Roadmap to Active Healing. Indications* The EXOGEN ® Ultrasound Bone Healing System, is indicated for the non-invasive treatment of established non-unions†

Roadmap to Active Healing

Indications*The EXOGEN® Ultrasound Bone Healing System, is indicated for the non-invasive treatment of established non-unions† excluding skull and vertebra.

In addition, EXOGEN is indicated for accelerating the time to a healed fracture for fresh, closed, posteriorly displaced distal radius fractures and fresh, closed or Grade I open tibial diaphysis fractures in skeletally mature individuals when these fractures are orthopedically managed by closed reduction and cast immobilization.

There are no known contraindications for the EXOGEN device. Safety and effectiveness has not been established for individuals lacking skeletal maturity; pregnant or nursing women; patients with cardiac pacemakers; on fractures due to bone cancer; or on patients with poor blood circulation or clotting problems. Some patients may be sensitive to the ultrasound gel. A non-union is considered to be established when the fracture site shows no visibly progressive signs of healingEXOGEN is a registered trademark of Bioventus LLC

Customers Categories

Title Description Usage Number

EXOGEN Users

Use EXOGEN regularly and appropriately

2.5 units/month

350

EXOGEN Dabblers

Use EXOGEN as their BGS of choice, but only as for “last resort” cases

1 unit/2 months

7,800

Spreaders Use whatever BGS is available. They are all the same

Variable 9,300

E-Stim users

Use only E-stim. Variable 8,000

Non BGS users

Haven’t prescribed in last 2 years.

Zero 3,900

Each territory has on average 30+ dabblers.Each dabbler converted to a “user” is worth $60k per yearPotential is therefore $1.8m per rep or $450m nationallyHow can you use EXOGEN science to realize some of this potential?

But….Don’t Forget The Spreaders

You have the key messages and tools with which to convince them:

•Unique Technology•86% non-union heal rate1

•Only product approved to accelerate the healing of indicated* fresh fractures•Only 20 minutes per day

•Peer to peer dialog is key•Ideal targets for Science Summits and/or local surgeon speaker meetings

1.Nolte PA, van der Krans A, Patka P, Janssen IM, Ryaby JP, Albers GH. “Low-intensity pulsed ultrasound in the treatment of nonunions.” J Trauma. 2001;51(4):693-703.

EXOGEN Dabblers

Assumptions

You know your key clinical information•Heckman, Kristiansen, Nolte, Gebauer, Cook..

You know where to find scientific information•MOA brochure, Exopedia, sales sheets….

You know the support you have in addition•Science summits, local meetings (surgeon speakers or Chris)

You are not totally comfortable with when and how to use the science and when to use the additional support

ProcessMeeting•Run through key science papers •Discuss when to use•Demonstrate how to use•Provide a Roadmap to guide you•Role play at District Breakout meeting

Post Meeting•Provide a new White Paper (coming soon) which contains and explains the new (and old) evidence•Reps – Identify Dabbler physicians•Reps/DOSs – Target strategic physicians•Use provided information•Use additional resources – Scientific liaison, Science Summits, Regional speakers

Assumptions

You have convinced them sufficiently that when they decide they need a bone stimulator they turn to EXOGEN

They don’t understand the product well enough for EXOGEN to be front of mind when planning treatment•Surgery is the main consideration•Biologics mean bone graft, growth factor, stem cell, etc.

DabblersRoadmap to Becoming Users

Risk Factors•Age•Diabetes•Smoking•Osteoporosis

Non-Unions•Hypertrophic•Atrophic

Not Healed Healed

Fracture

Fracture

(Surgical)

Technique(Surgical)

TechniqueFracture Factors:•Bone and location•Fracture type and severity•Soft tissue damage

Patient Factors:•Comorbidities•Lifestyle (e.g. smoking)•Medications

(Surgical) Technique:•Reduction•Stabilization•Gap filling•Soft tissue repair

Not Healed Healed

Fracture

Fracture

(Surgical) Technique


Often Sufficient

Not Healed Healed

Fracture Fracture (Surgical) Technique


Sometimes Not Enough•Fracture too severe•Patient factors can’t be addressed by surgery alone

Risk Factors Lead to:•Delayed Union•Non-Union

Not Healed Healed

Fracture

Fracture



Add something to help:•Bone graft•Growth Factor•Stimulation

Not Healed Healed

Fracture

Fracture



EXOGEN May Help Tip the

Balance

Risk Factors

Question

Which of these risk factors is most commonly thought of as a reason to use bone growth stimulation?

