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Overview of Treatment Options for Articular Cartilage Repair: Past Present & Future Ken Zaslav MD Medical Director: Advanced Orthopedic Centers: Richmond Virginia Clinical Asst. Prof. of Orthopedic Surgery. Virginia Commonwealth University

Acknowlegements: Author gratefully acknowledges additional content and photos from:Dr Brian Cole: Rush Medical Center: Chicago,ILDr. Bert Mandelbaum: Santa Monica Ortho. & Sports Medicine , Santa Monica, California Disclosures: K. Zaslav MD Scientific Advisory Board Member: Genzyme Biosurgery Scientific Advisory Board Member : Pegasus Biologics Member Int’l Cartilage Repair Society

Articular Cartilage Injury: A permanent injury • Poor vascularity…No healing potential • Adult chondrocytes don’t migrate or replicate to fill defects • Injury begins an inexorable cascade of events both chemical and then mechanical leading toward degenerative joint disease. • May progress to end stage arthritis

Symptoms of Articular Cartilage. Injury: • Pain • Catching / Clicking / Locking • Instability • Effusions

Prevalence of Cartilage Injuries • Cartilage injuries occur frequently.1,2 • Studies suggest that 20%-60% of knee arthroscopies reveal focal chondral or osteochondral defects.1,2 • Almost 10% of all arthroscopies in patients <50 years old, revealed a single, well-defined grade III or IV defect with an area of at least 1 cm2. 2 • Can cause significant disability in relatively young patients. • Can be painful and debilitating.2 • Limits employment, sports participation, and activities of daily living.2 • Cartilage is avascular, aneural, and will not regenerate on its own. Curl et al. Cartilage Injuries: A review of 31,516 Knee Arthroscopies. J Arthrosc. Rel. Surg. 1997;13:456-60 Hjelle et al. Articular Cartilage Defects in 1,000 Knee Arthroscopies. J Arthrosc. Rel. Surg. 2002;32:730-73. 4.

Unique building block of articular cartilage matrix is Type II collagen • Middle architectural zone called “the netting” is made of aggregates of proteoglycans called glycosamino- glycans (GAG’s): This netting holds water i.e.: gives this zone its hydrophilic character that yields the low friction, fluid wave enabling smooth joint motion

Goals of Cartilage Repair • Restore smooth articular cartilage surface • Relieve patient symptoms and improve function • Match biomechanical/biochemical properties of normal hyaline cartilage • Prevent or slow progression of focal chondral injury to end- stage arthritis

Early Treatment Options: • Most involved debridement to remove mechanical symptoms (palliative only/ No Repair tissue) • Moved to marrow stimulation techniques to bring in pluri-potential cells from the sub-chondral marrow to fill defects. ( abrasion/ drilling/ burr) • These all yield a fibro-cartilage repair and may affect the integrity of the sub-chondral plate: Therefore repair tissue is not as durable as normal hyaline articular cartilage • Late term clinical problems seen in larger lesions

Treatment Options for the Cartilage Bio-surgeon in 2009 CLINICAL UTILITY Autologous Chondrocyte Implantation Debridement & Lavage Osteochondral Grafting Microfracture Palliative Reparative Restorative

Treatment Decision Algorithm • Lesion ≥ 2 cm2 Lesion < 2 cm2 Primary Treatment Secondary Treatment Primary Treatment Secondary Treatment Low Demand High Demand • ACI • Osteochondral alloGrafting • D & L • MST • Osteochondral Autograft • ACI • Osteochondral Autograft • D & L • MST • Osteochondral Grafting • Osteochondral alloGrafting Special Issues exist for the competitive Athlete? It is always about time and timing!

The Knee Joint is an organ : • Ligamentous stability • Mechanical alignment • Functional meniscus Cartilage is only one component: The organ also includes bone, soft tissue, synovial fluid. Co-morbidities must be corrected prior to or concurrent with any cartilage repair procedure: Courtesy of Brian J. Cole, MD

Microfracture • Strengths: • Arthroscopicprocedure is relatively simple/reproducible • Inexpensive • Long history of clinical use (> 28 studies w/ 6 RCT’s in lit.) • Limitations: • Creates fibrocartilage/poor wear characteristics • More effective on smaller defect (< 4 cm2) • 6–8 weeks protected- wt. bearing and CPM required Courtesy of Brian J. Cole, MD • St • Knee. A Randomized Trial. J of Bone Joint Surg. 2004;86-A:455-464.

