- Aldurazyme; I2S; alpha-L-iduronidase, recombinant
Status: approved; marketed
Organizations involved:
BioMarin, Inc. – Manuf.; R&D; Tech.
Genzyme Corp. – Manuf. other; World mark.
University of California – R&D; Tech.
Transkaryotic Therapies, Inc. (TKT) – Patent dispute
Shire Pharmaceuticals Group plc – Parent
Description: Aldurazyme is an aqueous formulation of a recombinant form of human alpha-L-iduronidase (laronidase; glycosaminoglycan alpha-L-iduronohydrolase; E.C. 3.2.1.76) glycoprotein expressed by a transformed Chinese hamster ovary (CHO) cell line. This glycosidase lysozomal enzyme cleaves non-reducing terminal iduronate residues from certain polysaccharides/carbohydrates. Aldurazyme is used for enzyme replacement therapy in patients with mucopolysaccharidosis I (MPS I), a progressive, debilitating, fatal genetic disease for which no other specific therapeutics are available.
Laronidase is expressed from the gene for 658-amino acid full-length human alpha-L-iduronidase, with a 25-amino acid N-terminus sequence cleaved during manufacture to form laronidase. The predicted amino acid sequence of laronidase, and the nucleotide sequence that encodes it are identical to that of a polymorphic (iso)form of human alpha-L-iduronidase. The molecular weight of laronidase is about 83,000 daltons (83 kDa), with a predicted m.w. of 70.1 kDa based on amino acid content, and about 12 kDa being appended carbohydrates from post-translation glycosylation. Laronidase has a specific activity of ~172 U/mg.
The full-length human alpha-L-iduronidase enzyme has 653 amino acids, a molecular formula of C3169-H4854-N901-O884-S12, and a reported molecular weight of 85 kDa by SDS-PAGE. During CHO cell expression the human gene for full-length enzyme, the first (N-terminus) 25 amino acids of the signal peptide are cleaved, forming the “precursor protein” (laronidase), which is secreted into the culture medium, while enzyme that is not secreted (ramains in the yeast cells) is further processed in the lysosome to form the full-length “processed protein.” Of the six glycosylation sites, the third and sixth sites contain the bis mannose-6-phosphate oligosaccharide7 oligosaccharide required for human cellular uptake.
Isoelectric focusing of laronidase shows multiple isoforms due to glycosylation microheterogeneity, but “this heterogeneity is not a cause for concern” (according to the European Product Assessment Report). As part of its European Union approval, BioMarin committed to perform a study to demonstrate consistency in glycosylation site occupancy.
Aldurazyme is packaged in 5.3 mL single-use vials at a concentration of 100 Units/mL (0.58 mg/mL) and a pH of ~ 5.5 for intravenous infusion; along with 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80 (Tween 80). The vials contain an extractable volume of 5.0 mL (500 Units). Prior to administration, Aldurazyme is diluted in 0.9% Sodium Chloride Injection, USP, containing 0.1% Albumin (Human). Aldurazyme contains no preservatives. The dating period for Aldurazyme when stored at 2-8°C (refrigerated) is 24 months from the date of manufacture. The date of manufacture is the date of final sterile filtration of the final formulated product. The dating period for drug substance (bulk product) stored at 2-8°C is 12 months.
The units for measuring laronidase activity were revised during its development. Laronidase used in preclinical studies and the Phase I/II trial was defined as 125,000 units/mL. ‘Unit’ was later redefined as 100 Units/mL, with no change in absolute/actual product activity.
Nomenclature: Laronidase [FDA USAN INN; TR former]; Aldurazyme [TR]; glycosaminoglycan alpha-L-iduronohydrolase [CAS]; Iduronidase, alpha-L-(8-histidine) (human) [CAS]; 210589-09-6 [CAS RN] 50378-38-2 [CAS RN]; 9073-56-7 [CAS RN; human enzyme]; alpha-L-iduronidase [SY]; L-iduronidase [SY]; I2S [SY]; Hurler corrective factor [SY]; rhIDU [SY]; IDU, recombinant human; [SY]; E.C. 3.2.1.76 [EC]; NDC 58468-0070-1 [NDC]
Biological.: alpha-L-Iduronidase is an exoglycosidase enzyme. It removes nonreducing terminal iduronic acid (indu-ronate) residues from sulfated glycosaminoglycans (e.g., heparin/heparan sulfate and dermatan sulfate). Laronidase has substantially the same enzyme activity as human alpha-L-iduronidase. The enzyme cleaves alpha 1-4 linkages between iduronic acid and N-acetylglucosamine, 2-sulfaminoglucosamine or glucosamine, e.g., which occur in the repeating disaccharide structure of heparin sulfate and heparan sulfate. The enzyme also cleaves the alpha 1-3 linkage between iduronic acid and N-acetylgalactosamine in dermatan sulfate. The enzyme contains a mannose-6-phosphate residue. One unit of enzyme activity is defined as the amount of enzyme that hydrolyzes one µmole of 4-methylumbelliferyl-alpha-iduronide per minute at pH 5.0 and 37°C.
