The Foundation of Molecular Medicine cordially invites you to. Speakers from Orthopedics, Dermatology and Genetic Research

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1 The Fundatin f Mlecular Medicine crdially invites yu t Speakers frm Orthpedics, Dermatlgy and Genetic Research Exciting Science, Exciting Peple, Exciting City

2 Orthkine in the Treatment f Sprts Injuries, OA and Pain: what is the evidence, what is new? Peter Wehling Disclsures: Fundatin fr Mlecular Medicine Center fr Mlecular Orthpaedics and Regenerative Medicine (CEMOR) Orthgen AG Heinrich- Heine University, all Düsseldrf, Germany sme slides with friendly supprt f Chris Evans, May, Rchester and Paul Rbbins and Laura Niedenhfer, Scribbs, USA

3 Intrductin t Ostearthritis

4 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Inflammatry Prcess in Ostearthritis In additin t bimechanical factrs, a cascade f bilgical factrs are als imprtant Lcal release f cytkines triggers destructin f the hyaline cartilage and its matrix Agents that inhibit the actin f such cytkines have a high therapeutic ptential Interleukin-1(IL-1) is an imprtant mediatr f tissue destructin and pain in stearthritis Cartilage Synthesis Prteinases IL-1 TNFα MMPs IL-17 IL-18 LIF OSM IL-6 IL-8 stnfar IL-4 IL-10 IL-13 IL-1Ra IGF-1 BMPs TGF-β3 PGE2 Cartilage Degradatin ORTHOGEN AG All rights reserved

5 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Management f Ostearthritis Cmparisn t PRP Cnservative Educatin Exercise Physitherapy Pharmaclgical Pain killers: COX inhibitrs Nn-steridal anti-inflammatry drugs (NSAIDs) Intra-articular Crticsterid injectins Hyalurn injectins PRP injectins Orthkine injectins Surgical Arthrscpy Ostescpy Jint replacement Experimental A mre bilgical fcus is being taken gen/stem cell therapies (e.g. allgeneic mesenchymal stem cells)... Gives greater fcus t disease mdificatin - DMOADs targeting cartilage, bne, synvitis, (e.g. MMP-13 inh., TIMP-3 inh) ORTHOGEN AG All rights reserved

6 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Original Basis fr Orthkine Interleukin-1(IL-1) is an imprtant mediatr f tissue destructin and pain in stearthritis Grwth factrs play an imprtant rle in healthy tissue hmestasis The specific cnditins in the Orthkine device lead t a strng de nv synthesis and release f IL-1Ra and Grwth Factrs such as TGF-B, EGF and IGF in bld 1,2 The cmbinatin f these prteins enhances the natural regeneratin prcesses in damaged tissue 3,4,5 Re-injectin f this specific cell-free Autlgus Cnditined Serum leads t psitive clinical effects which are cnfirmed by cntrlled clinical studies 6,7,8 The cmpsitin f the cell-free Orthkine Serum differs significantly frm all ther autlgus prducts ORTHOGEN AG All rights reserved

7 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Orthkine Prcessing Serum filled syringes -18 C up t 7 mnths Injected lcally in a series f 3 t 6 injectins given nce r twice weekly always thrugh a sterile filter ORTHOGEN AG All rights reserved

8 Orthkine Experimental and Animal Studies

9 Orthkine Muscle Injuries

10 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Wright-Carpenter et al. Objective: T investigate the treatment f muscle injuries by lcal administratin f cell-free Orthkine ACS-injectin using a muscle cntusin mdel Study Design: Mice subjected t an experimental cntusin injury t their gastrcnemius muscle One grup received Orthkine ACS-injectins (N=3) at 2 hurs, 24 hurs and 48 hurs pst injury Cntrl grup received saline (N=3) Wright-Carpenter T et al. Int J Sprts Med. 2004;25: ORTHOGEN AG All rights reserved

Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Wright-Carpenter et al. Results: 1.

