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Speakers from Orthopedics, Dermatology and Genetic Research

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Orthokine® in the Treatment of

Sports Injuries, OA and Pain: what

is the evidence, what is new?

Peter Wehling

Disclosures:

Foundation for Molecular Medicine

Center for Molecular Orthopaedics and Regenerative Medicine (CEMOR)

Orthogen AG

Heinrich- Heine University, all Düsseldorf, Germany

some slides with friendly support of Chris Evans, Mayo, Rochester

and Paul Robbins and Laura Niedenhofer, Scribbs, USA

Introduction to

Osteoarthritis

4

Inflammatory Process in Osteoarthritis

4

• In addition to biomechanical factors, a cascade of biological factors are also important

• Local release of cytokines triggers destruction of the hyaline cartilage and its matrix

• Agents that inhibit the action of such cytokines have a high therapeutic potential

Interleukin-1(IL-1) is an important mediator of tissue destruction and pain in osteoarthritis

Cartilage Synthesis

Cartilage Degradation

Proteinases

IL-1

TNFα

MMPs

IL-17

IL-18

LIF

OSM

IL-6

IL-8

sTNFaR

IL-4

IL-10

IL-13

IGF-1

BMPs

TGF-β3

PGE2

IL-1Ra

� Orthokine® Animal StudiesClinical StudiesExperimental Studies SafetyOsteoarthritis �ACS Processing Comparison to PRP

© 2016 ORTHOGEN AG All rights reserved

5

Conservative

Management of Osteoarthritis

5

Pharmacological

Intra-articular

Surgical

► Education ► Exercise ► Physiotherapy

► Pain killers: ▼ COX inhibitors ▼ Non-steroidal anti-inflammatory

drugs (NSAIDs)

Experimental ► A more biological focus is being taken – gen/stem cell therapies (e.g. allogeneic

mesenchymal stem cells)

► Gives greater focus to disease modification - DMOADs targeting cartilage, bone, synovitis,

(e.g. MMP-13 inh., TIMP-3 inh)

► Arthroscopy ► Osteoscopy ► Joint replacement

► PRP injections ► Orthokine® injections► Hyaluron injections► Corticosteroid injections

...

� Orthokine® Animal StudiesClinical StudiesExperimental Studies SafetyOsteoarthritis �ACS Processing Comparison to PRP


6

Original Basis for Orthokine®

6

• Interleukin-1(IL-1) is an important mediator of tissue destruction and pain in

osteoarthritis

• Growth factors play an important role in healthy tissue homeostasis

• The specific conditions in the Orthokine® device lead to a strong de novo

synthesis and release of IL-1Ra and Growth Factors such as TGF-B, EGF

and IGF in blood1,2

• The combination of these proteins enhances the natural regeneration

processes in damaged tissue3,4,5

• Re-injection of this specific cell-free Autologous Conditioned Serum leads to

positive clinical effects which are confirmed by controlled clinical studies 6,7,8

• The composition of the cell-free Orthokine® Serum differs significantly from all

other autologous products

Osteoarthritis� Orthokine® Animal StudiesClinical StudiesExperimental Studies Safety �ACS Processing Comparison to PRP


77

• Serum filled syringes stored @

-18°C up to 7 months

• Injected locally in a series of 3

to 6 injections given once or

twice weekly always through a

sterile filter

Orthokine® Processing



Orthokine®

Experimental and Animal

Studies

Orthokine®

Muscle Injuries

10

Wright-Carpenter et al.

10

Objective:

• To investigate the treatment of muscle injuries by local administration of

cell-free Orthokine® ACS-injection using a muscle contusion model

Study Design:

• Mice subjected to an experimental contusion injury to their

gastrocnemius muscle

• One group received Orthokine® ACS-injections (N=3) at 2 hours, 24

hours and 48 hours post injury

• Control group received saline (N=3)

Wright-Carpenter T et al. Int J Sports Med. 2004;25:582-587



11

Wright-Carpenter et al.

