eptotermin alpha - Opgenra; Osteogenic Protein-1; OP-1 Implant; OP-1 Putty; Osigraft; BMP-7, recombinant
Status - FDA approved through HDE; marketed in U.S. and Europe
Organizations involved:
Olympus Biotech International – Manuf.; R&D; Tech.; USA mark.
Olympus Corp. – Parent
Stryker Biotech – Former
Stryker Corp. – Parent; Former
Curis Inc. – Former
Creative Biomolecules, Inc. – Former
Howmedica International S.de.R.L. – Former
Isomedix Operations, Inc. – Manuf. other
Ortho Biotech Products, L.P. – Former
Johnson & Johnson Co. – Parent; Former
Cross ref.: See the entries above for Bone Morphogenic Proteins and Bone morphogenic protein-2 (INFUSE Bone Graft).
Description: Osteogenic Protein-1 is a lyophilized (freeze-dried) formulation of recombinant osteogenic protein-1 (OP-1; BMP-7), a bone morphogenic (glyco)protein or growth factor that stimulates new bone formation (osteogenesis), expressed by a Chinese hamster ovary (CHO) cell line, mixed with a lyophilized resorbable bovine collagen carrier/scaffold/matrix. This OP-1 in resorbable collagen matrix is surgically implanted in bone fractures and defects, and induces normal bone regeneration. OP-1 Putty is similarly a combination of the OP-1 protein, a collagen carrier and a handling excipient. Osigraft (OP-1 Implant) and Opgenra (OP-1 Putty) include carboxymethylcellulose (CMC) in a separate vial. The CMC imparts the putty-like consistency for ease of molding, e.g., between the transverse processes of the spine. Opgenra is the same as OP-1 Putty but without CMC.
The bovine collagen is derived from diaphyseal bone powder from the midshaft of bovine femurs and is primarily type I collagen. The collagen matrix consists of insoluble particles in the size range 75-425 µm. The matrix serves as a physical support to hold the OP-1 in place (not for delivery to surrounding tissues) and as a framework for attachment of anchorage-dependent cells.
OP-1 in its mature native form is a glycosylated, single disulfide-linked dimer (two linked protein chains), with an apparent molecular weight of about 30 kDa as determined by SDS-PAGE, and a calculated molecular formula of (C683-H1061-N197-O208-S10)2. When reduced, the 30 kDa protein gives rise to two glycosylated polypeptide chains (subunits) having apparent molecular weights of about 16 kDa and 18 kDa. In this reduced state, the 30 kDa protein has no detectable osteogenic activity. Unglycosylated OP-1, which has osteogenic activity, has an apparent molecular weight of about 27 kDa. When reduced, the 27 kDa protein gives rise to two unglycosylated polypeptides having molecular weights of about 14 kDa to 16 kDa.
Each OP-1 vial, both Osigraft (OP-1 Implant) and Opgenra (OP-1 Putty), contains approximately 1 gram of dry powder, containing 3.5 mg of OP-1 powder for implantation in 1 gram of bovine bone-derived collagen. This is reconstituted with 2-3 mL of sterile sodium chloride solution (0.9% w/v) prior to use. The bovine collagen is U.S. sourced, is derived form diaphyseal bone, and is primarily type I collagen with particles in the size range of 75-475 µm. Unspecified animal-derived materials are used for CHO cell culture. OP-1 is stored at 2-8°C (refrigerated) with a shelf life of one year (in the U.S.). In the European Union (EU), Osigraft and OP-1 Putty have a 2 year shelf-life at ambient temperatures. The CMC component consists of 230 mg of sterile CMC in a 10 ml vial.
With OP-1 Putty, at the time of surgery, the contents of the OP-1 and CMC vials are transferred to a sterile mixing bowl, reconstituted with normal saline, and mixed with a spatula to produce a product with a putty-like consistency.
Glass vials are filled with defined amounts of components and the vials are vacuum-dried. The powder is mixed and separate vials are filled to yield units containing 1 g powder with 3.5 mg eptotermin alfa. The Drug Product is terminally sterilized by gamma irradiation.
