Status - marketed outside U.S.

Organizations involved:

Ortho Biologics LLC – Manuf.

Amgen, Inc. – Manuf.; R&D; Tech.

Ortho Biotech Inc. – USA mark.

Johnson & Johnson Co. – World mark.; Parent

Jannsen-Cilag – Europe mark.

OMJ Pharmaceuticals, Inc. – Former

Genetics Institute – Patent dispute; Former

Wyeth - Parent

Boehringer Mannheim GmbH – Patent dispute; Former

Hoffmann-La Roche Ltd. – Tech.; Patent dispute

Columbia University – Tech.; Patent dispute

Cross ref.: See the Erythropoietin Products entry (#132) and the entry for Epogen (#133). The EPO marketed by Ortho/J&J in the U.S. (Procrit) is manufactured by Amgen, is identical to Epogen (Albumin-stabilized formulation), while the EPO marketed as Eprex by Ortho/J&J outside the U.S. is manufactured by Ortho/J&J under license from Amgen (with the EPO from both companies, including different manufacturing facilities, considered and approved by FDA as being comparable).

Description: Eprex refers to epoetin alfa manufactured and marketed internationally by Ortho/Johnson & Johnson. Eprex is a liquid formulation of recombinant erythropoietin (EPO) glycoprotein expressed by Chinese hamster ovary (CHO) cell culture and having the same amino acid sequence as human EPO.

The bulk EPO in Eprex is manufactured by Ortho/JJ&J in its own facilities. Ortho/J&J also markets EPO as Procrit in the U.S., but using EPO manufactured by Amgen. The EPO in Eprex is essentially identical to EPO in Epogen manufactured and marketed by Amgen in the U.S. for renal disease/dialysis indications:, and marketed by Ortho/J&J as Procrit in the U.S. for other indications: (primarily anemia associated with cancer chemotherapy). The formulation of Eprex was originally the same as Epogen/Procrit, but has been changed (with considerable ramifications, as discussed below). Eprex is similar to (or biogeneric, biosimilar, a follow-on protein version of, etc.) Epogen/Procrit, with a major difference being that it has been reformulated with Albumin (Human) no longer used as a stabilizer (see Status section for adverse effects problems that have been associated with this).

Eprex is formulated as a sterile, colorless, liquid in an isotonic sodium chloride/sodium citrate buffered solution for intravenous or subcutaneous administration.

Nomenclature: EPO, rDNA/Ortho [BIO]; Epoetin Alfa [FDA CAS USAN INN BAN]; 1-165-erythropoietin (human clone lambda HEPOFL13 protein moiety) [CAS 9CI]; 1-165-erythropoietin (human clone lambdaHEPOFL13 protein moiety), glycoform alpha [CAS]; 113427-24-0 [CAS RN]; 113427-24-0 [CAS RN]; erythropoietin [SY]; erythropoietin, recombinant [SY]; EPO [SY]; rHuEPO [SY]; Eprex [TR used outside U.S.; formerly used in U.S.]; Espo [TR in Japan]; Erypo [TR in Germany, Austria]

Companies.: Epoetin alfa was originally developed and manufactured by Amgen, Inc. (Thousand Oaks, CA), FDA CBER est. no. 1080. See the Epogen entry above. In 1985, Ortho Biotech, a subsidiary of Johnson & Johnson Co. (J&J), exclusively licensed Epoetin alfa from Amgen for marketing for all indications: other than end-stage renal disease/kidney dialysis in the U.S. (retained by Amgen), and all international (i.e., non-U.S.) marketing rights. EPO is marketed as Eprex by Jannsen-Cilag, a Johnson & Johnson subsidiary, in most European countries and by Ortho/J&J affiliates internationally.

Procrit (Ortho/J&J’s trade name for EPO in the U.S. market) was originally and is still manufactured by Amgen for Ortho/J&J. Ortho/J&J has received FDA approval for manufacture of Epoetin alfa in its own facilities, and manufactures EPO (Eprex) for its own international (non-U.S.) marketing. Amgen supplied EPO to Ortho/J&J for international marketing (i.e., for Eprex) until 1995, and Amgen continues to manufacture EPO for Ortho/J&J marketing in the U.S. as Procrit.

