Epoetin alfa - Epogen; Procrit; erythropoietin, recombinant
Status - approved; marketed; manufacture halted in Aug. 2012
Organizations involved:
Amgen, Inc. – Manuf.; R&D; Tech.; USA mark.
Ortho Biologics LLC – USA. mark.
Johnson & Johnson Co. (J&J) – Parent
Kirin Pharmaceuticals, Ltd. – R&D; Tech.
Fresenius Medical Care N.A. –USA mark.
Transkaryotic Therapies, Inc. – Patent dispute
Shire Pharmaceuticals Group plc – Parent
Aventis Pharma AG – Patent dispute; Former
Sanofi Aventis S.A. – Patent dispute
University of Chicago – R&D; Tech.
Genetics Institute – Patent dispute; Former
Wyeth – Parent
University of Washington – Patent dispute
Columbia University – Tech.; Patent dispute
Ajinomoto Co., Ltd. –Patent dispute
Cross ref.: See the Erythropoietin (EPO) Products entry (#132) and the entry for the other EPO product (Eprex) (#136) manufactured by Ortho Biotech/J&J.
Description: Epoetin alfa, marketed as Epogen and Procrit, are aqueous formulations of recombinant human erythropoietin (EPO) glycoprotein expressed by Chinese hamster ovary (CHO) cell culture and having the same amino acid sequence as human EPO. Erythropoietin is a 165 amino acid, 30,400 Daltons (30.4 kDa) molecular weight glycoprotein (~62% protein, 38% carbohydrate). The carbohydrate moiety consists of three N-linked carbohydrate chains and one O-linked side chain. EPO has a calculated molecular formula of C809H1301N229OO240S5. Note, although these two products are each manufactured by different companies, they are considered to contain the same active ingredient. In some respects, Procrit may be considered an authorized biogeneric version of Epogen.
The recombinant EPO in both products, Epogen from Amgen and Procrit from Ortho/Johnson & Johson (Ortho/J&J), is identical and manufactured by Amgen, and Amgen manufactures both finished products. Ortho/J&J also manufactures its own EPO, but only for marketing (as Eprex) outside of the U.S. (see entry below). Amgen supplied bulk EPO to Ortho/J&J for international marketing (as Eprex), until Ortho/J&J received approval for its own manufacturing facility in 1995. Epogen is marketed in the U.S. by Amgen for kidney dialysis (renal failure; end-stage renal disease) indications: indications:, while Ortho/J&J markets Procrit for all other indications:, primarily cancer chemotherapy-associated anemia. See the Companies section below and the EPO Products entry above for further information about these companies’ respective markets.
Epogen and Procrit are formulated as a sterile, colorless, isotonic sodium chloride/sodium citrate buffered solution for intravenous (IV) or subcutaneous (SC) administration in both preservative-free and preservative (benzyl alcohol)-containing single-dose and multidose vials. Preservative-free single-dose vials of Epogen and Procrit each contain 1 mL of solution containing either 2,000, 3,000, 4,000 or 10,000 Units of Epoetin alfa, along with 2.5 mg Albumin (Human) as stabilizer, 5.8 mg sodium citrate, 5.8 mg sodium chloride, and 0.06 mg citric acid in Water for Injection, USP (pH 6.9 ± 0.3). Also, a 40,000 Units single-dose, 1 mL, preservative-free vial contains Epoetin alfa at 40,000 Units/mL, alone with 2.5 mg Albumin (Human), 1.2 mg sodium phosphate monobasic monohydrate, 1.8 mg sodium phosphate dibasic anhydrate, 0.7 mg sodium citrate, 5.8 mg sodium chloride, and 6.8 mcg citric acid in Water for Injection, USP (pH 6.9 ± 0.3). The 2 mL multidose preserved vial contains 20,000 Units Epoetin alfa, with each 1 mL of solution containing 10,000 Units of Epoetin alfa, 2.5 mg Albumin (Human), 1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid, and 1% benzyl alcohol as preservative in Water for Injection, USP (pH 6.1 ± 0.3). The 1 mL multidose preserved vial contains 20,000 Units Epoetin alfa, along with 2.5 mg Albumin (Human), 1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid, and 1% benzyl alcohol as preservative in Water for Injection, USP (pH 6.1 ± 0.3). The dating period for these formulations is 24 months from the date of manufacture when stored at 2-8˚C (refrigerated), with the date of manufacture defined as the date of the final sterile filtration of bulk product.
The EPO originally manufactured by Amgen and used in U.S. clinical trials differs slightly from the approved, commercial product. Modifications of the manufacturing process resulted in a slight difference in the distribution of EPO isoforms in the final product compared to that produced in the clinical research production facility (and used for various clinical trials). However, biochemical equivalence of the two products has been established using tryptic mapping, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), high pressure liquid chromatography (HPLC), Western blots, radioimmunoassay (RIA) and N-terminal protein sequencing. Clinical equivalence was demonstrated in a blinded, 74-patient, 6-week trial, with the same maintenance dosage of each showing comparable efficacy and safety.
This CHO-expressed recombinant EPO glycoprotein has a primary structural conformation duplicating that of native human erythropoietin and an average carbohydrate composition different from that of native human EPO. As described in a recent patent (5,955,422), purified human urinary EPO and recombinant CHO cell-produced EPO were subjected to carbohydrate analysis. Experimentally determined carbohydrate constitution values (expressed as molar ratios of carbohydrate in the product) for the urinary isolate were: hexoses, 1.73; N-acetylglucosamine, 1; N-acetylneuraminic acid, 0.93; fucose, 0; and N-acetyl-galactosamine, 0. Corresponding values for the recombinant product were: Hexoses, 15.09; N-acetylglucosamine, 1; N-acetylneuraminic acid, 0.998; Fucose, 0; and N-acetylgalactosamine, 0.
Nomenclature: EPO, rDNA/Amgen [BIO]; Epogen [TR reg. to Amgen]; Procrit [TR reg. to Ortho/J&J]; Epoetin alfa [FDA CAS USAN INN BAN]; 1-165-Erythropoietin (human clone lambda HEPOFL13 protein moiety) [CAS]; 1-165-Erythropoietin (human clone lambdaHEPOFL13 protein moiety), glycoform alpha [CAS]; 113427-24-0 [CAS RN]; EPO [SY]; erythropoietin, recombinant [SY]; Espo [TR Japan]; NDC 55513-126-10, NDC 55513-267-10, NDC 55513-148-10, NDC 55513-144-10, NDC 55513-823-10, NDC 55513-283-10, NDC 55513-478-10 [NDC for Epogen]; NDC 59676-302-01; NDC 59676-303-01; NDC 59676-304-01; NDC 59676-310-01; NDC 59676-340-01; NDC 59676-302-02; NDC 59676-303-02; NDC 59676-304-02; NDC 59676-310-02; NDC 59676-312-01; NDC 59676-320-01 [NDC for Procrit]
Companies.: EPO (marketed as Epogen and Procrit) was initially developed by Amgen, Inc. in collaboration with Kirin Pharmaceuticals, Ltd., and is approved for manufacture by Amgen, Inc., CBER/FDA est. no. 1080. In recent years, the bulk epoetn alfa has only been manufactured at Amgen facilities in Longmont, CO (with manufacture halted n 2012).
