Filgrastim - Neupogen; GRAN; granulocyte colony stimulating factor, recombinant
Cross ref.: See also the entry below for G-CSF, rDNA, Peg- (pegfilgrastim; Neulasta), a pegylated version of this product.
Status - approved; marketed
Organizations involved:
Amgen, Inc. – Manuf.; R&D; Tech.; USA mark.; Intl. mark
Hoffmann-La Roche Ltd. – Intl. mark.; Former
Kirin – R&D; Tech.; Asia mark.
Kirin-Kunpeng Bio-Pharmaceutic – Asia mark.
Sankyo Ltd. – Japan mark.
Sloan-Kettering Mem. Cancer Inst. – R&D; Tech.
Royalty Pharma, AG – Tech.
DRI Capital – Tech.
Inwest Investments Ltd. – Parent
Hospira - Patent dispute
Benzon Pharma A/S – Tech.
Genentech Inc. – Patent dispute
Teva Pharmaceutical Industries Ltd. – Patent dispute
Columbia University – Tech.; Patent dispute
Description: Filgrastim or Neupogen is an aqueous formulation of recombinant dimeric human N-methionyl granulocyte colony stimulating factor (r-metHuG-CSF) protein expressed by Escherichia coli (E. coli) bacteria transformed with the human granulocyte colony stimulating factor (G-CSF) gene.
The protein has an amino acid sequence identical to that of human G-CSF, except for an added N-terminal methionine and no glycosylation, both due to expression by E. coli. Filgrastim is composed of 175 amino acids, with two intrachain disulfide bonds, a molecular weight of ~18,800 Daltons (~18.8 kDa), and molecular formula of C845 H1339N223O243S9. The mature human G-CSF is a 18.8 kDa protein of 174 amino-acid polypeptide chain with two intra-molecular disulphide bonds between residues Cys36-Cys42 and Cys64-Cys74 and one free cysteine at residue 17. Native human G-CSF, but not bacterial-expressed filgrastim, has a single O-glycosylation site at Thr133, which protects the protein from aggregation but is not crucial for biological activity.
Neupogen has a potency of 1 x 108 units/mg (100 million units/mg). The National Institute for Biological Standards (U.K.) interim reference standard reagent and cell mitogenesis assay for G-CSF is used to determine potency.
Neupogen is packaged either as powder in single-use vials for reconstitution with Water for Injection USP, or as aqueous solution in single-use prefilled syringes. Vials contain either 300 µg (1 mL) or 480 µg (1.6 mL) of Filgrastim (at concentration of 300 µg/mL) with a specific activity of 1.0 ± 0.6 x 108 (~100 million) U/mg. This is formulated in a 10 mM sodium acetate buffer at pH 4.0, containing 5% mannitol, and 0.004% polysorbate 80 (Tween 80). Vial quantitative composition (per mL) is Filgrastim, 300 µg; acetate, 0.59 mg; mannitol, 50.0 mg; Tween 80, 0.004%; sodium, 0.035 mg; and Water for Injection USP q.s. ad 1.0 mL. The prefilled syringes contain either 300 µg or 480 µg filgrastim at a fill volume of 0.5 mL or 0.8 mL, respectively. The 300 µg, 0.5 mL syringe also contains 0.295 mg acetate; 0.0175 mg sodium (sodium acetate buffer); 25.0 mg sorbitol; 0.004% polysorbate 80; and 0.5 mL Water for Injection, USP. The 480 µg, 0.8 mL syringe contains the same excipients a the same concentrations. Neupogen is stored at 2-8˚C (36-46˚F; refrigerated).
Biological.: The native human G-CSF is encoded by a gene on chromosome 17 that encodes two protein products due to differential splicing; isoform A of 177 amino acids and isoform B of 174 amino acids. Isoform A differs from isoform B in that it contains an additional three residues (Val-Ser-Gln) inserted after Leu35. The 174 amino acid form is associated with greater biological activity and stability than the longer isoform and is the basis for commercial pharmaceutical G-CSF products, including Neupogen and its biosimilars. The active substance, where expressed by E. coli, is a recombinant form of the 174 amino-acid isoform that contains an additional N-terminal methionine residue not found in the native human protein. The naturally occurring G-CSF is also glycosylated at threonine residue 133, a modification which is absent in active substance as an E. coli expression product.
