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Osteoarthritis (OA): in vitro and animal models

Osteoarthritis (OA): in vitro and animal models. James Witter MD, PhD Division of Analgesic, Anti-inflammatory and Ophthalmic Drug Products (HFD-550) Center for Drug Evaluation (CDER) Food Advisory Committee Meeting June 7, 2004. OA: Are there links?. Human. Animal. Client

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Osteoarthritis (OA): in vitro and animal models

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  1. Osteoarthritis (OA): in vitro and animal models James Witter MD, PhD Division of Analgesic, Anti-inflammatory and Ophthalmic Drug Products (HFD-550) Center for Drug Evaluation (CDER) Food Advisory Committee Meeting June 7, 2004

  2. OA: Are there links? Human Animal Client (companion) Experimental model Histology cell enzyme

  3. There are currently no FDA approved therapies that alter joint structure in OA Osteoarthritis Initiative NIH/FDA/Industry/Academia February 28-29, 2000

  4. Human OA: Some Estimates • $76 billion, direct/indirect health care costs • 68 million lost work days (pain and loss of function) • clinical OA (MD diagnosis) • 12.1% of US or 21 million people • total joint replacements • 494,000/yr (hip-knee) • market size • symptoms- $4.0 billion • structure- $3.5 billion

  5. Human OA: Some Questions • is OA inevitable part of aging? • certain joints in most people normal in old age • what is the etiology of OA? • likely multiple, few examples… • genetic-developmental • overuse • acute and chronic trauma • underuse • atrophy • primary (idiopathic) vs. secondary

  6. Draft Guidance for OAJuly 1999www.fda.gov/cder/guidance

  7. Conceptual Model of Human OA Biochemical changes Structural changes Pain* and other signs and symptoms (OA) Functional limitation* Reduced quality of life* Surgical replacement* * important to the patient

  8. “Surrogate” ApprovalSubpart H21 CFR 314.510 FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible mortality.

  9. Surrogate Endpoint: Definition • A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions, or survives • Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint • Only valid if the effect on the surrogate leads to a clinical benefit

  10. Surrogates vs. Biomarkers • Surrogate endpoints are candidates for drug approval • Biomarkers do not have the same regulatory implication • Surrogates may be biomarkers, but not all biomarkers are surrogates.

  11. Clinically Meaningful Outcome Surrogate marker Biomarker

  12. Delay in Structural Progression • currently JSN (knee/hip) by X-ray accepted as surrogate • trial length: at least one year • include endpoints of pain, patient global, and patient reported outcome • can structure “stand alone”?

  13. Claim: OA StructureOA draft guidance-1999 • “Normalize” the X-ray (stand alone) • Improve JSN over baseline (stand alone) • reflects new or regrown “physiologic” cartilage • Slow JSN by “clinically relevant amount” • may not need symptom evidence for approval • approval contingent on commitment to define the actual symptom benefit in phase 4 studies • Slow JSN by < “clinically relevant amount” • subpart H approach • JSN is surrogate

  14. Structure of Hyaline Cartilage

  15. Adult Human Cartilage • chondrocytes in abundant extracellular matrix • 65-80% water • 20-35% dry weight is structural macromolecules • type II collagen ~50% • aggrecan ~ 25% • glycosaminoglycans (GAGs) • chondroitin sulfate (4 vs. 6) • keratan sulfate • other types of collagens (IX, XI) • other proteoglycans • hyaluronic acid

  16. The OA Joint as an Organ • cartilage (hyaline, fibrocartilage) • aneural avascular alymphatic • menisci (medial, lateral) • tendons, ligaments,capsule • bone • synovial • membrane • fluid • muscles

  17. Fixed Flexion Extended Knee Radiography Techniques Semi-flexed Fluoroscopy Semi-flexed MTP Schuss

  18. X-ray: Standardization issues • conventional knee X-ray not reproducible • solution: (Buckland-Wright technique) • Semi-flexed AP view • Fluoro-assisted to allow to superimpose anterior and posterior margins of medial tibial plateau • To provide alignment of plateau and x-ray beam • Magnification-corrected JSW using xJSW software • problem: Not reproducible in clinic for • Entry criterion • Monitoring of disease

  19. In Vitro: Considerations • maintain matrix equilibrium/environment • Chrondrocyte highly sensitive to feedback • anabolic • proteoglycans and GAGS • catabolic • matrix metalloproteinases (MMP) • biomarkers • cell-cell and cell-matrix interactions • loading stresses • nutrients and waste removal • temperature • core (37°C) vs. ankle joint (29°C)

  20. Mouse chondrocyteBiochem J. (2003) 376, 511-515 • without glucose, glucosamine sole source of glycosaminoglycans (GAGs) for cell • with glucose • strong competitive inhibitor to utilization of glucosamine to produce GAGs • with glucosamine • do not stimulate production of GAGs • higher concentration produced less GAGs • what are likely levels of glucose, glucosamine at level of human cell?