11

Results:

Wright-Carpenter T et al. Int J Sports Med. 2004;25:582-587

Orthokine® Treated Control

1. Seven days post injury % of large diameter regenerating CN myofibers [2] was higher

in the ACS-treated group than the control group 87.4% vs 60.3% (p<0.05)

[1] Small diameter regenerating CN microfibers; [2] Large diameter regenerating CN microfibers; [3] normal healthy muscle fibres; [4]

granulomatous tissue; [5] necrotic muscular tissue



Orthokine®

In Achillis Tendinopathy

13

Majewski et al.

13

Objective:

• To investigate the impact of cell-free Orthokine® ACS-injection on

the healing of transected rat Achilles tendon

Study Design:

• Achilles tendons of 80 rats were transected and sutured back

together

• One group received Orthokine® ACS-injections at 24 hours, 48

hours and 72 hours post operatively

• Control group received no injections

Majewski MT et al. Am J Sports Med. 2009;37(11)



14

Majewski et al.

14

Results:

Majewski MT et al. Am J Sports Med. 2009;37(11)

SutureSuture with

Orthokine® ACS

Week 1

Week 2

Week 4

Week 8

Compared to control, group receiving

Orthokine® ACS-injections had:

• Enhanced expression of the

Col1A1 gene

• Thicker tendons

• More type I collagen

• Accelerated recovery

• Histology: more structured, with

a more developed crimp

pattern, bigger collagen bundles



15

Frisbie et al.

15

Objective:

• To investigate the clinical, biochemical and histologic effects of cell-

free Orthokine® ACS-injection on experimentally induced

osteoarthritis in horses

Study Design:

• Osteoarthritis was induced arthroscopically in 1 middle carpal joint

of all horses

• 8 horses received Orthokine® ACS-injections in the osteoarthritis

joint on days 14, 21, 28 and 35

• Control group received saline (N=8)

Frisbie DD et al. American Journal of Veterinary Research. 2009;68(3):290-296



16

Frisbie et al. (2007)

16

Results:

More favourable result in horses with cell-free Orthokine® ACS

• Lameness improvement

• Reduced synovial membrane hyperplasia

• Reduced synovial membrane haemorrhage

• Less gross cartilage fibrillation

• IL-1Ra concentrations increased until day 70

Frisbie DD et al. American Journal of Veterinary Research. 2009;68(3):290-296

Placebo Orthokine® ACS



17

17

17

CT: Computerised tomography; GPA: Global patient assessment; HRQoL: Health-related quality of life; KOOS: Knee injury and osteoarthritis

outcome score; KSRS: Knee Society Clinical Rating System; RCT: Randomised controlled trial; VAS: Visual analogue scale; WOMAC:

Western Ontario and McMaster Universities Arthritis Index

Study Study Design Comparator(s)Study

Length

Number of

PatientsOutcomes Measured

Knee Osteoarthritis

Baselga & Hernandez,

2014Prospective observational Physiotherapy 2 years 118

WOMACGlobal; WOMACPain;

Pain VAS

Baltzer et al., 2009

(GOAT study)RCT, double-blind

Hyaluronan;

Saline

26 weeks,

2-year follow-up376

WOMACGlobal;

Pain VAS; GPA;

SF-8 (HRQoL)

Yang et al., 2008 RCT, double-blind Saline 1 year 167Pain VAS;

KOOS; KSRS

Baltzer et al., 2003 Prospective observational No comparator ≥ 3.5 years ~ 1000WOMAC; Pain VAS;

Patient satisfaction

Knee Osteoarthritis (Post-op)

Darabos et al, 2014 RCT, double-blind Saline 1 year 62CT; Lysholm Knee Questionnaire, IKDC