A genetic deficiency of alpha-L-iduronidase causes a lysosomal storage disorder known as mucopolysaccharidosis I (MPS I; see the “Disease” section below). Enzyme replacement therapy with laronidase can correct this enzymatic defect in Hurler cells in culture. The enzyme is taken up into cells, including fibroblasts, through receptor-mediated endocytosis, and is transported to the lysosomes where it breaks down and clears stored substrates of heparan sulfate and dermatan sulfate. Iduronidase can not cross the blood-brain barrier, and is not effective for treating the most severe forms of MPS I with neurological/brain involvement.
alpha-L-Iduronidase has been purified from human and animal sources. However, it is present at very low levels in tissues and urine, and enzyme isolated from these sources is usually not therapeutically functional, due to loss of the man-6-phosphate signal (i.e., altered glycosylation) either in lysosomes or during purification. Mammalian enzyme was first cloned in 1990 (J. Biol. Chem., 267:6570-6575, 1992), and human enzyme was cloned in 1991 (FASEB J., 6:A77, 1992). The carbohydrate structure (glycosylation) of laronidase was reported in the Journal of Biological Chemistry, 272 (36), 22,758-65, Sept. 1997 (by researchers from UCLA).
Companies.: BioMarin formed a 50/50 joint venture with Genzyme Corp., BioMarin/Genzyme LLC, in September 1998 to develop and commercialize Aldurazyme worldwide. All costs, expenses and profits associated with the development and commercialization of Aldurazyme would be equally shared. Genzyme also purchased about $18 million in BioMarin stock, and agreed to make a $12.1 million milestone payment upon FDA approval. BioMarin’s responsibilities include manufacturing, and Genzyme’s responsibilities include worldwide marketing and distribution. Bulk drug substance (bulk laronidase) is shipped to Genzyme and/or a contractor for final sterile filtration, filling into vials, packaging, etc. Filling and finishing for the European market are performed at Genzyme facilities in Waterford, Ireland.
In Jan. 2008, BioMarin and Genzyme modified their joint venture agreement regarding Aldurazyme. The operational responsibilities of the companies did not significantly change. Genzyme continues to globally market Aldurazyme for mucopolysaccharidosis I (MPS I) and BioMarin continue to manufacture Aldurazyme. But as of Jan. 1, 2008, instead of sharing all costs and profits equally through the 50/50 joint venture, Genzyme records sales of Aldurazyme and pays BioMarin a tiered payment ranging from ~39.5%-50% of worldwide net product sales, which will also be recorded by BioMarin as product revenue. Under the revised structure, payments are projected to result in both BioMarin and Genzyme receiving approximately the same profit as under the original joint venture structure. BioMarin receives benefits from increased manufacturing efficiencies and Genzyme receives benefits from increased commercialization efficiencies. Certain research and development activities related to Aldurazyme and intellectual property continue to be managed in the joint venture on a 50/50 basis.
Aldurazyme is manufactured by BioMarin, Inc., CBER/FDA est. no. 1649. Filling of final product is performed by another company (redacted/censored by FDA, suggesting a contractor). Labeling of unlabeled vials, packaging and distribution is performed by Genzyme Corp., which also handles all commercialization and marketing. Genzyme and BioMarin split profits 50-50.
IManufacture: BioMarin’s ‘Galli Drive’ manufacturing facility was designed for the production of Aldurazyme, and has 900 liters of continuous perfusion bioreactor cell culture capacity. BioMarin has invested ~$30 million (also reported as $40 million) in the facility. Design of the facility began in 1998, a year after that company was founded; most construction was completed in 1999; the facility was validated and clinical supply manufacturing began in 1st quarter 2000; and the facility was expanded in 2001. Manufacturing (including related quality assurance and quality control) occupies ~51,800 sq. ft., including 12,500 sq. ft. of cGMP process manufacturing areas.