Granulocyte colony stimulating factor (G-CSF) is one of several glycoprotein growth factors known as colony stimulating factors (CSFs) because they support the proliferation of hematopoietic progenitor cells. CSFs stimulate the growth of different types of cells found in the blood and the immune system. Endogenous human G-CSF is a lineage specific colony stimulating factor produced by monocytes, fibroblasts and endothelial cells. G-CSF is not species specific. G-CSF particularly increases the production of infection-fighting white blood cells, neutrophils by stimulating proliferation of specific bone marrow precursor cells and their differentiation into granulocytes. Neutrophils are a critical component of host defense mechanisms against bacterial and fungal infections. G-CSF is a potent stimulus for neutrophil proliferation and maturation in vivo. G-CSF also induces functional activation or “priming” of mature neutrophils in vitro.
Native human G-CSF is encoded by a gene on chromosome 17 that encodes two protein products due to differential splicing; isoform A of 177 amino acids and isoform B of 174 amino acids. Isoform A differs from isoform B in that it contains an additional three residues (Val-Ser-Gln) inserted after Leu35. The 174 amino-acid form is associated with greater biological activity and stability than the longer isoform, and is the basis for commercial pharmaceutical G-CSF products, including Neupogen. Recombinant E. coli-expressed forms of the 174 amino-acid isoform contains an additional N-terminal methionine residue not found in the native human protein. The naturally occurring G-CSF is also glycosylated at threonine residue 133, a modification which is absent in E. coli expression products.
G-CSF is produced by human endothelium, macrophages and a number of other immune cells. The natural human glycoprotein exists in two forms of a 174 and 180 amino acid-long protein. The more abundant and more active 174 amino acid form is used therapeutically. The human G-CSF gene has 4 introns, with two different polypeptides expressed from the same gene by differential splicing of mRNA.
G-CSF regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation, and selected end cell functional activation, including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, priming antibody dependent killing of foreign microorganisms, and the increased expression of some functions associated with cell surface antigens. G-CSF has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than those of neutrophil lineage. Thus, G-CSF is capable of inducing an increase in the absolute number of circulating neutrophils and enhancing neutrophil function.
Nomenclature: G-CSF, rDNA [BIO]; Neupogen [TR]; Filgrastim [USAN INN BAN]; Colony-stimulating factor (human clone 1034), N-L-methionyl- [CAS]; 121181-53-1 [CAS RN for filgrastim]; 143011-72-7 [CAS RN for human G-CSF]; r-metHuG-CSF [SY]; pluripoietin [SY]; NSC 614629 [SY NCI]; Granulocyte Colony Stimulating Factor [SY]; KRN-8601 [SY]; Gran [TR in Japan]; Granulokine [TR in Europe]; NDC 55513-546-10; NDC 55513-530-10;NDC 55513-924-10;NDC 55513-209-10 [NDC]
Companies.: Neupogen was developed and is manufactured (through the formulated bulk stage) by Amgen, Inc., CBER/FDA est. no. 1080, originally at its Thousand Oaks, CA, facility, later also at facilities in West Greenwich, Rhode Island, and/or Juncos, Puerto Rico. The product is (as reported upon approval) sterile-filtered, filled into containers, labeled and packaged by Parke-Davis Div., Warner-Lambert Co. (Rochester, MI), CBER/FDA lic. no. 0001. However, this may no longer be the case, since much of this facility was later sold to Parkedale Pharmaceuticals, a subsidiary of King Pharmaceuticals, Inc.; and its original owner, Warner-Lambert Co., has been acquired by Pfizer Inc. The product is now likely shipped to Amgen’s Puerto Rico facility for finishing and packaging.
In Sept. 2005, Amgen reported FDA approval of new facilities in Juncos, PR, for manufacture of Neupogen.