Ortho Biologics LLC (then OMJ), J&J received FDA approval in 1995 for manufacture of bulk EPO at OMJ Pharmaceuticals, Inc./J&J facilities in Manati, Puerto Rico, filling into containers at an undisclosed facility and labeling, packaging and distribution from Ortho-McNeil facilities in Don Mills, Ontario, Canada. Approval included authorization for export of bulk product. Despite having received FDA approval for its own manufacturing of EPO, Ortho/J&J still uses bulk EPO from Amgen for manufacture of Procrit (EPO for U.S. market), and manufactures bulk EPO for its own international marketing as Eprex exclusively at its Puerto Rico facility.

Manufacture: See the EPO, rDNA/Amgen (Epogen) entry (#133). Like Epogen, CHO cell culture for Eprex takes place in large numbers of roller bottles. As discussed above, Ortho/J&J has received approval for its own manufacture of EPO,and no longer markets product manufactured by Amgen outside the U.S., i.e., Ortho/J&J manufactures its own EPO for Eprex.

FDA class: Biologic PLA BLA

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, granted to OMJ Pharmaceuticals, Inc., J&J (for Procrit using EPO from Amgen); Indication = treatment of anemia associated with renal failure [See the Epogen/Procrit entry above].

Date = 19950929; supplemental approval, PLA ref. no. 89-0136, ELA ref. no. 91-0274; Indication = approval for manufacture (and export) of bulk product at OMJ/J&J facilities in Manati, Puerto Rico, filling into containers at an undisclosed facility and labeling, packaging and distribution from Ortho-McNeil facilities, Don Mills, Ontario, Canada

Date = 19981021; supplemental approval; Indication = approval for export of Eprex with new albumin-free formulation

Date = 19990225; PLA/ELA held by OMJ Pharmaceuticals revoked and BLA granted (reissued) to another J&J subsidiary, Ortho Biologics LLC (est. no. 1265)

Status: The 1995 approval for Ortho/J&J manufacture of Epoetin alfa in its own facilities in Puerto Rico was based on a direct technology transfer from Amgen to Ortho Biologics. Since this approval, Ortho/J&J exclusively uses bulk EPO it manufactures in its Puerto Rico facility for manufacture of Exprex for international markets (while continuing to use EPO from Amgen for manufacture of Procrit marketed by Ortho/J&J in the U.S.). Prior to this approval, Ortho/J&J manufactured Eprex using bulk EPO from Amgen.

Eprex has not received centralized EU approval, with European approvals country-by-country.

[Note, the FDA approval history for Eprex is unclear. Based primarily on copies of approval letters, OMJ Pharmaceuticals (Johnson & Johnson) received original approval (PLA) for Eprex for export on June 1, 1989 (with the company, at the time using EPO obtained from Amgen). A supplemental PLA ( ref. no. 89-0136, ELA ref. no. 91-0274) was granted on Sept. 29, 1995 for manufacture (and export) of bulk product at OMJ/J&J facilities in Manati, Puerto Rico, filling into containers at an undisclosed facility and labeling, packaging and distribution from Ortho-McNeil facilities, Don Mills, Ontario, Canada. This covered approval of Eprex manufactured by J&J, not Amgen, for export. On Feb. 25, 1999, the PLA/ELA held by OMJ Pharmaceuticals was revoked and granted (reissued) to another J&J subsidiary, Ortho Biologics LLC However, Dr. J.P. Siegel, FDA, in his presentation “CBER Centennial: Issues in Therapeutics Research,” at the FDA’s 100 year biologics celebration (online at the FDA Web site) states that Eprex was approved in 1998, but this refers to manufacturing changes including a new Albumin, Human-free formulation (the Eprex formulation that has been associated with PRCA, a serious adverse effect)]. Inexplicably, Drugs@FDA, the primary public FDA-approved products database, only reports one approval for Eprex, a BLA granted on Feb. 25, 1999, to Ortho Biologics (J&J), with absolutely no other information. [Neither Ortho/J&J nor FDA provided any clarification of the approval history of Eprex in response to the author’s inquiries].

