Pegfilgrastim - Neulasta; filgrastim, pegylated; PEG-N-L-methionyl-colony stimulating factor; Neupopeg
Status: marketed in the U.S.; withdrawn from the EU market in Dec. 2008
Organizations involved:
Amgen Inc. — Manuf.; R&D; Tech.; World mark.
Hoffmann-La Roche Ltd. – Intl. mark.; Former
Shearwater Corp. – Tech.; Former
Nektar Therapeutics, Inc. – Tech.; Manuf. other; Parent
Royalty Pharma, AG – Tech.
DRI Capital – Tech.
Sloan-Kettering Mem. Cancer Inst. – R&D; Tech.
Inwest Investments Ltd. – Parent
Kirin Pharmaceuticals Ltd.. –R&D; Tech.
University of Alabama – Tech.; Patent dispute
Genentech Inc. – Patent dispute
Columbia University – Tech.; Patent dispute
University of Alabama – Tech.
Cross ref.: See the entry above for G-CSF, rDNA (filgrastim; Neupogen), of which the active agent is this product is a pegylated form for sustained release. Many aspects of G-CSF, e.g., biological activity, are discussed in the Neupogen entry.
Description: Neulasta is an aqueous formulation of pegfilgrastim, a pegylated form of filgrastim (N-L-methionyl-granulocyte colony-stimulating factor; met-G-CSF), the active component in Neupogen also from Amgen. Pegylation involves attachment of a large inert polyethylene glycol (PEG) polymer strand to N-met-G-CSF (filgrastim, the active agent in Neupogen).
Pegfilgrastim is a covalent conjugate of recombinant human N-methionyl G-CSF (filgrastim), a non-glycosylated protein expressed by Escherichia coli (E. coli) bacteria, and synthetic methoxy-polyethylene glycol-priopionaldehyde (PEG-aldehyde; m.w. = 20 kDa ). The G-CSF portion has two intrachain disulfide bonds. PEG-aldehyde is reacted with the N-terminal amino acid of filgrastim, forming pegfilgrastim, with a molecular formula of C849H1346N223O244S9,(C2H4O)n. Attachment of the large inert linear PEG polymer to filgrastim protects the molecule from rapid metabolism, and significantly sustains its duration of activity due to decreased renal clearance.
Neulasta is supplied in 0.6 mL prefilled UltraSafe Needle Guard syringes for subcutaneous (SC) injection. Each syringe contains 6 mg pegfilgrastim (based on protein weight) in 0.6 mL preservative-free solution (pH 4.0) containing acetate (0.35 mg), sorbitol (30.0 mg), polysorbate 20 (Tween 20; 0.02 mg), and sodium (0.02 mg) in Water for Injection, USP. Neulasta contains pegfilgrastim with a concentration of 10 mg/mL based only on the protein portion of the molecule (20 mg/mL including the PEG moiety). The dating period for Neulasta is 12 months from the date of manufacture when stored at 2-8° C (refrigerated). The date of manufacture is the date of final sterile filtration of the formulated product.
Nomenclature: G-CSF, rDNA, PEG-/Amgen [BIO]; Neulasta [TR]; Neupopeg [TR Europe]; Neulastim [TR India]; pegfilgrastim [FDA INN]; N-(3-hydroxypropyl)methionylcolony-stimulating factor (human), 1-ether with alpha-methyl-v-hydroxypoly(oxyethylene) [CAS]; 208265-92-3 [CAS RN]; PEG–r-metHuG-CSF [SY]; granulocyte colony-stimulating factor, N-L-methionyl- , PEG- [SY]; filgrastim, peg- [SY]; NDC 55513-190-01 [NDC]
Biological.: Both filgrastim and pegfilgrastim involve the same functional component, filgrastim, a recombinant form of human granulocyte colony stimulating factor (G-CSF). This cytokine acts on hematopoietic cells and stimulates neutrophil proliferation, differentiation, commitment, and end cell functional activation. See the filgrastim (Neupogen) entry above for further biological activity information. Studies on cellular proliferation, receptor binding, and neutrophil function demonstrate that filgrastim and pegfilgrastim have the same mechanism of action. By virtue of attachment of an inert PEG polymer chain to filgrastim, pegfilgrastim has reduced renal clearance and prolonged persistence in vivo. The half-life of pegfilgrastim ranges from 15 to 80 hours after SC injection.