Neupogen is marketed in the U.S. and various other countries by Amgen. The product is available in most countries worldwide. Neupogen has not received centralized EU approval. It has been marketed (as Granulokine) in European Union countries, Switzerland and Norway by Hoffmann-La Roche Ltd. In May 2002, Amgen reacquired Roche’s marketing rights and assets in the European Union, Switzerland and Norway for $137.5 million. Roche continues as the licensee in certain countries in Eastern Europe, the Middle East, Africa, Asia, and Latin America. It is co-marketed by Dompe in Italy; and is marketed by Kirin in S. Korea. Kirin-Kunpeng Bio-Pharmaceuticals, a joint venture of Kirin (Japan) and Chinese companies, has marketing rights for China.
In Oct, 2013, Amgen reacquired all remaining Hoffman-La Roche marketing rights worldwide, effective January 1, 2014, for both Neupogen and Neulasta.
Neupogen and several other Amgen products were developed (R&D funded) through Kirin-Amgen, a joint venture company formed in 1984, 50% owned by Amgen and Kirin, with exclusive manufacturing, patent and marketing rights granted to Amgen in the U.S. (and other companies in certain other territories), Amgen (and other companies in other territories) paying Kirin-Amgen unspecified royalties on sales, and with Kirin-Amgen reimbursing Amgen for R&D expenses. However, most sources attribute Neupogen and other Kirin-Amgen products as originating from Amgen.
In June 1998, Royalty Pharma, AG acquired from a group of investors (presumably, Amgen Clinical Partners L.P., or other Amgen R&D-supporting limited partnership) for about $17 million an interest in royalty payments from Amgen’s sales of Neupogen (and Neulasta) originating from patents licensed from the Sloan-Kettering Memorial Cancer Institute. See the Tech. transfer section below. Over the next 8 years, Royalty Pharma receives 0.4% royalties on U.S. sales of Neupogen/Neulasta and a smaller rate on foreign sales. Royalty Pharma reported that it expects to receive about $3.4 million annually over the next 12 years. Amgen had sold certain rights to Neupogen royalties in 1987 through its Amgen Clinical Partners limited partnership program.
In 1998 and again in 2002, Drug Royalty Corp. Inc. (DRC; now DRI Capital) for a total of $27.2 million similarly acquired from an unspecified group of investors (presumably, Amgen Clinical Partners L.P., or other Amgen R&D-supporting limited partnership) an 8-year interest in royalty payments from Amgen’s sales of Neupogen (and Neulasta). DRC was acquired by Inwest Investments Ltd. in March 2002.
Manufacture: Filgrastim is prepared from recombinant N-methionyl G-CSF protein expressed by plasmid-transformed Escherichia coli (E. coli) bacteria containing the gene sequence for human G-CSF. Cultured cells are harvested and lysed. The extracted product is allowed to oxidize in its native state, and is purified by several chromatographic and filtration steps. It is then formulated in an acetate buffer with mannitol and polysorbate 80 (Tween 80). See the Tech. transfer section for further manufacturing-related information.
A generic method for commercial-scale manufacture of G-CSF by E. coli was reported in " Human granulocyte colony stimulating factor (hG-CSF): cloning, overexpression, purification and characterization ," Microbial Cell Factories, 7:13; April 4, 2008 (http://www.microbialcellfactories.com/content/7/1/13).
