Sargramostim - Leukine; Granulocyte/Macrophage Colony Stimulating Factor, recombinant
Status - approved; marketed
Organizations involved:
Genzyme Corp. – Manuf.; R&D; Tech.; World mark.
Berlex Laboratories – Former
Bayer Schering Pharma AG – Former; Parent
Amgen Inc. – Manuf.; R&D; Tech.; World mark.; Parent; Former
Immunex Corp. – Former
Research Corporation Technologies Inc. – Tech.
Washington Research Foundation – Tech.
Genentech, Inc. – Tech.
University of Washington – Tech.
Eliza Hall Inst. of Medical Research – R&D; Tech.
Ludwig Institute for Cancer Research – R&D; Tech.
Hoechst AG – Tech.; Former'
Wyeth – Former
Description: Leukine refers to aqueous and lyophilized (freeze-dried) formulations of sargramostim, a recombinant mutein (modified form) of an O-glycosylated human granulocyte-macrophage colony stimulating factor (rhuGM-CSF) produced by a transformed Saccharomyces cerevisiae (yeast) cell line. The amino acid sequence of sargramostim differs from that of native human GM-CSF by substitution of a single amino acid, a leucine for arginineine, at position 23. Sargramostim is a single chain glycoprotein of 127 amino acids, with three primary characterized molecular species having molecular masses of 19,500, 16,800 and 15,500 Daltons (19.5, 16.8 and 15.5 kDa). The molar specific activities of the three species are comparable. Sargramostim has a variable degree of glycosylation (by S. cerevisiae), and its side-chain carbohydrate glycosylation is different from native human protein and other recombinant GM-CSF products (marketed internationally). Biological potency is expressed in International Units as tested against the WHO First International Reference Standard. The specific activity of Leukine is approximately 5.6 x 106 or 5.6 million IU/mg. The molecular formula has been reported as C639H1002N6169O196S8.
Prokine is identical to Leukine. Prokine was formerly marketed in Europe by Hoechst AG (later became Aventis Pharma, now Sanofi Aventis S.A.), with the product manufactured by Immunex (now merged into Amgen) and relabeled for resale by Hoechst.
Leukine Liquid (until replacement by new formulation in 2006) is formulated in vials as a sterile, injectable solution containing 500 µg (2.8 x 106 or 2.8 million IU/mL) sargramostim with 1.1% benzyl alcohol as preservative in a 1 mL solution, plus 40 mg/mL mannitol, USP; 10 mg/mL sucrose, NF; and 1.2 mg/mL Tris (tromethamine USP) as excipients. The current liquid formulation, launched in Jan. 2006, contains 500 µg (2.8 x 106 IU/mL) sargramostim, 1.9 mg/mL ethylenediaminetetraacetic acid (sodium EDTA; edetate disodium), and 1.1% benzyl alcohol in a 1 mL solution. Lyophilized Leukine is a pure, sterile, white, preservative-free powder packaged in vials (250 µg; 1.4 x 108 or 1.4 million IU/vial) for reconstitution with either 1 mL Sterile Water for Injection, USP or 1 mL Bacteriostatic Water for Injection, USP. Liquid Leukine vials and reconstituted lyophilized Leukine vials also contain 40 mg/mL mannitol, USP; 10 mg/mL sucrose, NF; and 1.2 mg/mL tromethamine, USP, as excipients. Biological potency is expressed in International Units (IU) as tested against the WHO First International Reference Standard. The specific activity of Leukine is approximately 5.6 x 106 IU/mg. The dating period is 18 months for the liquid formulation and 24 months for the powder formulation. Both powder and solution should be stored at 2-8˚C (refrigerated)
In May 2008, FDA approved a new formulation that does not contain EDTA (edetate disodium), which was in the product's liquid 500 µg vial manufactured from Jan. 2006 to Jan. 2008. Liquid Leukine is now formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial, requiring reconstitution with 1 mL Sterile Water for Injection, USP or 1 mL Bacteriostatic Water for Injection, USP. Liquid Leukine has a pH range of 6.7 - 7.7. Liquiud Leukine contains 500 µg (2.8 x 106 IU/mL) sargramostim and 1.1% benzyl alcohol in a 1 mL solution. The vial of lyophilized LEUKINE contains 250 µg.