1.Osteoporosis

2.Smoking

3.Advanced age

4.Diabetes

US

Surgeon view on factors impacting the decision to use a bone healing adjunct

17

Q19. Think of the characteristics of all of your fracture patients. Then, please allocate 100 points across the listed characteristics based on their importance in your decision to treat with non-invasive bone stimulation. The more points you allocate, the more important that characteristic is to you.

DOF 12000.22

USMany of these are patient factors (green) not fracture factors (orange)

18

Q19. Think of the characteristics of all of your fracture patients. Then, please allocate 100 points across the listed characteristics based on their importance in your decision to treat with non-invasive bone stimulation. The more points you allocate, the more important that characteristic is to you.

DOF 12000.22

The remainder are the key fracture factors for which an adjunct to surgery may be required

Risk Factors

• Age

• Diabetes

• Smoking

• Osteoporosis

Question

Which of these molecules is an (upstream) signaling molecule that can lead to up-regulation of the others?

1.Alkaline Phosphatase

2.COX2

3.VEGF

4.BMP2

1. Heckman et al. 1994. Journal of Bone and Joint Surgery 76A:26–34.2. Heckman and Sarasohn-Kahn. 1997. Bulletin Hospital Joint Diseases 56(1):63–72.3. Naik et al., J Bone Miner Res. 2009 Feb;24(2):251-64

* p < 0.02

Age – The Problem

• Increasing age is a risk factor for fracture union1,2

• Older animals produce less COX23

• Reduced COX-2 expression in aged mice is associated with impaired fracture healing as seen with reductions in mineral and vascular volume at the fracture site3

Clinical & Pre-Clinical

mRNA levels of COX2 in young (Open bars) and old (Filled bars) in mice* p < 0.05 3

Heckman et al. 1994. Journal of Bone and Joint Surgery 76A:26–34.Heckman and Sarasohn-Kahn. 1997. Bulletin Hospital Joint Diseases 56(1):63–72.

Age – The EXOGEN Effect* p < 0.02

***p < 0.0001

0 30 60 90 120 150 180 210

≥ 3

0≤

30

Days to healing

Pa

tie

nt

ag

e (

yea

rs) LIPUS

Placebo84 days

103 days(n=21)

(n=12)

(n=18)

(n=15)

126 days

187 days

*

***84 days

42 days

33% Acceleration

45% Acceleration

Clinical

• Older patients are at increased risk of delayed fracture healing• EXOGEN lessened the effect of this risk

>30

Age – The EXOGEN Effect

10

14

21

Day

8 week old mice 40 week old mice 40 week old micewith EXOGEN

In Vivo

• Older animals are at increased risk of delayed fracture healing• EXOGEN lessened the effect of this risk

Katano et al., Exp Anim. 2011;60(4):385-95

10

21

28

Day

Radiographs of 8 week old mice were taken in situ, while the radiographs of the 40 week old mice were taken after excision. Therefore the internal fixation has been removed in the older mice

Tang Mol Pharmacol. 2006 Jun;69(6):2047-57

EXOGEN increased COX2 production in osteoblasts, a key fracture healing factor that is compromised in older animals

In Vitro

The EXOGEN Effect – A Possible Explanation

Age – Summary

• Age is associated with slower healing

• EXOGEN has been shown, in-vivo and clinically, to reduce this effect

• Age is related to lower COX-2 production, a factor which EXOGEN has been shown to upregulate

EXOGEN treatment lessened the effect of age on healing possibly through counteracting reduced COX2 expression

Diabetes – The Problem

• Patients with diabetes mellitus (DM) have many problems healing tissues including fracture

• One factor linked to healing problems in diabetics is vascular insufficiency

Diabetes – The EXOGEN Effect

Post marketing data on non-union fractures •In patients with diabetes the heal rate was 84.2% (n=181/215) compared to 84.4% (n=3,141/3,722) for all fractures

Clinical

DOF 12000.01

Question

What is angiogenesis?

