Status: marketed internationally, not in U.S.

Organizations involved:

Boehringer Mannheim GmbH – R&D; Tech.; Former

Hoffmann-La Roche Ltd. – Manuf.; R&D; Tech.; Intl. mark.; Parent

Genetics Institute – R&D; Tech.; Former

Wyeth – Parent

Chugai Pharmaceutical Co. Ltd. – Japan mark.

Amgen Inc. – Patent dispute

Ortho Biotech L.P. – Patent dispute

Johnson & Johnson - Parent

University of Washington – Tech.

Description: Epoetin beta or NeoRecormon refers to lyophilized (freeze-dried) and aqueous formulations of recombinant human erythropoietin (EPO) beta glycoprotein expressed by a Chinese hamster ovary cell line (CHO-DND-3.alpha.3) transformed with the human EPO gene. Epoetin beta has the same primary structure (165-amino acid sequence) as epoetin alfa, but a different glycosulation pattern. Excipients include urea, sodium chloride, polysorbate 20 (Tween 20), sodium dihydrogen phosphate, sodium monohydrogen phosphate, calcium chloride, glycine, leucine, isoleucine, threonine, glutamic acid, and phenylalanine. Shelf life is 3 years at 2-8˚C (refrigerated) for powder.

Epogen, Procrit, Eprex and NeoRecormon are often referred to as equivalent or generic (biogeneric, biosimilar, biocomparable, follow-on) versions of each other. Even though epoetin alfa (e.g., Epogen, Procrit and Eprex, each manufactured using Amgen’s manufacturing methods) and epoetin beta (NeoRecormon) result from the same gene expressed in CHO cells, the molecules are not identical due to differences in manufacturing. These products are generic or equivalent only in the sense of being essentially bioequivalent and generally substitutable in terms of clinical usage. EPO alfa and EPO beta do not exhibit identical electrophoretic patterns, indicating the products differ in terms of isoforms (e.g., glycosylation patterns, folding), which could be due to a number of factors relating to their manufacture.

NeoRecormon is available in 19 different forms and strengths, providing 39 presentations (perhaps, even more now) This includes packaging in vials containing 500 IU, 10,000 IU, 20,000 IU, 50,000 IU, and 100,000 IU of powder; 10,000 and 20,000 IU vials used with a pen delivery system; and prefilled syringes. One thousand IU of epoetin beta is correspond to 8.3 µg of epoetin beta glycoprotein. The lyophilized powder presentations have a shelf life at 2-8˚C (refrigerated) of three years and the liquid presentations have a shelf life of two years.

Nomenclature: EPO, rDNA/Roche [BIO]; NeoRecormon [TR]; Recormon [TR former]; Epogin [TR in Japan]; epoetin beta [INN EU]; erythropoietin, recombinant [SY]; 122312-54-3 [CAS RN]

Originally Recormon, NeoRecormon, with ‘neo’ meaning new, was adopted as the trade name with introduction of the newer aqueous formulation for use with a pen injector, and the 500 and 20,000 single usage vials and 50,000 and 100,000 vials of lyophiled powder. The active ingredient did not change with the renaming. However, concentrations of some excipients were changed.

Biological.: EPO beta is considered “identical in its amino acid and carbohydrate composition to erythropoietin isolated from the urine of anaemic patients,” and “EPO beta’s protein sequence, biological activity and immunological activity were found to be indistinguishable from erythropoietin isolated from the urine of anaemic patients,” according to a recent European Product Assessment Report (EPAR), European Union. However, much as EPO alfa and EPO beta are not truly identical, referring to EPO beta and endogenous human EPO as “identical” may be an oversimplification, since many would say it is impossible for a complex glycoprotein expressed in different species (hamster and human) to be identical, and for a purified glycoprotein from cell culture to be truly identical to glycoprotein produced in vivo in humans.