Amgen supplies EPO to Ortho/J&J for marketing in the U.S. as Procrit (for its licensed/designated non-dialysis-related markets). Epoetin alpha (Epogen and Procrit) manufactured by Amgen has only been marketed in the U.S., since 1995 when Ortho/J&J received approval for manufacture of its own EPO.
Kirin Pharmaceuticals, Ltd. assisted Amgen in development of EPO, and receives royalties from Amgen. In its deal originally negotiated in May, 1984 (prior to start of clinical trials), and renegotiated in Oct., 1989, with an investment of $44.5 million, Kirin receives 5% royalties from Amgen (according to Recombinant Capital). [Note, Epogen and several other Amgen products were actually developed through Kirin-Amgen, a joint venture company formed in 1984 and 50% owned by both 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 royalties on sales, and with Kirin-Amgen reimbursing Amgen for R&D expenses. However, most sources simply treat Epogen and other Kirin-Amgen products as though they originated solely from Amgen].
In 1985, Amgen licensed exclusive U.S. marketing rights for indications: other than end-stage renal disease and all international (non-U.S.) marketing rights, including cancer chemotherapy-associated anemia, to Ortho Biotech LLC, a subsidiary of Johnson & Johnson Co. (J&J). Amgen gets a 10 percent royalty on Procrit sales in the U.S. Thus, EPO is marketed (as Epogen) in the U.S. by Amgen, Inc., but only for treatment of anemia associated with end stage renal disease. At the time, it was presumed that renal disease would constitute about one-third of the EPO market (i.e., Amgen negotiated away 2/3’s or more of EPO’s potential market). Amgen received $10 million upon signing the deal. Ortho/J&J markets EPO (from EPO supplied by Amgen) under the trade name Procrit in the U.S., and markets EPO it manufactures itself internationally (outside U.S.) under the trade name Eprex. Marketing and patent disputes have persisted between Amgen and Ortho/J&J since EPO was first introduced. See the Erythropoietin (EPO) Products entry (#132) and the Tech. transfer and Status sections of this entry and the EPO, rDNA/Ortho (Eprex) entry (#136).
While some at the time accused Amgen of giving away too much in its deal with Ortho/J&J, in hindsight both parties have made considerable sums (now billions annually) from EPO (Amgen’s first product), and EPO remains the single most important revenue source and factor responsible for the growth and success of Amgen. Amgen badly needed funds at the time just to survive and continue EPO and Neupogen development, and was involved in costly patent disputes with Genetics Institute over EPO that cast doubts on its likelihood of being able to market EPO.
In early 2008, with Amgen continuing its patent dispute with Roche concerning marketing of PEG-EPO (Mircera) by Roche in the U.S. (see related entry), it was reported that Amgen receives a10% royalty on J&J sales of Procrit (EPO in U.S. markets outside of dialysis patients).
On July 6, 2000, Amgen received FDA approval for manufacture of EPO at its new Longmont, CO, facilities. The plant has three times the EPO production capacity of Amgen’s original plant in Thousand Oaks, CA.
It has been reported that Amgen initially invested $300 million in development of EPO, with the cost for manufacture being less than one-fifth of the $9-$12,000/patient/year’s paid by kidney dialysis centers.
Amgen’s primary facilities for manufacture of Epogen were originally in Juncos, Puerto Rico. Amgen constructed a second facility on this site for manufacture of Epogen and Aranesp. The expansion doubled the square footage of the PR facilities from 500,000 to one million square feet. However, in recent years, with decrease in sales, manufcturing was only performed at Longmont, CO, facilities.
In Oct. 2006, Fresenius Medical Care Holdings Inc. (FMC-NA), the U.S. subsidiary of Fresenius Medical Care AG & Co. KgaA (Fresenius AG), concluded an exclusive supplier deal with Amgen, which will be the sole supplier of EPO products to Fresenius for use in its U.S.-based dialysis centers (i.e., Fresenius will only use Epogen and Aranesp). Fresenius holds about 35% of the U.S. dialysis market (with DaVita having about 30%), and likely administers a comparable percentage of EPO products (Epogen and Aranesp) for treatment of U.S. kidney failure patients. The agreement runs from Oct. 1, 2006 to Dec. 31, 2011. The companies will also explore collaborations to develop new product formulations to further enhance standards of care. Deals such as this will be a major obstacle to CERA/Mircera, presuming it enters the U.S. market and breaks Amgen’s U.S. EPO product monopoly (see the Mircera entry). Fresenius can terminate this agreement, if a competitor offers a better product (so far, Mircera is the only near-term EPO product, and has only proven noninferiority); or there is a significant change in the reimbursement of for EPO products (which seems likely). As discussed in the Market section of the EPO Products entry above, dialysis centers, particularly large chains such as Fresenius than can negotiate significant discounts, are reimbursed a fixed fee for EPO treatment, with EPO products being a significant profit center.
In Nov. 2011, Amgen concluded long-term supply agreements with major U.S. dialysis center operators DaVita and Fresenius. With discounts and rebates, Amgen concluded a 7-year contract with DaVita to supply at least 90% of the dialysis company's anemia remedies, plus a "multi-year" deal with Fresenius Medical Care. Together, the two companies account for almost 60% of the U.S. dialysis market.
In Aug. 2012, Amgen reported its plans to halt manufacture of epoetin alfa at its then only manufacturing facility in Longmont, CO. Manufacturing will be ramped up, to build up supplies, and then the facility mothballed, to be restarted if needed. When Amgen PR dept. was asked, "With the halt in epoetin alfa manufacture, will Epogen (and Procrit) be withdrawn from the U.S. market (whether through withdrawal of its BLA or simply not resuming manufacture as existing supplies become outdated)?," the reply was "No, there are no plans to pull Epogen from the U.S. market." Depending on how interpreted, this is an incomplete response -- if manufacture is halted, with no plans for restart, won't this effectively remove the product from the market as supplies are used up? Keep in mind that with no in-date Epogen or Procrit, there can be no U.S. approvals of biosimilars, with no in-date/valid product to be tested in comparative trials. This would effectively force the markt to Aranesp, maintaining Amgen's EPO monopoly (until patents run out in 2013/4).
