Status: approved and marketed in U.S.; approved in EU in Jan. 2012

Organizations involved:

BioMimetic Pharmaceuticals Inc. – Manuf.; R&D; Tech.

Wright Medical Technology, Inc. - Parent

Luitpold Pharm., Inc. – R&D; World mark..

Sankyo Company, Ltd. – Parent

ZymoGenetics, Inc. – Tech.

Bristol-Myers Squib Co. (BMS) – Parent

Harvard University – Tech.

Institute of Molecular Biology, Inc. – Tech.

Cross ref.: See the two entries below for becaplermin concentrate (the bulk recombinant protein) and Becaplermin Gel (Regranex) for further information about rhPDGF-BB (becaplermin), the active biopharmaceutical ingredient in GEM21S. See also the Tooth Enamel Proteins (Emdogain) entry in the Other Products section regarding a related porcine (pig)-derived growth factor product used for periodontitis treatment.

Description: GEM 21S is a formulation of recombinant platelet-derived growth factor BB (rhPDGF-BB) in an osteoconductive matrix (a scaffold for bone growth) composed of synthetic inorganic beta-tricalcium phosphate (beta-TCP). GEM 21S is a complete grafting system for bone and periodontal regeneration. The rhPDGF-BB stimulates the ingrowth and proliferation of osteoblasts, cells responsible for the formation of bone, while the beta-TCP provides the physical framework for new bone growth. GEM 21S consists of beta tricalcium phosphate (beta-TCP) in a cup; and a physiologic solution containing recombinant human platelet-derived growth factor (rhPDGF-BB) packaged in a syringe. After mixing the two components, the material forms a mass of particles which is then packed into the bone defect.

Augment is GEM21S packaged and marketed for hindfoot and ankle fusion indications. GEM 21S is nearly identical to Augment Bone Graft, the Company’s orthopedic bone regeneration product. Each product consists of rhPDGF-BB and β-TCP bone matrix formulation.

GEM 21S is composed of two sterile components:

a) highly purified, recombinant human platelet-derived growth factor-BB (becaplermin; rhPDGF-BB). PDGF is a native protein constituent of blood platelets and a tissue growth factor that is released at sites of injury during blood clotting. As more fully described in the Becaplermin Gel (Regranex) entry below, becaplermin is recombinant human platelet-derived growth factor B chain homodimer (rPDGF-BB) expressed in Saccharomyces cerevisiae (yeast) cells. Becaplermin is a homodimer, i.e., composed of two identical PDGF B chain polypeptide chains, each chain composed of 109 amino acids, linked covalently by disulfide bonds. Becaplermin has a molecular weight of ~25 kDa. Sterile rhPDGF-BB is aseptically processed and filled into the syringe in which it is supplied.

b) beta-tricalcium phosphate (ß-TCP) [Ca3 (PO4)], a synthetic, highly porous, calcium phosphate-resembling, resorbable osteoconductive scaffold or matrix that provides a framework for bone ingrowth, aids in preventing the collapse of the soft tissues and promotes stabilization of the blood clot. Pore diameters of the scaffold are specifically designed for bone ingrowth and range from 1 to 500 µm. The particle size ranges from 0.25 to 1.0 mm. The contents of the cup of ß-TCP are supplied sterile by gamma irradiation. beta-TCP’s 90% open pore structure allows cellular ingrowth and vascular invasion. It is an osteoconductive bone void filler that has a good history of use and is currently marketed for orthopedic and dental applications. At the time of its approval, in more than 20 years of commercial use, no adverse events have been reported to the FDA’s MDR database, and the material had been recommended to be downclassified to Class II.

Biological.: See the entry below for Becaplermin Gel (Regranex) for further information about rhPDGF-BB (becaplermin). Implantation of rhPDGF-BB with a resorbable matrix, e.g., beta-TCP, results in bone formation in various animal models. Animals studies directly comparing the effectiveness of rhPDGF-BB to one of the best current treatments (surgery plus guided tissue regeneration, GTR) have shown that after two months rhPDGF-BB resulted in nearly 100% regeneration in periodontal defects vs. 19.2% regeneration with GTR.

rhPDGF-BB is an extensively characterized endogenous protein. It is a natural wound-healing hormone that operates by enhancing connective tissue formation, osteogenesis, and angiogenesis. rhPDGF-BB and its receptors are naturally induced during normal tissue and bone repair. It is chemotactic for periodontal ligament (PDL) and gingival fibroblasts and osteoblasts and is mitogenic for PDL and gingival fibroblasts, cementoblasts, and osteoblasts. rhPDGF-BB promotes matrix biosynthesis by PDL and gingival fibroblasts and osteoblasts. The material supports cell survival and enhances angiogenesis by promoting smooth muscle cells around new blood vessels, complementing vascular endothelial growth factor (VEGF) for blood vessel maturation, and increasing VEGF production by osteoblasts. It has been found to stimulate in vitro wound repair, and it retains its bioactivity even when released from TCP. Extensive in vitro and animal studies have demonstrated its potent mitogenic (proliferative) and chemotactic (directed cell migration) effects on bone and periodontal ligament derived cells. Animal studies have shown PDGF to promote the regeneration of periodontal tissues including bone, cementum, and periodontal ligament (PDL).