Eprex manufacture utilizes facilities, processes, and controls provided to Ortho/J&J and comparable or identical to those used by Amgen. These include an identical Master Cell Bank and essentially identical cell culture conditions, use of roller bottles, purification processes, formulation and filling operations, and quality controls spanning bulk production and lot release operations. This supplemental approval was further based on demonstration of biochemical equivalence, pharmacokinetic equivalence, and in vivo activity equivalence.

The epoetin alpha manufactured by Amgen (marketed as Epogen and Procrit) and by Ortho/J&J (marketed as Eprex) is considered by many to be equivalent, same, comparable, generic, etc. forms of the same protein, particularly because both are manufactured using substantially the same processes, recombinant constructs, raw materials, culture media, equipment, etc. (originating from Amgen). However, as illustrated by Eprex, with it having adverse effects not seen with product (Epogen, Procrit) manufactured by Amgen, even slight or undetectable differences in manufacturing methods and materials (and/or formulation) can result in a product with a different clinical adverse effects profile. Eprex, which is manufactured to be equivalent to Epogen/Procrit (except for lack of human albumin as stabilizer) is cited by many opposed to the implimentation of regulations allowing approval of generic biopharmaceuticals, particularly where the generic or follow-on product not been fully tested, e.g., in large Phase III trials, for safety and efficacy (vs. simply being shown to be comparable to the originator product based on identity and equivalent pharmacokinetics in smaller clinical trials, as is allowed for generic drug approvals).

In “The FDA’s assessment of follow-on protein products: a historical perspective,” Nature Reviews Drug Discovery (published online April 13, 2007), FDA reported on and rationalized its prior approvals of biogeneric/follow-on products. FDA noted, “Eprex was developed pursuant to a licensing agreement between Amgen and Ortho Biotech that provided Ortho Biotech with access to Amgen’s processes and procedures and source materials (the Master Cell bank), and the right to cross-reference Epogen clinical data in the Amgen licensing applications. The FDA approved Eprex for the same indications: as for Epogen based on information indicating that the manufacturing processes for Eprex and Epogen were identical or sufficiently similar and on data indicating that the products have high structural similarity, are pharmacokinetically and pharmacodynamically similar (in terms of their effect on haemoglobin levels), and have a similar clinical safety profile (incidence of adverse effects). These comparability data permitted reliance, in part, on clinical and preclinical data in Amgen’s application for Epogen to support approval of Eprex. “ The FDA also noted, “The definitive cause(s) of neutralizing anti-EPO antibodies and PRCA are still being discussed.”

Eprex, manufactured at dedicated Ortho/J&J facilities in Manati, PR, and packaged in vials in England for distribution outside the U.S., primarily Europe, has been associated with rare but very severe adverse events, particularly pure red-cell aplasia (PRCA), while Epogen/Procrit manufactured by Amgen has not. Ortho/J&J made some formulation changes in 1997, including (at the request of European Union authorities concerned with potential viral or prion contamination from a human-derived product) in 1998 eliminating use of human albumin [Albumin (Human); see related entry] as a stabilizer in Eprex vials. In Dec. 2001, J&J warned physicians in Europe and Canada that an immune response to Eprex could result in PRCA, a condition treatable only by lifelong Whole Blood and/or Red Blood Cell transfusions. In patients with PRCA having received Eprex, antibodies to the EPO protein backbone bind to both recombinant EPO (Eprex) and endogenous EPO, decreasing the levels and activity of EPO, and causing progressive loss of red blood cells (erythrocytes). At that time, J&J had discovered that 40 patients on Eprex had developed PRCA, and it revised its warning label on Eprex to reflect these cases. In Feb. 2002, French authorities identified 13 additional chronic dialysis patients who has developed severe transfusion-dependent anemia characteristic of PRCA between 1998 and 2000 after taking Eprex. In May 2002, FDA reported that post-marketing adverse event surveillance data had showed that Eprex (Ortho/J&J) is far more likely to cause pure red cell aplasia than either Epogen or Procrit (EPO manufactured by Amgen). By July 2002, about 141 suspected cases of PRCA in Eprex users had been reported, and J&J estimated incidence at 1.14 cases per 10,000 patient-years of use.

