Erythropoietin (EPO)

 

a) First generation Erythropoietin

Epoetins are recombinant human erythropoietins that have the same amino acid sequence as endogenous EPO. However, glycosylation varies and the three currently commercially available types of epoetin (alpha, beta and omega) contain a higher proportion of sialylated, acidic carbohydrate residues than endogenous EPO.

Patents for epoetin alpha are hold by Amgen & Kirin which market epoetin alpha under the brand name Epogen and ESPO, respectively. Epoetin alpha is also marketed by licensee Johnson & Johnson in the US as Procrit and in non-US territories as Eprex. Combined worldwide 2005-sales of epotein alpha were US$ 6.163 bln . Epoetin alpha is indicated for the treatment of anemia associated with chronic renal failure including patients on dialysis and not on dialysis.Epoetin alpha is also indicated for treatment of anemia in

• zidovudine-treated HIV-infected patients,
• cancer patients on chemotherapy, and
• patients scheduled to undergo elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusion.

The European patent for epoetin alpha already has expired in 2004 and the US patent expired in 2004 (for gene) or will expire in 2013 (for compound).

Patents for epotein beta are hold by Roche and Chugai originating from Genetics Institute. The companies market epotein beta only in non-US territories under the brand name Neo-Recormon (Roche) and Epogin (Chugai), respectively. Consolidated epotein beta sales in 2005 were US$ 1.726 bln . Approved indications for epotein beta are basically the same as those for epoetin alpha. The European patent for epotein beta expired in 2006.

Both epoetin alpha and epoetin beta are produced in Chinese Hamster Ovary (CHO) cells while epotein omega is produced in Baby Hamster Kidney cells. Baxter acquired epoetein omega from Elanex Pharmaceuticals. Epoetin omega is marketed in more than 15 countries outside the US , but Baxter abandoned the development of epoetin omega (also known as Epomax) in Europe due to a change in priorities.

Epoetin delta was developed by Transkaryotic and Aventis in Europe and obtained European Marketing Authorisation. Shire Pharmaceuticals which acquired Transkaryotic Therapies, plans European market launch of Dynepo (epoetin delta) in the first half of 2007. Dynepo is procuded by gene activation technology in a “human cell line” as emphasized by Shire.

b) Second generation Erythropoietin

To maintain their market shares in the EPO business, both major players, i.e. Amgen and Roche, developed next generation EPO molecules with a longer duration of action, thus reducing the frequency of administration. Amgen achieved this goal by glycoengineering of EPO and obtained darbepoetin alfa (Aranesp or KRN321 at Kirin ). Aranesp was already approved in 2001 and achieved sales of US$ 3.273 bln in 2005. The increase of 32 % in 2005 sales of Aranesp over the previous year marks the increasing conversion from epoetin beta (decrease of 6 % for Epogen or 7 % for Procrit/Eprex). Roche’s follow-up EPO-product CERA was recently filed in the US and in the European Union for renal anemia, but immediately caused Amgen to sue Roche over alleged violation of Epogen patents. The importation of Roche’s pegylated EPO (= CERA: Continuous Erythropoiesis Receptor activator) into the USA also is subject of an investigation by the US International Trade Commission (ITC) in response to Amgen’s filing.

Thus, in the short term, the current total EPO 2005-market of more than US$ 11 bln is subject of potential shifts of market shares from Amgen to Roche and to a lesser extent to Shire provided that Shire will launch its Dynepo in the first half of 2007 and Roche will obtain approval for renal anemia during the year 2007. The development of Aranesp in further indications such as anemia in patients with heart failure may compensate for the stagnation in EPO sales or potential loss of market shares in the future.

c) EPO Biogenerics in regulated markets

In contrast to the US FDA, the European Medicines Evaluation Agency has provided a rather clear regulatory framework of guidelines for “similar biological medicinal products” regarding quality and non-clinical and clinical issues with specific annexes for individual proteins. The erythropoietin specific annex comes into effect as of July 1, 2006. For the clinical part of EPO biosimilars, the guidance recommends a comparative single-dose pharmacokinetic study including pharmacodynamics. Furthermore, at least two adequately powered, randomized, parallel groou clinical trials should be conducted in a double-blind manner. Initial indication should be renal anemia, extrapolation to other approved indications might be possible. Safety of the biosimilar EPO should be demonstrated with at least 12-month comparative immunogenicity data. These data should be presented before marketing authorization. In addition, the EMEA provides Scientific Advice on development of biosimilars in a recently improved procedure.

While the US market still seems to be prohibitive for EPO biogenerics due to the Amgen patent position, the European field now is rather open for EPO biogenerics. The publicly known, most advanced EPO development in the European Union was conducted by German company Bioceuticals, a spin-off from generic company Stada which now has a 13 % stake in Bioceuticals, but holds marketing rights for the biosimilar EPO. The company has finalized development and plans submission of the regulatory file with the EMEA by June 2006 after a recent pre-submission meeting with the EMEA. Based on the timelines of recent biosimilar approvals by the EMEA, this might enable marketing authorization of the first European EPO biosimilar in the second half of 2007. DSM Biologics of The Netherlands is manufacturing Stada’s biosimilar erythropoietin. Apart from Stada/Bioceuticals, there are nine further companies with biosimilar EPO projects in various stages of development in Europe .

However, the recent EMEA guidelines also contributed to the beginning of a consolidation process of the EPO biogeneric developments because development requires a higher than expected investment, and revenues from the European market will be rather limited. The European EPO market is considered to be about 20 to 25 % of the global EPO market. On the other hand, intensive partnering discussions are ongoing as companies attempt to enrich their renal/hemodialysis or oncology franchises with an EPO product.

Japan is not excempt from biogeneric developments, as the first development of a biogeneric EPO in Japan recently has been disclosed.

d) EPO biogenerics in non-regulated markets

As erythropoietin is a rather high price product, many countries with healthcare systems which cannot afford to pay Western prices, approved erythropoietin products originating from manufacturers which do not respect patent protection. Such biogeneric erythropoietin products primarily come from companies with a home base in South America, India, Korea and China. These products mainly serve to satisfy the EPO needs of emerging countries, but especially Indian companies are working to qualify the manufacturing of biogeneric EPO to meet European or FDA standards. As the local low price markets are rather small, these companies are aiming at Western markets in their long term business strategy.

e) Next generation Erythropoiesis Stimulating Agents (ESA)

The large EPO market is not only “attacked” by biogeneric EPO, but also by next generation erythropoiesis stimulating agents (ESA), among them also molecules which can be orally administered. The most advanced development of an oral ESA are a group of compounds originating from Fibrogen, now in co-development with Astellas for certain territories, now including Europe .