Biological: GEM 21S is composed of the tissue growth factor, recombinant human Platelet-Derived Growth Factor (rhPDGF-BB), and a synthetic bone matrix, Beta-tricalcium phosphate (β-TCP). GEM 21S was the first totally synthetic product combining a purified recombinant growth factor with a synthetic bone matrix to be approved by the FDA for human application. The combination of the two components of GEM 21S is key to the overall effectiveness of the product. The rhPDGF-BB provides the biological stimulus for tissue repair by stimulating angiogenesis and the proliferation of osteoblasts, cells responsible for the formation of bone, while the β-TCP provides the framework or scaffold for new bone growth to occur.

Nomenclature: PDGF, rDNA/Bone matrix [BIO]; GEM 21S [TR]; Augment [TR (for foot and ankle fusions)]; becaplermin [FDA USAN INN]; 165101-51-9 [CAS]; platelet-derived growth factor, recombinant with bone matrix [SY]; rPDGF [SY]; rhPDGF-BB [SY]; beta-tricalcium phosphate [SY; for bone matrix]; beta-TCP [SY; for bone matrix]; GEM 21S [SY]

Note, other than the product’s trademark (GEM21S), the terms not specified as involving bone matrix refer solely to rhPDGF-BB, the biopharmaceutical component of GEM21S.

Companies.: BioMimetic Pharmaceuticals Inc. developed and manufactures GEM 21S. Major investors in BioMimetics include Novo Nordisk A/S, the former parent of ZymoGenetics (the source for rhPDGF-related technology), with ZymoGenetics now part of Bristol-Myers Squib (BMS; acquired in Oct. 2010).

In Jan. 2004, BioMimetic concluded an agreement with the Osteohealth division, Luitpold Pharmaceuticals, Inc., a subsidiary of Sankyo Co. Ltd., for research, development, manufacturing and worldwide marketing of GEM 21S for periodontal and cranio-maxillofacial indications:. BioMimetic expects this to generate revenues >$150 million. A large portion of payments to BioMimetic are for R&D expenses, marketing assistance, and regulatory milestones. BioMimetic will receive a low double digit royalty on sales, and manufactures the final product under a supply agreement.

In Nov. 2012, Wright Medical Technology, Inc. acquired BioMimetic Pharma.

FDA class: Medical device; PMA

Approvals: Date = 20051121; PMA (original medical device approval)

Indications: [full text of the "Indications” section of product insert/labeling]:

GEM 21S is indicated to treat the following periodontally related defects: Intrabony periodontal defects; Furcation periodontal defects; and Gingival recession associated with periodontal defects.

Status: The Premarket Approval Application (PMA) for GEM 21S for treatment of bone defects of the jaw in patients with advanced periodontal disease and other cranio-maxillofacial (CMF) indications: was accepted for filing on May 5, 2004. On July 15, 2004, the Dental Products Advisory Committee, FDA, voted unanimously to recommend approval of GEM 21S. However, it recommended that the label be limited to treatment of periodontal and related diseases, along with restrictions on claims regarding superiority to other treatments. The PMA was approved on Nov. 21, 2005 (approval time = ~1.54 years). FDA recognized GEM 21S as a first-in-class therapeutic in a newly created treatment category.

Augment is PDGF for hindfoot and ankle fusions. An advisory FDA panel voted in May 2011 that Augment was safe and effective as an alternative to autograft in hindfoot and ankle fusions. But the FDA responded with a non-approvable letter in Jan. 2012, seeking additional data.

BioMimetic received regulatory approval in 2009 and 2011 to market Augment in Canada, and in Australia for hindfoot and ankle fusion indications.

On Jan. 3, 2012 – The EU granged CE Mark approval of GEM 21S Growth factor Enhanced Matrix, with broader periodontal and alveolar bone regeneration indications for use than previously approved in the U.S. and Canada. The additional indications approved in the EU are for the treatment of osseous defects resulting from tooth extraction and trauma. Additionally, GEM 21S is approved in the EU for use in compromised patients where poor healing may occur. This approval, obtained on behalf of Luitpold Pharmaceuticals, Inc., triggered a $10 million final milestone payment from Luitpold to BioMimetic/Wright. This milestone payment was a condition of the sale of GEM 21S to Luitpold in 2008.

In Aug. 2013, FDA refused to grant Augment bone graft approval for use as an alternative to autograft in hindfoot and ankle fusion procedures. The FDA responded to the company’s pre-market approval (PMA) application with a not approvable letter, and based its rejection of the application on the clinical trial. FDA stated it is “concerned that the population enrolled was predominantly low risk and, therefore, may not have warranted the use of either autograft or Augment bone graft.” The agency went on to state it believes that “it will be necessary to perform a new clinical study that evaluates the use of Augment bone graft as a substitute for autograft in hindfoot and ankle fusion procedures in a well-defined high-risk target population, where the use of autograft would be clinically warranted.”