Manufacture: Some aspects of the cloning and manufacture of epoetin alpha are reported in “The Cloning and Production of Human Erythropoietin,” Pharmacotherapy, vol. 10, sup. 2, p. 3S-8S, 1990. The effort began with a search for the human gene encoding EPO. Two pools of synthetic radiolabeled oligonucleotide probes, based on available protein sequence data from urinary EPO, each consisting of 128 oligonucleotides, were used with a human genomic library for clones containing the desired gene. Isolated clones were expressed in CHO cells to identify and verify the complete functional gene, with the expressed glycoproteins compared to urinary-derived EPO using a variety of techniques.
A tranformed CHO cell line for commercial-scale production of EPO was constructed. The cloned EPO gene for expression of the 193-amino acid precursor glycoprotein was inserted adjacent to a viral promoter in an expression vector containing the gene for dihydrofolate reductase (DHFR). The promoter enhances expression by increasing the production (copy number) of RNA transcripts from the EPO gene. The inserted DHFR gene provides a selectable marker enabling isolation of transformed host cells and a means for gene amplification. This vector was used to transfect a DHFR-deficient (DHFR-) CHO cell line and the number of copies of the EPO gene amplified by selection with methotrexate, with successfully transformed cells able to grow in selective media due to their expresion of DHFR (which metabolizes otherwise toxic levels of methotrexate in the culture medium). This amplification and use of a strong promoter significantly increased EPO expression. A single cell was then isolated by two rounds of limiting-dilution cloning. The isolated clone was expanded in culture and used to create a Master Working Cell Bank (MWCB), consisting of hundreds of vials each containing millions of cells held in cryogenic storage.
Production begins with growth and expansion of CHO cells from the MWCB. The MWCB has been shown to be genetically stable, homogenous and free from contaminating adventitious agents (microorganisms). CHO cell culture takes place in large numbers of roller bottles. The cells are cultured in conditions favoring accumulation of expressed EPO in the cell culture medium. The secreted product is isolated from medium using sequential column chromatography. A number of in-process tests are performed to assure purity. At time of original approval, Amgen committed to development of a culture process which would allow sterile sampling from prepurified bulk material for purposes of mycoplasma testing. Purified EPO is formulated in a buffered isotonic saline solution containing 0.25% human Albumin as a stabilizer to prevent adsorption of the dilute EPO to glass and other surfaces. The product is then filled into vials.
The purified bulk product is tested for identity using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blot analysis, isoelectric focusing, and N-terminal protein sequence analysis. Potency is confirmed by radioimmunoassay (RIA) and in vivo bioassay. Purity is assessed by SDS-PAGE, high pressure liquid chromatography (HPLC), DNA analysis, and an immunoassay for potential contaminating proteins. Purified bulk product is also tested for mycoplasma. The formulated bulk product is tested for sterility, total protein, endotoxin, and potency (by RIA). The final vialed product is tested for appearance, potency (by RIA and in vivo bioassay), total protein, sterility, general safety, pyrogenicity, and endotoxin levels. The identity and quantity of all excipients are confirmed.
The product is manufactured through the formulated bulk phase by Amgen, and (as described in original approval-related FDA documents) then shipped under controlled conditions to Parke-Davis, subsidiary of Warner-Lambert Co., facilities in Rochester, MI . These facilities were later sold to Parkedale Pharmaceuticals, a subsidiary of King Pharmaceuticals (which may continue this task). Under supervision of Amgen personnel, the formulated bulk product is sterile-filtered, filled into final containers, labeled and packaged.
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19890601, first approval, PLA ref. no. 87-0535, ELA ref. no. 87-0536; orphan designation (granted 04/10/1986; expired 6/1996); Indication = treatment of anemia associated with end stage renal disease (ESRD); approval covered Epogen, Procrit and Eprex (EPO for export by Ortho/J&J), with Amgen then exclusively supplying bulk EPO to Ortho/J&J
Date = 19901231; PLA supplement; Indication = acute lymphocytic leukemia in HIV-infected patients
Date = 19901231; PLA supplement; orphan designation (07/01/1991); Indication = treatment of anemia associated with HIV infection or HIV treatment
Date = 19930401; PLA supplement; Indication = anemia associated with cancer chemotherapy
Date = 19961223; PLA supplement; Indication = reduce need for blood transfusions in anemic patients undergoing elective, non-cardiac, non-vascular surgery
Date = 19990726; BLA supplement (license converted from PLA to BLA); Indication = revision of package insert/labeling to include pediatric use
Date = 20000606; BLA supplement; Indication = manufacture of EPO at new facilities in Longmont, Colorado
Date = 20051200; BLA supplement; Indication = added warning to labeling/inser regarding pure red cell aplasia (PRCA) in chronic renal failure patients who received the drug subcutaneously, and recommended that patients on hemodialysis should receive the drug intravenously
Date = 20070309; BLA supplement; Indications: = new warnings added to the product insert/labelilng for both Epogen and Procrit, including a black box warning
Date = 20071108; BLA supplement; Indication = modification of the black box warning, added language in the Indications and USAGE section, addition of an oncology study to the WARNINGS section, and clarification of the hemoglobin range for chronic renal failure (CRF) patients in the DOSAGE AND ADMINISTRATION section.
Date = 20080307; BLA supplement; Indication = revised labeling (for all erythropoiesis-stimulating agents), including that ESAs should not be used to enhance the response to chemotherapy or radiotherapy, and should be administered to achieve a hemoglobin level of less than 12 g/dL
indications: [Epogen]: [full text of "INDICATIONS AND USAGE” section of Epogen product insert/labeling]:
Treatment of Anemia of Chronic Renal Failure Patients:
EPOGEN is indicated for the treatment of anemia associated with CRF, including patients on dialysis and patients not on dialysis. EPOGEN is indicated to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients.
Non-dialysis patients with symptomatic anemia considered for therapy should have a hemoglobin less than 10 g/dL.
EPOGEN® is not intended for patients who require immediate correction of severe anemia. EPOGEN® may obviate the need for maintenance transfusions but is not a substitute for emergency transfusion.
Prior to initiation of therapy, the patient’s iron stores should be evaluated. Transferrin saturation should be at least 20% and ferritin at least 100 ng/mL. Blood pressure should be adequately controlled prior to initiation of EPOGEN® therapy, and must be closely monitored and controlled during therapy.
Treatment of Anemia in Zidovudine-treated HIV-infected Patients
EPOGEN is indicated for the treatment of anemia related to therapy with zidovudine in HIV-infected patients. EPOGEN is indicated to elevate or maintain the red blood cell level (as manifested by the hematocrit or hemoglobin determinations) and to decrease the need for transfusions in these patients. EPOGEN is not indicated for the treatment of anemia in HIV-infected patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding, which should be managed appropriately. EPOGEN® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.
EPOGEN, at a dose of 100 Units/kg TIW, is effective in decreasing the transfusion requirement and increasing the red blood cell level of anemic, HIV-infected patients treated with zidovudine, when the endogenous serum erythropoietin level is ≤ 500 mUnits/mL and when patients are receiving a dose of zidovudine ≤ 4200 mg/week.
