®
SYNVISC is a registered trademark of Genzyme Biosurgery Corporation.

•
Prevalent
•
Resource intensive
•
Costly
•
Disabling
•
Significant comorbidity

•
Mechanical
Loss of muscle strength
Obesity
Joint structure
Overuse and trauma
•
Endogenous
Heritable disorders
Developmental disorders
Diseases
Nutrition
Reference: Pelletier JP, Martel-Pelletier J, Howell DS. Etiopathogenesis of osteoarthritis. In: Koopman
WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology . Philadelphia, PA: Lippincott
Williams & Wilkins; 2001;2:2195-2215.

Chondrocyte Proteases

Inhibitors
Matrix
Degradation

Collagen
&
Proteoglycans
Reference: Pelletier JP, Martel-Pelletier J, Howell DS. Etiopathogenesis of osteoarthritis. In: Koopman
WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology . Philadelphia, PA: Lippincott
Williams & Wilkins; 2001;2:2195-2215.

Synovial Fluid
Synovial
Membrane
Collagen &
Proteoglycan
Fragments
Matrix
Breakdown
Products
Neoepitopes
Crystals
Cartilage
Subchondral Bone
Reference: Pelletier JP, Martel-Pelletier J, Howell DS. Etiopathogenesis of osteoarthritis. In: Koopman
WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology . Philadelphia, PA: Lippincott
Williams & Wilkins; 2001;2:2195-2215.

Synovial Fluid
Synovial
Membrane
Anabolism

Collagen

Aggrecan
Cartilage
Subchondral Bone
Catabolism
Cytokines
Proteases
Nitric Oxide
Apoptosis
Necrosis
Reference: Pelletier JP, Martel-Pelletier J, Howell DS. Etiopathogenesis of osteoarthritis. In: Koopman
WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology . Philadelphia, PA: Lippincott
Williams & Wilkins; 2001;2:2195-2215.

•
Inflammation secondary to cartilage degradation
•
Morphological changes in OA synovium
Usually mild to moderate
At times comparable to rheumatoid arthritis (RA)
Characterized by increased numbers of:
•
Inflammatory mononuclear cells
•
Activated T-cells and B-cells
Reference: Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum . 2001;44(6):1237-1247.

•
Pro-inflammatory cytokines and mediators produced by chondrocytes act within cartilage
Autocrine
Paracrine
Promote catabolism
Reference: 1. Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum . 2001;44(6):1237-1247. 2.Goldring MB.
The role of the chondrocyte in osteoarthritis. Arthritis Rheum . 2000;43(9):1916-1926.

•
Pro-inflammatory cytokines
Interleukin-1

Tumor necrosis factor-

Interleukin-6
Interleukin-8
Reference: Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum . 2001;44(6):1237-1247.

•
Nitric oxide (NO) promotes catabolism
•
NO can
Inhibit synthesis of cartilage macromolecules
Enhance activity of matrix metalloproteases
Reduce the synthesis of anti-inflammatory cytokines
•
Increase levels of prostaglandins and leukotrienes, possibly promoting catabolism
Reference: Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum . 2001;44(6):1237-1247.

•
Hyaluronic acid (HA) plays a key role in homeostasis of the normal joint
Macro-homeostasis – the rheological environment
Mini-homeostasis – the fluid environment
Micro-homeostasis – the chemical environment
Reference: Adams, ME. Viscosupplementation as articular therapy. In: Laurent TC, ed. The Chemistry,
Biology, and Medical Applications of Hyaluronan and its Derivatives.
London, England: Portland Press,
Ltd; 1998:243-253.

•
Highly influences intercellular matrices of joint soft tissues
•
Unique combination of elasticity and viscosity
•
Hyaluronan responsible for elastoviscous properties
•
Elastoviscosity critical for joint function

Flow
Slow Impact
Viscosity
Fast Impact
Elasticity
Shock
Absorption

Dynamic Moduli at 2.5 Hz
Elasticity
(Pa)
Viscosity
(Pa)
Normal
(18- to 27-year-olds; 117 ± 13 n=16)
Osteoarthritic (n=11) 8 ± 5
45
5
± 8
± 3
Reference: Balazs EA. The physical properties of synovial fluid and the special role of hyaluronic acid. In: Helfet AJ.
Disorders of the Knee . 2nd ed. Philadelphia, Pa: JB Lippincott Company; 1983:61-74.

•
Intrinsic autoregulatory function
Regulates lymphatic flow
Regulates diffusion of nutrients
Regulates diffusion of waste products
Reference: Adams, ME. Viscosupplementation as articular therapy. In: Laurent TC, ed. The Chemistry,
Biology, and Medical Applications of Hyaluronan and its Derivatives.
London, England: Portland Press,
Ltd; 1998:243-253.

