Status: approved; marketed

Organizations involved:

Genzyme Biosurgery – Manuf.; R&D; Tech.; World mark.

Genzyme Corp. – Parent

Biomatrix Inc. – R&D; Tech.; Former

Wyeth – Former

Inamed Corp. – World mark.

Mentor Corp – World mark.

Allergan, Inc. – Parent

Novartis AG – Latin America mark.

Nicholas Piramal India Ltd. – India mark.

Cross ref.: See the Hyaluronic Acid Products entry (#925) above and the other hyaluronic acid product entries.

Description: Synvisc (hylan G-F 20), Hylaform, Hylaform Plus, and HylaSine are elasto-viscous gel formulations of a cross-linked form of natural sodium hyaluronic acid, termed hylan, obtained from rooster (chicken) combs. Hylans are cross-linked hyaluronic acid (HA; hyalu-ronan) molecules, in which the carboxylic acid and the N-acetyl-glucosamine groups are not affected by the cross-linking process, forming stiff gels having a very high degree of hydration, containing 95-99% water. Hylan polymers, like all hyaluronic acids, consist of repeating disaccharide units of N-acetylglucosamine and sodium glucu-ronate. The hylan in Synvisc has an average molecular weight of over 6 million (6,000 kDa). Divinyl sulfone (DVS) is used to cross-link hyaluronic acid derived from chicken (rooster) combs, reacting readily with hyaluronic acid in aqueous alkaline solutions at room temperature, providing cross-linked HA gels.

Synvisc is HA used for viscosupplementation treatment to relieve knee pain due to osteoarthritis. Visco-supple-men-tation refers to supplementing the viscous and elastic properties of synovial fluid. This elastoviscous joint fluid supplement acts as a shock absorber and lubricant for the knee, and is used in patients who do not obtain adequate relief from simple painkillers or from exercise and physical therapy. Synvisc contains hylan fluid and hylan gel slurry (8 mg ± 2 mg/mL) in buffered physiological sodium chloride solution (pH 7.2 ± 0.3). Synvisc is biologically similar to human hyaluronic acid, a component of synovial fluid, but its mechanical (elastoviscous) properties are superior to those of human synovial fluid and hyaluronic acid solutions of comparable concentration. Hylans are degraded in the body by the same pathway as hyaluronic acid, and breakdown products are nontoxic.

Each mL of Synvisc contains: hylan 8 mg, sodium chloride 8.5 mg, disodium hydrogen phosphate 0.16 mg, sodium dihydrogen phosphate hydrate 0.04 mg, and Sterile Water for Injection USP. Synvisc is supplied in 2.25 mL glass syringes of containing 2 mL Synvisc, packed aseptically in a blisterpack containing three syringes. The product is stored at 4-10˚C (refrigerated).

Hylaform is a hyalan gel-based dermal filler used for facial cosmetic uses, specifically for injection into the mid to deep dermis for correction of moderate to severe facial wrinkles and folds (such as nasolabial folds). Hylaform Plus has a larger mean hyaluronic gel acid particle size than Hylaform.

Hylasine is a hylan formulation used for Intercellular Matrix Therapy to prevent adhesion of tissues, e.g., to fill sinuses (space between tissues) during surgery or otherwise to prevent their outer tissue layers from adhering to each other. HylaSine gel mimics the human body’s own intercellular matrix and serves to strengthen, augment, and replace diseased intercellular matrices of the body, e.g., Hyla-Sine may be used in nasal sinus surgeries to fill the nasal sinuses after surgery. HylaSine coats surgically altered tissue to reduce bleeding, scarring, and other complications

Prevelle Silk (formerly Prevelle Plus) is a formulation of Hylan B Gel with added phosphate buffered saline (pbs) and lidocaine hydrochloride, a local anesthetic.