Treatment of Anemia in Cancer Patients on Chemotherapy
EPOGEN is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether EPOGEN® increases mortality or decreases progression-free/recurrence- free survival are ongoing.
• EPOGEN is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.
• EPOGEN is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of EPOGEN on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).
• EPOGEN is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response).
• EPOGEN use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.
Reduction of Allogeneic Blood Transfusion in Surgery Patients
EPOGEN is indicated for the treatment of anemic patients (hemoglobin > 10 to ≤ 13 g/dL) who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions.17-19 EPOGEN is not indicated for anemic patients who are willing to donate autologous blood (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION).
indications: [Procrit]: [Same as for Epogen (above), except “PROCRIT” substituted for “EPOGEN.”]
Status: Note, both Epogen from Amgen and Procrit from Ortho/J&J (containing the same EPO from Amgen, marketed in the U.S. only), in terms of FDA regulation, are the same, single product, with Amgen essentially transferring bulk EPO to Ortho/J&J for formulation, finishing and packaging. Epogen and Procrit are each approved for the same indications:, including for anemia associated with chronic renal failure. It is agreements between the companies that result in exclusive U.S. marketing rights for kidney failure an indication solely held by Amgen in the U.S. and cancer chemotherapy and other indications: held by Ortho/J&J. Thus, technically, both products hold approvals for indications: not allowed under the Amgen-Ortho/J&J licensing agreement. The 1985 Amgen/Ortho licensing agreement provides Ortho/J&J with exclusive U.S. rights to the market for indications: other than chronic renal failure and exclusive rights for all indications: outside the U.S., while Amgen retained exclusive U.S. rights for end-stage renal disease (kidney dialysis)-associated indications:.
Since the very beginning, Ortho/J&J and Amgen have tested the limits and encroached on each other’s U.S. markets, resulting in accusations and court cases. For example, the Ortho/J&J Procrit Web site (www.procrit.com) has included pages informing kidney disease patients (who are not on dialysis) that Procrit can treat their anemia, without mentioning dialysis, chronic renal failure, or end-stage renal disease. The companies have been through binding arbitration of marketing disputes multiple times. See the Erythropoietin (EPO) Products entry for further information.
Procrit, with its high cost, has been a target of counterfeiters. For example, an estimated 110,000 vials of Epogen (costing about $22 each) were relabelled and sold as high-strength Procrit at about $445/vial, with the counterfeiters taking in about $46 million before shut down by authorities in May 2002. Only less than 10% of the counterfeit product was ever recovered, meaning as many as 25,000 patients may have received counterfeit product.
In Nov. 2003, Ortho/J&J filed a BLA supplement for a once weekly 40,000 unit dose for Procrit (the current starting dose being 150 units/kg three times weekly).
In Aug. 2004, Ortho Biotech issued a warning letter to U.S. physicians and changed the labeling for Procrit based on reports of serious thrombotic vascular events, including death, observed in clinical trials of two EPO products marketed primarily in Europe, NeoRecormon and Eprex (see related entries), in which EPO was used above it current recommended dosage level.
In Dec. 2005, J&J issued a“Dear Healthcare Provider” letters and updated the labeling for Epogen and Procrit, respectively. These concerned modification of the warnings section of the product insert/labeling to include cases of pure red cell aplasia (PRCA) in chronic renal failure (CRF) patients who received the drug subcutaneously, and recommend that patients on hemodialysis should receive the drug intravenously. The label had previously warned of PRCA predominantly reported in CRF patients.
In the Nov. 16, 2007, issue of the New England Journal of Medicine, results from the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study sponsored by Ortho/J&J were reported. It was shown that among patients with chronic kidney disease, when treated with a more aggressive dose of epoetin to achieve a higher hemoglobin level (13.5 grams per deciliter), had a higher risk but no incremental improvement in the quality of life. The authors recommended a target hemoglobin level between 11 g/dL and 12 g/dL instead of a level of 11-13 g/dL for patients with chronic kidney disease to correct anemia, with the current labeling calling for 10-12 g/dL as the target. CHOIR evaluated 1,432 CKD patients, with 715 randomly assigned a dose of EPO to achieve a high hemoglobin level of 13.5 g/dL and 717 assigned to achieve a low hemoglobin level of 11.3 g/dL. Patients achieved a mean level of 12.6 g/dL in the high hemoglobin group. The primary endpoint was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal cell replacement) and stroke. The secondary endpoint was the four individual components of the primary endpoint, each evaluated separately. An increased risk of the primary composite end point was reported in the high-hemoglobin group, as compared to the low-hemoglobin group. The trial was halted after an analysis showed increased risk in those achieving a high Hb level. In total, 222 composite events occurred: 125 in the high-hemoglobin group compared to 97 in the low-hemoglobin group (hazard ratio 1.34; 95% confidence interval: 1.03-1.74). The authors noted, “aiming for a target value of 13.5 g of hemoglobin per a deciliter provides no additional quality of life benefit.
In March 2007, the product insert/labeling for Epogen and Procrit was revised, and Amgen and Ortho Biotech/J&J jointly issued a “Dear Healthcare Professional” letter to U.S. healthcare professionals. This included as “black box” warning regarding using Epogen and Procrit (and other EPO products) to increase hemoglobin above 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy, with increased the risk for death and for serious cardiovascular events. Physicians are advised in the boxed warning and “Dosing and Administration” section to use the lowest dose of EPO products that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red blood cell transfusions, and not to exceed 12 g/dL. Amgen noted that “The vast majority of oncologists and nephrologists do not appear to be maintaining Hb levels above 12 g/dL in approved indications:.” In an accompanying editorial, Dr. D. Coyne, Washington University School of Medicine, stated that physicians who work with dialysis centers may not know they are “making dubious dosing decisions” because they sign multipage standing orders and turn over anemia management to chain employees.
In the April 18, 2007 issue of the Journal of the American Medical Association, the Medical Technology and Practice Patterns Institute (MTPPI) reported results from a study showing that the majority of dialysis chains administer higher doses of Epoen than nonprofit dialysis centers, a practice that may be putting patients at risk. Chain-operated, for-profit dialysis centers consistently administered the highest doses of Epogen, regardless of patients’ anemia status, even when patients already had recommended levels of hemoglobin (red blood cells). This was linked to Medicare, which not only reimburses dialysis centers a fixed amount for each treatment, but also reimburses them separately for Epogen. With most for-profit chains, which handle the majority of dialysis patients, negotiating volume discounts from Amgen, the chains generally buy Epogen for less than Medicare reimburses, making Epogn a profit center. For example, DaVita Inc. stated in its 2006 annual report that one-fourth of its net operating revenue comes from administering Epogen, and Fresenius Medical Care AG reported that Epogen accounts for 21% of its net operating revenue in North America. In Feb. 2005, the National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), had awarded a two-year grant to MTPPI in collaboration with Harvard School of Public Health (HSPH) to explore the causal relationship between EPO dose received and outcomes in hemodialysis patients.
