Orthobiologics in Joint Preservation - What is working and How Would We Know?

Transcription

1 Orthobiologics in Joint Preservation - What is working and How Would We Know? George F. Muschler, M.D. - Cleveland Clinic Do you have the cells that you need?

2 Knee Osteoarthritis

3 Nat Rev Rheumatol Dec;9(12): doi: /nrrheum Epub 2013 Oct 1. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Andia I 1, Maffulli N.

4 OA Knee Population Management - Barbour KE et al. Morb Mortal Wkly Rep 2017 March 7 - Hootman JM et al. Arthritis Rheumatol. 2016;68(7):

5 Projected growth in TKA United States from 2005 to 2030 Kurtz S. et.al. J Bone Joint Surg 2007:89:

6 Knee Osteoarthritis Surgery - TKA - UKA

7 Knee Osteoarthritis

8 Knee Osteoarthritis Acta Orthop Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ

9 Knee Osteoarthritis Sellam. Nature Reviews Rheumatology Volume: 6 issue 11 (2010)

10 Nat Rev Rheumatol Jan;7(1): doi: /nrrheum Epub 2010 Nov 16. Pharmacologic therapy for osteoarthritis--the era of disease modification. Hunter DJ 1.

11 Biologic treatments Bios (Life) Any substance derived from animal products or other biological sources and used to treat or prevent disease Symptoms modifying and/or Structure modifying?

12 Biologic treatments Tissue engineering strategies

13 Biologic treatments Tissue engineering strategies Cells A 1 2 Scaffold 3 Signaling Molecules C 4 B JBJS 86A: , 2004

14 Cartilage Stem Cell Populations? Activation Attachment Proliferation Migration Differentiation Survival Self Renewal

15 Questions Problems - Opportunity What cells do we want? How can they assayed? Where are they? How many are there? Patient Variation Harvest Technique? Yield? Transplantation Environment? Processing/Selection Methods? Transplantation Method? Clinical Setting of Need? Preclinical Testing Safety and Efficacy? Regulatory Barriers Uncertainty? Market Size, IP Protection, Price? Clinical Trials Time/Money/ROI?

16 Questions Problems - Opportunity What cells do we want? How can they assayed? Where are they? How many are there? Patient Variation Harvest Technique? Yield? Transplantation Environment? Processing/Selection Methods? Transplantation Method? Clinical Setting of Need? Preclinical Testing Safety and Efficacy? Regulatory Barriers Uncertainty? Market Size, IP Protection, Price? Clinical Trials Time/Money/ROI?

17 Osteogenic CFUs Hematopoietic CFUs Fibroblasts/Endothelial Cells Chondrogenic CFUs Keratinocytes/Melanocytes

18 Osteoarthritis Early Changes

19 patients: 100 samples Idiopathic Knee OA

20 Osteoarthritis Early Changes Varied Mechanisms Acta Orthop Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ

21 Osteoarthritis Early Changes Acta Orthop Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ

22 Osteoarthritis Early Changes Acta Orthop Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ

23 Osteoarthritis Early Changes Acta Orthop Nov 9:1-7. High occurrence of osteoarthritic histopathological features unaccounted for by traditional scoring systems in lateral femoral condyles from total knee arthroplasty patients with varus alignment. Mantripragada VP, Piuzzi NS, Zachos T, Obuchowski NA, Muschler GF, Midura RJ

24 CTP-C Assay Development CTP-C Assay Development

25 CTP-C Assay Development Proteoglycan Synthesis Variation Between Cell Colonies AO = Acridine Orange

26 Time Lapse video - CTP-C heterogeneity Colony type A Colony type B

27 Dynamic Metrics of Colony Formation A B C A) Maximum intensity projection of live cell phase contrast image at Day 7 B) Mitosis events in time series (grey level = time frame, yellow=founding cell, red outline=colony footprint), C) histogram of mitotic events this colony. C) A histogram of the frequency of mitotic events.

28 Automated Colony Analysis Tools Ed Kwee Automated Colony Management Tools

29 Moving to Performance-Based Selection

30 Cell X Xvivo System Module

31 Cell X Xvivo System Module

32 Cartilage Health and Disease

33 Future Health?

34 OA Knee Biologic Therapy Repopulate the Lamina Splendans Synovium/Migration CTP-C Injection/Resurfacing Systemic Circulation Intrinsic CTP-C Activation Chondrocyte Clonal Separation Collagen II Synthesis? MMP Inhibition? Inhibit Chondrocyte Loss Inhibit Subchondral Erosion

35 OA Knee Biologic Therapy Repopulate the Lamina Splendans Synovium/Migration CTP-C Injection/Resurfacing Systemic Circulation Intrinsic CTP-C Activation Chondrocyte Clonal Separation Collagen II Synthesis? MMP Inhibition? Inhibit Chondrocyte Loss Inhibit Subchondral Erosion