1.The ability of cells to migrate to the fracture

2.The formation of new blood vessels

3.The formation of bone without cartilage

4.The process how bone remodels

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

Norm DM DM + E

Rat

io o

f VE

GF

to T

otal

Pro

tein

(ng/

mg)

*

Day 7

E = EXOGEN


Coords et al., J Orthop Res. 2011 Feb;29(2):181-8Ehrbar et al., Circ Res. 2004;94:1124-1132

In Vivo

• EXOGEN increased VEGF protein expression in diabetic animals• VEGF is a potent angiogenic (new blood vessel formation) factor

VEGF-mediated angiogenesis on the chicken chorioallantoic membrane

Control

VEGF


*

Coords et al., J Orthop Res. 2011 Feb;29(2):181-8

In Vivo

•Diabetic animals have compromised vascularity

•EXOGEN restored levels to those of non diabetic animals

New blood vessel production in response to EXOGEN (w/US) using PECAM (CD-31) to assess day 10 neovascularisation

Diabetes – Summary

• Diabetes mellitus patients are at risk of fracture healing problems potentially linked to compromised vascularity

• The EXOGEN effect in non-union patients was comparable to the overall population

• EXOGEN increases growth factors associated with new blood vessel formation, and with blood vessel formation itself

For patients with diabetes there was no significant change in the efficacy of EXOGEN possibly through increasing VEGF levels

and vascularity

Question

Which of these effects of smoking is most implicated in poor healing?

1.Cancer risk

2.Compromised blood supply

3.Reduced lung function

4.Coronary heart disease risk

Smoking – The Problem

• Smoking is a known risk factor in fracture healing 1

• Cigarette smoking diminishes vascularization at bone healing sites through the action of nicotine 2

2. Ueng J. Trauma 1999 47(4) 752-759

1.Bishop J Am Acad Orthop Surg. 2012 May;20(5):273-82

Smoking – The EXOGEN Effect

Cook et al.– 41% reduction in healing time for smokers with tibial fractures– 51% reduction in healing time for smokers with distal radius

fractures

Post marketing data on non-union fractures •In patients who were currently smoking, the heal rate was 81.3% (n=615/756) compared to 84.4% (n=3,141/3,722) for all fractures

Clinical

Cook et al Clin Orthop Relat Res. 1997 Apr;(337):198-207DOF 12000.01


Naruse et al., Ultrasound Med Biol. 2010 Jul;36(7):1098-108Ehrbar et al., Circ Res. 2004;94:1124-1132

In Vivo

EXOGEN increased VEGF signaling at the mRNA levelVEGF is a potent angiogenic (new blood vessel formation) factor

mRNA levels


Control

VEGF

Smoking – Summary

• Smoking is a known risk factor in fracture healing linked to diminished vascularization which delays mineralisation

• EXOGEN lessened this risk in fresh fractures and the effect in non-union patients was comparable to the overall population

• EXOGEN increases growth factors associated with new blood vessel formation

EXOGEN accelerated healing in patients who smoke possibly through increasing VEGF expression and vascularity

Osteoporosis – The Problem

• Osteoporosis is a metabolic condition where sufferers have lower bone mineral density than normal and are more likely to fracture

• Osteoporotic fracture healing is a problem due to difficulties of achieving fixation into poor quality bone stock

Osteoporosis – The EXOGEN Effect

• The post marketing data on non-union fractures showed that in patients who suffered from osteoporosis the heal rate was 91.7% (n=55/60) compared to 84.4% (n=3,141/3,722) for all fractures

Clinical

DOF 12000.01

This paper used a model of osteoporotic fracture repair to assess the effect of EXOGEN on fracture repair

The paper showed how a number of growth factors are up-regulated by EXOGEN (BMP2 & VEGF).

Fractures treated with EXOGEN had greater callus formation and enhanced endochondral ossification.

Cheung J Orthop Res. 2012 Jan;30(1):129-36

In VivoThe EXOGEN Effect – A Possible Explanation

Question

What is endochondral ossification?