In 2006 and 2007, problems continued to mount for Epoetin and EPO products in general (see the Status section of the EPO Products entry, #132). For example, Aranesp has been linked to increased tumor growth/proliferation and increased mortality (see the Aranesp entry below, particularly the Status and Trials sections). Besides broad safety concerning affecting all erythropoiesis products/EPOs (see the EPO Products entry above), Epoetin and Amgen are coming under scrutiny and criticism from many different sources, with this concerning safety, cost-benefit and marketing issues. In May 2007, the New York State Attorney General served a subpoena on Amgen related to promotional, sales and marketing activities and other issues; and the U.S. Senate Finance Committee sent a letter to Amgen requesting a briefing to discuss the issues and concerns reported in the media related to the marketing and safety of Epoetin. Also, various biosimilar EPO products are entering the European Union market (see related entries below), and Epoetin will face new competition in the U.S., breaking its monopoly, from Mircera (peglyalted EPO; see related entry) from Hoffmann-La Roche, although FDA approval has been delayed into 2008.
Eprex has not received EU centralized approval. EU approvals are country-by-country.
Tech. transfer: Amgen filed its first patent (Lin patent) application in Dec. 1983 for the EPO gene sequence and recombinant EPO (composition-of-matter). Amgen (Dr. Lin) completed its invention of recombinant CHO-expressed EPO several weeks before a team at Genetics Institute (now Wyeth) did likewise, with Amgen eventually receiving patent precedence in the U.S. U.S. patents assigned to Amgen (or Kirin-Amgen) having the title “Production of ery thropoietin” and including Dr. Lin as inventor include: 5,547,933; 5,618,698; 5,621,080; 5,756,349; and 5,955,422. Other Amgen EPO patents include 5,441,868. The earliest U.S. “Lin” patent is 4,703,008, granted to Amgen on Oct. 27, 1987. This patent expired Oct. 27, 2004. However, Amgen has obtained many patents, including divisions, particularly in the U.S. on diverse aspects of EPO, e.g., composition-of-matter, medical use, process, and formulation patents, and can be expected to aggressively defend its EPO patent-based exclusivity for as long as it can. Thus, it appears to be an oversimplification that Amgen’s EPO U.S. patent coverage expires in 2004, which is what some sources report. Amgen and J&J claim coverage into 2013, which is more likely accurate. Other sources have reported U.S. patent protection to June, 2005, and to 2016. European patent coverage for EPO as composition-of-matter is, similarly, often reported to expire in 2004. The patent situation in Europe is not as complex, the 2004 date may be accurate, and will likely be tested by biogeneric or follow-on produts.
Kirin Pharmaceuticals Ltd. licensed EPO-related technology, particularly highly purified human EPO (and associated patents), from the University of Chicago, where researchers had long studied the natural protein and had developed methods for manufacture of human urine-derived EPO by the mid-1970s.. As part of its collaboration with Amgen for EPO development, Kirin contributed this material as part of EPO’s development. Amgen researchers, particularly Dr. Fu Kuen Lin, et al., used this high purity urine-derived human EPO to determine its amino acid sequence. With knowledge of the protein sequence, oligonucleotide probes were designed and used to retrieve human EPO gene, which was cloned in bacteria. Once the proper human gene for EPO was confirmed, the gene was further cloned in CHO cells.
Amgen (Kirin-Amgen) was involved in patent disputes with Genetics Institute (now part of Wyeth), with both companies having developed methods for recombinant manufacture of EPO. The University of Washington joined the suit on behalf of Genetics Inst. Genetic Inst. had licensed its EPO technology to Boehringer Mannheim (now Hoffmann-La Roche), which markets epoetin beta (NeoRecormon) in international markets (see related entry). The disputes were resolved in favor of Kirin-Amgen. In July 2001, Roche settled its decade-long European patent dispute with Ortho/J&J, Amgen, and Genetics Inst (now Wyeth) concerning recombinant EPO. Terms were not disclosed, but all suits were dropped and European marketing of Eprex (Ortho/J&J) and (Neo)Recormon (Roche) continued unchanged (indicating the parties cross-licensed their patents).
U.S. 5,955,422, the most recent Amgen “Lin” patent, has only two claims: “1. A pharmaceutical composition comprising a therapeutically effective amount of human erythropoietin and a pharmaceutically acceptable diluent, adjuvant or carrier, wherein said erythropoietin is purified from mammalian cells grown in culture. 2. A pharmaceutically-acceptable preparation containing a therapeutically effective amount of erythropoietin wherein human serum albumin is mixed with said erythropoietin. “ This patent includes descriptions of EPO manufacture by various recombinant methods, including detailed descriptions of CHO expression, presumably relevant to the product’s actual manufacture.
Amgen was involved in an interference dispute (to determin first--to-invent) concerning a U.S. patent application assigned to Chugai Pharmaceuticals claiming aspects of recombinant purified EPO. The case was decided by the patent office in favor of Amgen in 1991.
Amgen filed suit in U.S. District Court in 1999/2000 alleging that Transkaryotic Technologies (TKT; acquired by Shire Pharmaceuticals Group plc in April 2005) and its collaborator, Aventis Pharma (now Sanofi Aventis S.A.), were infringing five of Amgen’s U.S. patents covering recombinant EPO. TKT and Aventis were collaboratively developing gene-activated EPO (see the GA-EPO or Dynepo entry below) involving selective induction of human cells to express EPO. TKT also challenged the five Amgen patents claiming recombinant EPO. GA-EPO would cost must less to manufacture in large quantities than EPO. TKT claims that because its EPO is made by selective activation of human genes in culture, rather than more traditional recombinant methods (using transformed Chinese hamster ovary cells in the case of Epogen/Procrit and Eprex), it is not covered by Amgen’s patents concerning recombinant EPO. A decision against TKT (and Aventis Pharma) was announced in Jan. 2001, ruling that claims 2 through 4 of Amgen’s U.S. 5,621,080, while not literally infringed, were valid and infringed under the doctrine of equivalents; four of the five claims (claims 1,3,4, and 6) of Amgen’s 5,756,349 were valid and literally infringed; and claim 1 of Amgen’s U.S. 5,955,422 was valid and literally infringed. The court ruled in favor of TKT/Aventis on some issues, finding that Amgen’s U.S. 5,547,933 (the original Dr. Lin patent) was not infringed, and that it would be invalid if it were infringed; Amgen’s U.S. 5,618,698 was not infringed; claim 7 of Amgen’s 5,756,349 was not infringed; and Amgen’s U.S. 5,621,080 was not literally infringed. The court essentially ruled that the EPO resulting from TKT’s in vivo expression system was basically equivalent to Amgen’s recombinant EPO molecule obtained from cell culture. The rulings of infringement of Amgen’s patents were sufficient to allow Amgen to bar commercial marketing of Dynepo in the U.S.