Neulasta pharmacokinetics (neutrophil-mediated clearance) are essentially self-regulating. Pegfilgrastim remains in the blood throughout the time during which a patient is neutropenic (when it is needed), and its is cleared rapidly by neutrophils when it is no longer needed (as neutrophil levels recover toward normal).
Companies.: Neulasta was developed and is manufactured and marketed in the U.S. and internationally by Amgen Inc., CBER/FDA est. no. 1080. Pegylation reagent is obtained from Nektar Therapeutics, Inc. (formerly Shearwater Polymers, subsidiary of Inhale Therapeutics). [Note, Neulasta and several other Amgen products were actually 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 treat Neulasta and other Kirin-Amgen products as though they originate from Amgen].
In May 2002, Amgen (re)acquired Hoffmann-La Roche’s Neulasta rights (and Neupogen) and assets in the European Union, Switzerland and Norway for $137.5 million. Roche continued as the licensee in certain countries in Eastern Europe, the Middle East, Africa, Asia, and Latin America.
In Oct, 2013, Amgen reacquired all remaining Hoffman-La Roche marketing rights worldwide, effective January 1, 2014, for both Neupogen and Neulasta.
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 Partners’ funding of early development of G-CSF by Amgen. Over the next 8 years, Royalty Pharma receives 0.4% royalties on U.S. sales of Neulasta (and Neupogen) and a smaller rate on foreign sales. Royalty Pharma has reported that it expected 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 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 (Amgen Clinical Partners or a related investors 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.
In Sept. 2005, Amgen reported FDA approval of new facilities in Juncos, PR, for manufacture of Neulasta.
In Nov. 2010, Nektar Therapeutics entered into a non-exclusive agreement with Amgen to manufacture and supply proprietary PEGylation reagents. Nektar will receive $50 million from Amgen for the supply of certain quantities of polymer material. Nektar said in case it fails to supply the required materials, Amgen will have the right to access the facility for the purpose of manufacturing the polymer material solely. Amgen has no minimum purchase commitments and Nektar is entitled to receive additional payments if Amgen orders more than specified quantities.
Manufacture: Bulk filgrastim (source material) and pegfilgrastim are manufactured in Amgen’s Thousand Oaks, CA, facility. Methoxy-polyethylene glycol-priopionaldehyde (PEG-aldehyde; m.w. = 20 kDa ) from Shearwater Corp., now Nektar Therapeutics, Inc., is reacted with the N-terminal amino acid (methionine) of filgrastim (175 amino acids; m.w. = ~19 kDa), forming pegfilgrastim (m.w. = ~39 kDa). Purification involves cation exchange chromatography. Bulk pegfilgrastim is stored in polypropylene containers at 2-8˚C (refrigerated), and shipped to Amgen’s Puerto Rico facility for finishing and packaging.
On Dec. 4, 2008, the European Union withdrew marketing approval for Neupopeg, after Dompe Biotec had notified EMEA of its "decision to voluntarily withdraw the marketing authorisation for Neupopeg for commercial reasons."
FDA class: Biologic; BLA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 20020131; BLA, first approval
Date = 20050915; BLA supplement; Indication = include in insert/labeling data from a Phase III study showing efficacy in patients with most types of cancer undergoing moderately myelosuppressive chemotherapy from infection, as manifested by febrile neutropenia
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 3/20/2006]:
Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non myeloid malignancies receiving myelosuppressive anti cancer drugs associated with a clinically significant incidence of febrile neutropenia (See CLINICAL STUDIES).