Nomenclature: Osteogenic Protein-1, rDNA [BIO]; Opgenra [TR in Europe]; OP-1 Implant [TR]; OP-1 Putty [TR]; Osigraft [TR in Europe for treatment of non-union of the tibia]; recombinant human osteogenic protein-1 [FDA]; eptotermin alpha [INN]; osteogenic protein-1 [CAS]; 129805-33-0 [CAS RN]; bone morphogenic protein-7 [SY]; BMP-7 [SY]; OP-1, recombinant [SY]
Companies.: OP-1 was originally discovered and developed by Creative BioMolecules Inc. (Hopkinton, Mass.), which licensed worldwide marketing rights for orthopedic applications to Stryker Biotech, a division of Stryker Corp., a major manufacturer and marketer of orthopedic equipment, including implants. In Oct. 2010, Olympus Biotech International, Olympus Corp. (which also owns Olympus Terumo Biomaterials Corp) acquired Stryker Biotech and its products. Styrker reportedly invested about $100 million in Lebanon, NH, manufacturing facilities.
In 2000, Creative BioMolecules merged with Ontogeny Inc. and Reprogenesis Inc. to form Curis Inc. In Nov. 2002, Curis exclusively licensed rights to BMP-7 and its other BMP products for neurological, renal, and other non-orthopedic indications: (none approved then) to Ortho Biotech, a subsidiary of Johnson & Johnson (J&J).
Recombinant OP-1 and the final product are manufactured and marketed in the U.S. by Stryker Biotech, now Olympus Biotech, at facilities in Hopkinton, MA. OP-1 is marketed (or was prior to the Olympus acquisition) in Europe by Howmedica International S.de.R.L., a subsidiary of Stryker Corp. In October 2002, Stryker paid Curis $14 million to end its obligation to pay royalties on sales of OP-1.
In May 2007, Ortho Biotech, Johnson & Johnson, terminated a research collaboration with Curis concerning new BMP-7 products.
In Dec. 2007, Curis granted Stryker Corp. the remaining rights for BMP-7 products not formerly licensed to the company. Thus, Stryker acquired the development and marketing rights to new products formerly licensed to Ortho/J&J.
In 2010, Olympus bought Stryker's OP-1 putty for $60 million, hoping to expand its market.
In March 2014, Olympus decided to sell the Lebanon, NH, plant where the putty is made at a bargain price--and if it can't make a deal it will close the facility.
Manufacture: OP-1 is expressed by transformed CHO cells by conventional fermentation. Materials of unspecified animal origin, presumably bovine, are used during fermentation. Purification involves ultrafiltration, viral filtration, and column chromatography steps. OP-1 is combined with collagen particles, filled into vials and sterilized with gamma radiation (by Isomedix Operations, Inc.) using a Batch-Carrier radiator process. Bovine collagen matrix powder is sourced from animals of U.S. origin.
The cDNA for the eptotermin alfa gene was cloned from human c-DNA libraries using an oligionucleotide probe based on peptide sequences of bovine osteogenic proteins. The host cell line used for the construction of the production cell line is a Chinese Hamster Ovary cell line.
During fermentation of eptotermin alfa, raw materials from animal origin are used. The purification process consists of ultrafiltration, viral filtration and column chromatography steps.
The starting material for the production of collagen matrix is bone powder derived from the midshaft of femurs and tibias that are sourced from animals of U.S. origin. The collagen is manufactured by chemical extraction of crushed bone. The collagen is particulate and is sieved to ensure a specific particle size range. The production process has been validated to ensure viral clearance using appropriate viral models.
FDA class: Medical Device HDE
Approvals: Date = 20011017; first approval; Humanitarian Device Exemption (HDE); Indication = for use as an alternative to autograft in recalcitrant long bone nonunions where autograft is unfeasible and alternative treatments have failed
Date = 20040408; Humanitarian Device Exemption (HDE); Indication = use of OP-1 Putty in revision spine surgery as an alternative to autograft in compromised patients requiring revision posterolateral (intertransverse) lumbar spinal fusion, for whom autologous bone and bone marrow harvest are not feasible or are not expected to promote fusion (e.g., osteoporosis, smoking and diabetes)
indications: [Full text of the indications for OP-1 Implant]:
OP-1 Implant is indicated for use as an alternative to autograft in recalcitrant long bone nonunions where autograft is unfeasible and alternative treatments have failed.