2000

Darabos et al, 2011 RCT, double-blind Saline 1 year 62 CT; WOMAC

Darabos et al, 2009 RCT, double-blind Saline 10 days 20Synovial cytokines;

serum cytokines

Summary of Clinical Studies- In Knee Osteoarthritis



1818

ACS: autologous conditioned serum; MHHS: Modified Harrison Hip Score; ODI: Oswestry disability index; TRIAM: Triamcinolone; RCT:

Randomised controlled trial; rIRAP: recombinant IL-1R antagonist protein; VAS: Visual analogue scale;

Study

(Author, year)Study Design Comparator(s)

Study

Length

Number of

PatientsOutcomes Measured

Hip osteoarthritis

Baltzer et al., 2013Retrospective

observational

ACS+cortisone;

ACS+cortisone

+anakinra

14 months 119 Pain VAS

Morgenstern et al.

2013Prospective observational No comparator 6 months 23 Functional and pain VAS, MHHS

Spine

Becker et al., 2007 RCT, double-blindTRIAM 10 mg,

TRIAM 5 mg6 months 84

Lower back pain VAS;

ODI

Muscle Injuries

Wright-Carpenter, 2004 Prospective observational

Actovegin®/

Traumeel®

therapy

To recovery 29Growth factor levels;

Recovery time

Summary of Clinical Studies- In Hip Osteoarthritis, Spine and Muscle Injuries



Orthokine® in

Knee Osteoarthritis

Baselga &

Hernández

(2015)Study of ACS with physiotherapy for the

treatment of osteoarthritis

April 2016

- pü

JOCA Febr 2009

Knee OA

376 patients

German ACS Trial - GOAT

376 SUBJECTS

KL Score 2-3

>30 years oldVAS pain 50-100mm

Autologous

Conditioned Serum

(ACS)

Hyaluronic Acid Placebo

(Saline)

Results: WOMAC (2 Years)

Results: VAS (2 Years)

Genotypes and Association in OA

in the GOAT Study Cohort depending

on Treatment Result and Modality

Back PainGCH1

IL1A/B

IL1RN

IL6

Burning Mouth Syndrome

IL1B

FibromyalgiaCOMT

HTR2A

SLC6A4

Vulvar VestibulitisIL1B

IL1RN

MC1R

Experimental PainCOMT

FAAH

GCH1

MC1R

OPRD1

OPRM1

TRPA1

TRPV1

Headache/MigraineMany

Irritable Bowel SyndromeIL10

HTR2A

SLC6A4

TNFA

Pelvic Pain

IL10

Non-steroidal anti-

inflammatory analgesiaPTGS2

Opioid analgesiaCOMT

CYP2D6

MC1R

OPRM1

Postoperative PainMAOB

Temporomandibular

DisorderADRB2

COMT

SLC6A4

o COL11A1

o PTGS2

o IL10

o MATN3

o RHOB

o APOB

o IL1R1

o IL1A

o IL1B

o FRZB

o TIMP4

o PPARG

o COL6A4 or DVWA

o TNF

o COL11A2

o VEGFA

o IL17A

o IL17F

o COL9A1

o ENPP1

o ESR1

o IL6

o TXNDC3

o WISP1

o ASPN

o LPAR1

o ADAM12

o LRP5

o MMP1

o APOA1

o VDR

o COL2A1

o IGF1

o KL

o LRCH1

o ESR2

o DIO2

o CALM1

o SERPINA3

o SMAD3

o ACAN

o IL4R

o CCL2

o COL1A1

o ACE

o COMP

o TGFB1

o GDF5

o COL9A3

o ADAMTS5

o A2BP1

o SCN9A

SNP GENE CHR BP VAS VAS (adj) WOMAC WOMAC (adj)