Both Amgen and TKT appealed this ruling before the U.S. Court of Appeals for the Federal Circuit (CAFC). In Jan. 2003, the CAFC agreed in part with the District Court’s ruling, including that TKT/Aventis infringes two of Amgen’s patents (5,756,349 and 5,955,422), disagreed in part, and remanded to the District Court various issues related to the appeal by TKT/Aventis. The lower court was to reconsider the validity of Amgen’s patents 5,756,349, 5,955,422, and 5,621,080; reconsider whether TKT infringes 5,621,080; and reconsider its finding that TKT does not infringe EPO process claims in Amgen’s patents 5,618,698 and 5,756,349.
With the CAFC affirming TKT’s infringement of at least two Amgen patents, Amgen believes that it will be able to keep GA-EPO out of the U.S. market (through the life of its patents found to be valid). However, with billions of dollars at stake (Dynepo potentially providing competition for Epogen, Procrit, Eprex, and Aranesp), TKT/Aventis appealed. [As noted below, the U.S. Supreme Court refused to review this case, so the infringment ruling stands, and Dynepo is effectively barred from entering the U.S. market.
In Oct. 2004, the U.S. District Court for the District of Massachusetts ruled that TKT and Aventis (now Sanofi Aventis) were not infringing two of Amgen’s patents with four claims covering purification of EPO. TKT (and Sanofi Aventis) is appealing the ruling.
In June 1999, Transkaryotic Therapies, Inc. (TKT) and its partner Aventis (now Sanofi Aventis), developers of epoetin delta (Dynepo; GA-EPO; see #141) filed in the U.K. for a declaration of non-infringement and revocation of Amgen’s European Patent No. 0148605 B2 (expiring in 2004) concerning recombinant production of EPO assigned to Amgen/Kirin-Amgen. The U.K. court responded that TKT and Aventis infringed the four claims of this patent. TKT and Aventis appealed, and in April 2001, the High Court of Justice in London found that one of the four claims asserted by Amgen against TKT and Aventis would not be infringed on a literal basis, but would be infringed when the claim is construed on a purposive basis (similar to the U.S. doctrine of equivalents), i.e., found in favor of Amgen. The court also found the other three claims of Amgen’s European patent were invalid, and even if valid were incapable of infringement. In Aug. 2002, the Court of Appeals of the U.K. unanamously reversed the lower court and ruled against Amgen Inc. and Kirin-Amgen, Inc., in favor of TKT, that TKT’s GA-EPO technology did not infringe Amgen’s European patent 0148605-B2. TKT reported that this removed all barriers to marketing its product in Europe. Despite a favorable verdict and European Union approval, Dynepo will not be launched in Europe until this and the patent situation in the U.S. is resolved. In Feb. 2003, the U.K. House of Lords ruled its would hear an appeal of the validity of Amgen’s patent.
In Oct. 2004, U.K.’s House of Lords upheld the 2002 unanimous decision by the Court of Appeal that Dynepo from TKT and Aventis, now Sanofi Aventis, did not infringe European patent No. 0148605B2 assigned to Amgen, and reversed the Court of Appeal’s finding that Amgen’s patent claims were valid. The ruling stated, ““It is clear that Amgen have got themselves into difficulties because, having invented a perfectly good and ground-breaking process for making EPO and its analogs, they were determined to try to patent the protein itself, notwithstanding that, even when isolated, it was not new.” Anyways, Amgen’s U.K. patent expired in Dec. 2004. If Amgen had prevailed, it could have delayed launch of Dynepo in the U.K. for amount of time that the patent was judged to be infringed. This leaves TKT/Aventis free to develop and market Dynepo in the U.K.
It is commonly reported that U.S. (and European) patent (and patent extension) protection for Epogen (and Eprex and Procrit) expires in Dec. 2004, based on expiration of the “Lin” patents. However, this apparently does not take into account the patents Amgen has received covering aspects of EPO other than its composition-of-matter (gene/protein sequences), including its manufacture, recombinant constructs, processes, formulations, and uses. In the U.K., patent and SPC (patent extension) protection for Eprex [and also for epoetin beta (NeoRecormon)] has been reported by the National Health Service (NHS) to expire on Dec. 11, 2004. Similarly, European Patent expiration is expected in 2004.
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 Nov. 2005, as many had expected, Amgen filed a suit in U.S. District Court in Boston, MA, alleging that both NeoRecormon (EPO) and CERA (pegylated EPO; see related entry) infringe its patents concerning recombinant erythropoietin (EPO). Since this does not affect Amgen’s U.S. EPO patents, this is discussed fully in the CERA entry. Roche asserts that CERA does not infringe Amgen’s U.S. patents. With Amgen now obtaining about $6 billion in profits annually from its EPO products (and licensing), some analysts have noted this promises to be “the mother of all biotech patent cases.”
In Aug. 2006, the Court of Appeals for the Federal Circuit (CAFC) affirmed the prior District Court’s decision that TKT and Aventis were infringing Amgen’s EPO patents. The CAFC found the production patents valid and infringed (5,618,698 and 5,756,349; sufficient to keep Dyepo off the market) But, the court reversed the District Court’s determination that TKT infringed Amgen’s 5,621,080 under the doctrine of equivalents, and remanded to the District Court for further consideration the remaining validity issue on one of the other product patents (5,955,422) after ruling that claim 1 of ‘422 patent is not invalid, with interpretation of ““therapeutically effective amount” being the main issue. This left Amgen with patent protection into 2015.
In Feb. 2007, Japan’s Intellectual Property High Court ruled in favor of Chugai Pharmaceutical in a patent infringement and invalidation suit brought by Ajinomoto, another Japanese pharmaceutical company. Ajinomoto filed its suit in 2004 alleging that Chugai was infringing one of its Japanese process patents with manufacture of Epogin and Neutrogin (Lenograstim). The circuit court dismissed the suit in 2006, and the Japanese patent office ruled the patent at issue invalid in Sept. 2005. Ajinomoto appealed both rulings, but lost after appealing to the highest court.
In May 2007, the U.S. Supreme Court refused to consider Amgen’s patent dispute with TKT/Shire and Sanofi Aventis, with this leaving prior findings of infringement by Dynepo in place and effectively keeping Dynepo from entering the U.S. market.
