Oprelvekin - Neumega; des-Pro Interleukin-11, recombinant; des-Pro IL-11
Status - approved; marketed
Organizations involved:
Wyeth – Manuf.; R&D; Tech.; World mark.
Pfizer – Parent
Genetics Institute, Inc. – R&D; Tech.; Former
Astellas Pharma Inc. – Japan. mark.
Yamanouchi Pharmaceutical Co., Ltd. – Former
Schering-Plough Corp. – Former
Columbia University – Tech.; Patent dispute
Description: Neumega is an aqueous formulation of oprelvekin (des-Pro IL-11), a recombinant protein expressed by Escherichia coli (E. coli) analogous to amino acids 22-199 of the full-length, 199-amino acid, human IL-11 precursor molecule; and to amino acids 2-178 of active human IL-11. The oprelvekin (des-Pro IL-11) protein is 177 amino acids in length and differs from mature active human 178-amino acid IL-11 only in lacking its amino-terminal (N-terminal) proline residue. The removal of the proline residue from human IL-11 does not result in measurable differences in bioactivity either in vitro or in vivo. Oprelvekin is expressed by recombinant E. coli as a thioredoxin/des-Pro IL-11 fusion protein, which is cleaved and further purified. Oprelvekin is a monomeric (single-chain)protein with a molecular weight of ~19,000 Daltons (19 kDa), and does not contain any cysteine residues or cysteine (disulfide) bridges.
Neumega is packaged in single-use vials for subcutaneous administration after reconstitution with 1 mL of Sterile Water for Injection, USP. Each vial contains 5 mg of oprelvekin (specific activity approximately 8 x 106 or 8 million Units/mg) as sterile lyophilized powder with 23 mg glycine, USP; 1.6 mg dibasic sodium phosphate heptahydrate, USP; and 0.55 mg monobasic sodium phosphate monohydrate, USP. When reconstituted with 1 mL of Sterile Water for Injection, USP, the solution has a pH of 7.0 and a concentration of 5 mg/mL.
Nomenclature: Interleukin-11, rDNA [BIO]; Neumega [TR]; oprelvekin [USAN FDA]; 2-178 interleukin-11 (human clone pXM/IL-11) [CAS]; 145941-26-0 [CAS RN]; adipogenesis inhibitory factor [SY]; AGIF [SY]; IL-11 [SY]; IL-11, des-Pro [SY]; rHuIL-11 [SY]; rhIL-11 [SY]; interleukin-11 [SY]; interleukin-11, des-Pro- [SY]; des-Pro-interleukin-11 [SY]; des-Pro IL-11 [SY]
Note, IL-11 was originally identified as interleukin-10 (in U.S. patent application no. 441,100 by the Genetics Institute), but was (re)named IL-11 to avoid confusion with another cytokine also reported as IL-10.
Note, terms such as interleukin-11 and IL-11 are often ambiguously or erroneously used to refer to oprelvekin (des-Pro-interleukin-11).
Biological.: des-Pro Interleukin-11 (oprelvekin) is a 178-amino acid polypeptide comparable to mature 179-amino acid human IL-11 without its N-terminal proline amino acid. Human IL-11 protein is apparently first expressed in vivo as a precursor of 199 amino acids which is further proteolytically cleaved after the end of the signal peptide at residue 20 to yield active mature 179 amino acid IL-11 polypeptide beginning with the sequence Ala-Pro at amino acid positions 21-22 and terminating after amino acid position 199 at the TGA termination triplet. The first 20 amino acids of mature precursor human IL-11 is a sequence of hydrophobic amino acids that resembles a mammalian secretory leader sequence, and is not required for cytokine activity.
Human interleukin-11 (various active forms) is a pleiotropic cytokine that stimulates primitive lymphohematopoietic progenitor cells and synergizes with other hematopoietic growth factors to stimulate the proliferation and maturation of megakaryocytes. IL-11 acts as a thrombopoietic cytokine or growth factor, directly stimulating the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells, and inducing megakaryocyte maturation, resulting in increased platelet production (the primary medical use for oprelvekin in patients receiving cancer chemotherapy). The human cellular IL-11 receptor alpha chain utilizes gp130 as its signal transducer (also a component of other cytokine receptors). IL-11 is a member of a family of human growth factors including human growth hormone (somatropin; hGH), granulocyte colony-stimulating factor (G-CSF), and other growth factors.
