Antihemophilic Factor (Recombinant), Formulated with Sucrose - Kogenate FS; Kogenate R
Status - approved; marketed
Organizations involved:
Bayer Schering Corp. – Manuf.; R&D; Tech.; USA mark.
Bayer Schering Pharma AG – Parent
Genentech, Inc. – Manuf. other; R&D; Tech.
Millipore Corp. – Tech.
Baxter Hyland Immuno – Patent dispute
CSL Behring AG– Tech.; Patent dispute
CSL Ltd. – Parent
Sanofi Aventis S.A. – Patent dispute
Behringwerke AG– Patent dispute; Former
Novo Nordisk A/S – Patent dispute
Novartis AG – Patent dispute
CSL Behring LLC –Patent dispute
New York Blood Center, Inc. – Tech.
Synbiotics Corp. – Tech.
Scripps Research Institute – Patent dispute
Biodome S.A. – Manuf. other
Cross ref.: See the Factor VIII Products entry in the Blood Products, Human section. See also Helixate FS, which is the same as Kogenate FS, but is relabeled by Bayer Schering Pharma for marketing by CSL Bioplasma/Behring.
Description: Antihemophilic Factor (Recombinant), Formulated with Sucrose or Kogenate FS is a lyophilized (freeze-dried) formulation of recombinant Factor VIII expressed by a transformed baby hamster kidney (BHK) cell line. Prior to introduction of this sucrose-stabilized formulation, Bayer manufactured and marketed Kogenate containing the same recombinant Factor VIII, but formulated with Albumin (Human) as stabilizer. In addition to use of rather standard Factor VIII purification methods of ion exchange chromatography and size exclusion chromatography, manufacture of Kogenate FS includes immunoaffinity chromatography using matrix-bound monoclonal antibody, other steps for purification, and solvent-detergent viral inactivation.
The recombinant Factor VIII glycoprotein in Kogenate FS has the same primary 2,332 amino acid sequence and activity as human Factor VIII. The molecule is a very large dimer of two chains including an 80 kDa chain and various extensions of the 90 kDa Factor VIII subunit, with a molecular weight of ~265 kDa before and over 300 kDa after glycosylation. The single chain protein is rapidly processed in cell culture, resulting in a heterodimer (2 different chains) with a 80 kDa light chain derived from the C-terminus, and a family of heavy chains with molecular weights 90-21 kDa, including the 90 kDa N-terminal sequence and varying amounts of the B-domain, which is not required by activity and is where most of the N-linked glycosylation sites are located. The glycoprotein contains 10-12 O-linked glycans, all or most residing in the B-domain.
Note, the same product as Kogenate FS is manufactured by Bayer Schering Corp., relabeled and marketed in the U.S. by CSL Behring as Helixate FS.
Among Factor VIII products, Kogenate FS (and Helixate FS) has the highest concentration and smallest fluid volume. This reduces the intravenous infusion time, allowing individuals to infuse more rapidly and conveniently.
Recombinant Factor VIII for Kogenate was originally manufactured by Bayer Corp. (now Bayer Schering Corp.) from bulk intermediate – Antihemophilic Factor Concentrate (Recombinant) (For Further Manufacturing Use) – manufactured by Genentech Inc. However, Bayer Schering now manufactures it fully in-house.
The cell culture medium used for manufacture of Factor VIII for Kogenate products contains Human Plasma Protein Solution (HPPS), including Plasma (Human), and recombinant human insulin, but does not contain any proteins derived from non-human animal sources.
Albumin (Human) was originally added as a stabilizer (in Kogenate), but the product has been reformulated (Kogenate FS) using sucrose as stabilizer and no longer contains added human albumin (although this is present in the culture medium). Kogenate FS contains 1,000 times less human plasma proteins than Kogenate. The recombinant Factor VIII in Kogenate and Kogenate FS are the same. The disaccharide sucrose is not metabolized in vivo in humans, so intravenous administration of sucrose contained in Kogenate FS does not affect blood glucose levels. Bayer reported that it, “committed five years to developing the technology to remove human albumin as a stabilizer in the process steps for Kogenate FS.”
