Orthobiologics in Joint Preservation - What is working and ... · Orthobiologics in Joint...

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

Do you have the cells that you need?

George F. Muschler, M.D. - Cleveland Clinic

Knee Osteoarthritis

www.arthritis.org

Nat Rev Rheumatol. 2013 Dec;9(12):721-30. doi: 10.1038/nrrheum.2013.141. Epub 2013 Oct 1. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Andia I1, Maffulli N.

4 - Barbour KE et al. Morb Mortal Wkly Rep 2017 March 7 - Hootman JM et al. Arthritis Rheumatol. 2016;68(7):1582-7

OA Knee Population Management

Projected growth in TKA United States from 2005 to 2030

Kurtz S. et.al. J Bone Joint Surg 2007:89:780-785

Surgery - TKA - UKA

Knee Osteoarthritis

Acta Orthop. 2017 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

Knee Osteoarthritis

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

Nat Rev Rheumatol. 2011 Jan;7(1):13-22. doi: 10.1038/nrrheum.2010.178. Epub 2010 Nov 16. Pharmacologic therapy for osteoarthritis--the era of disease modification. Hunter DJ1.

Biologic treatments

• Any substance derived from animal products or other biological sources and used to treat or prevent disease

Bios (Life)

Symptoms modifying and/or Structure modifying?

Biologic treatments Tissue engineering

strategies

Tissue engineering strategies Biologic treatments

Scaffold

Signaling

Molecules

JBJS 86A:1541-1558, 2004

Cartilage Stem Cell Populations?

• Activation • Attachment • Proliferation • Migration • Differentiation • Survival • Self Renewal

• 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?

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?

Questions – Problems - Opportunity

Osteogenic CFUs

Chondrogenic CFUs

Fibroblasts/Endothelial Cells

Hematopoietic CFUs

Keratinocytes/Melanocytes

Osteoarthritis – Early Changes

50 patients: 100 samples – Idiopathic Knee OA

Varied Mechanisms

CTP-C Assay Development CTP-C Assay Development

Proteoglycan Synthesis

Variation Between Cell Colonies

CTP-C Assay Development

AO = Acridine Orange

Time Lapse video - CTP-C heterogeneity

Colony type A Colony type B

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.

Dynamic Metrics of Colony Formation

Ed Kwee

Automated Colony Analysis Tools

Automated Colony Management Tools

Moving to Performance-Based Selection

Cell X Xvivo System Module

Cartilage Health and Disease

Future Health?

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

Cell Therapy Questions

Mechanisms

Degenerative

Trauma

Mechanical

Metabolic

Inflammatory

Genetic

Osteoarthritis

Demographics

Traditional Therapies

Biologic Therapies

Cartilage Kinetics

Variation in Human OA

Cell Sources Targets

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

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

Osteoarthritis Mechanisms

Symptoms modifying

Structure modifying

Steroids NSAIDS Other Anti-inflammatorys Hyaluronan IRAP

Osteoarthritis – Injectable Therapies

Cochrane 2015

• 27 Trials • 1767 participants

1-2 weeks

4-6 weeks

3 months

6 months

Nat Rev Rheumatol. 2018 Feb;14(2):73-74. doi: 10.1038/nrrheum.2017.219. Epub 2018 Jan 11. Osteoarthritis in 2017: Latest advances in the management of knee OA. McAlindon TE1, Bannuru RR1.

Normal Knee

Knee Osteoarthritis

Knee Osteoarthritis Decreased in hyaluronan

• Degradation • Reduced production • Increased clearance

Moreland LW. Arthritis Res Ther. 2003 Greenwald RA. Semin Arthritis rheum. 1991

• 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 106 Da

Balazs EA et al. Arhtritis Rheum 1967 Moreland LW Arthritis Res Ther 2003

• Viscoelastic shock absorber during high shear • Lubricant during slow movement • Chondroprotective • Anti-inflammatory • Other

HA Functions

HA concentration Molecular mass Viscosity of the synovial fluid

Exogenous intra-articular hyaluronan injections

• Peyron and Balazs (1974) Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints

Pathol Biol (Paris). 1974 Oct;22(8):731-6 J Rheumatol Suppl. 1993;39:3-9

“visco-supplementation”

HA concentration Molecular mass Viscosity of the synovial fluid

Knee OA

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, 2015

56 JBJS 2016;98:1429-35

JBJS 2016;98:1429-35

JAMA Internal Medicine October 2014 Vol. 174, 10

TODAY Multiple available commercial products

Johal H. et al. JBJS 2016;4(4) April 2016

Variation in:

• Molecular weight • Method of production • Half-life • Dosing regimen • Cost • …

Multiple available commercial products

American Journal of Sports Medicine, Vol. 44, No. 8 - 2015

• Molecular weight > 3000 kDa favorable efficacy results than MW < 3000 kDa

• Biological fermentation derived HA lower adverse events than Avian-derived HA

Knee Osteoarthritis

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

Impact Factor 3.9

Knee Osteoarthritis

CONCLUSION: In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events.

Ann Intern Med. 2012 Aug 7;157(3):180-91. Impact Factor 16.5

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

JBJS APRIL 2016 · VOLUME 4, ISSUE 4

HA injection in Knee Osteoarthritis

• 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

Based on the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach:

Symptoms modifying

Structure modifying

Cells Proliferation Retention

ECM Formation Retention

Osteoarthritis Overview

Growth Cells Collagen GAG Vascularity

Structure

Remodeling (Homeostasis) Cells Collagen GAG Vascularity

Degradation Cells Collagen GAG Vascularity

Structure

Mechanism Therapy Structure

Degenerative

Trauma

Mechanical

Metabolic

Inflammatory

Genetic

Late 1800 - Osteochondral Allografts

1980s – Microfracture

1990s – Mosaicplasty and OATS

1997 – Autologous Chondrocyte (ACI)

2007 – Juvenile Cartilage (DeNovo NT, ISTO)

2017 – Membrane ACI (MACI)

Cartilage Replacement Biologics Grade IV and Osteochondral Defects

Symptoms modifying

Structure modifying

Wnt Inhibitors A2 Microglobulin Toll-like receptors (TLR) 4 modulators TGF-B

Nat Rev Rheumatol. 2018 Feb;14(2):73-74. doi: 10.1038/nrrheum.2017.219. Epub 2018 Jan 11. Osteoarthritis in 2017: Latest advances in the management of knee OA. McAlindon TE1, Bannuru RR1.

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

Nat Rev Rheumatol. 2015 Mar;11(3):159-70. doi: 10.1038/nrrheum.2014.209. Epub 2014 Dec 16. TLR4 signalling in osteoarthritis--finding targets for candidate DMOADs. Gómez R1, Villalvilla A2, Largo R2, Gualillo O3, Herrero-Beaumont G2.

Toll-like receptors (TLR) 4 signaling in OA TLR4-regulating drugs could act as potential disease-modifying OA drugs

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

Nat Rev Rheumatol. 2011 Jan;7(1):13-22. doi: 10.1038/nrrheum.2010.178. Epub 2010 Nov 16. Pharmacologic therapy for osteoarthritis--the era of disease modification. Hunter DJ1.

Osteoarthritis Biologic Therapies

Mechanism Therapy Structure

Degenerative

Trauma

Mechanical

Metabolic

Inflammatory

Genetic

- Few Safety Concerns - Poor Low level of Evidence

- (only 6 of 420 articles useful for efficacy comparison) - High risk of publication bias

Recent Systematic Reviews

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

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)

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

Support

NIH - NIAMS

Maha Qadan

Cynthia Boehm

Ed Kwee Venkata Mantripragada

Terri Zachos

Viviane Luangphakdy

Alan Sumski Selvam Selvaanish

Nicholas Piuzzi Eben Alsberg

Bob Sah

Veronique Lefebvre Ron Midura

Vince Hascall

The Cleveland Clinic Foundation

THANK YOU

Orthobiologics in Joint Preservation - What is working and ... · Orthobiologics in Joint...

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