Viscosupplementation with SYNVISC ® (Hylan G-F 20) for the Treatment of Osteoarthritis Knee Pain SYNVISC is a registered trademark of Genzyme Biosurgery

Viscosupplementation with SYNVISC® (Hylan G-F 20)

for the Treatment ofOsteoarthritis Knee Pain

SYNVISC is a registered trademark of Genzyme Biosurgery Corporation.SYNVISC is a registered trademark of Genzyme Biosurgery Corporation.

Section 1: Osteoarthritis Overview

Osteoarthritis

• Prevalent

• Resource intensive

• Costly

• Disabling

• Significant comorbidity

Factors Contributing to OA

• 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.

OA Disease Processes

OA Disease Evolution – Stage I

Chondrocyte Proteases

Inhibitors

MatrixDegradation

Collagen&

Proteoglycans


OA Disease Evolution – Stage II

SynovialMembrane

Cartilage

Subchondral Bone

Synovial Fluid

Collagen &ProteoglycanFragments

MatrixBreakdownProducts

Neoepitopes

Crystals


OA Disease Evolution – Stage III

SynovialMembrane

Cartilage

Subchondral Bone

Synovial Fluid


Anabolism

Catabolism

CytokinesProteasesNitric Oxide

Collagen Aggrecan

ApoptosisNecrosis

The Role of Inflammation in OA

• 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.

The Chondrocyte in Inflammation

• Pro-inflammatory cytokines and mediators produced by chondrocytes act within cartilage

- Autocrine

- Paracrine

- Promote catabolism

Reference: 1. : 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



• 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


Functions of Synovial Fluid

Functions of Hyaluronic Acid (HA)in the Normal Joint

• 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.

Macro-homeostasis: HA in Synovial Fluid (SF)

• Highly influences intercellular matrices of joint soft tissues

• Unique combination of elasticity and viscosity

• Hyaluronan responsible for elastoviscous properties

• Elastoviscosity critical for joint function

Synovial Fluid Response to Movement

Fast Impact

ShockAbsorption

Viscosity

Flow

Slow Impact

Elasticity

Synovial Fluid Elastoviscosity

Dynamic Moduli at 2.5 Hz

Elasticity Viscosity (Pa) (Pa)

Normal

(18- to 27-year-olds; 117 ± 13 45 ± 8n=16)

Osteoarthritic (n=11) 8 ± 5 5 ± 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.

HA Mini-Homeostasis

• 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.

HA Micro-Homeostasis

• 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.

Section 2: Viscosupplementation Overview

Viscosupplementation

• Replaces pathologic synovial fluid

• Supplements elasticity and viscosity

• Reduces pain and improves mobility

Viscosupplementation: Historical Timeline

*Healon is a registered trademark of Pharmacia, Inc. *Healon is a registered trademark of Pharmacia, Inc.

Hylan G-F 20

1992

Hyaluronan

1960s

NIF-NaHAHealon® *

1970s

Hylans

1980s

Viscosupplementation Added to

American College of Rheumatology Treatment Guidelines for Knee OA

2000

11stst Generation Generation 22ndnd Generation Generation

Hylans

• Cross-linked hyaluronan

• Increased molecular weight (hylan A) or continuous molecular network (hylan B)

• Higher elastoviscosity than purified hyaluronan

• Longer tissue residence time

Purifiedhyaluronan

hylan Afluid

hylan Bgel

20%80%

SYNVISC®

Derivation of Hylans and SYNVISC®

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

Molecular Weight, Elasticity, and Viscosity1-7

Comparison of Rheologic FactorsMolecular Weight

(millions daltons)Shock Absorption

(elasticity PA at 2.5 Hz)Lubrication

(viscosity PA at 2.5 Hz)

SYNVISC 2 6 111 25

Healthy, Young* Synovial Fluid 2,3

* In 18- to 27-year-olds

4 – 5 117 45

Osteoarthritic Synovial Fluid 3,4 0.5 – 4 8 5

Hyalgan® (Sodium Hyaluronate) 5,6 0.6 – 0.7 0.6 3

Supartz® (Sodium Hyaluronate) 5,7 0.6 – 1 9 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.