Nomenclature: Hyaluronic acid/Genzyme [BIO]; Hyalu-ronan injection [FDA]; Hylan G-F 20 [TR]; Hylan B [TR]; HylaSine [TR]; Synvisc [TR]; Hylaform [TR]; Prevelle Plus [TR]; Prevelle Silk [TR]; Hylan G-F20 [SY]; hyaluronic acid, cross-linked [SY]; sodium glucuronate-N-acetylglu-cos-amine polymer [SY]; ß-(1,4)-D-GlcA-ß-(1,3)-D-GlcNAc- polymer [SY]; HA [SY]; NDC 0008-9149-02 [NDC]

Companies.: Hylan was originally developed by Biomatrix, Inc. (Ridgefield, NJ) and is manufactured in what originally was Biomatrix’s facility in Quebec, Canada (55,000 sq. ft.; completed in 1999). Wyeth obtained exclusive U.S. marketing rights from Biomatrix in 1997. Biomatrix Inc. merged with Genzyme Surgical Products in March 2000, forming Genzyme Biosurgery, a subsidiary of Genzyme Corp.

Synvisc was originally marketed in the U.S. by Wyeth, with the product launched in fall 1997. The product has been available in Canada since Sept. 1992, where it is co-promoted by Wyeth and Sanofi Aventis S.A. Novartis AG markets (or marketed) Synvisc in Mexico, Central and South America, and the Caribbean.

Synvisc is marketed internationally by Gen-zyme Biosurgery in over 15 countries, and the company has contracts for marketing in other countries. Hoffmann-La Roche Ltd. markets Synvisc in Sweden and South Africa; Recordati in Italy; Bayer Schering in Australia, Indonesia, Israel, New Zealand, Malaysia, Taiwan and Thailand; and it was marketed in France by Boehringer Ingelheim until 2003.

In Nov. 2004, Genzyme acquired all U.S. and certain European marketing rights (Germany, Poland, Greece, Portugal, Czech Republic) for Synvisc from Wyeth for $121 million upfront, plus milestone payments based on sales that could extend to June 2012 or a total of $294 million, whichever comes first. This included Genzyme acquiring a 105-person sales and marketing staff, which was integrated into Genzyme’s 36-person U.S. sales team for Synvisc and Carticel. With this, Genzyme became the only company to manufacture, distribute and sell its own viscosupplementation product in the U.S. and in major European countries.

Hylasine is marketed worldwide by Genzyme Biosurgery. Hylaform is marketed worldwide by Inamed Corp., recently acquired and merged into Allergan Inc.

In Aug. 2004, Nicholas Piramal India Ltd. licensed exclusive Indian marketing rights for a 5-year period.

Mentor Corp. and Genzyme have formed a collaboration for the development of new HA products, with Mentor having marketing rights. The first product resulting from this, Prevelle Silk, manufactured by Genzyme, will be marketed by Mentor worldwide. Prevelle Silk is the first dermal filler in the U.S. to incorporate a local anesthetic.

FDA class: Medical device; PMA

Approvals: Date = 19970808; first approval for Synvisc, PMA P940015

Date = 20000329; A 510(k) (equivalence to a currently approved product) approval granted to Hylasine

Date = 20040423; A 510(k) (equivalence to a currently approved product) approval granted to Hylaform; Indication = dermal filler for injection into the mid to deep dermis for correction of moderate to severe facial wrinkles and folds (such as nasolabial folds)

Date = 20041013; 510(k) approval; Indication = approval of Hylaform Plus, large particle size hyaluronic acid-based dermal filler, for the correction of moderate to severe facial wrinkles and folds

Date = 20080228; PMA supplement for Prevelle Silk; Indication = for injection into the mid to deep dermis for correction of moderate to severe facial wrinkles and folds (such as nasolabial folds; with the added lidocaine providing local anesthetic pain relief)

Indications: [full text of "Indications” section of Synvisc product insert/labeling, April 2000]:

Synvisc is indicated for the treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy and to simple analgesics, e.g., acetaminophen.

[indications: for Hylasine; unofficial]:

Hylasine viscoelastic gel is injected into anatomical compartments of the sinus during and following sinus surgery to coat surgically altered tissue, to still intra-operative and post-operative bleeding, to reduce post-surgical scarring and adhesions, to minimize patient discomfort and to shorten the patient post-operative rehabilitation period.