Each vial of Kogenate FS contains a labeled amount of recombinant Factor VIII in international units (IU). One IU, as defined by the World Health Organization standard for Factor VIII, human, is approximately equal to the level of Factor VIII activity found in 1 mL of fresh pooled human plasma. The specific activity pf Factor VIII in Kogenate FS is about 100 IU/ml.
Kogenate FS line of products includes the following vial sizes: 250, 500, 1000, 2000 and 3000 IU. Kogenate FS has one of the smallest diluent volumes available. The 250, 500 and 1000 IU vial sizes are provided with 2.5 mL of diluent; the 2000 and 3000 IU vial sizes are reconstituted with 5 mL of diluent.
Kogenate FS is formulated using sucrose (0.9-1.3%), along with glycine (21-25 mg/mL) and L-histidine (18-23 mM), as stabilizer in the final container in place of Albumin (Human), as used in Kogenate, and is then lyophilized. The final product also contains calcium chloride (2-3 mM), sodium (27-36 mEq/L), chloride (32-40 mEq/L), polysorbate 80 (Tween 80; not more than [NMT] 35 µg/mL), imidazole (NMT 20 µg/1000 IU), tri-n-butyl phosphate (NMT 5 µg/1000 IU; from solvent-detergent viral inactivation), and copper (NMT 0.6 µg/1000 IU). Kogenate FS contains no preservatives. The amount of sucrose in each vial is 28 mg.
A new 3000 IU vial size was approved by FDA in Aug. 2009.
Upon its original approval, Kogenate FS could be stored at room temperature (up to 25˚C) for up to 3 months. However, this was changed in mid-2001 to require storage at 2-8˚C (refrigeration). The supplemental approval in Nov. 2005 again allowed Kogenate FS with BIO-SET to be stored at room temperature (25 degrees C) for up to three months.
Kogenate FS contains trace amounts of mouse (murine) proteins (maximum of 0.03 ng/IU rAHF), from immunoaffinity chromatography purification, and hamster proteins (maximum of 0.04 ng/IU rAHF) from the host cell line, but no patients developed specific antibody titers to these in clinical trials.
Nomenclature: Factor VIII, rDNA/Bayer [BIO]; Kogenate FS [TR]; Kogenate [TR prior to sucrose formulation]; Kogenate Bayer [TR in Europe]; Antihemophilic Factor (Recombinant), Formulated with Sucrose [FDA]; Antihemophilic Factor (Recombinant) [FDA former, for Kogenate]; Antihemophilic Factor [USAN]; Antihemophilic Factor, Human [former USAN]; octocog alfa [INN]; Factor VIII (rDNA) [BAN]; Antihemophilic Factor USP [USP]; 169149-90-0 [CAS RN for BHK expressed Factor VIII]; Factor VIII, recombinant [SY]; BAY-w-6240 [SY]; NDC 0026-0670-20; NDC 0026-0670-30; NDC 0026-0670-50 [NDC]
Companies.: Recombinant Factor VIII used in Kogenate (and Kogenate FS) was originally developed and manufactured by Genentech Inc., FDA CBER est. no. 1048, for further manufacture and exclusive marketing by Bayer Schering Corp. (formerly Bayer Corp.; before that Miles Labs.; before that Cutter Labs.), CBER/FDA est. no 0008. Kogenate was previously manufactured by Bayer from Antihemophilic Factor Concentrate (Recombinant) (For Further Manufacturing Use) manufactured by Genentech. In April 2005, Talecris Biotherapeutics Inc., then a subsidiary of NPS Pharmaceuticals Inc., acquired Bayer’s plasma products business, but not Bayer’s recombinant hemophilia products.
Bayer Schering now manufactures all of its recombinant Factor VIII and the final product in its own facilities in Berkeley, CA. Kogenate FS is now the primary product manufactured at these facilities. Bayer Schering’s biological products business unit (fromerly in Research Triangle Park, NC; now in Berkeley, CA) is responsible for the global development and marketing.
Kogenate FS is marketed in the U.S. and internationally by Bayer Schering Pharma.
Product identical to Kogenate FS manufactured by Bayer Schering is relabeled, sold to and marketed by CSL Behring (formerly Aventis Behring) under the trade name Helixate FS. Bayer Schering normally shares product with CSL Behring 50-50, but during critical shortages 70% goes to Bayer and 30% to CSL.