Viscosupplementation Basic Principle

% E

last

icit

y

% V

isco

sity

Frequency (Hz)

0

10

20

30

40

50

60

70

80

90

100

0.01 0.1 1 10 20

0

10

20

30

40

60

70

80

90

100

50

walkingrunning

jumping

Normal

OA

500,000

Hylan G-F 20MW 6 million

HA MW

Reference: Weiss C, Band P. Basic principles underlying the development of viscosupplementation for the treatment of osteoarthritis. J Clin Rheumatol. 1999;5:S2-S11.

SYNVISC®

• Elastoviscosity similar to that of the synovial fluidof 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

-40

-20

0

20

40

60

80

100

10 /mL 25 /mL 50 /mL 100 /mL 200 /mL 400 /mLg g g g g g

880,000880,0004,700,0004,700,000 540,000540,000 340,000340,000

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.

% S

tim

ula

tio

n o

f H

A S

ynth

esis

The Role of Molecular Weight – Joint Pain

00.5

11.5

22.5

33.5

4

Cont 10 100 10 25 50 5 10 20

0.63

1.25 2.

5 5 100.

631.

25 2.5 5 10

mg/mL

HA 6.8 kD HA 40 kD HA 310 kD HA 860 kD HA 2300 kD

Alg

esic

Sco

re

Effect of hyaluronic acid (HA) with different molecular weights on Bradykinin-induced joint pain in rats

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)

Viscosupplementation with SYNVISC®

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

American College of Rheumatology 2000 Guidelines for OA of the Knee

Nonpharmacologic Modalities

At increased risk for an upper GI adverse event

Not at risk for an upper GI adverse event

Surgery

ViscosupplementsCOX-2–specific inhibitor

NSAID and GI-protective agentGlucocorticoid injection

ViscosupplementsCOX-2–specific inhibitor

Low-dose NSAIDGlucocorticoid injection

Acetaminophen

Experience with SYNVISC® in Routine Canadian Practice

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.

Experience with SYNVISC® in Routine Canadian Practice

• 336 patients, 458 knees, 1,537 injections

• 122 bilateral treatments

• Mean age: 65 ± 1 years

• 63% female, 37% male


Overall Response to SYNVISC® Viscosupplementation

Much Better35.0%

Same21.4%Worse or

Much Worse

1.3%

Better42.2%


SYNVISC® Is Effective Across All Radiologic Grades

Medial X-ray Percent Better or Grade Much Better

I 91

II 80

III 76

IV 58

Evaluation of SYNVISC® in Canadian Practice


Safety Profile in Clinical 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

Evaluation of SYNVISC® in Canadian Practice


Safety Profile – Influence of Injection Technique on the Rate of Local Reactions*

Injection Procedure

Straight (%) Flexed (%) Partially Bent (%)

Medial 23/944 (2.4) 0/0 (0) 15/287 (5.2)

Lateral 4/273 (1.5) 0/0 (0) 0/0 (0)

Infrapatellar 0/0 (0) 0/12 (0) 0/0 (0)

Position of the Knee†

*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.


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


Viscosupplementation with SYNVISC®

• 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 relievepain for months

• Generally well tolerated

Conclusions From Clinical Trials

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.

SD Goorman, TK Watanabe, EH Miller, and C Perry SD Goorman, TK Watanabe, EH Miller, and C Perry

USAUSA

Functional Outcome in Knee Osteoarthritis after Treatment with

SYNVISC®

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)



0

20

40

60

80

100

PhysicalFunction

Role-Physical

Bodily Pain GeneralHealth

Vitality SocialFunction

Role-Emotional

MentalHealth

Pre-treatment Post-treatment

** ** **

**††

††

*P < 0.001†P = 0.01


Sco

reS

core


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.”


Section 4: Tolerability, Safety, and Administration

Systemic Adverse Events inSeven Clinical Trials

• 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

Transient Local Reactions in the Injected Knee in Seven Clinical Trials

Symptoms Number of Events Number of Patients (% per Injection) (% per Patient)

Pain and/or swelling 39 (2.2) 37 (7.2)after SYNVISC® injection

•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.