By Dec. 2002, 165 cases of Eprex-related PRCA had been reported in Europe (out of 1.7 million patient years of clinical experience in chronic renal failure). In contrast, negligible (one out of several million patients) cases of pure red-cell aplasia had been reported among U.S. dialysis patients having received Epogen (or Procrit; manufactured by Amgen and formulated with human Albumin as stabilizer) or Aranesp. Eprex is commonly self-administered by subcutaneous injection in Europe for treatment of anemia in patients with chronic renal failure, not by intravenous infusion as is the practice in the U.S. There were no known cases of PRCA associated with intravenous use of Eprex. PRCA essentially only occured in those receiving Eprex for indications: other than renal disease/dialysis (primarily anemia in patients on cancer chemotherapy, elective orthopedic surgery and autologous blood donation), with these often involving Eprex administered by subcutaneous injection.

EPO administered subcutaneously has a longer in vivo half-life than EPO administered intravenously and the skin contains cells contributing to immune responses, perhaps contributing to induction of antibody responses to subcutaneous injections of Eprex. Also, CRF patients receive EPO regularly for the rest of their life, while most other patients receive and EPO product only for a period as needed to treat anemia. These factors and/or the removal of Albumin (Human) as a stabilizer in Eprex are believed to be related to pure red cell aplasia associated with Eprex vs. Epogen and Procrit. The Albumin added to Epogen/Procrit (and formally added to Eprex) is used to stabilized the EPO protein’s sulfhydryl groups and prevent protein denaturing and aggregation. Ortho/J&J and others have speculated that the EPO in Eprex without Albumin (Human) may be more prone to agglomeration (clumping) after exposure to heat or shaking, compared to product with Albumin (Procrit, Epogen).

In Dec. 2002, with the European Union and France threatening a temporary ban or recall of Eprex, Ortho/J&N modified its European labeling for Eprex to include a warning against subcutaneous injection use in dialysis patients. In fall 2003, an article in Nature Biotechnology cited the use of the stabilizer polysorbate 80 (Tween 20) in Eprex as leading to formation of micelles which form immunogenic clusters as the apparent cause of PRCA. However, this hypothesis was widely criticized, e.g., other EPO products in the world market using other stabilizers have been associated with PRCA, ruling out this hypothesis; and investigators noted that the article implied a stronger cause-and-effect than had reported in other technical communications.

In Oct. 2001, the Ortho/J&J plant underwent a two-week FDA inspection related to cases of immunogenicity associated with Eprex. This inspection resulted in only minor observations. In June 2002, French authorities conducted a four-day plant inspection and only minor observations were noted. In July 2002, Mr. H. Arce, a former Ortho/J&J employee at its Puerto Rico Eprex manufacturing facility (involved in an employment lawsuit filed in 3/2000) alleged that Eprex manufacturing practices were unsafe and that he was forced to falsify records, including records for fermentation conditions and water used in manufacture. FDA began a criminal investigation and J&J has denied the allegations.

By late 2003, most investigators presumed that Eprex-associated PRCA was apparently associated with multiple factors, including route of administration in dialysis patients, storage and handling, and changes in the stabilizer/formulation; and the shift from subcutaneous to intravenous administration had resulted in a marked decline in the incidence of PRCA (from 3.16 cases/10,000 patients in the first half of 2002 to 0.43 cases/10,000 patients in the first half of 2003. Despite considerable effort by Ortho/J&J and others, the cause(s) of Eprex-associated PRCA had yet to be determined conclusively.

In Sept. 2004, Dr. F.G. Bader, Centocor (J&J), reported results of a company investigation of Eprex immunogenicity. The highest incidence of PRCA was in renal dialysis patients patients who received Eprex by subcutaneous administration, with a frequency of 4 cases per 10,000 patient years. Immunogenicity was attributed to leachates from the interaction between the uncoated rubber syringe stopper and the polysorbate used in the new formulation. Conversion to a FluroTec coated stopper eliminated the leachates, and the incidence of anti-EPO antibodies subsequently diminished to background level.