In Oct. 2003, as part of a business realignment, Bayer divested its plasma products business to CSL Ltd., but retained Kogenate FS. Much of Bayer’s recent decreased profits in recent years is attributed to shortfalls in the manufacture of Kogenate (FS). Bayer estimated that it lost about $300 million dollars in operating profit in 2002 due to inability to manufacture sufficient product to meet demand (with associated shortages affecting patients).
In Feb. 2004, Bayer received the Industrial Biotechnology Award for 2003 from the Biochemical Technology Division, American Chemical Society, for continuous perfusion technology used in manufacture of Factor VIII.
Biodome S.A. developed and manufactures the BIO-SET needle-free delivery system approved for use with Kogenate. BIO-SET is a trademark registered to Biodome.
In fall 2008, EMEA, European Union, approved Bayer's new sterile filling facility in Berkeley, CA. The facility is now used in the late-stage production processes of filling and lyophilization (freeze-drying) for Kogenate FS, both for U.S. and European markets. Bayer cited several advantages of the new facility including increased automation to minimize risk of external contamination, greater assurance of product quality, improved process reliability and expanded capacity for future hemophilia therapies.
In Sept. 2009, Bayer reported it would invest more than $100 million at its Berkeley, CA, facility on a new manufacturing process to make future versions of Kogenate. The company,will take dvantage of an extension of Oakland’s tax-saving enterprise zone program into Berkeley.
Manufacture: Kogenate was originally manufactured by Bayer from Antihemophilic Factor Concentrate (Recombinant) (For Further Manufacturing Use) manufactured specifically for Bayer by Genentech, Inc.
Bayer Schering now completely manufactures Kogenate FS (and Helixate FS) in its own facilities using continuous perfusion mammalian bioreactors. This technology enables the cultivation of mammalian cells in high concentrations in small fermentation vessels over extended periods of time. Continuous harvest of cells and proteins is performed, with host cells returned to the fermentor for continued protein production using cell retention technology developed at Bayer’s Wuppertal, Germany, research center. The process improves yields of very fragile proteins, since they do not remain in the fermentor as long as in more traditional fed-batch bioreactors, and higher productivity of the Factor VIII molecule is achieved in a more efficient manner. Biotechnology companies are increasingly adopting continuous perfusion technology.
Bayer manufactured recombinant Factor VIII using 100 L fermentors for BHK cell culture until receiving approval in October 2002 for use of 200 L fermentors. Bayer reports that 26 separate glycosylation reactions are involved in manufacture of recombinant Factor VIII for Kogenate FS (and Helixate FS). See also Prog. Biotech., 9, 731-734, 1994. The Factor VIII molecule has 20 N-linked and at least 7 O-linked glycosylations sites. Recombinant Factor VIII is also highly unstable. Exposure to standard cell culture temperatures, e.g., 37˚C, results in significant loss of activity in less than 24 hours.
It has been reported that Bayer/Berkeley uses (or can use up to) 8 x 200 L bioreactors operating in perfusion mode using gravity settlers.
Factor VIII is the largest molecule among biopharmaceutical products manufactured by recombinant methods. Manufacture of recombinant Factor VIII must be carefully controlled to enable consistent folding, processing, and glycosylation of the molecule using transformed baby hamster kidney (BHK) host cells. The size of the molecule makes it very sensitive to denaturation by protease enzymes, e.g., from ruptured host cells. To minimize this, Bayer adopted a continuous perfusion process involving constant removal of recombinant Factor VIII-containing medium and replacement with new medium. This adds substantially to the complexity and cost of manufacture, and is prone to problems not encountered with simpler batch cell culture.
Continuous perfusion technology is utilized during the initial fermentation.
Continuous perfusion technology enables the cultivation of these cells in high
concentrations in small fermentation vessels over extended periods of time.
Continuous harvest of the proteins also is accomplished with cells returned to
the fermentor for continued protein production using cell retention technology
developed by Bayer BP's Wuppertal,
Germany, research center. Additionally, the process improves yields of very
fragile proteins since they do not remain in the fermentor as long as in more
traditional fed-batch processes. As a result, higher productivity of the
factor VIII molecule is achieved in a more efficient manner.