FDA class: Medical Device PMA

Status: The PMA for Synvisc was filed on May 31, 1994 and was approved on Aug. 8, 1997 (approval time = ~3.2 year). Synvisc is currently approved for use in the U.S., Europe and 60 countries around the world. Genzyme Biosurgery received European Union approval on July 10, 2002 for reduction of osteoarthritis hip pain (viscosupplementation); and has also received approval for reduction of knee pain. Genzyme filed for approval in Japan for treatment of pain from osteoarthritis in Sept. 2003, with launch projected for early-mid 2006.

On Oct. 2, 2006, Genzyme received CE mark (European Union medical device approval) for Synvisc labeling to include treatment of pain due to osteoarthritis of the ankle and shoulder. Approval of this new label will broaden the use of Synvisc beyond its established EU use for knee and hip osteoarthritis pain.

On Dec. 19, 2007, Synvisc-One received European Union (EU) CE Mark approval as a single treatment to provide up to six months of pain relief from osteoarthritis of the knee. Synvisc-One is now the only viscosupplementation product available in Europe that is labeled to provide this long-term duration of pain relief from a single injection. This provides added patient convenience, while reducing the overall cost of therapy associated with multiple injections.

Tech. transfer: The product insert for Synvisc cites coverage by U.S. 4,636,524; 4,713,448; 5,099,013, , "Hylan preparation and method of recovery thereof from animal tissues,", "Hylan preparation and method of recovery thereof from animal tissues;" and 5,143,724, "Biocompatible viscoelastic gel slurries, their preparation and use;" expired in 2011; all assigned to Biomatrix (now Genzyme Biosurgery). Cross-linked gels of hyaluronic acid and their use for drug delivery are described in U.S. 4,636,524, Balazs and Leshchiner, Jan. 13, 1987. Gels, known as hylan, formed from chemical modification of hyaluronan are described by Balazs, et al. in U.S. 4,713,448. All of these have expired.

Genzyme has reported, "Synvisc is protected by U.S. Patent Nos. 5,143,724 which expires on August 8, 2011; 5,399,351 ["Biocompatible viscoelastic gel slurries, their preparation and use"] which expires on March 21, 2012; and corresponding international counterparts."

FDA had determined that the regulatory review period for Synvisc Hylan G-F 20, for purposes of extending the term of U.S. 5,099,013 is 2,949 days (8.08 years). Of this time, 1,783 days occurred during the clinical testing phase period, while 1,166 days occurred during the approval phase. See announcement in the Jan. 15, 2001, Federal Register. However, looking at PTO listings (1/2013), U.S. 5,099,013 with calculated expiration date of Mar 24, 2009 did not receive any extension.

U.S. 5,143,724 did receive a patent extension of 395 days, expiring on Aug. 8, 2011.

EP 0466300, "BIOCOMPATIBLE VISCOELASTIC GEL SLURRIES, THEIR PREPARATION AND USE," expired in 2011.

Trials: In May 2005, the Cochrane Collaboration, an independent, international organization that disseminates systematic reviews of healthcare interventions and clinical trials data (evidence-based medicine), published a review of Synvisc and other viscosupplements concluding that this class of viscosupplements is superior to placebo (effective) and that several of the products have greater efficacy than steroid injections in treating pain associated with osteoarthritis of the knee. The review also showed that considerable, positive differences were reported for Synvisc versus placebo in a number of clinical trials, including statistically significant and clinically meaningful robust improvements in pain, stiffness, and physical functioning for patients with osteoarthritis of the knee. The review found that the overall treatment effect of each key Synvisc clinical trial studied was more robust than for the class of viscosupplementation products as a whole.

In June 2006, Genzyme reported results from an independent clinical study of the effectiveness, functional outcome and patient satisfaction following injections with Synvisc and Hyalgan (see related entry) in patients with osteoarthritis (OA) of the knee. Both treatment groups experienced pain reduction. However, patients receiving Synvisc experienced greater magnitude of pain relief which occurred earlier and lasted longer. Similarly, the functional outcome and physical activity scores were significantly better in the Synvisc group throughout the study.

In Nov. 2006, promising results were reported from a trial of Synvisc administered as a single 6 mL injection for knee osteoarthritis.