36 OA Knee Biologic Therapy Repopulate the Lamina Splendans Synovium/Migration CTP-C Injection/Resurfacing Systemic Circulation Intrinsic CTP-C Activation Chondrocyte Clonal Separation Collagen II Synthesis? MMP Inhibition? Inhibit Chondrocyte Loss Inhibit Subchondral Erosion

37 OA Knee Biologic Therapy Repopulate the Lamina Splendans Synovium/Migration CTP-C Injection/Resurfacing Systemic Circulation Intrinsic CTP-C Activation Chondrocyte Clonal Separation Collagen II Synthesis? MMP Inhibition? Inhibit Chondrocyte Loss Inhibit Subchondral Erosion

38 Cell Therapy Questions Mechanisms Degenerative Trauma Mechanical Metabolic Inflammatory Toxic Genetic

39 Osteoarthritis Demographics Traditional Therapies Biologic Therapies Cartilage Kinetics Variation in Human OA Cell Sources Targets

40 Osteoarthritis Overview Therapy Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, ) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, ips Genetic Modification

41 Osteoarthritis Mechanisms Sellam. Nature Reviews Rheumatology Volume: 6 issue 11 (2010)

42 Osteoarthritis Overview Therapy Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, ) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, ips Genetic Modification

43 Osteoarthritis Injectable Therapies Symptoms modifying Structure modifying Steroids NSAIDS Other Anti-inflammatorys Hyaluronan IRAP

44 27 Trials 1767 participants Cochrane 2015

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46 1-2 weeks

47 4-6 weeks

48 3 months

49 6 months

50 Nat Rev Rheumatol Feb;14(2): doi: /nrrheum Epub 2018 Jan 11. Osteoarthritis in 2017: Latest advances in the management of knee OA. McAlindon TE 1, Bannuru RR 1.

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53 Normal Knee Normal healthy adult knees 2mL of synovial fluid 0.5 to 4 mg/ml of Hyaluronan produced by type-b synoviocytes, fibroblasts mean molecular weight 5 x 10 6 Da Balazs EA et al. Arhtritis Rheum 1967 Moreland LW Arthritis Res Ther 2003 HA Functions Viscoelastic shock absorber during high shear Lubricant during slow movement Chondroprotective Anti-inflammatory Other Knee Osteoarthritis Knee Osteoarthritis Decreased in hyaluronan Why? Degradation Reduced production Increased clearance Moreland LW. Arthritis Res Ther Greenwald RA. Semin Arthritis rheum HA concentration Molecular mass Viscosity of the synovial fluid

54 Exogenous intra-articular hyaluronan injections Knee OA HA concentration Molecular mass Viscosity of the synovial fluid Peyron and Balazs (1974) Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints Pathol Biol (Paris) Oct;22(8):731-6 J Rheumatol Suppl. 1993;39:3-9 visco-supplementation Joint lubrication by restoring or supplementing synovial fluid viscoelasticity Approved as a biologic device for use in humans in Canada in 1992, and in the United States in 1997

55 NEJM 372;11 - March 12,

56 JBJS 2016;98:

57 JBJS 2016;98:

58 JBJS 2016;98:

59 JAMA Internal Medicine October 2014 Vol. 174, 10 59

60 TODAY Multiple available commercial products Variation in: Molecular weight Method of production Half-life Dosing regimen Cost Johal H. et al. JBJS 2016;4(4) April 2016

61 Multiple available commercial products American Journal of Sports Medicine, Vol. 44, No Molecular weight > 3000 kda favorable efficacy results than MW < 3000 kda Biological fermentation derived HA lower adverse events than Avian-derived HA

62 Knee Osteoarthritis Impact Factor 3.9 European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) The use of IA HA in knee OA patients with mild moderate disease, and for more severe patients wishing to delay TKR surgery, is recommended

63 Knee Osteoarthritis

64 Knee Osteoarthritis

65 Ann Intern Med Aug 7;157(3): Impact Factor 16.5 CONCLUSION: In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events. 65

66 JBJS APRIL 2016 VOLUME 4, ISSUE 4 Heterogeneous trials with conflicting conclusions - Unclear and discordant recommendations - Evidence favors clinically important reductions in pain and is safe in patients with knee OA

67 JBJS APRIL 2016 VOLUME 4, ISSUE 4

68 HA injection in Knee Osteoarthritis Based on the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach: HA injections for knee osteoarthritis provides a probable pain reduction and improvement of physical function Low-risk of harm It is a viable option in younger patients with less severe disease