The gene for human Factor VIII was inserted into an established baby hamster kidney (BHK) cell line. The secreted recombinant Factor VIII is processed by multiple purification steps, including two steps with ion-exchange chromatography and gel filtration/size exclusion chromatography, and two steps with immunoaffinity chromatography using a murine Factor VIII monoclonal antibody (apparently including use of C7F7 from Synbiotic Corp.). The original Kogenate formulation was then stabilized by the addition of pasteurized Albumin (Human). The current formulation, Kogenate FS, is formulated with sucrose and other excipients instead of Albumin (Human). Bayer Schering manufactures and packages the final product which it markets under the trade name Kogenate FS. This same product is relabeled and marketed by CSL Behring under the trade name Helixate FS.
The “Particularly Preferred Embodiment” section of U.S. 5,668,108, assigned to Genentech (See the Tech. transfer section of the Factor VIII Products entry) describes manufacture of Factor VIII in baby hamster kidney cells, and apparently applies to Kogenate. The process uses the BHK-21 (BHK21; C-13) cell line, deposited as ATCC No. CCL 10, transfected with an expression vector of DNA encoding human Factor VIII (including 3’- and 5’-untranslated DNA joined at the 3’-untranslated region with a 3’-untranslated terminator DNA sequence from the hepatitis B virus surface antigen gene). Expression of the Factor VIII gene is driven by transcriptional and translational control elements contributed by the adenovirus major late promoter together with its 5’ spliced leader, as well as elements derived from the SV40 replication origin region including transcriptional enhancer and promoter sequences. The expression vector may also contain a dihydrofolate reductase (DHFR) gene driven by an SV40 early promoter, which confers gene amplification ability, and a selectable marker gene (neomycin resistance via cotransfection with a separate vector bearing neomycin resistance potential). “Functional human Factor VIII” is produced in active form(s) corresponding to Factor VIII forms and activity native to the Factor VIII of human plasma.
Potency is determined using the FDA Mega-1 (an intermediate-purity plasma derived concentrate) standard, which was calibrated against the 3rd WHO standard in IU. European Union review documents indicate that Bayer was studying the use of a recombinant Factor VIII standard calibrated against the 6th International Standard.
A “human plasma-derived product” is used in the culture media during fermentation (according the European Product Assessment Report), presumably referring to Human Plasma Protein Solution (HPPS). Processing of this component includes pasteurization for viral inactivation. Materials of bovine origin were used during cell bank development. Two human plasma-derived components are used as media components during fermentation of the monoclonal antibody used for immunoaffinity purification. In Oct. 2004, Bayer reported that more than 5 billion units of Kogenate had infused with no confirmed viral transmissions during 16 years of clinical experience with the product.
Bayer is reported to have made improvements in its manufacture of Factor VIII in mammalian cells at constant yields, purity and cell densities using perfusion technology. Cell cultures are maintained at a concentration of 20 million cells/mL for more than 3 months at 95 per cent viability. Innovations include high productivity cell lines, metabolic flux analysis, cell retention systems, advanced process control and improved downstream processing.
In 2008, Bayer licensed Ubiquitous Chromatin Opening Element (UCOE) technology from Millipore to improve recombinant product expression. See the Tech. transfer section for further information. Presumably, Bayer will be upgrading its transformed host BHK cell lines with UCOE technology.
FDA class: Biologic PLA BLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19930225; PLA; first approval; Indication = for Kogenate manufactured by Bayer Schering from Antihemophilic Factor Concentrate (Recombinant) (For Further Manufacturing Use) manufactured by Genentech; orphan designation (granted 09/25/1989, expired 2/2000)
Date = 20000626; BLA supplement; Indication = for Kogenate FS (new formulation and manufacturing processes), including continuous perfusion culture, reformulation with sucrose, addition of solvent-detergent viral inactivation, improvements in purification, and full manufacture by Bayer
Date = 20021001; BLA supplement; Indication = manufacture using 200 L fermentors
Date = 20051028; BLA supplement; Indication = approval of Kogenate FS with the BIO-SET reconstitution system/device; labeling amendments allowing room temperature storage for Kogenate FS
Date = 20081010; BLA supplement; Indications: = include routine prophylaxis to reduce the frequency of bleeding episodes and the risk of joint damage in children
Date = 20090808; BLA supplement; Indication = new 3,000 IU vial size
Date = 20100318; BLA supplement; Indication = increase of non-refrigerated storage temperature
Date = 2010110; BLA supplement; Indication = routine prophylaxis to reduce the frequency of bleeding episodes and the risk of joint damage in children
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling, 10/15/2010]:
1.1 Control and Prevention of Bleeding Episodes
Kogenate FS is an antihemophilic factor that is indicated for the control and prevention of bleeding episodes in adults and children (0-16 years) with hemophilia A.