FDA class: Biologic PLA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19910220, first approval, PLA; orphan designation (granted 11/07/1990; expired 2/1998); Indication = febrile neutropenia associated with cancer chemotherapy, particularly in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy drugs associated with a significant incidence of severe neutropenia with fever
Date = 19940615; PLA supplement; orphan designation (granted 10/01/1990; expired 6/2001); Indication = treatment of neutropenia associated with bone marrow transplants
Date = 19941219; PLA supplement; Indication = treatment of patients with severe chronic neutropenia (absolute neutrophil count less than 500/mm3)
Date = 19951113; PLA supplement; Indication = transplantation, peripheral blood cells
Date = 19951228; PLA supplement; orphan designation (granted 7/17/1995; expired 12/2002); Indication = for use in the mobilization of peripheral blood progenitor cells for collection in patients who will receive myeloablative or myelosuppressive chemotherapy
Date = 19980402; BLA supplement; orphan designation (granted 11/07/1996; expires 4/2005); Indication = reduction in the duration of neutropenia, fever, antibiotic use, and hospitalization, following induction and consolidation treatment for acute myeloid leukemia
Date = 20000700; BLA supplement; Indication = new formulation/packaging (Neupogen SingleJect, a prefilled syringe containing a more concentrated formulation)
Date = 20050906; BLA supplement; Indication = approval of Amgen’s West Greenwich, Rhode Island, manufacturing facilities for the production of Neupogen
Indications: [full text of the "INDICATIONS AND USAGE” section from product insert/labeling, 6/2004]:
Cancer Patients Receiving Myelosuppressive Chemotherapy: NEUPOGEN is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever (see CLINICAL EXPERIENCE). A complete blood count (CBC) and platelet count should be obtained prior to chemotherapy, and twice per week (see LABORATORY MONITORING) during NEUPOGEN therapy to avoid leukocytosis and to monitor the neutrophil count. In phase 3 clinical studies, NEUPOGEN therapy was discontinued when the ANC was > 10,000/mm3 after the expected chemotherapy-induced nadir.
Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: NEUPOGEN is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with AML.
Cancer Patients Receiving Bone Marrow Transplant: NEUPOGEN is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, eg, febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation (see CLINICAL EXPERIENCE). It is recommended that CBCs and platelet counts be obtained at a minimum of 3 times per week (see LABORATORY MONITORING) following marrow infusion to monitor the recovery of marrow reconstitution.
Patients Undergoing Peripheral Blood Progenitor Cell Collection and Therapy: NEUPOGEN is indicated for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment compared with collection by leukapheresis without mobilization or bone marrow harvest. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care (see CLINICAL EXPERIENCE).
Patients With Severe Chronic Neutropenia: NEUPOGEN is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia (see CLINICAL EXPERIENCE). It is essential that serial CBCs with differential and platelet counts, and an evaluation of bone marrow morphology and karyotype be performed prior to initiation of NEUPOGEN therapy (see WARNINGS). The use of NEUPOGEN prior to confirmation of SCN may impair diagnostic efforts and may thus impair or delay evaluation and treatment of an underlying condition, other than SCN, causing the neutropenia.
Status: Originally approved through a PLA/ELA mechanism, Neupogen’s approval was converted to a Biologics License Application (BLA).
No centralized EU approval - country-by-country approvals in Europe.
Tech. transfer: Amgen claims patent protection for filgrastim (for Neupogen and Neulasta) until Dec. 2013, while the Generic Pharmaceutical Association has cited 2006). However, there is no question that European Union protection ended in 2006. Several manufacturers are expected to introduce generic (biogeneric; biocomparable, biosimilar, follow-on protein) versions in Europe and, eventually, the U.S.
Exemplary U.S. patents include U.S. 4,810,643 and 5,849,883 assigned to Amgen describing G-CSF gene sequences and recombinant methods and materials. U.S. patent 4,810,643 discloses human G-CSF like polypeptides, sequences encoding them and methods of their production.
Amgen has license from the Sloan-Kettering Memorial Cancer Institute for G-CSF patents including U.S. 5,532,341, “Human pluripotent hematopoietic colony stimulating factor,” claiming the isolated and purified native human protein. This is further discussed below.
U.S. patent 5,849,883, “Method for purifying granulocyte colony stimulating factor,” Dec. 15, 1998, assigned to Amgen, describes commercial-scale production, isolation and purification of G-CSF. The official abstract states: “Processes for isolating and purifying granulocyte colony stimulating factor (G-CSF) from a G-CSF producing microorganism are disclosed. The simplified processes include steps of lysing the microorganism and separating insoluble material containing G-CSF from soluble proteinaceous material; extracting the material with deoxycholate (optionally); solubilizing and oxidizing the G-CSF in the presence of a denaturant solubilizing agent and an oxidizing agent; removing the denaturant solubilizing agent from the G-CSF; subjecting the G-CSF to ion exchange chromatography; and recovering the purified G-CSF; yet excludes other cumbersome purification steps.”