05) Orthkine Treated Cntrl [1] Small diameter regenerating CN micrfibers; [2] Large diameter regenerating CN micrfibers; [3] nrmal healthy muscle

11 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Wright-Carpenter et al. Results: 1. Seven days pst injury % f large diameter regenerating CN myfibers [2] was higher in the ACS-treated grup than the cntrl grup 87.4% vs 60.3% (p<0.05) Orthkine Treated Cntrl [1] Small diameter regenerating CN micrfibers; [2] Large diameter regenerating CN micrfibers; [3] nrmal healthy muscle fibres; [4] granulmatus tissue; [5] necrtic muscular tissue Wright-Carpenter T et al. Int J Sprts Med. 2004;25: ORTHOGEN AG All rights reserved

12 Orthkine In Achillis Tendinpathy

13 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Majewski et al. Objective: T investigate the impact f cell-free Orthkine ACS-injectin n the healing f transected rat Achilles tendn Study Design: Achilles tendns f 80 rats were transected and sutured back tgether One grup received Orthkine ACS-injectins at 24 hurs, 48 hurs and 72 hurs pst peratively Cntrl grup received n injectins Majewski MT et al. Am J Sprts Med. 2009;37(11) ORTHOGEN AG All rights reserved

14 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Majewski et al. Results: Cmpared t cntrl, grup receiving Orthkine ACS-injectins had: Week 1 Suture Suture with Orthkine ACS Enhanced expressin f the Cl1A1 gene Thicker tendns Week 2 Mre type I cllagen Accelerated recvery Week 4 Histlgy: mre structured, with a mre develped crimp pattern, bigger cllagen bundles Week 8 Majewski MT et al. Am J Sprts Med. 2009;37(11) ORTHOGEN AG All rights reserved

15 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Frisbie et al. Objective: T investigate the clinical, bichemical and histlgic effects f cellfree Orthkine ACS-injectin n experimentally induced stearthritis in hrses Study Design: Ostearthritis was induced arthrscpically in 1 middle carpal jint f all hrses 8 hrses received Orthkine ACS-injectins in the stearthritis jint n days 14, 21, 28 and 35 Cntrl grup received saline (N=8) Frisbie DD et al. American Jurnal f Veterinary Research. 2009;68(3): ORTHOGEN AG All rights reserved

hyperplasia Reduced synvial membrane haemrrhage Less grss cartilage fibrillatin IL-1Ra cncentratins increased until day 70

16 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Frisbie et al. (2007) Results: Mre favurable result in hrses with cell-free Orthkine ACS Lameness imprvement Reduced synvial membrane hyperplasia Reduced synvial membrane haemrrhage Less grss cartilage fibrillatin IL-1Ra cncentratins increased until day 70 Placeb Orthkine ACS Frisbie DD et al. American Jurnal f Veterinary Research. 2009;68(3): ORTHOGEN AG All rights reserved

17 Ostearthritis Orthkine ACS Prcessing Clinical Studies Animal Studies Summary f Clinical Studies - In Knee Ostearthritis Experimental Studies Safety Cmparisn t PRP Study Study Design Cmparatr(s) Study Length Number f Patients Outcmes Measured Knee Ostearthritis Baselga & Hernandez, 2014 Prspective bservatinal Physitherapy 2 years 118 WOMAC Glbal; WOMAC Pain; Pain VAS Baltzer et al., 2009 (GOAT study) RCT, duble-blind Hyalurnan; Saline 26 weeks, 2-year fllw-up 376 WOMAC Glbal; Pain VAS; GPA; SF-8 (HRQL) Yang et al., 2008 RCT, duble-blind Saline 1 year 167 Pain VAS; KOOS; KSRS Baltzer et al., 2003 Prspective bservatinal N cmparatr 3.5 years ~ 1000 WOMAC; Pain VAS; Patient satisfactin Knee Ostearthritis (Pst-p) Darabs et al, 2014 RCT, duble-blind Saline 1 year 62 CT; Lyshlm Knee Questinnaire, IKDC 2000 Darabs et al, 2011 RCT, duble-blind Saline 1 year 62 CT; WOMAC CT: Cmputerised tmgraphy; GPA: Glbal patient assessment; HRQL: Health-related quality f life; KOOS: Knee injury and stearthritis Synvial cytkines; Darabs et al, 2009 RCT, duble-blind Saline 10 days 20 utcme scre; KSRS: Knee Sciety Clinical Rating System; RCT: Randmised cntrlled trial; VAS: Visual analgue scale; WOMAC: serum cytkines Western Ontari and McMaster Universities Arthritis Index ORTHOGEN AG All rights reserved 17