In the Sept. 30, 2004 issue of the New England Journal of Medicine and the Oct. 1, 2004 issue of the Journal of the American Society of Nephrology, studies of the incidence of EPO-associated PRCA were reported. Worldwide, there had been 191 reports of EPO-associated PRCA; with 92% of cases involving subcutaneous administration of Eprex to persons receiving renal dialysis. The worldwide incidence of EPO antibody-mediated pure red-cell aplasia (PRCA) peaked in 2001, and subsequently decreased by 83%. This was attributed to improved storage, handling and administration of Eprex, and the switch from subcutaneous to intravenous administration. Between 2001 and 2003, the estimated exposure-adjusted incidence of PRCA was 18 cases per 100,000 patient-years for Eprex formulated without human serum albumin, 6/100,000 patient years for Eprex formulated with human serum albumin, 1/100,000 patient years for Neorecormon, and 0.2/100,000 patient years for Epogen from Amgen.

In 2007, Ortho/J&J wanted to move beyond concerns about PRCA, but uncertainties, apparently associated with lack of full disclosures by the company, resulted in persisting questions about the actual cause(s) of Eprex-associated PRCA. For example, in “Erythropoietin-Associated PRCA: Still an Unsolved Mystery,” in the Journal of Immunotoxicology (vol. 3, p. 123-30, 2006), Dr. H. Schellekens and W.J. Jiskoot, note that after over four years, :the debate on what triggered the autoimmune disorder continues today…Leachates from uncoated rubber stoppers acting as adjuvant are blamed by the manufacturere of Eprex, but the experimental data substantiating this claim are poor and the leachates theory has no biological rationale and is also inconsistent with epidemiological and clinical data. A more likely explanation that is consistent with all data is a higher tendency for aggregate formation during handling and strorage due to the exchange of HAS by polysorbate 80 as stabilizer.” With no consensus on the cause of Eprex-associated PRCA, biogenric/biosimilar versions of the product will have a harder time receiving approval and their applications and testing will likely need to be more extensive than for most such products (clearly in favoring Ortho/J&J).

In March 2008, the insert/labeling was modified by FDA to included an updated boxed warning for the class of drugs known as erythropoiesis-stimulating agents (ESAs), including Aranesp. The warning states that ESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid and cervical cancers, when dosed to target a hemoglobin of ≥12 g/dL. In the "Increased Mortality and/or Tumor Progression" warning section of the updated labeling, the interim results of the Preoperative Epirubicin Paclitaxel Aranesp (PREPARE) study in neo-adjuvant breast cancer were added as well as follow up data from the Gynecologic Oncology Group study in cervical cancer. Amgen addressed the science and safety of ESAs in oncology, including these new data, at an ODAC meeting the next week (March 13, 2008). Amgen informed healthcare professionals about the revisions to the U.S. prescribing information through a joint "Dear Healthcare Professional" letter with Ortho Biotech.

Tech. transfer: See the EPO rDNA/Amgen (Epogen) entry. It is commonly reported that Amgen’s European patent coverage for recombinant EPO expired in 2004.

Ortho/J&J was involved in a patent dispute with Genetics Institute (now part of Wyeth), and its licensee, Boehringer Mannheim (now Hoffmann-La Roche). As discussed in the Epogen/Procrit entry, both Amgen (Kirin-Amgen) and Genetics Inst. had developed methods for recombinant manufacture of EPO. Genetic Inst. licensed its EPO technology to Boehringer Mannheim (now Roche), which markets epoetin beta (NeoRecormon) in international markets (see related entry). In July 2001, Roche settled its decade-long European patent dispute with Ortho/J&J, Amgen, and Genetics Inst. concerning recombinant EPO. Terms were not disclosed, but all suits were dropped and European marketing of Eprex (Ortho/J&J) and NeoRecormon (Roche) continued unchanged (indicating the parties cross-licensed their patents).

J&J 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 J&J 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.

Market: Total worldwide sales of Procrit and Eprex by Ortho/J&J were $1.623 billion in 2011; $1.95 billion in 2010; $2.245 billin in 2009; $2.245 billion in 2009; $2.44 billion in 2008; $3.29 billion in 2007; $1.4 billion in 2006; $1.4 billion in 2005.

Total Eprex sales were

In German pharmacies, six vials of 1 ml Erypo/Eprex dosed 2.000 IU have been reported to cost about 186.69 euros ($275 on 8/26/2008), or about $0.0229/IU.