•
Effective free-radical scavenger
•
Protects chondrocytes and synoviocytes from degradative enzymes, chemical agents, and toxins
•
Stabilizes cell membranes
•
Desensitizes sensory receptors
•
Auto-regulatory maintaining environment for normal HA synthesis
Reference: Adams, ME. Viscosupplementation as articular therapy. In: Laurent TC, ed. The Chemistry,
Biology, and Medical Applications of Hyaluronan and its Derivatives.
London, England: Portland Press,
Ltd; 1998:243-253.

•
Replaces pathologic synovial fluid
•
Supplements elasticity and viscosity
•
Reduces pain and improves mobility

1 st Generation
Hyaluronan NIF-NaHA
Healon
®
*
1970s
1960s
2 nd Generation
Hylans Hylan G-F 20
Viscosupplementation
Added to
American College of
Rheumatology Treatment
Guidelines for Knee OA
1980s 1992
2000
*Healon is a registered trademark of Pharmacia, Inc.

•
Cross-linked hyaluronan
•
Increased molecular weight (hylan A) or continuous molecular network (hylan B)
•
Higher elastoviscosity than purified hyaluronan
•
Longer tissue residence time

®
Purified hyaluronan hylan A fluid hylan B gel
80%
SYNVISC
®
20%

Left: Supartz ® (sodium hyaluronate)
MW 0.6-1
Center: SYNVISC ® (Hylan G-F 20)
MW 6 million
Right: Hyalgan ® (sodium hyaluronate)
MW 0.6-0.7

1-7
Comparison of Rheologic Factors
Molecular Weight
(millions daltons)
Shock Absorption
(elasticity P A at 2.5 Hz)
Lubrication
(viscosity P A at 2.5 Hz)
SYNVISC 2
Healthy, Young* Synovial Fluid 2,3
* In 18- to 27-year-olds
6
4
– 5
111
117
25
45
Osteoarthritic Synovial Fluid 3,4 0.5
– 4
8 5
Hyalgan ®
(Sodium Hyaluronate) 5,6
Supartz ®
(Sodium Hyaluronate) 5,7
0.6 – 0.7
0.6 – 1
0.6
9
3
16
References: 1.Synvisc
® (Hylan G-F 20) Product Information. 2.Balazs EA, Denlinger JL. Viscosupplementation: a new concept in the treatment of osteoarthritis. J Rheumatol.
1993;20(suppl 39):3-9. 3.Balazs EA, Denlinger JL. The role of hyaluronic acid in arthritis and its therapeutic use in: Peyron JG, ed. Osteoarthritis: Current Clinical and Fundamental
Problems . France: Rueil-Malmaison, Laboratories Ciba Geigy; 1985:165-174. 4. Data on file. Genzyme Biosurgery Corp. 5.
Peyron JG. A new approach to the treatment of osteoarthritis: viscosupplementation. Osteoarthritis Cartilage.
1993;1:85-87.
6. Hyalgan ® Product Information. Sanofi-Synthelabo, Inc. 7. Supartz
®
Product Information. Seikagaku Corporation.

100
90
80
0
10
20
30
70
60 40
50
50
40 60
30
20 walking running jumping
70
80
10 90
HA MW
0
0.01
0.1
1
Frequency (Hz)
10 20
100
Reference: Weiss C, Band P. Basic principles underlying the development of viscosupplementation for the treatment of osteoarthritis. J Clin Rheumatol.
1999;5:S2-S11.

®
•
Elastoviscosity similar to that of the synovial fluid of healthy 18- to 27-year-olds
•
Designed as a synovial fluid prosthetic device
•
A series of three injections can provide pain relief for months
•
Generally well tolerated in trials and clinical practice
Reference: Weiss C, Band P. Basic principles underlying the development of viscosupplementation for the treatment of osteoarthritis. J Clin Rheumatol.
1999;5:S2-S11.

The Role of Molecular Weight – HA Synthesis
 g
 g
 g
 g
 g
 g
100
80
60
40
20
0
-20
-40
4,700,000 880,000 540,000 340,000
MW of Exogenous HA Standards (daltons)
Reference: Smith MM, Ghosh P. The synthesis of hyaluronic acid by human synovial fibroblasts is influenced by the nature of the hyaluronate in the extracellular environment. Rheumatol Int . 1987;7:113-
122.