Nomenclature: GM-CSF, rDNA/Berlex [BIO]; Leukine [TR]; Prokine [TR Europe] Sargramostim [FDA USAN]; Colony-stimulating factor 2 (human clone pHG25 protein moiety), 23-L-leucine [CAS for sargramostim]; colony-stimulating factor-2 [CAS or human GM-CSF]; 123774-72-1 [CAS RN for sargramostim]; 83869-56-1 [CAS RN for human GM-CSF]; GM-CSF [SY]; Granulocyte-macrophage colony-stimulating factor [SY]; BI 61.012 [SY]; NSC 617589 [SY NCI]; NSC 613795 [SY NCI]; rhGM-CSF [SY]; NDC 58406-002-33; NDC 58406-050-30; NDC 58406-002-01; NDC 58406-001-01 [NDC]
Note, some terminology does not convey that sargramostim has a different amino acid composition than native human GM-CSF, and it is common for sargramostim and Leukine to be simply referred to as GM-CSF (and its synonyms). Also, Leukine, GM-CSF, and other terms are often used ambiguously to refer to the formulated product and/or active ingredient.
Biological.: GM-CSF belongs to a group of growth factors termed colony stimulating factors that support the survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways. GM-CSF is also capable of activating mature granulocytes and macrophages. GM-CSF is a multilineage growth f actor and, in addition to dose-dependent effects on cell of myelomonocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors. However, other factors are required to induce complete maturation in these other lineages. Cellular responses (i.e., division, maturation, activation) are induced through GM-CSF binding to specific receptors expressed on the cell surface of target cells.
The biological activity of GM-CSF is species (human)-specific. Thus, preclinical studies were performed on human cells to characterize the pharmacological activity of Leukine, with little or no animal testing. In vitro exposure of human bone marrow cells to sargramostim at concentrations ranging from 1-100 ng/mL results in the proliferation of hematopoietic progenitors and in the formation of pure granulocyte, pure macrophage, and mixed granulocyte-macrophage colonies. The chemotactic, anti-fungal, and anti-parasitic activities of granulocytes and monocytes are increased by exposure to sargramostim in vitro. Leukine increases the cytotoxicity of monocytes toward certain neoplastic cells and activates polymorphonuclear neutrophils to inhibit the growth of tumor cells.
Companies.: Leukine was originally developed and manufactured by Immunex Corp., CBER/FDA est. no. 1132, now merged into Amgen Inc. Leukine was formerly marketed in the U.S. and internationally by Immunex. Wyeth held certain international marketing rights and returned these in 1998.
Hoechst AG (later Aventis Pharma, now Sanofi-Aventis S.A.) received exclusive European and other international marketing rights from Immunex as the result of a patent dispute settlement with Immunex, with Immunex retaining exclusive U.S. rights. Hoechst marketed product manufactured and relabeled by Immunex as Prokine for sale in Europe and other territories.
Immunex, as part of an agreement with the Federal Trade Commission (FTC) allowing its acquisition by Amgen, divested Leukine U.S. marketing rights. In May 2002, Schering AG (now Bayer Schering Pharma AG) exclusively licensed from Immunex all marketing and development rights to Leukine/Prokine for about $390 million plus payments upon acheiving unspecified milestones. Leukine is now exclusively marketed in the U.S. and is being further developed by Berlex Labs., a U.S. subsidiary of Bayer Schering AG; and is marketed and under development internationally by Bayer Schering AG and affiliates. This licensing included Leukine rights for new indications:, including treatment of Crohn’s disease then in Phase II trials. Berlex/Schering also gained ~200 Immunex employees, including 70 sales representatives. Wyeth previously holding ertain international marketing rights and was the largest share holder in Immunex, and Immunex/Amgen continues to pay unspecified royalties to Wyeth on sales outside N. America.