18 Ostearthritis Orthkine ACS Prcessing Clinical Studies Animal Studies Summary f Clinical Studies - In Hip Ostearthritis, Spine and Muscle Injuries Experimental Studies Safety Cmparisn t PRP Study (Authr, year) Study Design Cmparatr(s) Study Length Number f Patients Outcmes Measured Hip stearthritis Baltzer et al., 2013 Retrspective bservatinal ACS+crtisne; ACS+crtisne +anakinra 14 mnths 119 Pain VAS Mrgenstern et al Prspective bservatinal N cmparatr 6 mnths 23 Functinal and pain VAS, MHHS Spine Becker et al., 2007 RCT, duble-blind TRIAM 10 mg, TRIAM 5 mg 6 mnths 84 Lwer back pain VAS; ODI Muscle Injuries Wright-Carpenter, 2004 Prspective bservatinal Actvegin / Traumeel therapy T recvery 29 Grwth factr levels; Recvery time ACS: autlgus cnditined serum; MHHS: Mdified Harrisn Hip Scre; ODI: Oswestry disability index; TRIAM: Triamcinlne; RCT: Randmised cntrlled trial; rirap: recmbinant IL-1R antagnist prtein; VAS: Visual analgue scale; ORTHOGEN AG All rights reserved

19 Orthkine in Knee Ostearthritis

20 Baselga & Hernández (2015) Study f ACS with physitherapy fr the treatment f stearthritis April 2016

21 German ACS Trial - GOAT - pü JOCA Febr 2009 Knee OA 376 patients

22 376 SUBJECTS KL Scre 2-3 >30 years ld VAS pain mm Autlgus Cnditined Serum (ACS) Hyalurnic Acid Placeb (Saline)

23 Results: WOMAC (2 Years)

24 Results: VAS (2 Years)

25 Gentypes and Assciatin in OA in the GOAT Study Chrt depending n Treatment Result and Mdality

26 Back Pain GCH1 IL1A/B IL1RN IL6 Burning Muth Syndrme IL1B Fibrmyalgia COMT HTR2A SLC6A4 Vulvar Vestibulitis IL1B IL1RN MC1R Experimental Pain COMT FAAH GCH1 MC1R OPRD1 OPRM1 TRPA1 TRPV1 Headache/Migraine Many Irritable Bwel Syndrme IL10 HTR2A SLC6A4 TNFA Pelvic Pain IL10 Nn-steridal antiinflammatry analgesia PTGS2 Opiid analgesia COMT CYP2D6 MC1R OPRM1 Pstperative Pain MAOB Temprmandibular Disrder ADRB2 COMT SLC6A4

27 COL11A1 PTGS2 IL10 MATN3 RHOB APOB IL1R1 IL1A IL1B FRZB TIMP4 PPARG COL6A4 r DVWA TNF COL11A2 VEGFA IL17A IL17F COL9A1 ENPP1 ESR1 IL6 TXNDC3 WISP1 ASPN LPAR1 ADAM12 LRP5 MMP1 APOA1 VDR COL2A1 IGF1 KL LRCH1 ESR2 DIO2 CALM1 SERPINA3 SMAD3 ACAN IL4R CCL2 COL1A1 ACE COMP TGFB1 GDF5 COL9A3 ADAMTS5 A2BP1 SCN9A

28 SNP GENE CHR BP VAS VAS (adj) WOMAC WOMAC (adj) y E-05 y y y y y y y y y

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

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

31 Cnclusin Orthkine cnfers a strnger therapeutic effect fllwing a single treatment regiment than HA and Placeb at 6 and 24 mnths as determined by GPA, VAS and WOMAC.

32 Overview Effect Sizes f RCT s Mdality ES-Pain ES-Functin Crticsterids (1-4 w.) < HA (24 w.) < Orthkine ( w.) < PRP (24-52 w.) < Small = 0.2 Medium = 0.5 Large = 0.8

33 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Darabs et al. Results: All adverse events were mild t mderate There were n differences in the adverse event prfile between the 2 grups Summary: Orthkine ACS injectin reduced bne tunnel widening after ACL cnstructive surgery The risk-benefit rati f Orthkine ACS was favrable Darabs N. et al. Knee Surgery Sprts Traumatlgy Arthrscpy (2011) 19 (Suppl 1): S36-S ORTHOGEN AG All rights reserved

34 Orthkine In Meniscus Injuries

35 Orthkine In Meniscus Lesins

36 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Strümper ACS Meniscus Study Results: Clinical parameter measured with Oxfrd Knee Scre (OKS) imprved significantly during the bservatin ver 6 mnths, including significant pain reductin. MRI findings measured with Bstn Leeds Ostearthritis Knee Scre (BLOKS) imprved in the same manner significantly. Nn f the 39 patients needed surgery during the 6 mnths berservatin duratin There were n adverse events bserved in this pen Orthkine ACS bservatinal study ver 6 mnths Summary: Orthkine ACS significantly imprved clinical signs and symptms f meniscal lesins in an pen bservatinal study Orthkine ACS represented an effective and well-tlerated alternative t surgery (meniscectmy) ORTHOGEN AG All rights reserved