Companies.: Epoetin beta was originally developed by Genetics Institute (GI; later merged into Wyeth), which in 1992 exclusively licensed European rights to Boehringer Mannheim GmbH (BM; later merged into Hoffmann-La Roche) and Japanese rights to Chugai Pharmaceutical. In Jan. 1996, the GI-BM collaboration and licensing agreement was expanded to provide BM with additional marketing rights in Asia and the Pacific Rim.

Epoetin beta (Recormon/NeoRecormon) was further commercially developed and manufactured by Boehringer Mannheim AG, which was acquired by and merged into Hoffmann-La Roche AG. Recormon/Neorecormon have been manufactured by Boehringer Mannheim/Roche facilities in Penzberg, Germany, since 1990. Although NeoRecormon is not FDA regulated, this manufacturing facility is included in the establishment license held by Roche (CBER/FDA est. no. 0136). New European NeoRecormon manufacturing facilities, the Biotechnology Research and Production Centre of Roche Diagnostics, came online in early 1999.

Manufacture: A vial of Working Cell Bank (WCB) containing CHO-DND-3.alpha.3 cells is expanded and used for batch refeed process fermentation. A single process run consists of a maximum of 10 harvests per fermentation, resulting in a maximum of 10 batches per purification.

Each harvest undergoes purification which leads to 10 batches of purified EPO. The purification process consists of five chromatographic steps. This process starts with a capture step using Blue Sepharose chromatography. Further purification is performed using a hydrophobic interactio chromatography (HIC) on Butyl Toyopearl; adsorption chromatography on Hydroxyapatite Ultrogel; a Reversed Phase HPLC on Vydac C4; and finally an anion exchange chromatography on diethylamminoethyl (DEAE) Sepharose. This results in 10 batches of purified product, which are later pooled. The product is characterized by amino acid analysis, carbohydrate analysis, and physiochemical and biochemical characterization. The drug substance pool is 0.2 µm filtered into 2 L Teflon bottles and the EPO solution is stored at -60 to -90°C. The drug substance is aseptically filled (for liquid presentations) or lyophilized (for powder presentations), sealed, and packaged.

Status: Boehringer Mannheim received approvals and started marketing Recormon in Europe in 1990. NeoRecormon (replaced Recormon) was approved in the European Union (EU) on July 16, 1997. EU approvals include the various kidney dialysis- and cancer-related and other anemia-related indications: for which Epogen and Procrit are approved in the U.S.; and various EU-approved indications: for Eprex.

In Jan. 2007, the European Union (EU) approved the use of the once-weekly subcutaneous dosage (30,000 IU) of Neorecormon to treat anemia in patients with solid tumors using a prefilled syringe. Previously, it had been approved only for three-times weekly administration.

In June 2006, Chugai received supplemental approval for Epogin in Japan for treatment of anemia in premature infants.

Tech. transfer: Genetics Institute (prior to acquisition and merger into Wyeth) originally patented epoetin beta in many countries worldwide, including Europe and Japan. U.S. patents assigned to Genetics Inst. include 4,677,195 and its continuation, 5,322,837, concerning use of reverse phase high performance liquid chromatography (RP-HPLC) to obtain homogeneous EPO from human urine.

In 1992, Genetics Inst. licensed European development, manufacturing and marketing rights for its recombinant EPO beta to Boehringer Mannheim GmbH, which commercially developed Recormon/NeoRecormon. During much of the 1980s and 1990s, Boehringer Mannheim challenged Amgen/Kirin-Amgen’s EPO patents in a number of countries. As discussed in the Epogen/Procrit and EPO Products entries, Amgen prevailed in the U.S., leaving Genetics Inst. and Boehringer Mannheim without U.S. patent protection for recombinant EPO. In July 2001, Roche (after having acquired Boehringer Mannheim) settled a decade or longer European patent disputes with Amgen concerning recombinant EPO. Terms were not disclosed, but all suits were dropped and European marketing of Eprex (Ortho/J&J) and NeoRecormon continued unchanged (indicating patents were cross-licensed).