  21. Animal model: Considerations • pain • primary clinical symptom • surgical intervention • not mimic human situation • species differences • 4 vs. 2 legs • biochemistry • underuse • muscle weakness (elderly women)

  22. PainArthritis Advisory CommitteeJuly 29-30, 2002

  23. Pain: The Symptom • studied directly (by patient) in humanOA • WOMAC for hip and knee • studied indirectly (veterinarians) in animalOA • chronic • lameness (function) • acute • vocalization • behavioral changes • decreased appetite • increases or decreases in activity • physiologic changes (pulse, blood glucose)

  24. Osteoarthritis: treatment of signs and symptoms claim • Primary efficacy endpoints: • Pain • Function • Patient global • Trial length: • 3 months

  25. WOMAC pain index 1. Walking on flat surface 2. Going up or down stairs 3. At night while in bed 4. Sitting or lying 5. Standing upright

  26. Animal Models of OA: chemically-induced (intra-articular) • iodoacetate • chicken • papain • guinea pig, mouse • chymopapain • dog • collagenase • mouse • TGF-ß • mouse

  27. Animal Models of OA:physically induced • anterior cruciate ligament transection • unilateral or bilateral • dog, rabbit • meniscectomy • rabbit, guinea pig • immobilization • rabbit, dog • patellar contusion • rabbit

  28. Animal Models of OA:spontaneous • Age/obesity • Hartley guinea pig • Genetic • unidentified • mouse, primate • Transgenic mice • type IX or II collagen mutation • hip dysplasia • dog (purebred vs. mixed bred)

  29. Cruciate-Deficient Dog: Lessons • chondrocytes can repair damage • hypertrophic cartilage • increased GAGs • true in humans, rabbits and Rhesus macaques • neurogenic acceleration • dorsal route ganglionectomy • more rapid cartilage damage • not good model for primary (idiopathic) OA • homeostatic phase of hypertrophic repair differs • importance of periarticular muscle • immobilized joint has atrophic loss of GAGs • quadriceps weakness in elderly women

  30. Domain Structure of Matrix Metalloproteinase (MMP) Family Pre Pro Catalytic Hemopexin-like Fibronectin 1(V) Transmembrane MMPPre Pro Cat Fn1(V) TmHpx Matrilysin Collagenase-1,-2,-3 Stromelysin-1,-2,-3 Macro elastase MT MMP-1 to -4 Gelatinase A Gelatinase B

  31. Evidence for MMPs in Pathophysiology of Osteoarthritis • hydrolyze relevant matrix substrates in vitro • upregulated by disease mediators (IL-1, TNF) • in situ hybridization and immunofluorescence at sites of tissue degeneration • signature cleavage fragments in vivo • Collagen neoepitopes • blockage by natural compounds and selective MMP inhibitors in vitro models

  32. Collagenases Present in Different Species CollagenaseHumanRatMouseRabbitDog 1 Yes No No Yes Yes 2 Yes ? Yes Yes ? 3 Yes Yes Yes Yes Yes

  33. Protection of Cartilage by Therapy X in Rabbit Meniscectomy Model Therapy X (mg/kg/d) 1 3 10 Parameter Normal Sham Vehicle 2.1 Fibrillation 0.1 0.1 3.6 4.1 2.7 Fissures 0.1 0.1 3.5 4.5 2.1 0.7 Erosions 0.0 0.0 2.9 2.9 1.0 0.9 Global 0.3 0.5 13.1 15.9 8.8 5.5 p < 0.01

  34. Protection of Cartilage by Therapy X in Dog Cruciotomy Model (8 months) Treatment Area Composite Vehicle 32  10 1.7  0.6 Low Dose X 22  7.7 1.4  0.8 High Dose X 19  8.4 1.0  0.8

  35. Hypothesis Limit joint destruction Results (clinical trials) MMP inhibitors No effect in RA or OA Some stopped due to safety data in oncology trials Stiffness/pain particularly in shoulders and hands Bisphosphonates Suggestion of efficacy in phase 2 trial, not confirmed in phase 3 trials (ACR-Orlando, 2003) OA and Structure Modifiers

  36. Timing of Approval and: Structural Benefit Clinical Benefit RA Drug approval Time OA OA: structural modifier

  37. OA: JSN progression Rapid JSN Slow No change b a c a Time

  38. “Virtual” TJR endpoint in OA • to facilitate and standardize development of disease-modifying agents • consists of the following key elements: • pain • function • radiographic endpoints • idea that agreed upon endpoint of joint failure reached (and surgery may occur)

  39. Osteoarthritis: The “Joint Organ” Total Joint Replacement Clinical Function 3 or 4 Pain 2 Surrogate Tendon/Ligament 1 Synovium Bone Drug development phase Biomarkers Cartilage

  40. …validation of a molecular target in human disease can be obtained only after positive results are obtained in Phase III clinical trials in humans. Ken Brandt, Biorheology 39 (2002) 221-235 Human OA In vitro animal

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