In Spring 2006, Bayer AG acquired Schering AG, with the company renamed Bayer Schering Pharma AG.
Manufacture of the dosage form, including formulation, sterilization, filling, lyophilization, labeling and packaging was originally (at time of original approval) performed under contract by Sterling Drug Inc. (McPherson, KA).
Berlex (later Bayer) has constructed a plant in Snohomish County, WA, for manufacture of Leukine, with FDA approval expected in 2010, with the company expecting increased demand for treatment of Crohn’s disease. The plant doubled Schering’s manufacturing capacity for Leukine.
In March 2009, Genyzme Corp. assumed full rights to Leukine from Bayer (Bayer Schering). Genzyme will pay Bayer royalties based on sales. Genzyme paid between $75-100 million to Bayer for its new WA Leukine manufacturing facility.
Manufacture: Sargramostim is produced in a recombinant Saccharomyces cerevisiae (yeast) expression system. The host yeast strain, S. cerevisiae XV2181, was transformed with the piXY15 plasmid containing the GM-CSF mutein gene. A single colony was used to establish the Master Cell Bank (MCB) and all subsequent production cultures. At the time of approval, the Master Production Stock Culture contained over 100 vials maintained at -60˚C or below. Vials are used to initiate fermentation in 50 L vessels. Testing includes non-host contamination assay, immuno dot blot, SCS-PAGE silver stain, structural gene sequencing and plasmid restriction mapping. The stability of the Master Product Stock Culture is evaluated at annual intervals (involving 50 L culture). At biannual intervals, a sample is also DNA sequenced.
Working Production Stock Cultures are made by using a released vial of the Master Production Stock Culture to inoculate a flask containing broth medium selective for the host and plasmid. The culture is incubated, diluted with sterile glycerol, distributed into individual cryovials, and stored at -60˚C or below. Each lot of Working Production Stock Culture is tested and characterized using the same methods for the Master Production Stock Culture. After testing, the vials are released for use in fermentation.
During fermentation, the secretion of sargramostim from the yeast host is guided by the leader sequence encoded by the gene for the yeast mating pheromone, alpha factor. The alpha factor leader peptide is proteolytically cleaved from the molecule by the yeast KexII protease during the secretion process, yielding mature sargramostim ready for purification from the yeast broth. Following fermentation, tangential flow filtration is used to separate crude sargramostim from the biomass and the filtrate is concentrated by ultrafiltration.
Concentrated crude sargramostim is purified using successive high performance liquid chromatography (HPLC) columns. In-process testing includes HPLC and SDS-PAGE analyses. Purified sargramostim is processed further by ion exchange chromatography, and the protein is eluted and filtered to produce Purified Bulk Concentrate (PBC). Each PBC lot undergoes quality control testing and, after release by the company, is transferred to an undisclosed contract packager for compounding into the final dosage form. The compounded bulk is sterile filtered through a 0.2 micron filter, aseptically filled, lyophilized, capped, labelled, and packaged.
FDA class: Biologic PLA/ELA
CBER class: Biological Response Modifiers
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19910305, first approval, PLA 90-0182 and ELA 90-0181; orphan designation (granted 05/03/1990; expired 3/1998); Indication = acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease, and acute lymphoblastic leukemia (ALL) undergoing autologous bone marrow transplantation; also referred to as hematopoietic reconstitution after autologous bone marrow transplantation [from Summary Basis of Approval (SBA)]
Date = 19911231; PLA supplement 91-0393; Indication = treatment of neutropenia associated with bone marrow transplant, for the treatment of graft failure and delay of engraftment, and for the promotion of early engraftment; also referred to as bone marrow transplant failure
Date = 19950915; PLA supplement 94-0291; orphan designation (granted 03/06/1995; expired 9/2002); Indication = for use following induction chemotherapy in older adult patients with acute myelogenous leukemia in shortening time to neutrophil recovery and reducing incidence of severe and life-threatening infections and infections resulting in death [from SBA]
Date = 19951124; PLA supplement 95-0639; Indication = treatment of leukopenia associated with myeloablative chemotherapy administered to patients receiving an HLA matched sibling allogeneic bone marrow transplant [from SBA]
Date = 19951222; PLA supplement; Indication = for transplantation of peripheral blood progenitor (stem) cells
Date = 19961107; PLA supplement (note, conversion from PLA to BLA); Indication = new 500 µg/mL and 1,000 µg/mL multidose liquid formulations
Date = 20060100; BLA supplement; Indication = approval of new 500 µg/mL vial with EDTA preservative
Date = 20080519; BLA supplement; Indication = new formulation not containing EDTA (edetate disodium)
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling; 3/16/2006]:
Use Following Induction Chemotherapy in Acute Myelogenous Leukemia: Leukine is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The safety and efficacy of Leukine have not been assessed in patients with AML under 55 years of age. The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification.
Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progentior Cells: Leukine is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. 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. Myeloid reconstitution is further accelerated by administration of Leukine following peripheral blood progenitor cell transplantation.
Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation: Leukine is indicated for acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin’s disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin’s disease, Leukine has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to Leukine can be detected by complete blood count (CBC) with differential cell counts performed twice per week.
Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation: Leukine is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors. Leukine has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization.
Use in Bone Marrow Transplantation Failure or Engraftment Delay: Leukine is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. Leukine has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous
Renal and Hepatic Dysfunction: In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Leukine has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of Leukine administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between Leukine (250 mcg/m2/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during Leukine administration.
Status: The original approval for Leukine included the manufacture of the dosage form, lyophilization, labeling and packaging at Sterling Drug Inc. (McPherson, KS) under a contractual agreement. The approval also noted that the product would also be distributed under another trade name (Prokine) by Hoechst-Roussel Pharmaceutical, Inc., now Sanofi Aventis S.A. (i.e., this approval also covered Prokine). This trade name is currently used in European countries.
In Jan. 2006, a new reformulated liquid 500 µg/mL vial with extended shelf life was approved and launched in the U.S. The new formulation includes the preservative edetate disodium (EDTA). The 250 µg vial will continue to be marketed in its current formulation of lyophilized powder. Reformulation did not affect reimbursement.
In Jan. 2008, Bayer withdrew the previously marketed liquid Leukine 500 mcg vial from the U.S. market in order to reformulate it to eliminate edetate disodium (EDTA) in light of an increase in spontaneous reporting of certain labeled adverse events, including syncope (fainting). The timing of increased reporting of these adverse events coincided with the change in the formulation of liquid Leukine to include EDTA in 2006. With the approval and relaunch of liquid Leukine in a non-EDTA formulation, Bayer closied a special access program that reserved priority access to lyophilized Leukine 250 mcg vials, which do not contain EDTA, for patients with the greatest medical need. Sufficient supply of the new, non-EDTA liquid and lyophilized formulations of Leukine is available to meet cancer care market demand..
No centralized EU approval granted -- country-by-country approvals in Europe.
Tech. transfer: U.S. patents cited in the product insert/labeling are 5,391,485, "DNAs encoding analog GM-CSF molecules displaying resistance to proteases which cleave at adjacent dibasic residues." expired in 2012; 5,393,870, "Analogs of human granulocyte-macrophage colony stimulating factor," expired in 2012; and 5,229,496, "Analogs of human granulocyte-macrophage colony stimulating factor," expired in 2002. I
mmunex has licensed, presumably with exclusivity for GM-CSF, U.S. 5,602,007, "Recombinant DNA molecules," expiring in 2014, concerning GM-CSF vectors and bioprocessing, from Research Corporation Technologies (RCT). RCT’s patents were acquired from the Ludwig Institute for Cancer Research and the Eliza Hall Institute of Medical Research, both in Melbourne, Australia. RCT reports that related patents have issued in the U.S., Europe and Australia; and patent applications are pending in Canada and Japan.