In 1996, Genentech Inc. filed suit in U.S. District Court against Amgen alleging infringement of its patents U.S. 4,704,362; 5,221,619; and 4,342,832 (and another patent added in Dec. 1996) concerning bacterial vectors and methods for expressing cloned genes in relation to both Neupogen and Neulasta. The court dismissed one patent’s claims in May 1998, and ruled in Oct. 2000 that Amgen had not infringed the other three patents. In April 2002, on appeal by Genentech, the Court of Appeals for the Federal Circuit (CAFC) reinstated the infringement suit against Amgen. In Aug. 2003, Amgen and Genentech settled their G-CSF-related patent disputes, with both parties dismissing their lawsuits, and Amgen making an unspecified one-time payment to Genentech, but not taking any license to Genentech patents.
In June 1998, Royalty Pharma, AG acquired from a group of investors, Amgen Clinical Partners, for about $17 million an interest in royalty payments from Amgen’s sales of Neulasta and Neupogen arising from the limited partnership’s funding of development of G-CSF by Amgen. Over the next 8 years, Royalty Pharma receives 0.4% royalties on U.S. sales of Neupogen/Neulasta and a smaller rate on foreign sales; and expects to receive about $3.4 million annually over the next 12 years. Amgen had originally sold certain rights to Neupogen royalties in 1987 through its Amgen Clinical Partners limited partnership program.
In Jan. 2004, Royalty Pharma paid Sloan-Kettering Memorial Cancer Center $263 million to acquire a major portion of its rights to G-CSF (Neupogen and Neulasta)-related royalty income from Sloan-Kettering’s licensing of G-CSF patents to Amgen. Sloan-Kettering will also receive additional payments if sales exceed certain levels, and invested $7 million in Royalty Pharma. G-CSF U.S. patents assigned to Sloan-Kettering include U.S. 5,532,341, “Human pluripotent hematopoietic colony stimulating factor,” claiming the isolated and purified protein (the most important patent); 5,808,008, claiming methods for isolation/Manufacture of G-CSF from tumor cell culture; 5,670,146, claiming formulations; and 5,662,895, claiming methods of administration and use.
In 1998 and again in 2002, Drug Royalty Corp. Inc. (DRC; now DRI Capital) for a total of $27.2 million similarly acquired from an unspecified group of Amgen limited partnership investors an 8-year interest in royalty payments from Amgen’s sales of Neupogen and Neulasta. DRC was acquired by Inwest Investments Ltd. in March 2002.
Amgen was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Amgen and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
Orion Inc. reports having assisted Benzon Pharma A/S in licensing technology for Neupogen, with Amgen paying $25 million/year for 10 years. This likely involves patents assigned to Benzon concerning temperature-sensitive plasmids, e.g., U.S. 4,499,189, “Bacteria carrying plasmid having temperature dependent plasmid copy number;” 4,495,287, “Process for producing gene products of plasmid having temperature dependent plas-mid copy number;” and 4,487,835, “Plasmid having temperature dependent plasmid copy number.”
U.S. patent protection for Neupogen is projected by Decision Resources to expire in 2013, and in most European countries in 2016. However, with diverse entity/active agent, use, manufacturing process, formulation and other patents, this may well be an oversimplification of the patents that may be expected to be asserted against competitors.
In Dec. 2007, Sloan-Kettering Memorial Cancer Center filed suit against Amgen alleging the company has underpaid royalties on Neupogen and Neulasta by more than $72 million. In Dec. 2003, Sloan-Kettering sold a portion of its royalty stream for these products to Royalty Pharma, which then sold that portion to Royalty Pharma Finance Trust, according to the lawsuit. However, the complaint says Sloan- Kettering retains the right to sue for and collect any underpayments.