The Role of Molecular Weight – Joint Pain
2
1.5
1
0.5
0
4
3.5
3
2.5
C on t
10
10
0
10 25 50
HA 6.8 kD HA 40 kD
5
10 20
HA 310 kD
0.
63
1.
25
2.
5 5
HA 860 kD
10
0.
63
1.
25
2.
5 5
HA 2300 kD
10
Effect of hyaluronic acid (HA) with different molecular weights on Bradykinin-induced joint pain in rats mg/mL
Reference: Gotoh S, Onaya J-I, Abe M, Miyazaki K, et al. Effects of the molecular weight of hyaluronic acid and its action mechanisms on experimental joint pain in rats. Ann Rheum Dis. 1993;52:817-822.

Role of Molecular Weight – Pain Receptors
•
Objective
Compare the effects of commercial viscoelastic substances with different molecular weights on the discharges of joint nociceptors evoked by movement of the inflamed rat knee joint
•
Methods
Electrical activity of median articular nerve
Inflammation – kaolin and carrageenan
Mechanical stimulation – controlled joint rotation
Sodium hyaluronate injected in joint cavity (MW <1,000,000 &
<2,000,000 and high MW ~6,000,000 [Hylan G-F 20])
Impulse discharge before and after injection measured with movement
Reference: Gomis A, Pawlak M, Schmidt RF, Belmonte C. Effects of elastoviscous substances on the mechanosensitivity of articular pain receptors. Presented at the World Congress on Osteoarthritis,
September 30
– October 3, 2001. Washington DC, USA. (abstr).

Role of Molecular Weight – Pain Receptors
•
Results
SYNVISC
®
(MW ~6,000,000) significantly reduced the number of nerve impulses evoked by movement after 1 hour.
MW <2,000,000 hyaluronan solutions were slightly faster and had a weaker effect after 30 minutes.
MW <1,000,000 did not significantly reduce mean impulse frequency.
•
Conclusion
“…it is to be expected that high MW hylan solutions will have more pronounced analgesic effects on human joint pain than hyaluronan solutions of lower MW.”
Reference: Gomis A, Pawlak M, Schmidt RF, Belmonte C. Effects of elastoviscous substances on the mechanosensitivity of articular pain receptors. Presented at the World Congress on Osteoarthritis,
September 30
– October 3, 2001. Washington DC, USA. (abstr)

®
Indicated for the treatment of pain in osteoarthritis of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy and simple analgesics, e.g., acetaminophen

Nonpharmacologic Modalities
Acetaminophen
At increased risk for an upper GI adverse event
Viscosupplements
COX-2 –specific inhibitor
NSAID and GI-protective agent
Glucocorticoid injection
Not at risk for an upper GI adverse event
Viscosupplements
COX-2 –specific inhibitor
Low-dose NSAID
Glucocorticoid injection
Surgery

®
AJ Lussier, AA Cividino, CA McFarlane, WP Olszynski,
WJ Potashner, R DeMédicis
Canada
Reference: Lussier A, Cividino AA, McFarlane CA, Olszynski WP, et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol . 1996;23(9):1579-1585.

®
•
336 patients, 458 knees, 1,537 injections
•
122 bilateral treatments
•
Mean age: 65 ± 1 years
•
63% female, 37% male
Reference: Lussier A, Cividino AA, McFarlane CA, Olszynski WP, et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol . 1996;23(9):1579-1585.

®
Much Better
35.0%
Better
42.2%
Worse or
Much Worse
1.3%
Same
21.4%
Reference: Lussier A, Cividino AA, McFarlane CA, Olszynski WP, et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol . 1996;23(9):1579-1585.

®
Evaluation of SYNVISC
® in Canadian Practice
Medial X-ray
Grade
Percent Better or
Much Better
I
II
III
IV
91
80
76
58
Reference: Lussier A, Cividino AA, McFarlane CA, Olszynski WP, et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol . 1996;23(9):1579-1585.

Evaluation of SYNVISC
® in Canadian Practice
•
No systemic adverse events
•
Forty-two transient local reactions noted in 28 patients (no sequelae)
•
Rate of local reaction in this study: 2.7% of injections, 8.3% of patients
•
Local reaction does not predict treatment failure
69% still clinically improved
66% received subsequent injections
Reference: Lussier A, Cividino AA, McFarlane CA, Olszynski WP, et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol . 1996;23(9):1579-1585.

Safety Profile – Influence of Injection Technique on the Rate of Local Reactions *
Injection
Procedure
Position of the Knee
†
Medial
Lateral
Infrapatellar
Straight (%)
23/944 (2.4)
4/273 (1.5)
0/0 (0)
Flexed (%)
0/0 (0)
0/0 (0)
0/12 (0)
Partially Bent (%)
15/287 (5.2)
0/0 (0)
0/0 (0)
*The rate of local reaction is reported as the number of reactions/number of injections.
†
The injection technique was not reported for 33 of the 1537 SYNVISC
® injections.
Reference: Lussier A, Cividino AA, McFarlane CA, Olszynski WP, et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol . 1996;23(9):1579-1585.