Status: Neulasta is exempt from CBER/FDA lot release requirements.
European Union (EU) approval was granted on Aug. 28, 2002 “for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).”
Prior to the Sept. 2005 supplemental approval, first and subsequent cycle administration of Neulasta to stimulate production of infection-fighting white blood cells was indicated for patients receiving myelosuppressive chemotherapy associated with a more than 30-40% risk of febrile neutropenia. Administration of Neulasta beginning in the first cycle of chemotherapy is now approved for patients receiving myelosuppressive chemotherapy associated with at least a 17% risk of febrile neutropenia.
Tech. transfer: Amgen claims U.S. patent protection for Neulasta until 2015. See the Neupogen (filgrastim) entry above for further information about filgrastim-related patents and licensing. Pegylation technology was acquired from Shearwater Corp., now Nektar Therapeutics, Inc. See the peginterferon alfa-2a (Pegasys) entry for further information about pegylation technology.
In 1996, Genentech Inc. filed a 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 added another patent in Dec. 1996) concerning bacterial vectors and methods for expressing cloned genes in relation to both Neupogen and Neulasta. The court dismissed the claims of one of the patents 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 reinstated the infringement suit against Amgen. In Aug. 2003, Amgen and Genentech settled their G-CSF (Neupogen and Neulasta)-related patent disputes, with both dismissing their lawsuits, and Amgen making an unspecified one-time payment to Genentech, but not taking any license to Genentech patents.
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, related to 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 patents assigned to Sloan-Kettering include U.S. 5,532,341, “Human pluripotent hematopoietic colony stimulating factor,” claiming isolated and purified G-CSF; 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 now DRI Capital, for a total of $27.2 million acquired from a 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.
In July 2006, the University of Alabama (Huntsville, AL; UAH) settled a patent dispute brought against Nektar and its original founder, Dr. Milton Harris, formerly with the university through a cash payment of $25 million. Nektar and Dr. Harris jointly made an upfront payment totaling $15 million to UAH; and Nektar will pay UAH $1 million/year for ten years. UAH dismissed all claims related to the Nektar’s PEGylation patent portfolio and Nektar dismissed all counterclaims. UAH had sued Nektar in U.S. District Court for patent infringement, breach of contract license, violation of the Alabama Trade Secrets Act and unjust enrichment. Dr. Harris and another researcher developed a PEGylation technology, which was patented by UAH (U.S. 5,252,714, “Preparation and use of polyethylene glycol propionaldehyde “). The university had entered into a royalty agreement with Dr, Harris for products developed from this discovery, and Harris created Shearwater Polymers, now Nektar. UAH claimed that Harris, without UAH’s knowledge, made a number of other discoveries related to the PEG technology in the following years, patented 28 of them, that Harris was required to notify UAH of any discovery related to the original PEG patent, and that the patents were “obvious derivatives” of and “equivalent” to the original UAH PEG patent. The lawsuit began after Nektar informed the university in spring 2005 that it would no longer pay royalties from sales of Neulasta, and Nektar informed the university that the PEG reagent used for Neulasta does not involve any patents assigned to the university.
U.S. patent protection for Neulasta is projected by Decision Resources to expire in 2015, and in most European countries in 2017. 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.
In Oct. 2010, Maxygen, Inc. announced that the U.S. Patent and Trademark Office (PTO) has issued a Right of Appeal Notice in an inter partes reexamination proceeding for Amgen;s U.S. Pat. No. 7,381,804 that includes a final rejection of all claims in the 804 patent . Amgen's 804 patent includes certain claims to mutated granulocyte colony stimulating factor (G-CSF) molecules that potentially cover Maxyge's MAXY-G34 product candidate, a next-generation, pegylated G-CSF. Maxygen submitted the request to the PTO for an inter partes reexamination of the Amgen patent in 2009. Amgen had the right to appeal the decision to the PTO's Board of Patent Appeals and Interferences.