I In December 2009, Teva brought a declaratory judgment action in the U.S. District Court for the Eastern District of Pennsylvania, seeking to invalidate claims of U.S. Patent Nos. 5,580,755 and 5,582,823, which cover Neupogen. In July 2011, the U.S. District Court in Pennsylvania entered final judgment and a permanent injunction against Teva Pharmaceutical Industries Ltd. and Teva Pharmaceuticals USA prohibiting them from infringing Amgen's patents relating to human G-CSF and methods for its use. -- 5,580,755 and 5,582,823 (which expire in early December 2013). This was accompanied by Teva's admission that its Neutroval product infringes the two Amgen patents at issue in the litigation and that those patents are valid and enforceable. The Court's injunction extends until November 10, 2013, after which date Teva may sell Neutroval in the U.S. Regarding Neugranin, another Teva G-CSF product, Teva agrees not to sell Neugranin until Nov. 10, 2013 unless it first obtains a final court decision that Amgen's patents are not infringed by Neugranin. Pursuant to the parties' agreement, the launch date for either product could be sooner if certain unexpected events occur: a third party launches a similar G-CSF product and Amgen fails to sue that third party, or the patents are held invalid or unenforceable in a final court decision in an action brought by a third party. The settlement terms do not include any financial payments between the parties.
Trials: In March 2006, results from the randomized Phase III International Acute Myeloid Leukemia Study were published in Leukemia. Use of Neupogen to support intensive induction and consolidation chemotherapy was shown to not affect long-term survival of patients with acute myeloid leukemia (AML).
Clinical studies are increasingly showing that use of Neupogen or Neulasta during chemotherapy allows use of accelerated drug dosing regimens with significantly increased efficacy. For example, use of Neupogen in breast cancer chemotherapy recipients allows faster recovery of drug-destroyed white cells, allowing patients to receive chemotherapy every two instead of every three weeks, with this accelerated regimen showing improved efficacy. Adoption of accelerated chemotherapy schedules using Neupogen or Neulasta could significantly increase their use.
Medical: Neupogen is used to decrease the incidence of infection related to febrile neutropenia (loss of neutrophils), e.g., in patients receiving myelosuppressive cancer chemotherapy drugs associated with a significant incidence of severe neutropenia with fever. The use of a G-CSF product and associated increase in the level of neutrophils helps physicians deliver planned cancer chemotherapy doses on time and can help improve chemotherapy outcomes. The only consistently observed adverse clinical reaction attributed to Neupogen in this setting is mild-to-moderate medullary bone pain.
For treatment of neutropenia due to cancer chemotherapy, Neupogen is injected daily. Until approval of Neulasta, Neupogen was the only neutrophil stimulating therapeutic available for chemotherapy patients. The recommended starting dose is 5 µg/kg/day, administered as a single daily injection by subcutaneous (SC) bolus injection, by short intravenous (IV) infusion (15 to 30 minutes), or by continuous SC or continuous IV infusion. Doses may be increased in increments of 5 µg/kg for each chemotherapy cycle.
G-CSF-stimulated peripheral blood cells obtained from G-CSF-treated donors have become an alternative treatment to bone-marrow transplantation (BMT) for patients with some hematologic cancers. These cells are easier to obtain than bone marrow, and can result in faster recovery from chemotherapy and a better survival rate. Animal studies suggest that G-CSF-stimulated peripheral blood cells, whether autologous or from a donor, may be useful for treatment of stroke.
In June 2004, Amgen reported results from a Phase III trial showing that Neulasta in the first and subsequent cycles of chemotherapy in breast cancer patients receiving moderately myelosuppressive chemotherapy significantly lowered rates of infection, as manifested by febrile neutropenia, hospitalization, and the use of intravenous anti-infectives. Such results may further expand Neulasta’s prophylactic use (before, rather than after, development of neutropenia).