1.2 Peri-operative Management
Kogenate FS is indicated for surgical prophylaxis in adults and children with hemophilia A.
1.3 Routine Prophylaxis in Children with Hemophilia A with No Pre-existing Joint Damage
Kogenate FS is indicated for routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children with no pre-existing joint damage.
Kogenate FS is not indicated for the treatment of von Willebrand’s disease.
Status: The original PLA for Kogenate was approved on Feb. 25, 1993 using recombinant bulk Factor VIII manufactured by Genentech, Inc. The BLA supplement for approval of Kogenate FS was filed in spring 1998 and approved on June 28, 2000, approval time = >2 years.
Kogenate FS is marketed in over 20 countries worldwide, including the European Union (EU). In Oct. 2004, Kogenate FS received supplemental EU approval for use with BIO-SET, a self- contained, fully assembled, needleless reconstitution system “that virtually eliminates the risk of accidental needle-stick injuries during reconstitution.” Compared to currently available systems, BIO-SET involves fewer than half the components for reconstitution and offers a compact size for easy portability. EU approval was also granted in fall 2004 for labeling amendments allowing room temperature storage for Kogeneate plust BIO-SET at up to 25˚C (room temparature) for up to two months.
In Sept. 2000, Bayer settled allegations of market manipulation raised by the Federal Trade Commission (FTC) and various state investigators. Prosecutors reportedly obtained Bayer AG documents outlining the need to quote higher average wholesale prices (AWPs) to physicians and health care providers as a way to induce them to promote Bayer products. Physicians and health care providers often receive reimbursement on the basis of costs (with higher prices boosting their income/profits). Bayer paid the federal government $14 million, but admitted no wrongdoing.
On Aug. 7, 2000, Kogenate received EU MAA approval for for Actilyse® (alteplase).
The Oct. 1, 2002 sBLA approval enabled expansion of production capacity for Kogenate FS, including use of 200 liter bioreactors/fermentors for baby hamster kidney (BHK) cell culture, twice the volume (100 L) then used to manufacture the product. With the approval, Bayer released product already manufactured in the larger bioreactors.
In Nov. 2003, Bayer filed a BLA supplement for approval of BIO-SET, a needleless device for reconstitution of Kogenate FS. An application was filed in the European Union in Dec. 2003. Approval was granted on Oct. 15, 2004. Kogenate FS with BIO-SET became the first and only self-contained device that provides a prefilled syringe for rapid and safe reconstitution and infusion without exposed needles. Bayer is also working on approval of room temperature storage labeling for Kogenate products.
In Nov. 2005, Kogenate FS with BIO-SET became the first integrated needleless reconstitution system for recombinant Factor VIII that eliminates the risk of accidental needle-stick injuries during reconstitution. With fewer components, fewer steps in the reconstitution process, and fewer exposed needles, Kogenate FS with BIO-SET is expected to provide patients with a safe, convenient way to prepare their own hemophilia treatment. Kogenate FS with BIO-SET eliminates the need for double-sided transfer and filter needles, and involves 50% fewer steps during the reconstitution process.
The Oct. 2008 approval provided a new prophylactic approach to pediatric hemophilia treatment. Regular weekly infusions can help prevent repeated joint bleeds that can cause chronic pain, impaired mobility and arthritis. Administering Kogenate FS to children with hemophilia A on a daily basis before a bleeding event occurs will reduce bleeding into joints and help prevent joint damage, a major cause of disability in hemophiliacs Prophylaxis has also been recommended by the National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) in its Recommendation #179, "Concerning Prophylaxis (Regular Administration of Clotting Factor Concentrate to Prevent Bleeding). The council considered it an optimal therapy for young children with severe hemophilia A and B..