y1 1 23 122364958 0.00883 0.006791 0.002666 7.55E-05

y2 2 11 113312817 0.005222 0.003548 0.00152 0.0002558

y3 3 1 205011268 0.006987 0.00294 0.01821 0.001306

y4 4 20 47224258 0.07851 0.01421 0.03535 0.002322

y5 5 22 20549449 0.00339 0.00178 0.06782 0.002519

y6 6 1 205013257 0.005413 0.002768 0.04402 0.002857

y7 7 3 149897867 0.03967 0.02955 0.05565 0.003078

y8 8 3 115335421 0.05842 0.005934 0.2118 0.003109

y9 9 3 115341863 0.05842 0.005934 0.2118 0.003109

y10 10 1 11773514 0.004347 0.000883 0.141 0.003242


1

11 18 59236106 0.01208 0.01211 0.000634 0.0005152

2 12 4 1.58E+08 0.02266 0.01319 0.0005749 0.0008672

2 13 4 1.58E+08 0.02012 0.01039 0.00171 0.001005

3

14 7 1.5E+08 0.04163 0.02611 0.006617 0.001121

4 15 6 88906819 0.05123 0.03036 0.005708 0.00117

5 16 7 87068129 0.3466 0.1211 0.07796 0.001388

6 17 12 1.16E+08 0.002377 0.0009615 0.001604 0.001761

7 18 5 37876802 0.03962 0.006376 0.1726 0.002226

8 19 1 62129178 0.02686 0.01126 0.01082 0.002351

9 20 20 43158293 0.02755 0.02147 0.01839 0.00269


x21 21 3 62110395 0.02936 0.02319 0.0419 0.0007347

x22 22 7 55207473 0.04619 0.01636 0.00523 0.001153

x23 23 23 37537458 0.01414 0.02704 0.01849 0.00203

x24 24 7 55196749 0.01584 0.02009 0.002862 0.002313

x25 25 23 43487623 0.01937 0.01059 0.01105 0.003196

x26 26 23 43488335 0.01937 0.01059 0.01105 0.003196

x27 27 23 43489785 0.01937 0.01059 0.01105 0.003196

x28 28 7 142265373 0.09273 0.06894 0.00162 0.003675

x29 29 23 43475980 0.0379 0.01943 0.009545 0.003695

x30 30 22 20492126 0.0005328 0.002735 0.001443 0.004188

Conclusion

Orthokine® confers a stronger therapeutic

effect following a single treatment regiment

than HA and Placebo at 6 and 24 months as

determined by GPA, VAS and WOMAC.

Overview Effect Sizes of RCT´s

Modality ES-Pain ES-Function

Corticosteroids (1-4 w.) < 0.55 0.06

HA (24 w.) < 0.46 0.33

Orthokine®(24-104 w.) < 0.73 0.54

PRP (24-52 w.) < 0.4 0.4

Small = 0.2 Medium = 0.5 Large = 0.8

33

Darabos et al.

33

Summary:

• Orthokine® ACS injection reduced bone tunnel widening after ACL constructive surgery

• The risk-benefit ratio of Orthokine® ACS was favorable

Darabos N. et al. Knee Surgery Sports Traumatology Arthroscopy (2011) 19 (Suppl 1): S36-S46

Results:

• All adverse events were mild to moderate

• There were no differences in the adverse event profile between the 2 groups



Orthokine®

In Meniscus Injuries

Orthokine®

In Meniscus Lesions

36

Results:

• Clinical parameter measured with Oxford Knee Score (OKS) improved significantly during the

observation over 6 months, including significant pain reduction.

• MRI findings measured with Boston Leeds Osteoarthritis Knee Score (BLOKS) improved in

the same manner significantly.

• Non of the 39 patients needed surgery during the 6 months oberservation duration

• There were no adverse events observed in this open Orthokine® ACS observational study

over 6 months

Summary:

• Orthokine® ACS significantly improved clinical signs and symptoms of meniscal lesions in an

open observational study

• Orthokine® ACS represented an effective and well-tolerated alternative to surgery

(meniscectomy).