U.S. 5,391,485 and 5,393,870, Deeley, et al., assigned to Immunex Corp., describe recombinant expression of human GM-CSF with substitution of a single amino acid, a leucine, at position 23 (i.e., sargramostim). The level of unmodified GM-CSF recovered from yeast (Saccharomyces cerevisiae) was found to be significantly restricted by the existence of a cleavage site for the protease encoded by the KEX 2 gene of the yeast. This enzyme cleaves at double basic amino acid residues, i.e., two adjacent basic amino acid residues located along the amino acid sequence of the protein. To increase the levels of mature protein product recovered in yeast systems, the human gene sequence was altered to eliminate multiple basic amino acid residues.
U.S. 5,602,007, Dunn, et al., “Recombinant DNA molecules,” February 11, 1997, assigned to Research Corporation Technologies, describes GM-CSF gene sequences, plasmid expression constructs, and proteins.
Amgen has also received other seemingly relevant patents, e.g., 5,580,755, concerning sequence/composition, expiring in Dec. 2013.
Yeast expression technology used for manufacture of sargramostim was developed by the Univ. of Washington and Genentech, and was nonexclusively licensed to Immunex by the Washington Research Foundation (WRF; acting as patent agent for the university and Genentech). Related patents include U.S. 5,618,676 (issued April 8, 1997) and continuations, 5,854,018 and 5,856,123, concerning recombinant production of proteins in yeast expression systems including Saccharomyces, Kluyveromyces, Pichia and Hansenula. All three U.S. patents will expire in 2014. The new patents are broader, as they claim processes and materials for expression of proteins in recombinant yeast systems generally. WRF is the exclusive licensing agent for this family of yeast expression patents. The issued patents, particularly the more recently issued patents, broadly claim processes and materials for expression of proteins in yeast.
Immunex (also Amgen) was a licensee of the Columbia University patents concerning cotransformation, a broadly-useful genetic engineering method for selection and isolation of transformed cells. The patents and license expired in 2000, but Columbia received another patent in 2002 and is again seeking royalties, which Amgen and other companies are challenging in court. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
Trials: In Oct. 2003, Leukine showed promise for treatment of Crohn’s disease in a study in 124 women. In 2004, Berlex, initiated two Phase III trials for Leukine in Crohn’s disease. These trials are part of N.O.V.E.L (New Opportunities to Verify Evolving Logic in Crohn’s disease), a comprehensive worldwide clinical trials program for the ongoing development of Leukine for Crohn’s disease.
In May 2004, results were reported from a multi-center, randomized, double-blind, placebo-controlled Phase II showing that patients with moderately to severely active Crohn’s disease treated with Leukine maintained improvements in disease severity and quality of life even after the treatment was discontinued. Response to therapy continued beyond six months of follow-up in approximately 15 percent of patients; with nearly half of patients maintaining clinical response and remission for a median of 8 to 10 weeks after therapy was discontinued. Leukine was generally well-tolerated.
In July 2004, Schering initiated multiple trials of Leukine in Crohn’s disease. A North American Phase II trial (NOVEL 2) began in first-line patients, and a double-blind, placebo-controlled U.S. Phase III trial (NOVEL 3) began in ~300 Crohn’s disease patients who responded to an initial treatment cycle of Leukine. The primary endpoints for both of these trials are the percent of patients with 100 point drop in CDAI score and the percent of patients in remission (CDAI <150). A double-blind, placebo-controlled international Phase III trial (NOVEL 4) began in about 200 patients. The primary endpoint is the percent of patients with 100 point drop in CDAI score percent of patients in remission (CDAI<150).
The ongoing New Opportunities to Verify Evolving Logic (NOVEL) Phase III trials are expected support approval for Crohn’s disease. In Oct. 2005, Schering reported results from from NOVEL 1, a multi-center, randomized, double-blind, placebo-controlled Phase II trial evaluating the efficacy and safety of sargramostim 6 µg/kg/day for 8 weeks in patients (N=124) with moderately to severely active Crohn’s disease. Sargramostim therapy was associated with improved and maintained quality-of-life (QOL) from baseline to Day 57 versus placebo, as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Short Form 36 (SF-36) health surveys. Improvements in QOL ranging from moderate to large occurred early and were maintained throughout the treatment. Patients who received sargramostim had a 20-22% improvement from baseline total IBDQ Day 29 and thereafter versus 7% to 13% in the placebo group (P = 0.0059 to 0.0397).