The National Comprehensive Cancer Network (NCCN) guidelines recommending recommend Neupogen or Neupogen use, if there is a ≥20% probability of febrile neutropenia, i.e., with moderate-risk chemotherapy regimens, while the American Society for Clinical Oncology (ASCO) recommends use if there is ≥40% probability.
Disease: Febrile neutropenia is a serious and common complication of many cancer chemotherapies. Approximately 1.4 million U.S. patients received chemotherapy in 2001. About 1.27 million new cancer cases were expected in 2001. A large proportion of cancer patients receive chemotherapy drug treatment, and up to half of these patients develop severe neutropenia, placing them at risk for life-threatening infections. Studies have shown that 30%-40% of patients receiving certain types of chemotherapy who do not get a white blood cell booster will experience neutropenia with fever. Thousands of patients are hospitalized for neutropenia and its complications each year in the U.S.
G-CSF products have been underutilized. On average, prior to approval of Neulasta (see the entry below), less than 10% of eligible cancer patients received prophylactic treatment with Neupogen to prevent neutropenia.
Market: A number of biosimilar/biogeneric versions of Neupogen are already in world commerce. See the entries for current and upcoming European (and U.S.) biosimilars.
In Jan. 2013, Amgen reported its Neupogen 2012 sales at $312 million, including $251 million in the U.S., with tis total Neulasta/Neupogen sales at $1,306 million, including $1,026 in the U.S.
For the 12 months that ended June 30, 2008, Neupogen had worldwide sales of ~$1.3 billion and approximately $300 million in the EU, based on IMS sales data.
Total worldwide 2009 sales of Neupogen/Gran were $1.341 billion; $1.512 billion in 2008; $1.446 in 2007; and ~$1.344 billion in 2006. Neupogen had $300 million in sales in the EU for the twelve months that ended June 30, 2008, based on IMS data.
Total sales of Neupogen by Amgen were roughly $1.213 billion in 2006, $1.25 billion in 2005 (see above paragraph); $1.18 billion in 2004; ~$1.3 billion in 2003; $1.4 billion in 2002; $1.3 billion in 2001; $1.2 billion in 2000; $1.26 billion in 1999; $1.12 billion in 1998; and $1.06 billion in 1997 (achieving blockbuster status).
Total 2006 sales of GRAN in Japan were ~$130 million.
In May 2005, a Research & Markets study reported, “By the end the end of 2004 the world market for Colony Stimulating Factors [Neupogen and Neulasta, plus biogenerics in other countries, a minor factor] was valued at $3.6 billion, a growth of 11% over 2003. The market has been growing at an average annual growth rate of 16% over the previous 5 years.”
Total worldwide sales of Neulasta and Neupogen were $3.5 billion in 2005 and $3.2 billion in 2004. From examination of a chart in Amgen’s 2005 annual report, roughly 33-40% of sales are attributed to Neupogen (~$1.25 billion). Combined sales were $2.9 billion in 2004, $2.5 billion in 2003, and $1.8 billion in 2002, a 37% increase from 2001.
In March 2007, Friedman, Billings, Ramsey & Co. (FBR) estimated worldwide Neupogen sales to be $1.248 billion in 2007, $1.205 billion in 2008, $1.209 billion in 2009, $1.196 billion in 2010, $1,175 billion in 2011, and $1.129 billion in 2012.
There will be continued conversion of patients from Neupogen to Neulasta, and biosimilar versions approved in the European Union will further lower Neupogen sales.. Eventually, pegfilgrastim (Neulasta), also from Amgen, will largely replace Neupogen, probably before biogeneric versions enter major markets. With most patients transitioned to using Neulasta, biogenerics will have a hard time gaining market share in Europe and other major markets where/when they become available.
Amgen reported in early 2002 that 90% of Neupogen sales were for chemotherapy-induced neutropenia, but with only about 10% receiving Neupogen for infection prophylaxis during their first round of chemotherapy. This is slowly changing.