Tech. transfer: See also the Tech. transfer section of the Factor VIII Products entry and the Manufacturing section above.
Bayer has received U.S. 5,763,401 (and equivalent EP 818 204) with claims including Factor VIII formulations without albumin, comprising 15-60 mM sucrose, up to 50 mM NaCl, up to 5 mM calcium chloride, 65-400 mM glycine, and up to 50 mM histidine.
In April 2003, Aventis Behring (now CSL Behring) filed suit against Bayer alleging that Bayer was infringing its patents related to recombinant Factor VIII formulations without stabilization by addition of Albumin (Human). This involves the “Freudenberg patents,” including U.S. 5,565,427 assigned to Behringwerke AG (now Sanofi Aventis S.A.), with certain right licensed or co-assigned to CSL Behring, concerning formulations to stabilize Factor VIII, with claims including use of amino acids, non-ionic detergents and carbohydrates (e.g., sucrose) to stablize Factor VIII. With the Dec. 2003 acquisition of Aventis Behring by CSL, forming ZLB Behring (now CSL Behring), CSL reported that ZLB and Aventis Pharma (became Sanofi Aventis S.A. in late 2004) would jointly prosecute these patents (apparently, including Bayer as an infringer).
Solvent detergent viral inactivation technology was developed by and nonexclusively licensed from the New York Blood Center. For example, see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) for further information about solvent detergent viral inactivation, useful primarily for inactivation of membrane-coated (enveloped) viruses.
Genentech was involved in a decade-long precedent-setting patent infringement dispute (Scripps vs. Genentech, resolved in 1994) related to Genentech’s early research and development of recombinant Factor VIII (for Kogenate FS marketed by Bayer Schering). In its early efforts to clone the Factor VIII gene, Genentech used recombinant Factor VIII purified by immunoaffinity chromatography purification of Factor VIII:vWF complex using matrix-bound vWF monoclonal antibody, with Factor VIII later eluted from the bound complex. This process had been patented by Scripps in U.S. reissue 32,011, but with this patent specifically claiming purification of plasma-derived, not recombinant, Factor VIII. Genentech refused to license immunoaffinity purification technology from Scripps and challenged Scripps’ U.S. patent alleging, among other things, that it was invalid because of inadequate “best mode” disclosures and that the patent did not apply to recombinant Factor VIII. Scripps’ patents did not claim the specific monoclonal antibody/hybridoma used by Genentech, and Scripps had not provided a patent depository culture collection deposit for its patent-related hybridomas. However, Scripps’ patents did describe generation of multiple hybridomas and monoclonal antibodies. Genentech alleged that a culture collection deposit of the hybridoma was required to fulfill requirements for full disclosure, including the best mode of practice (the 2.2.9 hybridoma/Mab) .
The Circuit Court eventually ruled that Scripps’ inclusion of methods for making the hybridomas and monoclonal antibodies was sufficient, i.e., that the exact method (cell line) best used for the purposes of the invention need not be identified, fully described, or deposited (as long a someone else could fully reproduce this, irrespective of the effort required). However, the patent was ruled to be rather specific in its product-related claims, and was found not to apply to recombinant Factor VIII
In Feb. 2008, Novartis AG and Novartis Vaccines and Diagnostics, Inc. (formerly Chiron Corp.) jointly filed a suit in federal court alleging that Kogenate infringes a U.S. patent received in 2006. This apparently involves U.S. 7,138,505, "Factor VIII:C nucleic acid molecules," assigned to Novartis, a continuation-in-part of 4,716,117 and 5,004,804. This patent has 74 claims covering various Factor VIII:C sequences and vector constructs. Novo Nordisk A/S apparently later joined this suit.