Status: The primary indication for which OP-1 was originally developed (not its current HDE indication) was the repair of nonunion fractures of the tibia (broken leg bone repair), particularly treatment of trauma-related non-union of the tibia of at least 9 months duration in skeletally mature patients, where prior autograft treatment has failed or is not feasible. Stryker completed its first pivotal trial with OP-1 for repair of nonunion fractures of the tibia. Stryker Biotech had originally filed a pre-market approval application (PMA) for this indication. In Feb. 2001, FDA issued a non-approvable letter, citing lack of statistical equivalence/superiority compared to autografts, the current standard of care. FDA recommended a new clinical trial. Stryker is continued efforts, including conducting further trials, to gain full FDA approval for tibia and long bone fracture repair indications:.
On May 21, 2001 Stryker filed for its current Humanitarian Device Exemption (HDE) approval of OP-1; and the HDE was granted Oct. 17, 2001 (approval time = ~5 months). An HDE is an FDA medical device application similar in content to a premarket approval (PMA) application. HDE applications are exempt from the effectiveness requirements of a PMA. HDE approval allows full commercial marketing of a Humanitarian Use Device (HUD), a device is intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the U.S. per year (essentially orphan indications:). There can be no comparable device already approved for a similar indication, and approval may be revoked when an equivalent device receives full approval. An HDE device must be approved by the hospital’s Institutional Review Board (IRB) before it can be used in patients for its designated indication(s). However, the IRB does not need to review and approve individual cases. The FDA reviews the preclinical and clinical data and determines the benefits of using the product outweigh the associated risks (when no alternatives are available).
On May 17, 2001, EMEA/EU granted a MAA to Stryker for Osigraft for “treatment of non-union of the tibia of at least 9-month duration, secondary to trauma, in skeletally mature patients, in cases where previous treatment with autograft has failed or use of autograft is unfeasible."
In June 2008, the European Union (CHMP, EU) adopted a negative opinion concerning a suppliemental filing by Howmedica for Opgenra for posterolateral lumbar spinal fusion in adult patients with spondylolisthesis where autograft has failed or is contraindicated.. However in Oct. 2008, the CHMP adopted a final positive opinion following a re-examination of a negative opinion. Approval was granted on Feb. 23, 2009.
In July 2011, Olympus Biotech International (re)launched Opgenra in Europe.
In April 2004, FDA granted HDE approval to OP-1 Putty, which is wetted and then surgically implanted across the transverse processes of the posterior spine to promote fusion. OP-1 Putty is indicated for use as an alternative to autograft in compromised patients requiring revision posterolateral (intertransverse) lumbar spinal fusion, for whom autologous bone and bone marrow harvest are not feasible or are not expected to promote fusion.
Howmedica (Stryker) received European Union approval on May 17, 2002 for the treatment of nonunion of the tibia of at least nine months duration, secondary to trauma, in skeletally mature patients, in cases where previous autograft has failed or use of autograft is unfeasible. OP-1 has also been approved in Australia, and in Canada (on Feb. 15, 2002).
In June 2006, Stryker submitted a PMA seeking full approval for OP-1 Putty for spinal fusion indication.
In April 2007, FDA requested additional data to support the PMA , which could result in another clinical study.
In April 2009, an FDA advisory panel voted 6-1 that Stryker's PMA for its OP-1 Putty for uninstrumented posterolateral fusion for the treatment of lumbar spondylolisthesis was "not approvable." Stryker was seeking this approval based on 24 months of clinical outcome data and 36 month CT scan and reoperation rates. The CT scan and reoperation data was gathered via an extension study to the company's original PMA.
In Oct. 2009, : Stryker Biotech LLC and four current and prior employees were indicted by a federal grand jury. In March 2009, the Stryker Biotech unit was the target of a federal grand jury investigation conducted by the U.S. Attorney’s Office for the District of Massachusetts. The charges filed included wire fraud, conspiracy to defraud the FDA, distributing a misbranded device, and making false statements to the FDA. Former employees had already pled guilty to charges related to the investigation. Stryker was accused of submitting false reports to the FDA regarding the number of patients who were treated with OP-1 under one of the Humanitarian Device Exemptions granted to the company, with HDEs having a limit of 4,000 patients, even if the product hasn’t completed clinical trials. Also, some Stryker executives allegely encouraged doctors to inappropriately mix Stryker products.