511 patients received 1,771 SYNVISC® injections in 559 knees

Safety Experience – 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


Worldwide Postmarketing Safety Experience

• Spontaneous reports of local reactions (e.g., pain, swelling, and/or effusion)

• Variable synovial fluid cell counts (some exceeding 50,000 cells/mm3)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.

Dosing and Administering SYNVISC®

• Prepare knee for injection11

• Aspirate joint fluid11

• ImplantSYNVISC®11

1SYNVISC® (Hylan G-F 20) Product Information.

Reference: SYNVISC® (Hylan G-F 20) Product Information.

Dosing and Administering SYNVISC®

• Course of therapy: 3 intra-articular injections over 15 days

- Day 1: 2 mL

- Day 8: 2 mL

- Day 15: 2 mL

Precautions and Contraindications

• 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

Section 5: Impact of OA

Reference: : MacLean CH, Knight K, Paulus H, Brook RH, et al. Costs attributable to osteoarthritis. J Rheumatol. 1998;25:2213-2218.

The Costs of Osteoarthritisfor OA Patients vs Those Without OA...

• 34% to 53% more total costs34% to 53% more total costs11

• 42% to 59% more doctor costs42% to 59% more doctor costs11

• 32% to 51% more hospital care costs32% to 51% more hospital care costs11

• 33% to 59% more drug costs33% to 59% more drug costs11

*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.

The Costs and Impact of NSAID Use

• COX-2–specific inhibitors have been associated with renal3 and cardiac complications4

NSAID-related complications*,2 Number of arthritis patients annually

Serious GI 7 in 100†

Hospitalization 103,000 (at $15,000 to $20,000 per hospitalization)

Death 16,500

NSAID- related morbidity and mortalityNSAID- related morbidity and mortality

• NSAIDs and associated costs account for a large part of arthritis treatment costsNSAIDs and associated costs account for a large part of arthritis treatment costs11 - $3.9 billion for managing side effects of NSAIDs annually$3.9 billion for managing side effects of NSAIDs annually11

Cost Comparison of SYNVISC® to NSAIDs and COX-2–Specific Inhibitors*

$705$369–$883

6 months of efficacy 6 months of efficacy

3 implantations of SYNVISC3 implantations of SYNVISC®®

6 months6 months

of daily NSAID useof daily NSAID use

•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

Clinical Outcomes – Tools for Success

Clinical Outcomes TrackingThis 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

OUTCOME EVALUATION (circle a number)

DiseaseSeverity Pain Relief

Treatment 2

Activity Level

Patient Name:

Much BetterBetterSameWorseMuch Worse

MildModerateSevereVery Severe

54321

54321

Pain Relief

Treatment 3

Activity Level

54321

54321

Pain Relief

Posttreatment*

Activity Level

54321

54321

Other Observations or Comments

The charts below should be filled in to measure treatment pain relief and activity level improvement. The patient’s progress should be plottedfor 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:

Much Better 5

Better 4

Same 3

Worse 2

Much Worse 1

PAIN RELIEF

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.

1.MildModerate

SevereVery Severe YES NO YES NO

2.MildModerate


3.MildModerate


4.MildModerate


5.MildModerate


6.MildModerate


6.MildModerate


8.MildModerate


9.MildModerate


10.MildModerate


Clinical Outcomes SummaryThis form is a summary of each patient’s clinical outcomes. Complete the form after treatment for ten patients has been administered.

PATIENT I.D. NUMBER DISEASE SEVERITY PAIN RELIEF IMPROVED ACTIVITY LEVEL*

*Any degree of improvement;week 12 compared to week 1.

# of patients withpain relief

% of patients withpain relief

# of patients withimproved activity levels

% of patients withimproved activity levels

x10 = x10 =

Discussion/Remarks

Documents

Viscosupplementation with SYNVISC ® (Hylan G-F 20) for the Treatment of Osteoarthritis Knee Pain SYNVISC is a registered trademark of Genzyme Biosurgery