In Feb. 2008, Bayer reported nonexclusively licensing Ubiquitous Chromatin Opening Element (UCOE) techology from Millipore Corp., to improve transformed host cell lines for the manufacture of its recombinant proteins, presumably including Factor VIII. Originally developed by Celliance, later Serologicals Ltd., now Millipore, UCOE provides major improvements in gene expression in stably-transfected mammalian cells through effects on the structure of chromatin. UCOE prevents transgene silencing and gives consistent, stable and high-level gene expression irrespective of the chromosomal integration site. UCOE expression elements are small DNA elements (isolated from the area around house-keeping genes, which need to be active most of the time) that create a transcriptionally active, open chromatin environment around an integrated transgene, maximizing its potential to be transcribed into protein, irrespective of the position of the transgene in the chromosome. This has potential advantages over transient transfection, minimizing the quantities of DNA and costly transfection agent, as well as allowing aliquots of the pool to be stored frozen for future use if the protein is required at a later stage. UCOE improves the yield, consistency and stability of protein production in cultured mammalian cells, allowing simpler and quicker generation of stable, highly productive cell lines suitable for larger-scale manufacture of protein therapeutics.
Trials: A recent study using Kogenate FS with BIO-SET showed 74% of respondents — including patients, caregivers, and healthcare professionals — preferred Kogenate FS with BIO-SET over the evaluated reconstitution methods (the standard reconstitution method and the plastic double-spike stopcock reconstitution device). Kogenate FS with BIO-SET ranked highest as “favorite device overall” in this study. See the Journal of Outcomes Research, 2004; 8:63-78.
The 2008 pediatric prophylactic use approval by FDA was based on the Joint Outcomes Study, a multi-center trial designed to compare on-demand vs. prophylaxis treatment approaches and their effect on joint health. Study participants included 65 boys with Factor VIII deficiency who were between one and two-and-a-half years old. The study measured key results, such as frequency of joint hemorrhages and level of joint function, for up to 5.5 years. While 32 of the prophylaxis patients were given regular, every-other-day infusions of Kogenate FS, 33 were treated intensively with multiple infusions of the product but only at the onset of a joint hemorrhage. The boys participated in the study until they reached 6 years old. Their joint structure and function were then measured using X-rays, magnetic resonance imaging (MRI) and physical exams. Results indicated that 93% of children in the prophylaxis group showed normal joints, in contrast to 55% in the on-demand group. The trial results showed that an early, every-other-day treatment regimen improved joint function in contrast to an aggressive, on-demand approach. Overall, there was an 83% reduction in the risk for joint damage in patients receiving prophylaxis from an early age. The findings justify consideration of prophylaxis treatment for children with severe and moderate severity hemophilia A, uncomplicated by pre-existing joint damage, to be the medical standard of care. The standard of hemophilia care in the U.S. is now on par with other developed countries, especially those in Western and Northern Europe.
In March 2010, Bayer settled the lawsuit brought in 2008 by Novartis and Novo Nordisk A/S. Terms weren’t disclosed. CSL Behring unit, which also had sued, settled as well. The case was Novartis Vaccines & Diagnostics Inc. v. Bayer Healthcare LLC, 08cv68, U.S. District Court, Eastern District of Texas (Marshall).
Market: Kogenate worldwide sales have been reported to be ~1.02 billion in 2006; ~$480 million in 2004, and ~$497 million in 2003; $367 million in 1999; and $360 million in 1998.
The 2007 Average Wholesale Price (AWP) is $1.68/IU for all vial sizes and presentations, including Bio-Set (Red Book, 2007). AWPs are unchanged since 2004.
Medicare reimbursement is set at $1.29/IU for inpatient and home care, and $1.01/IU for outpatient care.
Estimated Acquisition Costs (for hospitals, treatment centers) is $1.05-$1.09/IU [from NHF].
In its March 22, 2006 price list, FFF Enterprises, a major biologics distributor, reported its price as $0.91/IU ($1.01 in 2004).
In July 2006, Bayer HealthCare launched the Kogenate FS with BIO-SET Free Trial Program, providing individuals with hemophilia A in the U.S. a one-time opportunity to experience treatment with Kogenate FS with BIO-SET, a needleless reconstitution system, as well as the accompanying support programs and services available through Bayer. Enrollees receive up to six free infusions of Kogenate FS with BIO-SET (not to exceed a maximum of 20,000 IU) at no cost. With Kogenate costing over $1.00/IU, Bayer Schering is giving away potentially over $20,000 worth of product to gain each new user.