69 Osteoarthritis Injectable Therapies Symptoms modifying Structure modifying Cells ECM Proliferation Retention Formation Retention

70 Osteoarthritis Overview Structure Growth Cells Collagen GAG Vascularity Remodeling (Homeostasis) Cells Collagen GAG Vascularity Degradation Cells Collagen GAG Vascularity

71 Osteoarthritis Overview Structure Growth Cells Collagen GAG Vascularity Remodeling (Homeostasis) Cells Collagen GAG Vascularity Degradation Cells Collagen GAG Vascularity

72 Osteoarthritis Overview Structure Growth Cells Collagen GAG Vascularity Remodeling (Homeostasis) Cells Collagen GAG Vascularity Degradation Cells Collagen GAG Vascularity Mechanism Degenerative Trauma Mechanical Metabolic Inflammatory Toxic Genetic Therapy Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, ) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, ips Genetic Modification

73 Osteoarthritis Overview Therapy Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, ) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, ips Genetic Modification

74 Cartilage Replacement Biologics Grade IV and Osteochondral Defects Late Osteochondral Allografts 1980s Microfracture 1990s Mosaicplasty and OATS 1997 Autologous Chondrocyte (ACI) 2007 Juvenile Cartilage (DeNovo NT, ISTO) 2017 Membrane ACI (MACI)

75 Osteoarthritis Injectable Therapies Symptoms modifying Structure modifying Wnt Inhibitors A2 Microglobulin Toll-like receptors (TLR) 4 modulators TGF-B

76 Nat Rev Rheumatol Feb;14(2): doi: /nrrheum Epub 2018 Jan 11. Osteoarthritis in 2017: Latest advances in the management of knee OA. McAlindon TE 1, Bannuru RR 1.

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79 Alpha 2 Macroglobulin (A2M) plasma protease inhibitor inhibits activities of ADAMTS-4,-5,-7, -12, MMP-13 activity

80 Toll-like receptors (TLR) 4 signaling in OA TLR4-regulating drugs could act as potential disease-modifying OA drugs Nat Rev Rheumatol Mar;11(3): doi: /nrrheum Epub 2014 Dec 16. TLR4 signalling in osteoarthritis--finding targets for candidate DMOADs. Gómez R 1, Villalvilla A 2, Largo R 2, Gualillo O 3, Herrero-Beaumont G 2.

81 Allogeneic human chondrocytes transduced with a viral vector containing the gene for TGF-b1 transcription

82 Allogeneic human chondrocytes transduced with a viral vector containing the gene for TGF-b1 transcription

83 Osteoarthritis Biologic Therapies Nat Rev Rheumatol Jan;7(1): doi: /nrrheum Epub 2010 Nov 16. Pharmacologic therapy for osteoarthritis--the era of disease modification. Hunter DJ 1.

84 Osteoarthritis Overview Structure Growth Cells Collagen GAG Vascularity Remodeling (Homeostasis) Cells Collagen GAG Vascularity Degradation Cells Collagen GAG Vascularity Mechanism Degenerative Trauma Mechanical Metabolic Inflammatory Toxic Genetic Therapy Weight/Activity/Bracing Diet Alignment Debridement Meniscal Repair Ligament Repair (ACL, ) Osteochondral Procedures Injectables Steroids HA Antibodies Small Molecules Growth Factors Cells PRP BMC Adipose, MSC, ips Genetic Modification

85 Recent Systematic Reviews Few Safety Concerns - Poor Low level of Evidence - (only 6 of 420 articles useful for efficacy comparison) - High risk of publication bias 2017

86 Platelet Rich Plasma Knee OA Campbell K et al. Arthroscopy 2016, Meheux C. et al. Arthroscopy 2016, Laudry A. et al. BJSM 2015, Riboh J. et al AJMS 2015 Sadabad H. et al. EP 2015 Lai L. et al. IJCEM 2015

87 Platelet Rich Plasma Knee OA 1) Safe 1) Transient local adverse events such as pain or swelling, for 2 or 3 days (<5%) 1) Improves pain and function for up to 12 to 24 months 1) Low leukocyte concentration (LP-PRP) Campbell K et al. Arthroscopy 2016, Meheux C. et al. Arthroscopy 2016, Laudry A. et al. BJSM 2015, Riboh J. et al AJMS 2015 Sadabad H. et al. EP 2015 Lai L. et al. IJCEM 2015

88 Support NIH - NIAMS

89 Team Cynthia Boehm Viviane Luangphakdy Veronique Lefebvre Ron Midura Nicholas Piuzzi Ed Kwee Venkata Mantripragada Vince Hascall Eben Alsberg Maha Qadan Alan Sumski Selvam Selvaanish Terri Zachos Bob Sah

90 THANK YOU The Cleveland Clinic Foundation

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