Tech. transfer: BioMimetics has exclusively licensed recombinant human platelet-derived growth factor BB (rhPDGF-BB) technology from ZymoGenetics, Inc. for orthopedic applications. See the PDGF, rDNA conc. entry below for further information about rhPDGF-BB patents. The companies concluded a second licensing agreement in Feb. 2003, expanding licensed indications: to broadly include regeneration and repair of hard tissues. BioMimetics paid an initial licensing fee and will make development milestone and royalty payments.

The product insert cites U.S. 4,845,075; 5,045,633; and 5,124,316. U.S. 4,845,075 and 5,045,633 are the main patents covering aspects of recombinant PDGF-BB (becaplermin; see related entry below) assigned to ZymoGenetics, Inc., formerly a subsidiary of Novo Nordisk A/S, then became independent, now part of Bristol-Myers Squib (BMS; acquired in Oct. 2010). .

U.S. 5,124,316, “Method for periodontal regeneration,” assigned to Harvard College (Harvard Univ.) and Institute of Molecular Biology, Inc., has just one claim: “1. A method of promoting growth of damaged bone, periodontium, or ligament of a living mammal, comprising the steps of producing a surgical flap of skin to expose said damaged bone, periodontium, or ligament, planing said damaged bone or periodontium to remove organic matter from said bone or periodontium applying platelet derived growth factor in a pharmaceutically acceptable carrier to said exposed bone, periodontium, or ligament, replacing said flap, and allowing said damaged bone, periodontium, or ligament to regrow.”

Trials: Trials with related agents supported the efficacy of GEM 21S. A significant increase in bone formation was noted in a blinded, placebo-controlled, 38-patient trial testing rhPDGF-BB plus insulin-like growth factor I (IGF-I) vs. current surgical therapy alone. In a trial in 88 patients, a natural preparation containing PDGF (platelet-rich plasma) plus bone autograft was compared to autograft alone. PDGF use resulted in faster and denser bone formation in large craniomaxillofacial defects than did autograft alone.

Results from the pivotal periodontitis trial with GEM 21S were published in J. Periodontol 2003; 74: 1282-1292. The pivotal 180-patient, double-blind, randomized, controlled, trial with GEM 21S evaluated GEM 21S for the regeneration of bone and other periodontal tissues in the treatment of osseous (bone-related) periodontal defects in subjects who required surgical intervention to treat periodontal bone defects. This was the largest single prospective randomized controlled clinical study to date for periodontal defect indications:. Patients received standard periodontal surgery followed by treatment with two doses of either GEM21S (rhPDGF-BB in beta-TCP) or beta-TCP. Patients were studied for six months following implantation of the product for the regeneration of new bone using radiographs, and for increases in attachment of the gingival tissue to the tooth surface, which leads to a decrease in gingival pocket depth, using direct clinical measurements. The results demonstrated significant bone formation and acceleration of gingival tissue attachment. GEM 21S treatment led to statistically significant benefits in bone growth and accelerated tissue attachment level gain compared to the control group that received the beta-TCP plus buffer, without the addition of the growth factor. The study revealed no evidence of either local or systemic adverse effects resulting directly from placement of GEM21S.

Disease: About two million periodontal surgeries for treatment of periodontal disease are performed annually in the U.S.. Periodontal disease results from inflammation of the gum tissue adjacent to the tooth, and commonly leads to loss of bone and ligament structures supporting the tooth. Patients often require therapeutic treatment to avoid tooth loss. Current therapies include surgical intervention consisting of root planning, placement of grafts and/or barrier products, and the use of antibiotics. These methods primarily work to eliminate the inflammatory response adjacent to the tooth, but do not routinely stimulate the regeneration of the supporting tissues (bone and ligaments). Note, this discussion of current therapy (derived from BioMimetic’s materials) fails to include porcine-derived growth factor (Emdogain) used for periodonitis treatment. See the Emdogain entry (#931) for further information about periodontitis and its treatment.

Medical: GEM 21S is used to improve bone and gingival tissue regeneration following surgical treatment for periodontal disease.

Market: The 2007 Average Wholesale Price (AWP) is not available (not in 2007 or prior years’ Red Book).

As of Aug., 2013, Augment was approved and marketed in Canada, Australia and New Zealand by BioMimetic.

Total 2006 sales by BioMimetic to Luitpold/Sankyo (not sales in the open market, which were likely a muliptle of this) were $2.6 million. Even allowing a 10-fold mark-up by Luitpold, sales total would be on the order of only about $25 million.

Ongoing: BioMimetic is conducting trials with GEM21S for treatment of various maxillofacial bone defects. The company is also developing a 2nd-generation product, GEM OS1, and in March 2007 inititate a pivotal Phase III trial for bone regeneration in foot and ankle fusion procedures requiring open surgery.