • Insert Smart Tip A B – Apply pressure during treatment • Perform treatment cycle • Move to adjacent site on • If relief is not achieved: treatment line – Continue treating towards the inside (overlapping one (medially) of the thigh

needle) – In some cases, the nerve may be at a

• May also use ultrasound depth unreachable by the Smart Tip Medial Lateral guidance Not to scale

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Treatment The iovera° System Treatment Technique Safe and Effective

ISN • Mechanism of action is well understood Treat from A to B along the treatment line – Nerves reliably degenerate and then regenerate • Decades of safe clinical experience • If relief is not achieved: – Used for chronic and post-op pain since the 1970s – Continue treating inferior to the – Similar concept as using a cold pack to numb skin treatment line (not exceeding 1cm past B) A – Exercise caution; other nerves may • 2nd degree nerve injury results in Wallerian reside in area degeneration of peripheral nerves: • If relief is still not achieved: B – Degeneration of the axons and dedifferentiation of the myelin sheaths

– Treat superior to the treatment line until

relief is achieved (not exceeding the mid- – Regeneration ensues with proliferation and differentiation

line patella) of the myelin sheaths, shortly followed by the regeneration Medial Lateral of axons Not to scale – The newly regenerated axon will mature to its original state

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