IL-11 is secreted by bone marrow stromal cells (fibroblasts), and also by a number of mesenchymal cells. Iin vivo production of IL-11 is induced by IL-1 and phorbol esters. IL-11 promotes primary and secondary immune responses in vitro and in vivo, modulates antigen-specific antibody reactions, and promotes the proliferation of IL-6 dependent plasmacytoma cell lines in the presence of neutralizing IL-6 antibodies. IL-11 also stimulates the T-cell-dependent development of IgG-secreting B-cells in spleen cell cultures. Blast cells cultured in a medium containing IL-11 and erythropoietin (EPO; see related entries) differentiate specifically into macrophages. IL-11 may regulate malignant cells of the megakaryocytic lineage in part by an autocrine growth control mechanism. In the presence of IL-3 or stem cell factor (SCF), IL-11 has potent in vitro stimulatory effects on primitive multilineage hematopoietic progenitors and on precursors representing various stages of erythroid differentiation. The combination of SCF with IL-11 also stimulates highly proliferative erythroid progenitors. IL-11 has been shown to prevent cell death by apoptosis and to accelerate recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation.
Companies.: Neumega was developed and manufactured by Genetics Institute, Inc., CBER/FDA lic. no. 1163, merged into Wyeth, CBER/FDA est. no. 0003, in 1997, now part of Pfizer. The product is marketed in the U.S. by Pfizer and internationally by Pfizer affiliates.
Neumega is jointly marketed by Wyeth and Yamanouchi Pharmaceuticals in Japan. In spring 2005, Fujisawa completed its merger with Yamanouchi Pharmaceutical Co. Ltd.. forming Astellas Pharma Inc. Yamanouchi is also pursuing approval of the product for treatment of aplastic anemia and osteomyelodysplasia-induced thrombocytopenia indications:. Schering-Plough Corp. previously held marketing rights in Europe, Latin America and Africa, but these were returned to Genetics Inst./Wyeth.
FDA class: Biologic BLA
CBER class: Biological Response Modifiers
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19971125; BLA no. 96-l 433; first approval; orphan designation, (expires 11/25/2004)
Date = 20020918; BLA supplement; Indication = updated the Warnings and Precautions sections and added important safety information to the product insert
Indications: [full text from "Indications & Usage” section of product insert/labeling]:
Neumega is indicated for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusions following myelosuppressive chemotherapy in patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia. Efficacy was demonstrated in patients who had experienced severe thrombocytopenia following the previous chemotherapy cycle. Neumega is not indicated following myeloablative chemotherapy.
Status: The BLA was submitted to FDA on Dec. 20, 1996 and approved on Nov. 25, 1997; review time = ~11.1 months or ~.925 years. Prior to approval, the Biologic Response Modifiers Advisory Committee, FDA, unanimously voted for approval (for its approved indication); voted 14-3 with one abstention not to recommend (available data did not support) approval for primary prophylaxis starting with the initial chemotherapy cycle; and voted 18-0 that Neumega’s toxicity did not outweigh its benefits.
Nuemega has not received centralized EU approval. European approvals are country-by-country.
Tech. transfer: A cDNA encoding human IL-11 and the deduced amino acid sequence (amino acids 1-199) of the full-length IL-11 (precursor) are described by researchers from Genetics Institute (GI; now Wyeth) in Proc. Natl. Acad. Sci. USA, 87:7512 (1990). U.S. 5,215,895, “DNA Encoding a Mammalian Cytokine, Interleukin-11,” June 1, 1993, and also 5,854,028 and 5,700,664, assigned to GI, concern recombinant active mature 178-amino acid (amino acids 22-199) human IL-11. U.S. Pat. No. 5,292,646, assigned to GI, describes the des-Pro form of IL-11 (oprelvekin) in which the N-terminal proline of mature active human IL-11 has been removed.
Due to the time Neumega spent in FDA regulatory review (under 35 USC §156), the expiration date of 5,215,895 was extended 542 days to Nov. 24, 2011.
Wyeth (originally Genetics Inst.) 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 Wyeth and other companies achallenged 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.