Trials: In Dec. 2004, Amgen reported that new data from Neulasta’s pivotal Phase III study in 928 breast cancer patients showed that the majority of neutropenic complications occur in the first cycle of chemotherapy treatment for breast cancer patients who are not administered Neulasta.. This was thee largest randomized placebo-controlled study to date for Neulasta. First and subsequent-cycle administration of Neulasta resulted in a 94% reduction in the incidence of febrile neutropenia, a 93% reduction in the incidence of hospitalization and an 80% reduction in the incidence of intravenous anti-infective use in patients receiving myelosuppressive chemotherapy previously considered at moderate risk for neutropenic complications. Starting Neulasta beginning in the first and subsequent cycles of chemotherapy reduced the rate of infection, as manifested by febrile neutropenia (low white blood cell count with fever), by more than 90%. Neulasta administered 24 hours after chemotherapy profoundly reduced the rate of febrile neutropenia from 17% to 1%. During the first cycle of chemotherapy, 1% of the patients (2/463) in the Neulasta arm developed febrile neutropenia, as compared to 11% of the patients (52/465) in the placebo arm. Hospitalization and the use of intravenous anti-infectives in breast cancer patients were also significantly lower in the group receiving Neulasta in the first and subsequent cycles of chemotherapy. This may support earlier and increased use of Neulasta. Results from this study were published in the Feb. 20, 2005, issue of The Journal of Clinical Oncology.
The Sept. 2005 expansion of indications: for Neulasta was based on a randomized, placebo-controlled study of 928 metastatic or non-metastatic breast cancer patients. First and subsequent-cycle administration of Neulasta resulted in a 94% reduction in the incidence of febrile neutropenia (1% versus 17% with placebo), a 93% reduction in the incidence of hospitalization (1% versus 14 % with placebo) and an 80% reduction in the incidence of intravenous anti-infective use (2% versus 10% with placebo), compared to placebo, in patients receiving moderately myelosuppressive chemotherapy.
Medical: The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. Neulasta should not be administered in the period between 14 days before and 24 hours after administration of chemotherapy. Until approval of Neulasta, Neupogen was the only neutrophil stimulating therapeutic available for chemotherapy patients.
Neupogen also from Amgen, containing non-pegylated filgrastim, like Neulasta, is effective for decreasing the risk of infection and hospitalization as a result of chemotherapy induced neutropenia. However, Neupogen requires daily injection (for up to 14 days) following each cycle of chemotherapy. Almost half of chemotherapy patients who receive Neupogen require 10 or more daily injections. Because of this inconvenience, costs, etc., many healthcare professionals wait until a neutropenic infection is diagnosed before administering Neupogen. Neulasta requires only a single weekly injection, significantly reducing the injection burden, inconvenience, costs, and increasing compliance. Neulasta allows treatment of neutropenia with in a single dose per chemotherapy cycle. With the availability of Neulasta, more patients are starting to receive prophylaxis to prevent initial onset of neutropenia. Hundreds of 1,000s of chemotherapy patients in the U.S. at risk for infection may now receive Neulasta prophylactically at the onset of each treatment cycle before complications arise.
The National Comprehensive Cancer Network (NCCN) guidelines 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.
Market:
Total Neulasta sales were $3.95 billion in 2011; $3.59 billion in 2010; $3.355 billion in 2009; $3.318 billin in 2009; $2.710 billion in 2006; $2.1-$2.2 billion in 2005 (from examination of a chart in Amgen’s annual report); $1.7 billion in 2004; and $1.3 billion in 2003 (first full year on the market; essentially matching sales of Neupogen). Sales were $416 million in 2002 (launched in the 2nd quarter; reported by another source as $464 million).