Tech. transfer: Recombinant OP-1-related U.S. patents assigned to Styker or licensed from Creative Biomolecules/Curis and cited by the available product insert are: 4,968,590; 4,975,526; 5,011,691; 5,108,753; 5,162,114; 5,171,574; 5258,494; 5,266,683; 5,324,819; 5,354,557; 5,496,552; 5,750,651; 5,840,325; 5,863,758; 5,674,292; 5,958,441; 6,013,856, "Terminally sterilized osteogenic devices and preparation thereof, expiring June 7, 2015; and 6,028,242, "Terminally sterilized osteogenic devices and preparation thereof," expiring June 7, 2015. More recent patents include U.S. 6,261,835 and 6,586,388.
A key aspect of the development of recombinant OP-1 was the isolation and amino acid sequencing of substantially pure native osteogenic protein (see 4,968,590). This enabled elucidation of the protein’s amino acid sequence and other structural features, which enabled the identification and cloning of genes encoding native osteogenic proteins.
Medical: OP-1 Implant is wetted to form a paste (putty) which is surgically implanted into the bone defect. Reconstituted OP-1 matrix is administered by direct surgical placement at the bone defect site in contact with the prepared bone surface, and the surrounding tissues are closed around the implant. The fracture may be stabilized by intramedullary nailing. A single vial is usually used, but another may be used if required for large bone defects. OP-1 Implant is radiotranslucent and not apparent on x-rays, allowing distinction between the implant and new bone formation. No severe adverse events have been reported in clinical studies conducted over the past 10 years, and OP-1 Implant has had excellent clinical results.
Both OP-1 and collagen matrix are immunogenic, and repeated use of OP-1 Implant/Putty is not recommended. However, antibodies to OP-1 are not detectable for several weeks, by which time OP-1 is no longer involved in the bone formation process.
Market: Average Wholesale Price (AWP) not available (product not in the Red Book). Most insurance plans cover the cost of OP-1 Implant.
In Dec. 2010, Olympus reported, "Approximately 40,000 patients have been treated globally with OP-1 products."
Ongoing: Stryker Biotech/Olympus is conducting clinical trials with OP-1 for spinal fusion indications:, and is developing OP-1 based products for other trauma, spine, oral/maxillofacial, total joint arthroplasty, and sports medicine indications:. The long-term goal is to establish a family of skeletal repair products based on OP-1 that address the needs of a broad range of surgical specialties.
Companies involvement:
Full monograph
109 Bone morphogenic protein-7, rDNA
Nomenclature:
Bone Morphogenic Protein-7, rDNA [BIO]
OP-1 Putty [TR]
Opgenra [TR in Europe]
Osigraft [TR Europe]
recombinant human osteogenic protein-1 [FDA]
eptotermin alpha [INN]
OP-1 Implant [TR EU]
osteogenic protein-1 [CAS]
129805-33-0 [CAS RN]
BMP-7 [SY]
bone morphogenic protein-7, rDNA [SY]
OP-1, recombinant [SY]
osteogenic protein-1, rDNA [BIO]
molecular weight (kDa) = 30
FDA Class: Medical Device PMA
Year of approval (FDA) = 2001
Date of 1st FDA approval = 20011017
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2015, Jan., based on extension of 5,258,494); 2018, based on 6,261,835; 2017, based on 6,586,388; approved as medical device - no biosimilars possible, no BLA/NDA approval-based data exclusivity |
U.S. Patent Expiration Year: | 2015 |
U.S. Biosimilars Data Exclusivity Expiration: | |
U.S. Biosimilars Orphan Exclusivity Expiration: | |
U.S. Biosimilars Launchability Year: | |
U.S. Biobetters Launchability Year: | 2015 |
Biosimilars/biobetters-related EU Patents: | 2016, if device process patent EP 0837701 applies |
EU Patent Expiration Year: | 2016 |
EU Biosimilars Data Exclusivity Expiration: | 2010 |
EU Biosimilars Orphan Exclusivity Expiration: | 2010 |
EU Biosimilars Launchability Year: | 2016 |
EU Biobetters Launchability Year: | 2016 |
Index Terms:
BHK-21 (C-13)
bone growth factors
bovine lymph
exempt from CBER lot release requirements
growth factors
hamster proteins
implants
recombinant DNA
rodent cells <!-- rodentcells -->
chicken source materials
mammalian cell culture
ribose
carbon dioxide (CO2 gas; dry ice)
collagen, bovine
galactosidase
lymphoma, non-Hodgkin's (NHL)
sodium carboxymethylcellulose
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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