37 Orthkine in Shulder Inpingement

38 Orthkine (ACS) Prject Shulder Nemanja Damjanv, Brank Barać, Jelena Člić, Vladan Stevanvić, Gran Tulić, Institute f Rheumatlgy Belgrade University, Serbia

39 Orthkine (ACS) Prject: Shulder Title The efficacy and safety f Autlgus Cnditined Serum (ACS)-Orthkine injectins, cmpared t Betamethasne (Diprfs) and placeb injectins in the treatment f chrnic shulder jint pain: Prspective, randmizied,duble-blind, cntrlled study.

40 Lateral shulder Subacrmial-subdeltid bursa Humeral head Infraspinatus tendn Teres minr tendn Supraspinatus tendn

41 Supraspinatus tendn trans Full internal rtatin and adductin Subacrmial-subdeltid bursa Supraspinatus tendn Humeral head

42 Antiseptic swabbing f the injectin site

43 ACS treatment - Assessment f pain (VAS scale) p<0.001 p< p< ,5 There was significant decrease in intesity f 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) (Wilcxn test)

44 Betameth/pl. treatment - Assessment f pain (VAS scale) p<0.001 p< P> There was significant decrease in intesity f 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 deteriratin bewteen week 4 and week 24 (p>0.05) (Wilcxn test)

45 Results: CSS Scre Orthkine & gluccrticids ACS Betamethasne/pl. Pr Excell. Pr Pr Excell. Pr Excell. Excell.

46 Orthkine Lumbar Radicular Cmpressin

47 Pain: Cytkines and the Nerve Rt

48 IL-1ra and the Nerve Rt Wehling, Schulitz et al: Spine 1996

49 University Hspital f Orthpedic Surgery St. Jsef Hspital Bchum, Germany Epidural Perineural Injectin f ACS fr Lumbar Radicular Pain A prspective, randmized, duble-blind clinical study C. Becker, S. Heidersdrf, S. Zirke de Rdriguez, J. Krämer, R. Willburger Spine

50 Back Pain Study Evident pain reductin (VAS) after 3 Injectins in all grups 90 Visual analgue scale (VAS) Pain reductin persists in Orthkine- ACS grup Difference between Orthkine and Triam Injectin 2.Injectin IRAP grup Triam 5 mg grup Triam 10 mg grup N difference between Triam 5 mg and 10 mg [cm ] Injectin weeks t 1 t 2 t 3 t 4 t 5 t 6

51 Cnclusins Lumbar Spine ACS is mre effective as sterids in reducing pain Analgesic effect is lnger-lasting than that f sterids Lack f side effects make ACS an attractive lcal medicatin fr lumbar nerve rt cmpressin

52 Safety

53 Ostearthritis Orthkine ACS Prcessing Experimental Studies Clinical Studies Safety Animal Studies Cmparisn t PRP Safety Overview in Real Life Use Adverse Events Reprted with Orthkine Since 2004 Since January 2004 t present, mre than 100,000* patients wrldwide have been treated with Orthkine. During this time: A ttal f 45 adverse events in 27 patients treated with Orthkine have been reprted. Of these, the mst cmmnly reprted adverse events were: Adverse Event Number f Reprted Events Pain 15 Swelling 13 Haematma 7 There were n reprted infectins. *Value estimated based n the assumptin that, since January 2004, mre than 400,000 EOTII have been sld and patients typically require treatment with 4 EOT II syringes. Patients may have experienced mre than ne adverse event ORTHOGEN AG All rights reserved

54 Summary and Acknwledgments

55 The Fundatin f Mlecular Medicine crdially invites yu t Speakers frm Orthpedics, Dermatlgy and Genetic Research Exciting Science, Exciting Peple, Exciting City

Itay Perets, MD Lyall Ashberg, MD Edwin O. Chaharbakhshi, BS, John P. Walsh, MA Mary R. Close, BS Benjamin G. Domb, MD. Hinsdale Orthopaedics

Clinical utcmes and return t sprt in cmpetitive athletes underging ilipsas fractinal lengthening as a part f hip arthrscpy minimum 2 year fllw-up Itay Perets, MD Lyall Ashberg, MD Edwin O. Chaharbakhshi,