Microfracture has been a good step ….but not ideal: not truly restorative • good 2 yr clinical effect with waning clinical effect in larger lesions • "osteochondral" perforating the subchondral bone plate/tidemark • moving up of the bone front leading to intralesional osteophytes • Over time deterioration of the repair tissue • Declination of function and athletic activity Mithoefer: JBJS Am 2005; 87 (9) 1911-20 Buckwalter, Grodzinsky: Articular cartilage and osteoarthritis: Instr. Course Lect 2005; 54: 465-80 Minas; Orthopedics 1997; 20 (6) 525-38 Kreuz: Osteoarthritis and Cartilage (2006) 14, 1119-1125 Kreuz: The Journal of Arthroscopic and Related Surgery Vol 22, No 11(November) 2006, 1180-1186 Brown : Clin Orthop Relat Res 2004; 422: 214-23

Osteochondral Autograft • Strengths: • May be performed arthroscopically/open • Fills defect with native cartilage • Limitations: • Limited to smaller defects • Donor site morbidity • No lateral integration • Congruity of joint difficult to reproduce with multiple plugs Courtesy of Brian J. Cole, MD • Levy, A.S. Osteochondral Autograft ofr the Treatment of Focal Cartilage Lesions. Operative Techniques in Orthopedics. Management of Chondral Injury: Perspectives in the Millennium. 2001;11:108-114. • Levy, A.S. and Meire, S.W. Osteochondral Autograft Replacement. In: Cole, B.J. and Malek, M.M. Articular Cartilage Lesions. Practical Guide to Assessment and Treatment. New York, New York: Springer, ; 2004:73-81.

Osteochondral Allograft • Strengths: • Bone fixation • Hyaline cartilage • Fresh Allografts have excellent long term results (Garrett/ Gross) • Limitations: • Limited supply • Disease transmission • ( partially mitigated by cold storage: 20 days) • ?Viability of chondrocytes • appx. 20 % Non-union Courtesy of Brian J. Cole, MD

Cell Therapy: U.S.A. Clinical Development and Regulatory Background 1994: Brittberg-Petersen Study Published JAMA AutologousChondrocyte Transplantation 1995 • Genzyme Corp. manufactures and commercializes the first cell-based therapy in orthopaedics (approved as unregulated medical device status) First Articular Cartilage Transplants performed in USA 1996 • FDA develops new cell therapy regulations 1997 • Carticel® receives FDA approval (Accelerated Approval) under new FDA cell therapy regulations; however Post approval studies are required 1999 – 2000 • Two new post approval study designs are approved by FDA • Registry based (completed 2000) Pub. Mandelbaum B, et al: Am J Sports Med 2007;35:915-921 • Prospective Cohort study: (STAR) (completed 2006) Pub. Zaslav,K Cole B. et al : Am J Sports Med 2009;37(1):42-55;

AutologousChondrocyte Implantation : ACI • Strengths: • Can produce hyaline-like cartilage • Not limited by defect size • Most commonly used for moderate-to-large defects in patients who have failed previous interventions • 15 year hx of clinical use • > 80 citations in literature • Limitations: • Open/More invasive • Expensive • Longer recovery period • 2 stage procedure • Ultrastructurally still not true articular cartilage Courtesy of Jack Farr, MD .

ACI is a 2 stage procedure: • Biopsy Procurement: Arthroscopicharvest from non- weight bearing, non-articulating surface (Best: inter-condylar notch) • 2nd stage is an open surgical implantation of cells under a periosteal patch sewn in with 6-0 suture. Courtesy of Scott D. Gillogly, MD

Polarized Alcian Blue Van Giesson AutologousChondrocytes - Objective Analysis indicates durable result Second look with matching histology Patient #6 Arthroscopic Assessment = 10 Indentation Normal 3.8-Repair Tissue 3.7 8 years post implant Courtesy of Lars Peterson

Study of the Treatment of Articular Repair Clinical Trial: An overview • Objective: • To examine the safety and efficacy of ACI in patients who had an inadequate response to a prior surgical treatment for articular cartilage defects of the knee. (FDA approved indication ) • A prospective, four-year, open label, multi-center GCP -FDA approved study of 154 patients treated with ACI. • Level II evidence: cohort study (20 Centers N. America) • Patients had at least one symptomatic grade III or grade IV defect (Outerbridge) located on the femoral condyle and a Modified Cinncinnatt Score of less than 5. (First and only cartilage study to delineate a pre-treatment severity level) . • A challenging patient pop. : Avg. age 34.5 / mean defect size 4.63 cm • All patients were required to have failed at least one non-ACI surgical repair procedure. (debridement, micro-fracture or OATS) Mean # prior knee surgeries = 1.9 • An industry sponsored study Zaslav K. Cole B. et al. A Prospective Study of AutologousChondrocyte Implantation in Patients Who Failed Prior Treatments for Articular Cartilage The American Journal of Sports Medicine. 2009;37(1):42-55.