In Oct. 2004, Bayer reported that more than 5 billion units of Kogenate had infused with no confirmed viral transmissions during 16 years of clinical experience with the product.
Ongoing: In Nov. 2004, Bayer concluded and exclusive global technology license with Zilip-Pharma N.V. (The Netherlands) for the development and commercialization of a longer-acting Kogenate formulation, “a product with the potential to shift current treatment paradigms in hemophilia and simplify the lives of thousands of patients around the world.” Prolonging Kogenate’s half-life would result in fewer infusions for hemophilia A patients. This product involves using Factor VIII in Zilip-Pharma’s non-biological (synthetic) pegylated (ethylene oxide polymer attachment) liposomes which non-covalently bind proteins and peptides. Clinical results obtained by Zilip-Pharma suggest that a prolonged interval between bleeding episodes -- one week or more -- occurs when Factor VIII attached to liposomes is administered to individuals with hemophilia A. The companies report this next-generation Kogenate could be launched in five years. Zilip-Pharma could receive a total of $100 million in upfront and milestone payments, plus royalties from sales. Phase I trials began in June 2005.
Companies involvement:
Full monograph
149 Factor VIII, rDNA/Bayer
Nomenclature:
Factor VIII, rDNA/Bayer [BIO]
Kogenate FS [TR]
Kogenate [TR prior to sucrose ormulation]
Antihemophilic Factor (Recombinant), Formulated with
Sucrose [FDA]
Antihemophilic Factor (Recombinant) [FDA prior to sucrose formulation]
Antihemophilic Factor [USAN]
octocog alfa [INN]
Antihemophilic Factor, Human [former USAN]
Factor VIII (rDNA) [BAN]
Antihemophilic Factor USP [USP]
AHF [SY]
BAY-w-6240 [SY]
Factor VIII, recombinant [SY]
NDC 0026-0670-20; NDC 0026-0670-30; NDC 0026-0670-50 [NDC]
molecular weight (kDa) = 300
FDA Class: Biologic PLA BLA
Year of approval (FDA) = 1993
Date of 1st FDA approval = 19930225
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2014 (based on 5,668,108 agent patent)
2016 based on 5,763,401 formulation patent
[The company doesn't plan to launch NovoEight in the U.S. until early 2015, however, for fear of stepping on some unspecified "third-party" patents] |
U.S. Patent Expiration Year: | 2014 |
U.S. Biosimilars Data Exclusivity Expiration: | 2005 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2000 |
U.S. Biosimilars Launchability Year: | 2016 |
U.S. Biobetters Launchability Year: | 2016 |
Biosimilars/biobetters-related EU Patents: | 2017, based on EP 0818204 formulation patent; expired (based on agent patents including EP 0150735, EP 0152746 and EP 0160457) |
EU Patent Expiration Year: | 2017 |
EU Biosimilars Data Exclusivity Expiration: | 2010 |
EU Biosimilars Orphan Exclusivity Expiration: | 2010 |
EU Biosimilars Launchability Year: | 2017 |
EU Biobetters Launchability Year: | 2017 |
Index Terms:
antihemophilic factors
biopharmaceutical products
blepharospasm
blood products
exempt from CBER lot release requirements
human materials used<!-- humansource -->
murine (mouse) materials used
recombinant DNA
rodent source materials
ATCC CCL 10
baby hamster kidney (BHK) cells
BHK-21 (C-13)
bioreactors, 10,000 Liter
keratinocytes, human
mammalian cell culture
perfusion bioreactors
plasma proteins, immunoglobulin-depleted
rodent cells <!-- rodentcells -->
U.S. Standard Rabies Vaccine
U.S. Standard Rabies Vaccine
Albumin (Human)
C7F7 monoclonal antibody
calcium chloride
Factor VIII monoclonal antibodies
glycine
hamster proteins
imidazole
immunoaffinity chromatography
lyophilized (freeze-dried)
monoclonal antibody C7F7
murine monoclonal antibody, Factor VIII
murine proteins
polysorbate 80 (Tween 80)
sodium chloride
Sterile Water for Injection
sucrose
viral inactivation, solvent detergent
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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