In the U.K. (and likely the rest of the European Union), patent, including SPC (patent extension), protection for NeoRecormon [and also for epoetin alpha (Eprex)], based on Amgen’s patents, is reported by the National Health Service to expire on Dec. 11, 2004.

See the CERA (pegylated EPO from Roche) entry for further discussion of Roche’s U.S. EPO patents, and an ongoing patent infringement suit against CERA brought by Amgen.

Medical: Cancer patients are generally at increased risk of thromboembolism, and EPO treatment was thought to increase this slightly. In Nov. 2004, results were reported from a meta-analysis of clinical studies involving over 1,400 patients showing that cancer patients with anemia treated with NeoRecormon appeared to benefit from a reduced risk of tumor progression. The high efficacy of NeoRecormon for EPO was also confirmed. A total of 1.413 patients were included in the analysis (NeoRecormon, n=800; control, n=613); 56% had hematological malignancies and 44% solid tumours. The rate of tumor progression was lower with NeoRecormon than in the control group (0.62 vs. 0.81 events/patient year), and there was a trend towards a reduced risk of progression among patients treated with NeoRecormon (relative risk 0.78, 95% CI 0.62, 0.99; log-rank, p=0.042). The meta-analysis confirmed the proven safety profile of NeoRecormon, and that is had no negative effect on survival in anemic cancer patients. Although NeoRecormon was associated with a slightly higher frequency of thromboembolic events compared with control treatments, it was not associated with any increase in related mortality. If studies with other EPO products do not find lack of increased risk for thromboembolism, this may allow Roche’s marketing to differentiate NeoRecormon as superior.

Market: Total 2006 worldwide sales for Neorecormon/Epogin were CHF 2.227 billion (~$1.829 billion, at 7/6/2007 exchange rate), down 1% from 2005. Total sales were ~$1.00 billion (achieving blockbuster status) in 2003, up 30% from $861.7 million in 2002. Total 2006 sales of Epogin in Japan were ~$0.5 billion.

For 2006, Roche reported that, combined sales of NeoRecormon and Epogin declined slightly overall for the year (which conflicts with available sales data reported immediately above, although difference in exchange rates at different times could account for these differences). As in 2005, market share gains in the oncology setting were driven by continued adoption of the convenient once-weekly prefilled syringe formulation, with EU authorities approving once-weekly dosing to treat anemia in patients with solid tumors in Jan. 2006. In Japan sales of Epogin declined due to government mandated price cuts and the introduction of flat-rate reimbursement for EPO products used in dialysis patients, which has reduced the overall size of the anemia market.            

Reviewing its 2005 sales, Roche reported, “Sales of Roche’s NeoRecormon and Chugai’s Epogin, for the treatment of anemia, showed healthy growth in 2005. NeoRecormon retained its leadership position in its markets despite sustained pricing pressure, with both indications: (cancer-related anemia and renal anemia) contributing to an 11% increase in sales. In the oncology setting NeoRecormon continued its strong market penetration, posting growth of 21%, well ahead of the market (9%), thanks primarily to continued adoption of the convenient once-weekly prefilled syringe formulation. NeoRecormon is now indicated for the treatment of anemia in patients with all solid and lymphoid cancers receiving any form of chemotherapy.”

The EPO market in Europe is different than in the U.S., with more companies marketing more EPO products. NeoRecormon competes with epoetin alpha (Eprex) marketed by Ortho/J&J; Dynepo marketed by Sanofi Aventis; and Aranesp marketed by Dompe Biotec S.p.A. See the related product entries.

With the adverse effects problems associated with Eprex (see related entry), sales and market share in Europe for NeoRecormon had increasing at the expense of Eprex.

R&D: Roche is developing Mircera/CERA (see related entry), a next generation of follow-on version of NeoRecormon. In Europe, Mircera will likely be positioned to replace NeoRecormon and capture market share from other EPO products.