CHO cell culture is performed using a perfusion process, with continuous removal of culture medium and its replacement with fresh medium. The CHO cells secrete the enzyme into the culture medium. Using relatively small but continuously operating perfusion bioreactors vs. batch bioreactors using a series of large tanks, perfusion production runs can take four months or longer, while batch runs take generally take only 30-40 days. Formulated bulk is shipped to Genzyme (Allston Landing facility) or to a contract manufacturer for filling into vials. Genzyme labels and packages the product for distribution.
Investigators from the University of California, Los Angeles, CA (UCLA), reported the development of the 2.131 CHO cell line that expresses large quantities of laronidase in Protein Expression and Purification, vol. 5, p. 225-32, 1994 . This cell line and related methods have presumably been adopted/adapted for large-scale manufacture, since this is listed among the few laronidase-related references presented at BioMarin’s Web site. The pCMVhldu plasmid expression vector was constructed containing alpha-L-iduronidase cDNA, along with the cytomegalovirus (CMV) immediate early gene promoter/enhancer, a murine immunoglobulin C-alpha region intron, and the bovine polyadenylation signal. Following cotransfection of CHO cells with pCMVhldu and a plasmid containing the neomycin resistance gene (for selection of transformed cells), stable transfected cell lines were selected by their resistance to G-418 (neomycin). Scaled-up culture used a 6 L Bellco microcarrier flask with a perfusion wand stirrer containing Cultisphere G gelatin (bovine origin) microcarriers (1 g/L) with medium including 2-3% fetal bovine serum (FBS), 10 mg/L insulin, ethanolamine, and G-418 (300 µg/mL). Production rates of about 4-10 million units/day for 5 L of culture volume were attained, while exchanging 7 L/day of media. The highest-expressing CHO cell line (2.131) contained about 10 copies of the pCMVhldu construct and expressed 1,400-6,000 units of alpha-L-iduronidase per mg protein or 0.6-2.4% of total cell protein, with about 5,000 units accumulating in 24 hours per 107 cells, with about half of enzyme secreted from the cells. Higher expression levels were attained with increased exchange of fresh media. Production in 5 L microcarrier culture provided 15 mg or more per day, and specific enzyme activity of up to 500,000 IU/mg was attained. Purification to homogeneity was achieved using sequential chromatography with concanavalin A-Sepharose, FPLC heparin-Sepharose, and Sephacryl S-200 (all from Pharmacia), with ultrafiltration for concentration. Overall, purification yield was 25%. The enzyme was post-translationally modified comparable to human fibroblast-expressed enzyme, and was taken-up and active (corrected glycosaminoglycan accumulation) in Hurler fibroblasts in vitro.
For large-scale manufacture of laronidase (e.g., as described at BioMarin’s Web site), the Chinese hamster ovary (CHO) cell line Working Cell Bank is thawed, expanded and cultured using Cytopore (Amersham Biosciences) microcarriers in stirred suspension bioreactors. These small (200-280 µm) highly porous beads (very high surface area/volume ratio) remain suspended in the culture medium and enable optimized growth of anchorage-dependent CHO cells, while protecting the cells from shear forces, enabling increased aeration and stirring, resulting in higher yields. The laronidase enzyme, with its N-terminus 25-amino acid signal peptide sequence removed, the “precursor protein,” is secreted into the culture medium.
Purification involves six major steps, including three column chromatography steps using several different methods, DNA removal, and viral filtration. “Initial purification” by passage through multiple chromatography columns separates the product from other host proteins secreted during the cell culture phase and from medium components in the harvest fluid. “Final purification” involves further chromatography. Viral filtration involves both size-exclusion membrane filtration using Ultrapor VF grade DV50 polyvinylidine fluoride membrane cartridges from Pall and adsorptive membrane chromatography using Mustang Q membrane from Pall. This was the first approval involving both of these methods. In the final bulk processing step, the enzyme is formulated into the final solution by an ultra filtration/diafiltration (UF/DF) step, resulting in the Formulated Bulk. Through the UF/DF step, the solution is first concentrated, and then the buffer is exchanged to bring laronidase and the excipients to the correct concentrations. The Formulated Bulk is shipped to Genzyme in 20 L Flexboy Flexible Carboy System (from Stedim) plastic bag-like containers. The Formulated Bulk is sterile filtered and aseptically filled into sterile vials and capped. The reference standard for the bulk and final products is based on 500 mL each pooled from multiple production lots.
