1. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. New Concepts for Management of Osteoarthritis in the Knee— An Interactive Forum Presented by Mark D Hopkins, M.D. Board-certified Orthopedic Surgeon Flagstaff, Arizona

2. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Objectives Discuss etiology of osteoarthritis (OA) of the knee Explain why hyaluronans are so important for proper knee function Go over fundamental differences between the different types of hyaluronans Discuss mechanisms of action of hyaluronans Provide an opportunity for physician exchange of ideas and clinical experiences

3. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Audience Poll: How many have osteoarthritis? Which specialties are represented? Who uses hyaluronan compounds?

4. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Prevalence of osteoarthritis Advertisements from a recent issue of American journal of Orthopedics 75% of ads covered some aspect of osteoarthritis -8 ads on joint replacement -2 on NSAID -3 on hyaluronans -4 on other osteoarthritis categories

5. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Osteoarthritis Osteoarthritis is a degenerative joint disease resulting in cartilage erosion, subchondral bone remodelling, osteophyte formation, and synovial inflammation. Osteoarthritis has multiple origins Current evidence suggests that both mechanical and biochemical factors play an important role in its progression

6. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Joint injuries leading to osteoarthritis Articular cartilage contusions Partial or complete meniscectomy Ligamentous instability Overuse or repetitive trauma Secondary weakness in quadriceps, loss of damping effect on knee impact Posttraumatic joint deformities from fractures

7. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Joint deformities leading to osteoarthritis Varus knee Valgus knee Ankle and foot problems leading to altered gait Hip problems

8. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Genetic predisposition for osteoarthritis Cartilage degradation time clock Starts early in some people, later in others

9. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Osteoarthritis Imbalance of biosynthesis and degradation in cartilage, synovial fluid, bone, muscle and ligaments In essence: increased degradation, decreased synthesis Leads to decrease in concentration and average molecular weight of hyaluronic acid in synovial fluid

10. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Osteoarthritis Hyaluronic acid normal average molecular weight is 7,000,000 daltons In knees with osteoarthritis the average molecular weight can drop to 4,800,000 daltons or even as low as 20,000 daltons

11. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. ACR 2000 Guidelines— Pharmacologic/Surgical Therapy American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000;43:1905-1915. Mild to Moderate Pain Simple analgesics (eg, acetaminophen) OTC NSAIDs Topical creams Moderate to Severe Pain Rx NSAIDs plus gastroprotective agent, or COX-2–selective inhibitors Additional Therapies IA hyaluronans IA steroids Surgical Intervention Total knee replacement

12. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. How to treat osteoarthritis Imagine a freighter traveling towards the arctic circle directly in to the path of icebergs What would you do? Some would not alter the course, but would continue directly ahead and repair damages along the way (treat symptoms) And if necessary replace the freighter when they returned home. (total knee replacement)

13. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. How to treat osteoarthritis Others might attempt to alter the course of the freighter to avoid the icebergs. (disease modifying treatments for osteoarthritis, alter the course of the disease) Perhaps the treatment for osteoarthritis should be broken down in to disease modifying or simply symptom relieving

14. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Modified ACR 200 guidelines Symptom relieving Simple analgesics OTC NSAID Cox 2 inhibitors Steroids Knee replacement Disease modifying Hyaluronans Glucosamine Chondroitin Sulfate Unloader braces HTO Weight loss Increase muscular strength Improve flexibility

15. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. What is your choice? What would you want if you were the patient? Crash in to icebergs? Avoid them?

16. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Product comparisons, hyaluronans ProductHyalganSynviscSupartz MW (kDa)500-730 80% 6,000 20% > 6,000 620-1,170 ManufactureNaturalCrosslinkedNatural Treatment 3 or 5 inj. X 20 mg/2ml 3 inj. X 16 mg/2ml5 inj. X 25mg/2.5ml Repeat series FDA approvedNot FDA approved Inflammatory reactions 0%2.2% per injection 0% Stimulates endogenous hyaluronase production YesNoYes

17. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Mechanisms of Action of Hyaluronans Based on research dating back to the 1980’s Increases the viscosity and elasticity of OA synovial fluid Stimulates endogenous hyaluronic acid production Inhibits induction and activity of degradative enzymes Reduces inflammatory response Analgesic effect

18. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Increased viscosity and elasticity of synovial fluid This is a temporary effect For hyalgan 24 hours For supartz 24-72 hours For synvisc 3-8 days

19. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. How important is this temporary increased viscosity and elasticity? When the original patents were being developed, it was thought that the viscosity increase was the primary effect by which these substances worked. They were thought of as a lubricant for the knee joint. Synvisc was thought to be superior because of its larger molecular weight. It would stay in the knee longer and lubricate it better. This is why during the development process for synvisc, it was crosslinked.

20. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Possible sequelae of crosslinking Some have pointed to the cause of synvisc’s inflammatory reactions being linked to its larger size. Possible foreign body reaction Possible autoimmune response

21. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Stimulates endogenous hyaluronase production How could injecting hyaluronase stimulate hyaluronase production? One would logically think that the body would sense the substance was increased and limit its production.

22. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Hyaluronase Is present as a polydisperse species with an average MW of up to 10,000,000 Daltons. The concentration in normal synovial fluid is 3mg/ml. Is responsible for the normal viscosity of synovial fluid. Also lubricates the joints. A knee with low quantities of hyaluronase or the wrong molecular weight is like an engine with not enough oil or the wrong type.

23. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Hyaluronase Type B fibroblasts in synovium are responsible for hyaluronase production. The response of fibroblasts to different molecular weights of hyaluronase was studied. High MW fractions (4,000,000) were less effective in stimulating hyaluronase synthesis than lower MW (500,000-4,000,000)

24. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Stimulation of endogenous hyaluronase production Synovial fibroblasts do not increase the biosynthesis of hyaluronase when the hyaluronase in their environment is of a MW within a range which could be functionally acceptable. The stimulus for increased biosynthesis of hyaluronase only becomes operational when the hydrodynamic size distribution of extrinsic hyaluronase falls within a particular mean range.

25. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Stimulation of endogenous hyaluronase production Receptor binding as a function of molecular weight. MW < 500,000, weak binding no HA synthesis MW 500,000-4,000,000, strong binding because # of receptors stimulated increases HA biosynthesis MW > 4,000,000 maximal receptor binding, large domains limit # of sites, decrease HA production

26. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Mechanism of action of hyaluronans Inhibit induction and activity of degradative enzymes Hyaluronase suppresses MMP-3 (matrix metalloproteinase-3) MMP-3 degrades cartilage proteoglycan and type 2 collagen IL-1Beta (interleukin-1 Beta) IL-1Beta is responsible for cartilage catabolism

27. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Mechanism of action of hyaluronans Hyaluronase reduces inflammatory response Hyaluronase inhibits leukocyte and mononuclear cell phagocytosis, adherence and mitogen-induced proliferation Hyaluronase protects tissues and synovial proteins from free radicals Hyaluronase decreases levels of prostaglandin E2 and cyclic AMP. HA impairs migration of AA (arachidonic acid) away from cells. Since extracellular AA is rapidly taken up by activated leukocytes within joints and may be converted to inflammatory prostanoids, the observed inhibitory effects of HA on AA release could be considered antiinflammatory.

28. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Mechanism of action of hyaluronans Analgesic activities of hyaluronase By modulating inflammatory cell activities, including their release of pro-inflammatory mediators, cytokines and free radicals, HA could indirectly influence the sensitization of pain receptors in arthritic joints.

29. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Summary All of the effects are centered around hyaluronase The most important effect of administering hyaluronase in to a joint is its effect on stimulating endogenous hyaluronase production because it is the hyaluronase that mediates all of the other effects.

30. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Summary, continued Only two of the substances on the market stimulate endogenous hyaluronase production, hyalgan and supartz. We have to understand that the treatment of osteoarthritis is a long term problem. The only substance FDA approved for repeat series is hyalgan. It makes no sense to treat a long term problem for six months, then stop. Hyalgan, then, by deduction is currently the most logical choice for the long term treatment of osteoarthritis. Remember, we’re not treating the symptoms, we are trying to alter the course of the disease. Avoid the icebergs.

31. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Focus Questions Use of hyaluronans in other joints? What do we do when a patient does not respond to hyaluronan treatment? What is the reason that some patients don’t respond and some do with the same type and degree of osteoarthritis? Which grades of osteoarthritis respond best to hyaluronan therapy?

32. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. Focus Questions, continued Does obesity play a role in response to hyaluronase treatment? When a patient has a total knee on one side, do you try hyaluronase on the other side or just go to a TKA? What do you do with a patient with a meniscus tear that may be degenerative and osteoarthritis on the same side? TKA? Scope? Hyaluronase? Therapy? Other?

33. DRAFT for internal Sanofi-Synthelabo use only. Not for distribution. The End