In Jun 2005, results from a 39-patient trial indicated that addition of Leukine improves the eficacy of Rituxan (see related entry) for treating the most common form of Non-Hodgkin’s lymphoma.
Also, in Oct. 2005, Schering announced plans for a third Phase III trial in Crohn’s disease. The new trial was needed as a result of a patient recruitment delay faced by NOVEL 3, one of two ongoing Phase III studies of Leukine in Crohn’s disease, and aims to achieve finalization of the Phase III program as soon as possible. Patient enrollment for NOVEL 4, the other pivotal Phase III clinical trial of sargramostim in Crohn’s disease, recently completed enrollment of more than 240 patients (ahead of schedule). Data from NOVEL 4 were expected to be available in 2006.
In July 2006, results were reported from two completed placebo-controlled, randomized, double-blind clinical studies of Leukine for the treatment of Crohn’s disease. Results from a Phase III induction trial (n.o.v.e.l. 4) indicated a treatment benefit, but failed to show superiority in the two primary endpoints of response and/or remission at eight weeks compared to placebo, but the data did show a trend toward a treatment benefit. N.o.v.e.l. 4 was a Phase III multi-center, 288 patient, randomized, double-blind, placebo-controlled study to evaluate the induction of response and remission in patients with moderately-to-severely active Crohn’s disease. Patients received 6 µg/kg/day sargramostim or placebo via subcutaneous injection for eight weeks. Efficacy was based on the Crohn’s Disease Activity Index (CDAI). Response was defined as a CDAI decrease of at least 100 points and remission was defined as a CDAI score of 150 points or below. The results in this study were achieved without the use of steroids or immunosuppressants.
In the n.o.v.e.l. 2 study reported in July 2006, unlike n.o.v.e.l. 4, primary and secondary endpoints were met. N.o.v.e.l. 2 was a multi-center, randomized, double-blind, placebo-controlled study conducted in the U.S. and Canada in 129 patients with active corticosteroid-dependent Crohn’s disease requiring 10-40 mg of prednisone or equivalent. Patients received 6 µg/kg/day sargramostim or placebo via subcutaneous injection. Treatment duration was between 12-22 weeks depending on the baseline corticosteroid dose. The primary efficacy endpoint was corticosteroid-free clinical remission (CDAI less ≤150) four weeks after complete corticosteroid withdrawal. This trial showed that sargramostim was significantly more effective than placebo for induction of corticosteroid-free clinical remission in steroid-dependent Crohn’s disease patients. This study was the first randomized, double-blind, placebo-controlled trial conducted with any biological therapy in active steroid-dependent Crohn’s disease patients.”
In Nov. 2006, Berlex Oncology initiated the PREMIER trial evaluating the efficacy and safety of combining rituximab and the cytokine sargramostim with Rituxan (from Genentech/Roche) in patients with relapsed follicular B-cell lymphoma. Patients in this randomized, open-label, Phase II study receive either four doses of rituximab 375 mg/m2 administered intravenously once weekly for four weeks or the same rituximab regimen plus Leukine 250 µg administered subcutaneously, three times weekly for eight weeks.
In 2009, Genzyme has fully acquired the product and continues to enroll patients in two Phase III trials of alemtuzumab for multiple sclerosis. The company expects to complete enrollment in one of the studies by the middle of this year, which includes previously untreated patients. Enrollment is ongoing in the other study, which involves treatment-experienced patients. Data are expected to be available in 2011, and approval is expected in 2012..
Medical: GM-CSF is used for indications: including treatment of several types of leukemia and for failing allogenic bone marrow transplant (BMT) recipients. Acute myelogenous leukemia (AML), also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification. Leukine is also used for treatment of leukopenia in cancer chemotherapy recipients, and in recipients of transplanted peripheral blood progenitor (stem) cells.