1.Something geeky scientists refer to

2.Formation of Bone within cartilage

3.Formation of Bone without cartilage

4.A process that produces BMPs

Osteoporosis – Summary

• Osteoporosis is a potential risk factor for compromised fracture healing due to poor quality bone stock

• The EXOGEN effect in non-union patients was comparable to the overall population

• EXOGEN upregulated key growth factors and enhanced endochondral ossification and callus formation

EXOGEN has been shown to resolve osteoporotic non-unions possibly through enhanced growth factor expression and

callus formation

Hypertrophic Non-Unions

Question

What does hypertrophic mean?

1.Too much movement

2.Over sensitive

3.Above the fracture line

4.Enlarged

Hypertrophic Non-Unions – The Problem

• Hypertrophic non-unions are thought to be caused by excessive motion at the fracture site

• However, if the fracture is grossly stable, then all that is needed is to enhance the callus to mineralize through endochondral ossification

Hypertrophic Non-Unions – The EXOGEN Effect

Nolte•80% (n=10/12) of established hypertrophic non-unions healed successfully with only the addition of 20mins. per day of EXOGEN treatment

Gebauer• 100% (n=11/11) of established hypertrophic non-unions healed successfully with only the addition of 20mins. per day of EXOGEN treatment

Package Insert•Summary of non-union clinical data

Clinical

Nolte et al., J Trauma. 2001 Oct;51(4):693-702Gebauer et al., Ultrasound Med Biol. 2005 Oct;31(10):1391-402

German study of delayed unions (> 16 weeks)

Key findings:

Bone mineral density was significantly improved (p=0.002) in the fracture gap of EXOGEN treated patients

A significant mean reduction in bone gap areaalso favored EXOGEN treatment

Mineralization at the fracture site was increased

Schofer et al., BMC 8;11:229 2010

Clinical

Hypertrophic Non-Unions – The EXOGEN Effect

EXOGEN significantly increased alkaline phosphatase (p < 0.04) a marker of bone formation

The formation of calcium nodules was significantly greater (p < 0.001) with EXOGEN treatment

EXOGEN positively impacted mineralization of relevant cells


Leung et al., Clin Orthop Relat Res. 2004;(418):253-9.

In Vitro

A&B - human osteoblasts stained with alizarin redto demonstrate calcium formation Lower panel shows image analysis of representativecultures (* p < 0.001)

EX

OG

EN

CO

NT

RO

L

Hypertrophic Non-Unions - Summary

• Grossly stable hypertrophic non-unions may be resolved via enhanced mineralization

• Clinical data shows resolution with EXOGEN alone and increased mineral content at the fracture site

• Both markers of bone formation and mineral content have been demonstrated to be positively impacted with EXOGEN

EXOGEN has been shown to resolve hypertrophic non-unions possibly through enhanced callus formation

Atrophic Non-Unions

Atrophic Non-Unions – The Problem

• Healing has stopped, probably due to some aspect of the patients biology

• The fracture gap still exists on X-Ray and the ends of the bone may become sclerotic (thickened) and/or avascular (“dead”)

• A surgical option is to remove this bone, find bleeding bone and then re-unite the ends.

Atrophic Non-Unions – The EXOGEN Effect

Nolte•80% (n=4/5) of established atrophic non-unions healed successfully with only the addition of 20 mins. per day of EXOGEN treatment

Gebauer• 86% (n=30/35) of established atrophic non-unions healed successfully with only the addition of 20 mins. per day of EXOGEN treatment

Package Insert•Summary of non-union clinical data

Clinical

Nolte et al., J Trauma. 2001 Oct;51(4):693-702Gebauer et al., Ultrasound Med Biol. 2005 Oct;31(10):1391-402

Question

What cell removes / resorbs bone?

1. Osteoblast

2. Osteoclast

3. Osteocyte

4. Pericyte

Control

EXOGEN

This paper showed that bone can be resorbed biologically by osteoclasts and then remodelled

EXOGEN enhanced bone removal at the fracture site and this was linked to more osteoclasts

EXOGEN caused improved bone remodelling

Freeman J Orthop Res. 2009 May;27(5):673-9.