Efficacy and Adverse Events
•
The majority of joints (69%) experiencing local reaction were considered clinically improved
•
Of 32 joints in which a local adverse event occurred, 21 (66%) went on to receive subsequent
SYNVISC
® injections
Reference: Lussier A, Cividino AA, McFarlane CA, Olszynski WP, et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol . 1996;23(9):1579-1585.

®
Conclusions From Clinical Trials
•
SYNVISC
® treatment is clinically and statistically superior to placebo and active controls
•
SYNVISC
® is as good as or better than continuous
NSAID therapy
•
Three injections over 15 days can relieve pain for months
•
Generally well tolerated

®
SD Goorman, TK Watanabe, EH Miller, and C Perry
USA
Reference: Goorman SD, Watanabe TK, Miller EH, Perry C. Functional outcome in knee osteoarthritis after treatment with
Hylan G-F 20: a prospective study. Arch Phys Med Rehabil. 2000;81:479-483.

Functional Outcome after Treatment with SYNVISC
®
•
Design
Prospective case series with 6-month follow-up
•
Setting
Outpatient community orthopaedic practice
•
Participants
84 consecutive patients with unilateral or bilateral knee OA
•
Intervention
3 weekly injections of SYNVISC
®
•
Outcome assessment
SF-36 Health Survey (pretreatment and 6 months posttreatment)
Reference: Goorman SD, Watanabe TK, Miller EH, Perry C. Functional outcome in knee osteoarthritis after treatment with
Hylan G-F 20: a prospective study. Arch Phys Med Rehabil. 2000;81:479-483.

Functional Outcome after Treatment with SYNVISC
®
100
80
60
40
20
0
* *
*
†
*
†
Physical
Function
Role-
Physical
Bodily Pain General
Health
Vitality Social
Function
Role-
Emotional
Pre-treatment Post-treatment
Mental
Health
* P < 0.001
† P = 0.01
Reference: Goorman SD, Watanabe TK, Miller EH, Perry C. Functional outcome in knee osteoarthritis after treatment with
Hylan G-F 20: a prospective study. Arch Phys Med Rehabil. 2000;81:479-483.

Functional Outcome after Treatment with SYNVISC
®
Conclusion
“Efficacy of intra-articular injection of Hylan G-F 20 for knee OA 6 months after injection is demonstrated in several categories of the SF-36, indicating a measurable improvement in overall functioning in these patients.”
Reference: Goorman SD, Watanabe TK, Miller EH, Perry C. Functional outcome in knee osteoarthritis after treatment with
Hylan G-F 20: a prospective study. Arch Phys Med Rehabil. 2000;81:479-483.

•
10 out of 511 (2%) patients treated with SYNVISC
®
(559 knees) reported systemic adverse events
•
Isolated unique events
•
Rate no different from that of control treatments

511 patients received 1,771 SYNVISC
® injections in 559 knees
Symptoms Number of Events Number of Patients
(% per Injection) (% per Patient)
Pain and/or swelling 39 (2.2) after SYNVISC
® injection
37 (7.2)
•The ratio of local reactions among female and male patients was 2:1, the same ratio as the entire OA population.
• Clinical improvement was noted in the majority of patients.
•There were no sequelae following local reactions.

•
Incidence rate ~ 2 –3% of injections or 7–8% of patients
•
Most occur within 1 –2 days of injection
•
Typically resolve spontaneously within a week
•
Efficacy not necessarily impacted by local reaction
Reference: Lussier A, Cividino AA, McFarlane CA, Olszynski WP, et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol . 1996;23(9):1579-1585.

•
Spontaneous reports of local reactions
(e.g., pain, swelling, and/or effusion)
•
Variable synovial fluid cell counts
(some exceeding 50,000 cells/mm 3 ) 1
•
Treatments included rest, ice, heat, elevation, simple analgesics, NSAIDs, intra-articular corticosteroids, and rare reports of arthroscopic debridement.
1
Reference: Data on file, Wyeth-Ayerst Laboratories.

®
•
Prepare knee for injection 1
•
Aspirate joint fluid 1
•
Implant
SYNVISC
®
1
1 SYNVISC
®
(Hylan G-F 20) Product Information.

®
•
Course of therapy: 3 intra-articular injections over 15 days
Day 1: 2 mL
Day 8: 2 mL
Day 15: 2 mL
Reference: SYNVISC
®
(Hylan G-F 20) Product Information.