36 © 2016 ORTHOGEN AG All rights reserved

StrümperACS Meniscus Study


Orthokine®

in Shoulder Inpingement

Orthokine® (ACS)

Project Shoulder

Institute of

Rheumatology

Belgrade University,

Serbia

Nemanja Damjanov, Branko Barać, Jelena Čolić, Vladan Stevanović, Goran Tulić,

Orthokine® (ACS) Project: Shoulder

Title

The efficacy and safety of Autologous Conditioned Serum

(ACS)-Orthokine injections, compared to Betamethasone

(Diprofos) and placebo injections in the treatment of chronic

shoulder joint pain:

Prospective, randomizied,double-blind, controlled study.

Subacromial-subdeltoid bursa

Lateral shoulder

Teres minor

tendon

Infraspinatus

tendon

Supraspinatus

tendon

Humeral head

Supraspinatus

tendon trans

Full internal rotation and adductionSubacromial-subdeltoid bursa

Supraspinatus tendon

Humeral head

Antiseptic swabbing of the injection site

ACS treatment - Assessment of pain (VAS scale)

There was significant decrease in intesity of pain between week 0 and

week 4 (p<0.001), as well as between week 0 and week 24 (p<0.001) and

bewteen week 4 and week 24 (p<0.05) (Wilcoxon test)

p<0.001

p<0.001

p<0.05

70

2112,5

There was significant decrease in intesity of pain between week 0 and

week 4 (p<0.05), as well as between week 0 and week 24 (p<0.001), but

there was unsignificant deterioration bewteen week 4 and week 24

(p>0.05) (Wilcoxon test)

p<0.001

p<0.001

P>0.0565

31

Betameth/pl. treatment - Assessment of pain (VAS scale)

38

Results: CSS Score Orthokine & glucocorticoids

Poor

Poor

Excell.

Excell.

Excell.

Excell.

Poor Poor

ACS Betamethasone/pl.

Orthokine®

Lumbar Radicular

Compression

Pain: Cytokines and the Nerve Root

IL-1ra and the Nerve Root

Wehling, Schulitz et al: Spine 1996

Epidural Perineural Injection of ACS for

Lumbar Radicular Pain

A prospective, randomized, double-blind clinical study

C. Becker, S. Heidersdorf, S. Zirke de Rodriguez, J. Krämer, R. Willburger

Spine

University Hospital of Orthopedic Surgery

St. Josef Hospital Bochum, Germany

Visual analogue scale (VAS)

0

10

20

30

40

50

60

70

80

90

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 weeks

[cm

]

IRAP group

Triam 5 mg group

Triam 10 mg group

1.Injection

t 4 t 5t 3t 2t 1

2.Injection

t 6

3.Injection

Back Pain Study

• Evident pain reduction (VAS) after 3 Injections in all groups

• Pain reduction persists in Orthokine-ACS group

• Difference betweenOrthokine and Triam

• No differencebetween Triam 5 mg and 10 mg

Conclusions Lumbar Spine

• ACS is more effective as steroids in

reducing pain

• Analgesic effect is longer-lasting than that

of steroids

• Lack of side effects make ACS an

attractive local medication for lumbar

nerve root compression

Safety

53

Adverse Events Reported with Orthokine® Since 2004Safety Overview in Real Life Use

53

• Since January 2004 to present, more than 100,000* patients worldwide have been

treated with Orthokine®.

• During this time:

• A total of 45 adverse events in 27 patients treated with Orthokine® have been

reported.

• Of these, the most commonly reported adverse events were:

• There were no reported infections.

*Value estimated based on the assumption that, since January 2004, more than 400,000 EOTII® have been sold and

patients typically require treatment with 4 EOT®II syringes.†Patients may have experienced more than one adverse event.

Adverse Event Number of Reported Events†

Pain 15

Swelling 13

Haematoma 7



Summary and Acknowledgments

The Foundation of Molecular Medicine cordially invites you to…

Speakers from Orthopedics, Dermatology and Genetic Research

Exciting Science, Exciting People, Exciting City

The Foundation of Molecular Medicine cordially invites you to… · 4 Inflammatory Process in...

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