Disease: There were an estimated 12,000 allogenic bone marrow transplants (BMT) performed worldwide in 1998. About 50% of allogenic BMT patients experience graft vs. host disease (rejection), and associated rejection treatment costs in the U.S. are estimated at about $80,000 per patient. About 50% of rejection patients fail to respond to current rejection treatments (and may be candidates for Leukine).
Market: Total worldwide sales of GM-CSF products from Berlex/Schering (now Bayer Schering) and Schering-Plough have been reported to be about $200 million (in 2004).
In 2009, with acquisition of CAMPATH-1H by Genzyme, the company reported that it believes CAMPATH-1H has the potential to be the best therapy for MS, a market that is projected to reach $8-9 billion annually by 2012.
In Jan. 2008, Bayer reported that Leukine has been used to treat nearly 350,000 patients in the US since 1991.
In March 2006, Schering AG reported that it expected potential peak Leukine annual sales of more than EUR250 million ($304.5 million), presuming it receives approvals for Crohn’s disease).
The author’s rough guess for 2006 total sales of Leukine is ~$200 million. Total U.S. sales were $108 million in 2001, $69.1 million in 1999, $63.8 million in 1998, $53 million in 1997, $43 million in 1996, $41 million in 1995, $46 million in 1994, and $43 million in 1993.
The 2007 Average Wholesale Price (AWP) is $862.44 for five 250 µg vials; $1,724.88/five 500 µg mulit-dose vials; and $1,627.44/five 500 µg vials (Red Book, 2007).
Competition: In Aug. 2006, Zenotech Laboratories (India) received approval in India for its generic (biogeneric, follow-on protein, biosimilar, biocomparable, etc.) version of Leukine, becoming the first Indian company to receive approval for generic GM-CSF.
Companies involvement:
Full monograph
169 GM-CSF, rDNA/Berlex
Nomenclature:
GM-CSF, rDNA/Immunex [BIO]
Leukine [TR]
Prokine [TR Europe]
Sargramostim [FDA USAN]
Colony-stimulating factor 2 (human clone pHG25 protein moiety), 23-L-leucine [CAS]
colony-stimulating factor-2 [CAS for human GM-CSF]
123774-72-1 [CAS RN]
83869-56-1 [CAS RN]
BI 61.012 [SY]
GM-CSF [SY]
granulocyte-macrophage colony stimulating factor, recombinant [SY]
NSC 613795 [SY NCI]
NSC 617589 [SY NCI]
rhGM-CSF [SY]
NDC 58406-002-33; NDC 58406-050-30; NDC 58406-002-01; NDC 58406-001-01 [NDC]
molecular weight (kDa) = 20
FDA Class: Biologic PLA
Year of approval (FDA) = 1991
Date of 1st FDA approval = 19910305
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2014 based on licensed 5,602,007; 2013, based on 5,580,755, a sequence/composition patent; others expired
Genzyme had previously reported patent coverage by licensed patents 5,393,870 and 5,229,496, expired in 2010, and 5,391,485, licensed from Bayer, expired in 2012 |
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: | 2014 |
U.S. Biobetters Launchability Year: | 2014 |
Biosimilars/biobetters-related EU Patents: | 2016, presuming EP 0212914 and related patent families apply; No centralized EU approval granted (country-by-country) |
EU Patent Expiration Year: | 2016 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | 2016 |
EU Biobetters Launchability Year: | 2016 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
growth factors, hematopoietic
recombinant DNA
yeast source materials
pIXY15 plasmid
plasmid pIXY15
Saccharomyces cerevisiae (yeast)
XV2181, Saccharomyces cerevisiae (yeast) strain
alpha factor leader peptide
Bacteriostatic Water for Injection
benzyl alcohol
ethylene glycol
heat treatment (pasteurization)
lyophilized (freeze-dried)
mannitol
protease, yeast KexII
Sterile Water for Injection
sucrose
tris (tromethamine)
yeast KexII protease
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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