The phosphate buffer used was selected to maintain enzyme activity. Polysorbate 80 (Tween 80), a hydrophobic nonionic surfactant, is added to minimize precipitate formation. Laronidase used in the original Phase I/II trial and MPS I studies in dogs did not contain polysorbate 80. The commercial formulation was used since August 2000, including preclinical toxicology studies and trials. During development, potency was redefined and the protein content adjusted. The enzyme activity measurement was also redefined, based on improvements in the activity assay and changes in the definition of an activity unit to be consistent with International Unit nomenclature. This change did not affect dosage or formulation, just assay conditions and unit definitions. [primarily from the European Product Assessment Report (EPAR), EMEA/EU].
Fetal bovine serum (FBS) and porcine (pig) trypsin are used in the culture medium, and were used in the establishment of the Master (MCB) and Working Cell Banks (WCB). The FBS used for the MCB was from Mexican cattle, has an EDQM Certificate of Suitability, was irradiated to minimize viral contamination, and “is considered TSE compliant.” (by EMEA/EU). Cytopore microcarriers are from plant-derived materials. Polysorbate 80 used is of plant origin [from EPAR].
FDA class: Biologic BLA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 20030430; first approval, BLA (BL 125058/0); orphan designation (expires 4/2010)
Date = 20111128; BLA supplement; Indications = Novato, CA, manufacturing facility expansion
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:
ALDURAZYME is indicated for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established. ALDURAZYME has been shown to improve pulmonary function and walking capacity. ALDURAZYME has not been evaluated for effects on the central nervous system manifestations of the disorder.
Status: BioMarin and Genzyme initiated a “rolling” BLA on April 20, 2002. In Jan. 2003, the Endocrinologic and Metabolic Drugs Advisory Committee, FDA, voted unanimously to recommend approval of Aldurazyme for treatment of MPS-1. The committee voted that Aldurazyme improved lung function and was linked to increased endurance. The public meeting included dramatic presentations from several families of MPS-I patients, including one family that had to choose which of two brothers to enter into Aldurazyme Phase trials (since only 1 family member was allowed to enter), with the untreated brother experiencing irreversible deterioration. In early Feb. 2003, the companies received a complete response letter asking for additional information, but not including clinical data/issues. Although not an “approvable letter,” FDA noted that the BLA supported the safety and effectiveness of Aldurazyme.
The BLA was completed on July 26, 2002, was accepted and granted priority review (≤6 months review target) status on Sept. 16, 2002, and received approval on April 30, 2003 (approval time = ~7.5 months) with orphan designation. Aldurazyme is exempt from CBER lot release requirements. The BLA filing included clinical data from a six-month, placebo- controlled Phase III trial of Aldurazyme, six months of data from an open-label extension of the Phase III study, and three years of data from a Phase I trial and extension study.
Aldurazyme is exempt from CBER/FDA lot release/inspection requirements.
Genzyme and BioMarin are obligated to conduct post-approval, Phase IV studies including completing an ongoing trial of safety and pharmacokinetics in children under age five; a open-label dose-optimization study in 32 patients; and continuation of a Phase III extension trial for four years from the trial’s start. The companies also will collect long-term data through a patient registry.
Genzyme received European Union (EMEA) approval on June 11, 2003 with orphan medicinal product designation (providing 10 years market exclusivity). Aldurazyme has also been approved in various other countries worldwide.
Aldurazyme received approval in Japan in Oct. 2006 for treatment of mucopolysaccharidosis I (MPS I), with approval as an orphan drug.
Tech. transfer: Technology for production of recombinant laronidase was licensed from the Harbor-UCLA Research and Education Institute, University of California (Los Angeles, CA), including U.S. 6,426,208; and 6,585,971 (and 6,569,661, assigned to BioMarin, including inventors affiliated with UCLA); each titled, “Recombinant alpha-L-iduronidase, methods for producing and purifying the same and methods for treating disease caused by deficiencies thereof.” The exemplary claim (no. 1) of U.S. 6,426,208 includes, “A purified human recombinant alpha-L-iduronidase having a purity of greater than about 99%.” This patent describes recombinant constructs, cell culture methods using microcarrier Cytodex 2 beads, and purification methods for producing recombinant enzyme. In one embodiment, plasmid-tranfected Chinese hamster ovary (CHO) cell line 2.131 provides particularly high levels of expression, about 5,000- to 7,000-fold more enzyme than normal human cells (see the “Manufacture” section above). U.S. 6,585,971 claims methods of treating deficiencies of alpha-L-iduronidase using laronidase. U.S. 6,569,661 includes methods of purification.