Some of Amgen’s key U.S. patents concerning recombinant EPO assigned to Amgen are or will soon expire, but Amgen still holds other patents that may still block marketing of competing EPO products in the U.S. and elsewhere, potentially extending U.S protection into 2015. Certain process patents expire in 2012, a composition of matter patent expires in 2013, and others expire as late as 2015. Amgen attributes the potential 32 year life of its U.S. patents to patent office delays in issuing its patents in large part due to years of challenges from Amgen’s competitors. But critics note that Amgen played a role in the protracted process, frequently resubmitting rejected or abandoned applications with different wording, continuing the patent application process. All of Amgen’s key U.S. EPO patents concern the original work performed by Dr. F.-K. Lin, but each have different claims, e.g., for the gene sequence, transformed cells for manufacture of EPO, manufacturing processes, methods of treatment, etc. This practice of splitting inventions into component patents was common until the mid-1990’s and, in some cases, examiners requested that a patent be divided. Since then, Amgen’s patents have been critically examined and re-examined by many parties, and withstood various challenges. If Roche prevails, with the court ruling that Amgen’s in-force patents are insufficient to block marketing of CERA, a number of companies can be expected to begin development of biogeneric (follow-on protein, biosimilar, biocomparable, etc.) versions of EPO. For example, to get around Amgen’s later patents concerning mammalian cell EPO expression, Neose had been developing baculovirus expressed, insect cell cultured EPO, but abandoned this in early 2008; and GlycoFi, now part of Merck, is developing yeast expressed EPO.
U.S. patent protection for Epogen is projected by Decision Resources to expire in 2013, and in most European countries in 2007, and 2004 in the U.K. 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.
Trials: In the Aug. 2005 issue of Clinical Nephrology, results from the open-label PROMPT study in 519 patients not on dialysis showed that Procrit can be dosed less frequently than the approved dose of 50-100 units/kg of body weight 3 times/week. Patients received either 10,000 units once-weekly (QW), 20,000 units every 2 weeks (Q2W), 30,000 units every 3 weeks (Q3W) or 40,000 units every 4 weeks (Q4W). Data showed 89.5%, 77.2% and 76% of patients in the Q2W, Q3W and Q4W groups, respectively, maintained hemoglobin levels ≥11 grams compared with 93.5% in the QW group. The Q2W and Q4W groups were non-inferior to the QW group. Reducing the dosing interval would provide significant cost savings. This could result in increased use of Procrit (and Epogen), perhaps reducing total sales or even increasing sales by increasing the patient population.
Medical: See the Erythropoietin (EPO) Products entry above. Patients with end-stage renal disease (ESRD) generally receiving dialysis on a regular basis, and usually receive Epogen intravenously while undergoing dialysis. These patient generally receive an EPO product for the rest of his life (unlike most non-ESRD indications: where EPO is used on an as-needed basis). For adult chronic renal failure patients, the starting dose is 50 to 100 Units/kg TIW, with dosage reduced as the hematocrit approaches 36% or increases by more than 4 points in any 2-week period. The dosage must be individualized to maintain the hematocrit within the suggested target range. Epogen/Procrit may be given either as an intravenous (IV) or subcutaneous (SC) injection. Patients on hemodialysis usually receive an IV bolus TIW. Dosage is titrated to maintain hematocrit in the 30%-36% range. For cancer patients on chemotherapy, the starting dose is 150 Units/kg SC TIW, with dosage adjusted up to 300 Units/kg TIW, if needed (in terms of reducing transfusion requirements or increasing hematocrit), after 8 weeks of therapy. Patient not responding to 300 Unit/kg are unlikely to respond to higher doses. If the initial dose of includes a very rapid hematocrit response (e.g., an increase of more than 4% in any 2-week period), the dose should be reduced. EPO is also less frequently used to boost red blood cells for those expecting to undergo elective orthopedic surgery and autologous blood donation, and HIV-infected patients experiencing anemia as a side effect of AZT (zidovudine) drug treatment.
Market: Epogen is used by most of the 300,000 dialysis patients in the U.S. It generally costs about $7,000 to $10,000 a year per patient.
Government purchasers comprise ~80% of EPOGEN sales," with 75% of that 80% handled under the Medicare Part B program. The actual average annual cost of epoetin alfa (Epogen) for patients with end-stage renal disease who are undergoing maintenance hemodialysis was reported in 2010 to be $8,767 per patient, of which the Centers for Medicare and Medicaid Services (CMS) pays 80%. This cost was calculated on the basis of the most recent publicly posted data from the U.S. Renal Data System (USRDS) and corresponding data from the CMS. For the second half of 2007, the mean epoetin alfa dose of 18,566 units per patient per week was reported in the 2009 USRDS Annual Data Report, which reflects 2007 data, and the CMS reimbursement rate for epoetin alfa was $9.081 per 1000 units, based on the average sales price reported by the Healthcare Common Procedure Coding System.
CMS is in the process of changing EPO for dialysis reimbursement to a flat rate. The change has been expected to cut into Epogen sales, because dialysis providers won't be paid any more for higher doses used than they are for lower doses. This has been another incentive for Amgen to conclude long-term Epogen supply deals with major U.S. purchasers.
The 2007 Average Wholesale Prices (AWPs) for Epogen are $28.81/2000 U vial, $288.12 for 10; $43.22/3000 U vial, $432.24 for 10; $57.62/400 U vial, $576.24 for 10; $144.06/10000 U 1 mL vial, $1440.60 for 10; $288.12/10000 U 2 mL vial; $2,881.20 for 10; $309.79/20000 U vial, $3097.92 for 10; and $607.82/40000 U vial, $6,078.24 for 10 (Red Book, 2007).
The 2007 AWPs for Procrit are $180.299 for six 1 mL, 2,000 u/mL vials; $751.20 for 25 1-mL, 2,000 u/mL vials; $270.43 for six 1 mL, 3,000 u/mL vials; $1,126.80 for 25 1-mL, 3,000 u/mL vials; $360.58 for six 1 mL, 4,000 u/mL vials; $1,502.40 for 25 1-mL, 4,000 u/mL vials; $901.44 for six 1-mL, 10,000 u/mL vials; $3,756.00 for 25 1-mL, 10,000 u/mL vials; $1802.88 for six 1 mL, 20,000 u/mL vials; and $2,403.84 for 4 1-mL, 40,000 u/mL vials (Red Book, 2007). For comparison, the AWPs in 2005 were $171.79 ($160.27 in 2004) for six 1 mL, 2,000 u/mL vials; $715.80 ($667.80 in 2004) for 25 1-mL, 2,000 u/mL vials; $257.69 ($240.42 in 2004) for six 1 mL, 3,000 u/mL vials; $1073.70 ($1,001.70 in 2004) for 25 1-mL, 3,000 u/mL vials; $345.58 ($320.54 in 2004) for six 1 mL, 4,000 u/mL vials; $1431.60 ($1,335.60 in 2004) for 25 1-mL, 4,000 u/mL vials; $858.96 ($801.36 in 2004) for six 1-mL, 10,000 u/mL vials; $3.579.00 ($3,339.00 in 2004) for 25 1-mL, 10,000 u/mL vials; $1717.92 ($1,602 in 2004) for six 1 mL, 20,000 u/mL vials; and $2,290.56 ($2,136.96 in 2004) for 4 1-mL, 40,000 u/mL vials (Red Book, 2005).