The 2007 Average Wholesale Price (AWP) is $237.72/1 mL, 300 µg/mL vial, $2,377.20 for 10; $378.72/1.6 mL, 480 µg/1.6 mL vial ($330.60 in 2005), $3,787.20 for 10; $260.88/0.5 mL, 300 µg/0.5 mL syringe, $2,608.80 for 10; and $415.50/0.8 mL, 480 mµg/mL vial ($362.60 in 2004), $4,155.50 for 10 (Red Book, 2007). For comparison, the 2005 AWPs were $215.00/1 mL, 300 µg/mL vial ($207.50 in 2004), $2,154 for 10; $343.00/1.6 mL, 480 µg/1.6 mL vial ($330.60 in 2005), $3,432.00 for 10; $236.28/0.5 mL, 300 µg/0.5 mL syringe ($227.50 in 2004), $2,2362.80 for 10; and $376.44/0.8 mL, 480 mµg/mL vial ($362.60 in 2004), $3,626.00 for 10 (Red Book, 2005).
In July 2004, Centers for Medicare & Medicaid Services (CMS) announced it would reduce the Medicare in-hospital reimbursement rate for Neupogen by 10%.
Ongoing: Viacell, inc. has nonexclusively licensed filgrastim from Amgen for ex vivo therapeutic uses, and is developing cellular therapies for hematological malignancies and genetic diseases.
Competition:
Grafeel from Dr Reddy's Labs. (India), when it was launched locally in 2007, was priced at Rs 2,500 for a 300 micro-gram vial, almost half the price of the innovator product marketed in India by Roche. Roche matched the price of biosimialar competitors. With the cost of G-CSF treatment significantly reduced, its use reportedly increased 10-fold. The company expects to launch the product in Europe in 2010. Note, although approved in India as being identical to Nuepogen, Dr. Reddy's Labs. notes, "The Indian market is a branded generics market and substitutability in the U.S. sense is not relevant." Grafeel is also marketed in Brazil, Ukraine, Sri Lanka and Vietnam.
Companies involvement:
Full monograph
158 G-CSF, rDNA/Amgen
Nomenclature:
G-CSF, rDNA/Amgen [BIO]
Neupogen [TR]
Filgrastim [USAN INN BAN MESH]
143011-72-7 [CAS RN for human C-CSF]
colony-stimulating factor (human clone 1034) , N-L-methionyl- [CAS]
121181-53-1 [CAS RN]
none [CAS according to Amgen MSDS]
granulocyte colony stimulating factor, recombinant [SY]
KRN-8601 [SY]
N-metG-CSF [SY]
NSC 614629 [SY NCI]
pluripoietin [SY]
r-metHuG-CSF [SY]
Gran [TR in Japan]
Granulokine [TR in Europe]
NDC 55513-546-10; NDC 55513-530-10;NDC 55513-924-10;NDC 55513-209-10 [NDC]
molecular weight (kDa) = 19
FDA Class: Biologic PLA BLA
Year of approval (FDA) = 1991
Date of 1st FDA approval = 19910220
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2013, based on 5,582,823 and 5,580,755 |
U.S. Patent Expiration Year: | 2013 |
U.S. Biosimilars Data Exclusivity Expiration: | 2003 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1998 |
U.S. Biosimilars Launchability Year: | 2013 |
U.S. Biobetters Launchability Year: | 2013 |
Biosimilars/biobetters-related EU Patents: | Expired - Biosimilars versions already marketed in EU; 2008, date for first EU biosimilar approval arbitrarily adopted as expiration date
Decision Resources has reported expiration in most European countries in 2016. |
EU Patent Expiration Year: | 2008 |
EU Biosimilars Data Exclusivity Expiration: | has not received EU approval; country-by-country approvals in Europe |
EU Biosimilars Orphan Exclusivity Expiration: | has not received EU approval; country-by-country approvals in Europe |
EU Biosimilars Launchability Year: | 2008 |
EU Biobetters Launchability Year: | 2008 |
Index Terms:
biopharmaceutical products
blepharospasm
exempt from CBER lot release requirements
growth factors, hematopoietic
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
mannitol
polysorbate 80 (Tween 80)
sodium acetate
Sterile Water for Injection
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
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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