Three U.S. patents (6,524,835; 6,238,662 and 6,149,909) and foreign applications by Dr. J. Hopwood, assigned to the Women and Children’s Hospital (North Adelaide, Australia), concerning CHO-expression of apha-L-iduronidase have been exclusively licensed to Transkaryotic Therapies Inc. (TKT; becoming part of Shire Pharmaceuticals Group plc). These patents are entitled “Synthetic .alpha.-L-iduronidase and genetic sequences encoding same,” with synthetic defined to include recombinant. BioMarin asserts that “these patents are invalid or not infringed on a number of grounds.” On Oct. 8, 2003, Genzyme (Biomarin’spartner) and TKT announced a collaboration to develop and commercialize an unrelated product. In connection with this, the companies signed an agreement involving an exchange of non-suits between the companies, including TKT agreeing not to initiate any patent litigation against Genzyme or the Biomarin/Genzyme joint venture relating to Aldurazyme. If any or all of these patents are deemed (or ruled) to cover Aldurazyme, the BioMarin/Genzyme joint venture will have to license the patents from TKT. A European patent application with similar claims was rejected by the European Patent Office due to prior art, was abandoned, and cannot be refiled.
Trials: The BLA included data from a six-month placebo-controlled Phase III trial in 45 patients. See N. Engl. J. Med., 344, 182 (2001). This open-label extension study showed efficacy for pulmonary function as measured by percent predicted Forced Vital Capacity (FVC), and endurance as measured by distance covered in a six-minute walk test. At 62-weeks, the 22 Aldurazyme recipients had an improved mean FVC change of +5.4 percentage points; improved six-minute walk test (mean +40.0 meter change); and maintained FVC and six-minute walk test improvements observed after 50 weeks. At 36 weeks, 23 placebo recipients having switched to open-label Aldurazyme had a improved mean FVC change of +2.6 percentage points; improved six-minute walk test (mean +32.4 meter change). Aldurazyme’s adverse effect profile was acceptable and predictable. Three years of data from a ten-person Phase I trial and extension were also submitted.
Disease: Mucopolysaccharidosis I (MPS-1 or MPS I), historically known as Hurler, Hurler-Scheie, and Scheie syndromes, is a rare life-threatening genetic disease caused by deficiency of the enzyme alpha-L-iduronidase. This leads to the accumulation of complex carbohydrates in the lysosomes of cells, leading to the progressive dysfunction of cellular, tissue and organ systems. Lysosomal accumulation of partially degraded glycosaminoglycans, e.g., heparin and dermatan, causes characteristic clinical manifestations that include corneal clouding, skeletal abnormalities, cardiovascular disease, limited joint mobility, and organomegaly. MPS-1 affects only about 3,000 to 4,000 persons worldwide. Currently, only palliative treatment is available for affected patients, and most patients die from the disease prior to adulthood.
Differences in disease severity are caused by allelic mutations of the alpha-iduronidase gene. In its most severe form, MPS I is commonly known as Hurler syndrome and is associated with multiple problems such as mental retardation, clouding of the cornea, coarsened facial features, cardiac disease, respiratory disease, liver and spleen enlargement, hernias, and joint stiffness. Skeletal deformities and retarded motor and mental development are the main symptoms, and radiological examination of the skeleton reveals a characteristic pattern (dysostosis multiplex). Patients with Hurler syndrome usually die before age 10. In an intermediate form (between Hurler and Scheie syndromes) known as Hurler-Scheie syndrome, mental function is generally not severely affected. Hurler-Scheie syndrome is less severe than Hurler syndrome, but patients usually do not survive beyond their early 20’s. Scheie syndrome is the mildest form of MPS I. It is compatible with a normal life span, but joint stiffness, corneal clouding, and heart valve disease cause significant problems.
BioMarin and Genzyme estimate that about 3,400 individuals in developed countries have MPS I, including about 1,000 in the U.S. and Canada. The frequency of Hurler syndrome is estimated to be 1:100,000 according to a British Columbia survey of newborns (Human Genetics, 85:389-390, 1990) and 1:70,000 according to an Irish study (Human Genetics, 101:355-358, 1990). The estimate for Hurler-Scheie syndrome is one in 115,000, and for Scheie syndrome is one in 500,000. There appears to be no ethnic predilection for this disease. It is likely that the disease is often underdiagnosed, either because patients die of a complication before the diagnosis is made or because the milder forms of the syndrome may be mistaken for arthritis or missed entirely. Newborn screening for MPS I, currently not routinely performed, would likely find some infants with MPS-1 that would otherwise likely remain undetected.