In Jan. 2013, Amgen reported its Neulasta 2012 sales at $4,092 million, including $3,207 million in the U.S., with tis total Neulasta/Neupogen sales at $5,352 million, including $4,214 million in the U.S. In Jan. 2012, Amgen reported its Neulasta 2011 sales at $5,212 million.
In July 2010, Amgen reported the for the full year 2009, worldwide combined sales of Neulasta and Neupogen were relatively unchanged at $4,643 million in 2009 versus $4,659 million in 2008.
In March 2007, Friedman, Billings, Ramsey & Co. (FBR) estimated worldwide Neulasta sales to be $2.710 billion in 2006, $2.990 billion in 2007, $3.215 billion in 2008, $3.406 billion in 2009, $3.682 billion in 2010, $3.824 billion in 2011, and $3.824 billion in 2012.
Sales of Neulasta have now surpassed those of Neupogen. As an improved, 2nd-generation product, Neulasta will continue to capture market share from Neupogen. In early 2007, Neulasta was being used in slightly less than 50% of ~600,000 first-cycle chemotherapy patients.
The 2007 Average Wholesale Price (AWP) is $3,348.00/6 mg vial ($2,950.00 in 2004) (Red Book, 2007), up from $3062.40 in 2005 and $2,950.00 in 2004.
In May 2010, Roche launched Neulastim (pegfilgrastim) in India.
Competition: As discussed in the Neupogen entry above, many companies are developing biogeneric versions of G-CSF and also pegylated G-CSF. The most serious competitor to Neulasta appears to be a pegylated G-CSF from Berlex/Bayer Schering Pharma currently in development for treatment of Crohn’s disease (a new market for G-CSFs).
Companies involvement:
Full monograph
159 G-CSF, rDNA, PEG-/Amgen
Nomenclature:
G-CSF, rDNA, PEG-/Amgen [BIO]
Neulasta [TR]
Neulastim [TR India]
Neupopeg [TR Europe]
pegfilgrastim [FDA INN]
N-(3-hydroxypropyl)methionylcolony-stimulating factor (human), 1-ether with alpha-methyl-v-hydroxypoly(oxyethylene) [CAS]
208265-92-3 [CAS RN]
filgrastim, peg- [SY]
filgrastim, recombinant pegylated [SY]
granulocyte colony-stimulating factor, N-L-methionyl- , PEG- [SY]
PEG–r-metHuG-CSF [SY]
NDC 55513-190-01 [NDC]
C849H1348N223O244S9,(C2H4O)n [MF]
molecular weight (kDa) = 39
FDA Class: Biologic BLA
Year of approval (FDA) = 2002
Date of 1st FDA approval = 20020131
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2014 (based on 5,662,895; 5,662,895; and 5,670,146)
2015 according to Amgen. 2015 also reported by IMS.
|
U.S. Patent Expiration Year: | 2014 |
U.S. Biosimilars Data Exclusivity Expiration: | 2014 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2009 |
U.S. Biosimilars Launchability Year: | 2015 |
U.S. Biobetters Launchability Year: | 2015 |
Biosimilars/biobetters-related EU Patents: | 2015 (based on EP 0733067) |
EU Patent Expiration Year: | 2015 |
EU Biosimilars Data Exclusivity Expiration: | 2012 |
EU Biosimilars Orphan Exclusivity Expiration: | 2012 |
EU Biosimilars Launchability Year: | 2015 |
EU Biobetters Launchability Year: | 2015 |
Index Terms:
biopharmaceutical products
blepharospasm
exempt from CBER lot release requirements
growth factors, hematopoietic
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
filamentous hemagglutinin (FHA), Bordetella pertussis
methotrexate
PEG-Intron Diluent
polyethylene glycol (PEG)
polyethylene glycol (PEG)
polysorbate 20 (Tween 20)
sodium acetate
somatropin, recombinant
Sterile Water for Injection
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
exempt from CBER lot release requirements
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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