•
Side effects other than local pain/swelling reported rarely
•
Contraindicated in patients with known hypersensitivity to hyaluronan products
•
Use caution in patients allergic to avian proteins, feathers, and egg products
•
Results of repeat use have not been established

•
34% to 53% more total costs 1
•
42% to 59% more doctor costs 1
•
32% to 51% more hospital care costs 1
•
33% to 59% more drug costs 1
Reference: MacLean CH, Knight K, Paulus H, Brook RH, et al. Costs attributable to osteoarthritis. J Rheumatol.
1998;25:2213-2218.

•
NSAIDs and associated costs account for a large part of arthritis treatment costs 1
$3.9 billion for managing side effects of NSAIDs annually 1
NSAID- related morbidity and mortality
NSAID-related complications* ,2
Serious GI 7 in 100 †
Number of arthritis patients annually
Hospitalization 103,000 (at $15,000 to $20,000 per hospitalization)
Death 16,500
•
COX-2
–specific inhibitors have been associated with renal 3 and cardiac complications 4
*Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) data. † Patients with osteoarthritis only.
References: 1. Bloom BS. Direct medical costs of disease and gastrointestinal side effects during treatment for arthritis.
Am J Med.
1988;84 (suppl 2A):20
–24. 2. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N.Engl J Med . 1999;340:1888-1899. 3. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA . 2001;286:954-959. 4. Physicians’ Desk
Reference ® . 55th ed. Montvale NJ: Medical Economics Company, Inc.; 2001:981-984, 2049-2053,2985-2988,2977-
2980,2993-2995,3120-3122.

Cost Comparison of SYNVISC ® to
NSAIDs and COX-2 –Specific Inhibitors *
6 months of daily NSAID use
6 months of efficacy
3 implantations of SYNVISC ®
$369 –$883 $705
•
Rx drugs are not covered by Medicare
•
Discount for timely payment of SYNVISC
® account (2% net 120 days)
* Cost calculations based on recommended dosing as published in Physicians’ Desk
Reference , 55th ed. 2001, and on average wholesale prices as quoted in Red Book UPDATE
Top Volume Rx Products, August 2001

This form tracks a patient’s clinical outcome. It should be updated after each treatment and at the 8 week to 12 week posttreatment evaluation.
Patient Information Disease
Severity
Patient Name:
Mild
Moderate
Severe
Very Severe
Other Observations or Comments
Much Better
Better
Same
Worse
Much Worse
OUTCOME EVALUATION (circle a number)
Treatment 2
Pain Relief Activity Level
Treatment 3
Pain Relief Activity Level
5
4
3
2
1
5
4
3
2
1
5
4
3
2
1
5
4
3
2
1
Posttreatment*
Pain Relief Activity Level
5
4
3
2
1
5
4
3
2
1
The charts below should be filled in to measure treatment pain relief and activity level improvement. The patient’s progress should be plotted for the corresponding time interval, and when treatment is completed, the dots are to be connected to show the patient’s overall response to therapy
DISEASE SEVERITY:
PAIN RELIEF
Much Better 5
Better 4
Same 3
Worse 2
Much Worse 1
Treatment 2 Treatment 3 Posttreatment*
Much Better 5
Better 4
Same 3
Worse 2
Much Worse 1
ACTIVITY LEVEL
Treatment 2 Treatment 3 Posttreatment*
*Suggested at 8 to 12 weeks after first injection.

This form is a summary of each patient’s clinical outcomes. Complete the form after treatment for ten patients has been administered.
9.
10.
6.
8.
5.
6.
3.
4.
1.
2.
PATIENT I.D. NUMBER DISEASE SEVERITY
Mild
Moderate
Mild
Moderate
Mild
Moderate
Mild
Moderate
Mild
Moderate
Mild
Moderate
Mild
Moderate
Mild
Moderate
Mild
Moderate
Mild
Moderate
Severe
Very Severe
Severe
Very Severe
Severe
Very Severe
Severe
Very Severe
Severe
Very Severe
Severe
Very Severe
Severe
Very Severe
Severe
Very Severe
Severe
Very Severe
Severe
Very Severe
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
PAIN RELIEF
NO
NO
NO
NO
NO
NO
NO
NO
NO
NO
IMPROVED ACTIVITY LEVEL*
YES
YES
YES
YES
YES
YES
YES
YES
YES NO
YES
*Any degree of improvement; week 12 compared to week 1.
NO
NO
NO
NO
NO
NO
NO
NO
NO
# of patients with pain relief x10 =
% of patients with pain relief x10 =
# of patients with improved activity levels
% of patients with improved activity levels