Medical: The recommended dose of Neumega in adults is 50 µg/kg given once daily (with a 100 kg adult administered the contents of a 5 mg vial), administered subcutaneously as a single injection in either the abdomen, thigh, or hip (or upper arm if not self-injecting). Neumega administration is initiated 6-24 hours after the completion of cancer chemotherapy. Platelet counts should be monitored periodically to assess the optimal duration of therapy. Dosing should be continued until the postnadir platelet count is > 50,000 cells/µL. In controlled clinical trials, doses were administered in courses of 10 to 21 days. Dosing beyond 21 days per treatment course is not recommended. Treatment should be discontinued at least 2 days before starting the next planned cycle of chemotherapy.
Oprelvekin (des-Pro IL-11), like IL-11, stimulates the production of blood platelets, which are essential to the blood-clotting process. See the Platelets entry in the Blood Products, Human section. Chemotherapy patients often develop thrombocytopenia, a significant a drop in the number of blood platelets. Without sufficient amounts of blood platelets, chemotherapy must often be reduced, delayed, prematurely halted, and/or patients must receive platelet transfusions to replenish platelets. These alternatives can impact on planned disease treatment and increase the complexity, costs, and risks of cancer treatment. By decreasing the proportion of patients requiring platelet transfusions, the use of Neumega reduces risk of developing thrombocytopenia and reduces the incidence of potential complications associated with platelet transfusions. In clinical studies, Neumega has been shown to reduce the need for platelet transfusions while full planned chemotherapy doses were maintained.
Market: Total 1999 sales of Neumega were $45 million, down from $53 million in 1998. The potential market includes the approximate 150,000 persons annually in the U.S. with chemotherapy-associated thrombocytopenia.
Wyeth does not report annual sales of Neumega. The author’s rough/crude guess for 2006 and later sales is in on the order of $100 million.
The 2007 Average Wholesale Price (AWP) is $2,056.32/seven 5 mg vials (week supply), with a Direct Price (discount price) of $1,713.60; and $2,937.60//ten vials, with a Direct Price of $2,448.00/ten vials (unchanged since 2005)(Red Book, 2007).
With Neumega administered for ~10-21 days, at the 2007 AWP of $293.76/vial, the cost ranges from $2,973-$6,243.
The average cost (at time of approval) for a standard course of therapy with Neumega was reported to be about $1,500. This compared favorably with platelet transfusions which require careful and costly matching of donor and recipient tissues, often costing about or over $1,000, but avoids the risks associated with platelet transfusions.
Companies involvement:
Full monograph
216 Interleukin-11, rDNA
Nomenclature:
Interleukin-11, rDNA [BIO]
Neumega [TR]
oprelvekin [USAN FDA]
2-178 Interleukin-11 (human clone pXM/IL-11) [CAS]
145941-26-0 [CAS RN]
adipogenesis inhibitory factor [SY]
AGIF [SY]
des-Pro IL-11 [SY]
interleukin-11 [SY MESH]
interleukin-11, des-Pro [SY]
recombinant human interleukin-11 [SY]
rhIL-11 [SY]
rHuIL-11 [SY]
molecular weight (kDa) = 19
FDA Class: Biologic BLA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19971125
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2011, based on extension of 5,215,895); 2014, if process patent 5,646,016 applies |
U.S. Patent Expiration Year: | 2011 |
U.S. Biosimilars Data Exclusivity Expiration: | 2009 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2002 |
U.S. Biosimilars Launchability Year: | 2011 |
U.S. Biobetters Launchability Year: | 2011 |
Biosimilars/biobetters-related EU Patents: | 2012, based on agent patent EP 0574506 and process patents EP 1231217 and EP 1231217 |
EU Patent Expiration Year: | 2012 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | 2012 |
EU Biobetters Launchability Year: | 2012 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
growth factors, hematopoietic
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
megakaryocytes
glycine
interleukin-11/thioredoxin fusion protein
lyophilized (freeze-dried)
Platelets
sodium phosphate
sodium phosphate, monobasic
Sterile Water for Injection
thioredoxin/interleukin-11 fusion protein
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
orphan status
Park-William no. 8, Corynebacterium diphtheriae
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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