In Vivo



Naruse et al., Ultrasound Med Biol. 2010 Jul;36(7):1098-108Ehrbar et al., Circ Res. 2004;94:1124-1132

In Vivo

EXOGEN increased VEGF signaling at the mRNA levelVEGF is a potent angiogenic (new blood vessel formation) factor

mRNA levels


Control

VEGF

Atrophic Non-Unions – Summary

• These are characterised by thick and/or dead bone

• Clinical data showed that EXOGEN alone resolved these

• EXOGEN enhanced bone resorption and increased vascularity necessary to re-initiate healing

EXOGEN has been shown to resolve atrophic non-unions possibly through enhanced bone resorption and vascularity

Follow Up

EXOGEN Dabblers – Follow Up

• Understanding our data and how it applies to fracture healing is one of the keys for this group of people.

• Identify these people• Use the roadmaps to guide your discussions and provide useful

leave behinds• They are ideal targets for Chris to follow up with and engage in a

dialogue about how the clinical and basic science might inform their treatment considerations

– Face to face meetings– Tel-con/Video con to address specific questions– Meet at trade-shows– Follow-up at science summits

Papers

Delayed union RCT (> 16 weeks)(Delayed union has a non-union definition)

Key EXOGEN findings:

Significant increase in bone mineral density in the fracture gap (p = 0.002)

Significantly smaller fracture gap area (p = 0.014)

Therefore, EXOGEN increased mineralization at the fracture site

Schofer et al., BMC 8;11:229 2010

Clinical

In vitro study (Cells) of human periosteal cells


Significant increase in VEGF expression (p < 0.03)

Significantly increased mineralization (p < 0.001)

Therefore, EXOGEN increased factors and enhanced processes important for

fracture healing in an animal model

Leung et al., Clin Orthop Relat Res. 2004;(418):253-9.

In Vitro

Tang et al.,Mol Pharmacol 69:2047–2057, 2006

Tang Mol Pharmacol. 2006 Jun;69(6):2047-57

In vitro study (Cells)


Integrin is essential for transducing the signal into the cell

Significantly increased COX2 and PGE2 production (p ≤ 0.05)

Significantly increased mineralization (p < 0.05)

Therefore, EXOGEN worked through a well defined pathway to

increase mineralization

In Vitro

In vivo (animal) study


Significantly increased number of osteoclasts in early and middle weeks

(p < 0.05)

Enhanced bone removal at the facture site

Therefore, EXOGEN caused the biological removal of bone in an

animal model

Freeman J Orthop Res. 2009 May;27(5):673-9.

In Vivo

In vivo (animal) study of healing of old and young animals


Accelerated healing response in old animals compared to young animals

Therefore, EXOGEN lessened the effect of age on healing time in an animal

model

Katano et al., Exp Anim. 2011;60(4):385-95

In Vivo

In vivo (animal) study


Many growth factors were increased at the fracture site

These include VEGF and BMP’s

Therefore, EXOGEN increased factors required for fracture healing in an

animal model

Naruse et al., Ultrasound Med Biol. 2010 Jul;36(7):1098-108

In Vivo

In vivo (animal) study of Type I diabetes


Reversed deficits in VEGF production

Significantly increased the number of blood vessels (p < 0.017)

Therefore, EXOGEN mitigated the effects of diabetes on fracture healing

in an animal model

Coords et al., J Orthop Res. 2011 Feb;29(2):181-8

In Vivo

Heckman Bull Hosp Jt Dis. 1997;56(1):63-72

Cost analysis of Heckman JBJS study (1994)


Significantly improved fracture healing in all patients studied (p = 0.0001)

Maximum benefit in the over 30 group that otherwise healed more slowly

Therefore, EXOGEN lessened age-related delays in healing

Clinical

Cheung J Orthop Res. 2012 Jan;30(1):129-36

In Vivo (animal) study of osteoporotic fracture healing


Increased BMP2 and VEGF

Greater callus formation and enhanced endochondral ossification

Therefore, EXOGEN enhanced osteoporotic fracture repair in an

animal model

In Vivo

Roadmap to Active Healing. Indications* The EXOGEN ® Ultrasound Bone Healing System, is indicated for the non-invasive treatment of established non-unions†

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