Overall Modified Cincinnati Knee Scale Zaslav K. Cole B. et al. The American Journal of Sports Medicine. 2009;37(1):42-55. • Data on file, Genzyme Corporation, Cambridge, MA. Exhibit B.

ResultsKOOS Subscale Scores 90 80 70 60 50 Baseline 40 48 Month 30 p<0.001 20 10 0 QOL ADL SportsRecreation Pain Symptoms ADL

Results:CARTICELTime-to-Treatment Failure (TTF)1 • (76%) were a success by apriori definition at 4 years • Of the 154 patients that were treated with ACI, 126 patients (82%) completed the 4 year protocol. Post ACI Survivorship (Intent to treat Population) Zaslav K. Cole B. et al: The American Journal of Sports Medicine. 2009;37(1):42-55.

Results: Adverse Events: SSPs • Subsequent Surgical Procedures (SSPs) were common following ACI implantation. • 49% of patients (n=76) underwent an SSP on the treated knee, irrespective of relationship to ACI. • Majority of SSPs occurred within the first 24 months post implantation. • 0-6 months: lysisof adhesions was the most frequently performed intervention • After 6 months, periostealdebridement for hypertrophy was the most frequently performed intervention. • All SSP’s were arthroscopic. • SSPs were not predictive of treatment failure. • Of the patients who required an SSP, 61% (46 out of 76 patients) went on to have successful results.1 • Zaslav K. Cole B. et al: The American Journal of Sports Medicine. 2009;37(1):42-55.

Level I Evidence: RCT Journal of Bone and Joint Surgery Am. March 2004

Comparative Outcome 5 yrACI vs Microfracture • RCT: Level I Evidence No industry sponsorship • 80 Patients @ 5 years • ICRS, Lysolm, SF 36 and Tegner • Study includes all patients 2-10 cm lesions • Conclusion: Clinical Outcome shows no stat. sig. difference between treatment groups : both 77% @5yrs • 1/3 pts showed radiographic evidence OA at 5yrs. • Pts. with higher cartilage scores at 2 yrs. had no failures at 5 yrs. • Micro Fx results best in lesions < 4 cm w/ ACI no size effect seen Knutsen G. et al J Bone Joint Surg Am.2007;89:2105-12

European RCT Study powered for histology (at 12-18m) • Industry sponsored study

Next surgical step to simplify use of existing technology and decrease SSP’s/SAE’s : C-ACI • Use of collagen Patch instead of periosteum in ACI • Type I / III Porcine Bilayer collagen membrane • Removes need to harvest periosteum • British study showed significant decrease in SSP due to patch hypertrophy or adhesions < 10% • Gooding CR, Bartlett W, Bentley G, et al. A prospective, randomized study comparing two techniques of autologous chondrocyte implantation for osteochondral defects in the knee: Periosteum covered versus type I/III collagen covered. Knee 2006;13:203-210

Cartilage Repair: US Procedural Share Small Defects Persistent Pain 30% Revisedat 10 months Disease Available for future pipeline procedures Current US Cartilage Repair Market – Value = ~ $52/660M

Next Generation Techniques: • Scaffolds to enhance Micr0-fx marrow cell stimulation • 2nd Generation Cell Techniques • Minced Cartilage ( One stage techniques) • 3rd Generation cell techniques • Concurrent Use of Growth factors/ BMP’s • Enhanced Stem cell derived:

Scaffolds • Region-specific • Conductive : several substrates Including chitosan/ fibrinogen • Bio-replaced • Cost-effective • May act as Micro-fx adjunct ie: Scaffold guided regeneration

2nd Generation Cell Therapies • Autogenous cells • Seeded scaffold or liquid gel • Minimizes periosteal related complications • Allows arthroscopic implant

2nd Generation Cell therapy enhancements continued: • Assays for Phenotypic selection • Molecular markers to find an uber chondrocyte • Possibly yield improved chondrogenesis • Possibly more durable matrix

Next Generation Techniques: • Scaffolds to enhance Micr0-fx marrow cell stimulation • 2nd Generation Cell Techniques • Minced Cartilage ( One stage techniques) • 3rd Generation cell techniques • Concurrent Use of Growth factors/ BMP’s • Enhanced Stem cell derived:

Minced Cartilage • Autogenous • Allogeneic • Time =O decision making • May use scaffold/ staple • May implant in fibrin glue Fragments +Scaffold

3rd Generation Cell Based • Autogenous • Allogeneic • 3-D Cartilage graft • Technical ease might allow arthroscopic insertion with bioadhesive

Other 3rd Generation Potential Enhancements: • Expanded Juvenile chondrocytes • Scaffold independent cx • Clinical: Phase I completed: • FDA Phase II/III IND/BLA pending Sheep Allograft 8 Weeks Juvenile Cartilage Adult Cartilage

Next Generation Techniques: • Scaffolds to enhance Micr0-fx marrow cell stimulation • 2nd Generation Cell Techniques • Minced Cartilage ( One stage techniques) • 3rd Generation cell techniques • Concurrent Use of Growth factors/ BMP’s • Enhanced Stem cell derived

Articular Cartilage Healing by OP-1( BMP-7) Jelic et al 2004 • 12 Sheep (1 year, 60 kg) • 1 knee, 1 trochlear defect • Deep cartilage layer intact • Cocktail of factors: continuous delivery (28 d) via mini-osmotic pump • Arthroscopic monitoring of repair • Sacrification at 12 months

Microfracture/BMP-7(OP-1)ResultsKuo Rodrigo et al Osteoarthritis 2006 • RabbitsTrochlear ACDs • Microfracture vs Microfracture plus collagen Type l sponge with BMP-7 • Results • Microfracture mostly fibrocartilage • Microfracture plus BMP-70% hyaline or hyaline like repair

OP-1PreclinicalDose Response in OA model Osteogenic Protein-1 inhibits the progress of posttraumatic osteoarthritis Masaya Hayashi, MD, et al ICRS 2007 Warsaw

Other Synovial Fluid Factors: • Growth Factors: -IGF-1, FGF, TG-Beta super family Can we stimulate these to increase GAG synthesis after cartilage injury • Catabolic Factors: Cytokines: - IL-1, TNF, IL-6,7,8 Can we inhibit these to avoid matrix breakdown after cartilage injury

Next Generation Techniques: • Scaffolds to enhance Micr0-fx marrow cell stimulation • 2nd Generation Cell Techniques • Minced Cartilage ( One stage techniques) • 3rd Generation cell techniques • Concurrent Use of Growth factors/ BMP’s • Enhanced Autologous Stem cell derived Techniques - Early animal work promising

Cells Ultimate goal: 3 Key Requirements • Biodegradable Scaffolds to anchor, deliver and orient cells • Bioactive factors (Reagents) to • provide instructional cues to cells • Cells: responsive to their environment therefore milieux shape/ O2 Tension effects should be considered to optimize growth Scaffold Reagents

Next Gen. Cartilage Repair: Conclusions • Exciting developments in evolution • Now is the time for Profiling and stratification of patients • To consider issues concerning timing of surgery and cohort details • Scaffolds and Stem cell and cellular optimization techniques • Effective Meniscus replacements • Delineate effective growth factors • Develop Arthroscopic delivery techniques

Ultimately What will yield the perfect clinical result? • An effective and available cell source • Enhanced architecturally with effective scaffold • Enhanced biologically with BMP’s • Surgery: minimally invasive or arthroscopic • Single stage • Cost effective (market driven cost) • High success rates and Low complication rate (similar to TKA) NORMAL CARTILAGE

In The Near Future? • A dialogue among scientists, surgeons, regulators and industry is needed to find the best paradigm to allow new treatments available in Europe and Asia to become available to help U.S. patients. • ICRS is ready to help facilitate this discussion: Recent Miami summit was very successful in delineating the problems and resources needed to address solutions • We need to move forward responsibly, however, to avoid poor treatment paradigms and patient complications while providing cost effective care. • Regarding cell technology: Currently neither scientists nor industry have a clear path to design effective studies to bring new technology to market.

Questions to be considered to move forward with study design. • Need to consider what is the best comparator for RCT’s. Is micro-fx the truly best comparator for all Rx • Are alternate Level I or II study designs available in other medical lit. as option to std. RCT when needed • Should different size lesions be treated as different cohorts rather than considering all lesions equivalent? • Should patients entered into cohorts have some validated score for pre-RX symptoms? Or are symptomatic and asymptomatic lesions equivalent? • What cohort sizes are needed to see statistically significant treatment differences clinically, structurally and histologically.

What is our largest unmet need? 35 - 40 yr. old patient Thank-you for your attention!

U.S. Food and Drug Administration