Medical: Prior to use, Aldurazyme is reconstituted (dissolved) with 0.9% sodium chloride solution in an infusion bag. The recommended dosage regimen of is 0.58 mg/kg of body weight administered once-weekly as an intravenous infusion.
Except for bone marrow transplantation (BMT), there are no other significant therapies for MPS I. BMT can be effective in treating some of the symptoms of the disorder, but BMT has high morbidity and mortality in MPS I, and often is not available to patients because of lack of suitable donors.
Market: The 2007 Average Wholesale Price (AWP) is $783.60/vial, and the Direct Price (Manufacturer’s discount price) is $653.00/vial (Red Book, 2005). For comparison, the AWP was $746.40/vial in 2005, and $678.00 in 2004; and the Direct Cost was $653.00/vial in 2005 and $565.00 in 2004.
Aldurazyme is relatively expensive, with treatment typically costing about $175,000/year. The products’s very small market and high development and manufacturing costs are primarily responsible for this.
Wordwide revenue was $166.8 in 2010; $155.1 million in 2009 and $152 million in 2008. [Aldurazyme is marketed through a joint venture with BioMarin/Genzyme, and product sales are not reflected in Genzyme’s revenue]. Net sales of Aldurazyme by BioMarin/Genzyme LLC were $123 million in 2007; $93.6 million in 2006, and $76.4 million in 2005 (with more than 400 patients in over 30 countries are receiving Aldurazyme), $42.6 million in 2004, and $11.5 million in 2003..
BioMarin’s share of the profit from BioMarin/Genzyme LLC was $71.2 million in 2010 and $70.2 million in 2009.
Genzyme has been marketing Aldurazyme to physicians through an expanded sales force of nearly 40 professionals who specialize in providing its enzyme replacement therapies for rare genetic diseases. Sales efforts are focused on raising awareness of MPS I and the availability of Aldurazyme among geneticists, pediatricians, and sub-specialists involved in the multi-disciplinary care of patients with MPS I.
Companies involvement:
Full monograph
187 Iduronidase, rDNA
Nomenclature:
Aldurazyme [TR to BioMarin/Genzyme LLC]
laronidase [FDA USA INN]
glycosaminoglycan a-L-iduronohydrolase [CAS]
iduronidase, alpha-L-(8-histidine) (human) [CAS]
210589-09-6 [CAS RN]
50378-38-2 [CAS RN]
alpha-L-iduronidase [SY]
Hurler corrective factor [SY]
IDU, recombinant human [SY]
L-iduronidase [SY]
rhIDU [SY]
Alronidase [TR former]
E.C.3.2.1.76 [EC]
NDC 58468-0070-1 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 2003
Date of 1st FDA approval = 20030430
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2020, based on 6,569,661, 6,585,971 and 6,858,206. |
U.S. Patent Expiration Year: | 2020 |
U.S. Biosimilars Data Exclusivity Expiration: | 2015 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2010 |
U.S. Biosimilars Launchability Year: | 2020 |
U.S. Biobetters Launchability Year: | 2020 |
Biosimilars/biobetters-related EU Patents: | 2020 (based on EP 1332206 and EP 1792983) |
EU Patent Expiration Year: | 2020 |
EU Biosimilars Data Exclusivity Expiration: | 2013 |
EU Biosimilars Orphan Exclusivity Expiration: | 2013 |
EU Biosimilars Launchability Year: | 2020 |
EU Biobetters Launchability Year: | 2020 |
Index Terms:
biopharmaceutical products
enzymes
exempt from CBER lot release requirements
hamster source materials
human materials used<!-- humansource -->
recombinant DNA
rodent source materials
2,3,5,6-tetrafluorophenyl-4,5-bis-S-(1-ethoxyehtyl)-thioacetoamidopentoate)
Chinese hamster ovary (CHO) cells
CYT-351 monoclonal antibody
glycosaminoglycans
mammalian cell culture
mice, Viral Antigen Free
rodent cells <!-- rodentcells -->
4-acetylphenylacetic acid
Albumin (Human)
glycosaminoglycans
idiopathic thrombocytopenic purpura (ITP)
Lysine-Biogel chromatography matrix
N-acetyl-O-acetyl mannosamine phosphate
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
exempt from CBER lot release requirements
orphan status
priority review 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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