Medicare reimbursement for Epogen use in kidney dialysis in 2005 was reduced to $9.76 per 1,000 units, down from $10 per 1,000 units. In April 2007, Amgen reported that the average cost for Epogen treatment for a dialysis patient at wholesale was about $8,920/year.
The author’s estimates of total U.S. sales of recombnant EPO, i.e., Epogen (in the U.S. by Amgen) and Procrit (from Ortho/J&J) are $3.4 biilion in 2012; 1.953
~$3.73 billion in 2011; $4.59 billion in 2010; $5.03 billion in 2009; $5.12 billion in 2008; $5.764 billion in 2007; $5.680 bilion in 2006; and $4.85 billion in 2005.
Total Procrit sales by J&J were $814 million in 2011 and $1.070 billion in 2010.
Total Epogen sales (all U.S.) by Amgen were 1.953 billion in 2013
$479 million in 2012 [outlier, suspect data]; $2.6 billion in 2009;
~$2.5 billion in 2004; $2.4 billion in 2003; $2.3 billion in 2002; $1.96 billion in 2000, $1.76 billion in 1999, $1.38 billion in 1998, $1.107 billion in 1997, $1.071 billion in 1996, $883 million in 1995, $721 million in 1994, and $586 million in 1993. Total EPO product sales (U.S.) by Amgen (i.e., Epogen sales for end-stage renal disease/kidney dialysis indications:, plus Aranesp sales for chemotherapy and renal disease indications:) were ~$5 billion in 2004, ~$4 billion in 2003, ~$2.7 billion in 2002 (48% of total Amgen sales), and nearly $2.2 billion in 2001.
See the Eprex entry for combined Procrit and Eprex by J&J.
In March 2007, Friedman, Billings, Ramsey & Co. (FBR) estimated Epogen sales (by Amgen; limited to U.S.) to be $2.511 billion in 2006, $2.486 billion in 2007, $2.362 billion in 2008, $2.314 billion in 2009, $2.326 billion in 2010, $2.338 billion in 2011, and $2.349 billion in 2012.
Procrit, long the only available erythropoiesis therapeutic in the U.S. for cancer indications:, now holds a minority share of U.S. sales of EPO-like agents in these patients. In Oct. 2005, Ortho/J&J reported in a court brief charging Amgen with monopolistic bundling sales practices related to Aranesp (see discussion in the Market section of the Aranesp entry) that Aranesp holds an approximate 66% of U.S. erythropoiesis (EPO-related) agent sales to cancer clinics, while the U.S. market share in oncology clinics for Procrit fell to 34% from 55% in the first quarter of 2004. In Feb. 2006, J&J reduced the size of its Procrit sales staff by about 100 persons (out of an sales force of undisclosed size).
Procrit is heavily promoted and advertised, including direct-to-consumer advertising (e.g., television advertising showing cancer patients with renewed energy and active lives). Procrit was ranked 12th in terms of most medical journal advertising in the first half of 2003 (PERQ/HCI Mid-Year Ad Review 2003, Medical Marketing & Media, Oct. 2003), with 1.8% of the Ad Market in 2003, up from 0.60% in 2002 when it ranked 27th.
Since signing their original licensing agreement in 1985, Amgen and Ortho/J&J have long been involved in various marketing disputes, with each charging the other with encroaching on their respective exclusive U.S. marketing rights.
Medicare spends more on those EPO products (Epogen and Procrit) than almost any other products, spending at least $1,5 billion a year for each. In May 2004, a report from the Office of Inspector General, Department of Health and Human Services (DHHS), surveyed the four largest dialysis centers (those likely to get the most discounted price), and found their average profit spread on EPO (Epogen) was 12%, versus the 22% average spread for all Medicare-reimbursed dialysis drugs. These findings are counter to what had been presumed (i.e., that dialysis centers were making considerable/excessive profit from EPO), and indicated that CMS may not lower reimbursement rates for Epogen.
In 2004, Medicare paid out $1.4 billion for coverage of Epogen. In July 2004, Centers for Medicare & Medicaid Services (CMS) announced it would decrease its in-hospital Medicare reimbursement rate for Epogen for ESRD by 11%. CMS also increased the reimbursable hematocrit level for EPO therapy to 39% from 37.5%, so more patients qualify. These actions are not expected to significantly affect overall sales of Epogen (and with the reimbursement rate for Aranesp reduced by 15%, Epogen has gained a slight advantage, relative to Aranesp).
Competition: The EPO market in Europe is different than in the U.S., with more companies marketing EPO products – Eprex marketed by Ortho/J&J; Epoetin beta (NeoRecormon) marketed by Boehringer Mannheim/Hoffmann La Roche Inc.; Dynepo marketed by Sanofi Aventis; and Aranesp marketed by Dompe Biotec S.p.A. See the related product entries.
Companies involvement:
Full monograph
133 EPO, rDNA/Amgen
Nomenclature:
EPO, rDNA/Amgen [BIO]
Epogen [TR reg. to Amgen]
Procrit [TR reg. to Ortho/J&J]
epoetin alfa [FDA USAN INN BAN]
1-165-Erythropoietin (human clone lambda HEPOFL13 protein moiety) [CAS]
1-165-Erythropoietin (human clone lambdaHEPOFL13 protein moiety), glycoform alpha [CAS]
113427-24-0 [NUM CAS RN]
EPO [SY]
erythropoietin, recombinant [SY]
Espo [TR Japan]
C809H1301N229OO240S5 [MF USAN]
18.23606 +/- 400 kDa [MW USAN]
30.400 kDa [MW]
molecular weight (kDa) = 34
FDA Class: Biologic PLA
Year of approval (FDA) = 1989
Date of 1st FDA approval = 19890601
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2013 (for Procrit and Epogen marketed in the U.S. |
U.S. Patent Expiration Year: | 2013 |
U.S. Biosimilars Data Exclusivity Expiration: | 2001 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1996 |
U.S. Biosimilars Launchability Year: | 2013 |
U.S. Biobetters Launchability Year: | 2013 |
Biosimilars/biobetters-related EU Patents: | see the entry for Eprex; Epogen and Procrit are reference products (the same products for different indications marketed by different companies, but identical and with the same approvals) |
EU Patent Expiration Year: | |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | |
EU Biobetters Launchability Year: |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
growth factors, hematopoietic
hamster source materials
hormones
human materials used<!-- humansource -->
recombinant DNA
rodent source materials
Chinese hamster ovary (CHO) cells
mammalian cell culture
rodent cells <!-- rodentcells -->
Albumin (Human)
benzyl alcohol
citric acid
fucose
hexoses
N-acetyl galactosamine
N-acetyl glucosamine
N-acetyl neuraminic acid
sodium chloride
sodium citrate
Sterile Water for Injection
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
orphan status
EU000 Not yet/Never filed with EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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