Medical Synvisc is administered into the knee during a 15-day period, with a total of three 2 mL intra-articular injections. This viscosupplementation provides long-term pain relief, and increases mobility of the joint, acting as a lubricant, shock absorber, and general protectant. Trials have indicated that Synvisc appears to result in a clinically significant improvement in reducing pain and increasing levels of mobility in the majority of individuals treated, as compared with placebo, and may even slow down deterioration of joints.

Hylasine is injected into compartments of the sinus during and following nasal sinus surgery, primarily to coat surgically altered tissue to prevent tissue adherence. The product also reduces intra-operative and post-operative bleeding, post-surgical scarring, minimizes patient discomfort, and shortens post-operative rehabilitation.

Hylaform is used as a dermal filler, ie., it is injected deep under the skin for cosmetic treatment to improve the appearance of moderate to severe facial wrinkles and folds (such as nasolabial folds). The hyaluronic acid (HA) fills the spaces between collagen and elastin fibers of the underlying skin tissue, replenishing the natural volume lost during aging, while facilitating delivery of essential nutrients and hydration. The body naturally absorbs Hylaform gel over time. Redness, bruising and swelling, common adverse events with the use of HA dermal fillers, are generally mild and less severe than some other HA filler products.

Disease: Osteoarthritis of the knee is a painful, debilitating and progressive condition that affects approximately 10 million knee joints in the U.S. alone. Within this patient population, there are two primary groups who are candidates for Snyvisc – late-stage patients who anticipate having total knee replacements and patients with mild to moderate pain who suffer from varying degrees of chronic arthritis pain. Synvisc is effective in both of these groups.

Intra-operative and post-operative complications appear in almost all of the 300,000 nasal sinus surgical procedures that are performed annually in the U.S., many associated with improper adherence of tissues. Use of Hylasine improves the outcome of the procedure, benefits the patient, and helps prevents costly re-operations.

Market: In Dec. 2006, Genzyme reported “Synvisc is registered in more than 70 countries and has been used to treat more than 3 million people.” Genzyme notes, “Because market penetration is still in the early stages, there is much room for future growth.

In Jan. 2006, Genzyme reported that 4th quarter Synvisc sales were $58 million (indicating annual sales at a rate equivalent to $232 million), compared with sales of $15 million in the same quarter a year ago, prior to Genzyme’s acquisition of sales and marketing rights for the product. Genzyme reported that Synvisc “has only begun to penetrate a broad and growing worldwide market.” Genzyme expects that new indications: for Synvisc and new formulations under development will contribute to sales growth over the long term.

Total end-user worldwide sales of Synvisc were about $240 million in 2004, according to Genzyme. Total Synvisc sales by Genzyme (before acquisition of U.S. and certain European country marketing) were $88.3 million in 2004; $105-$115 million in 2003 (reported as expected sales); $90 million in 2002, $83 million in 2001, 83.0 million in 2001, and $66.2 million in 2000.

Synvisc is Genzyme Bio-surgery’s leading product. Genzyme reported improved manufacturing efficiencies are expected to provide gross margins of 77-78% for 2005. Synvisc is marketed in over 90 countries, and is the largest selling viscosupplementation product in the U.S. and Canada for the treatment of pain due to osteoarthritis of the knee.

The Center for Medicare and Medicaid Services (CMS) has approved Medicare reimbursement for Synvisc.

The 2007 Average Wholesale Price (AWP) for Synvisc is $306.80/vial ($245.42 in 2005) (Red Book, 2007).

In Fall 2006, the Centers for Medicare and Medicaid Services (CMS) ruled that Synvisc and all aother viscosupplement products would have the same J-Code reimbursement code for billing starting in 2007. In Dec. 2006, CMS reversed this and ruled that Synvisc (and other viscosupplementation products) would have its unique Medicare reimbursement Q-code and rate, making it easier for physicians to specify and obtain reimbursement for Synvisc. Effective Jan. 1, 2007, the Medicare payment rate continues to be 106% of Synvisc’s Average Selling Price (ASP), calculated from data submitted to CMS.