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Trials and tribulations

Erythropoiesis-stimulating agents face uncertainy over patent litigation and safety concerns

Recombinant erythropoietin (EPO) has been prescribed since 1989 for the treatment of anaemia associated with chronic kidney disease. This 165-amino recombinant glycoprotein has the same mechanism as endogenous human EPO, a protein produced by the kidneys to stimulate production of red blood cells (erythropoiesis).

Since they were launched, recombinant EPOs have also been approved for the treatment of anaemia associated with various treatments and procedures, including cancer chemotherapy, zidovudine HIV therapy and surgery requiring blood transfusion.

However, the commercial viability of erythropoiesis-stimulating agents (ESAs) has come under threat in recent times due to safety concerns over the treatment of anaemia in patients with cancer, and also due to patent infringement lawsuits preventing the sale of new EPO products in the US.

The first two EPO products marketed for the treatment of anaemia were epoetin alpha (Epogen / Eprex / Procrit) and epoetin beta (NeoRecormon). Epogen was developed through a joint venture between Kirin and Amgen and was the first EPO product launched in both the US and Europe. NeoRecormon was developed by the Genetics Institute (now Wyeth) and Boehringer Mannheim, and was launched during 1997 in the EU only.

Roche acquired Boehringer Mannheim in 1998 and took on the marketing of NeoRecormon under licence from Wyeth. Both agents are produced in Chinese hamster ovary (CHO) cells and have the same amino acid sequence, but a different glycosylation pattern. Despite differing purification processes, the agents share similar efficacies and pharmacokinetic characteristics.

Kirin-Amgen has also developed and launched a second generation EPO product known as darbepoetin alpha (Aranesp). The addition of two sialic acid-containing carbohydrate chains has resulted in a longer serum half-life, less frequent dosing and more convenience for the patient compared with first generation products such as Epogen. The dosing of Aranesp reflects these improvements; the labelling recommends weekly dosing for patients who are receiving Epogen two or three times a week, or dosing once every other week for patients who are receiving Epogen on a weekly basis. 


Abarelix Plenaxis (Specialty European Pharma) Prostate cancer Germany
Hydroxocobalamin Cyanokit (Merck Serono) Cyanide intoxication Japan
Rilonacept Arcalyst (Regeneron Pharmaceuticals) Cryopurin-Associated Periodic Syndromes US
Sevelamer carbonate Renvela (Genzyme Corporation) Hypophosphataemia US
Hydrocodone/ibuprofen Ibudone (ProEthic Pharmaceuticals) Acute pain US

Patent disputes
Two new ESAs, epoetin delta (Dynepo) and methoxy polyethylene glycol-epoetin beta (Mircera), are both commercially available in the EU but not in the US due to patent disputes with Amgen. Dynepo was developed by Shire Pharmaceuticals and sanofi-aventis, and is the first ESA to be produced in human cells. This elimination of animal components reduces the potential of Dynepo to produce adverse immune reactions. The gene activation technology used in the development of Dynepo involved inserting genetic regulatory elements into chromosomes near the human gene responsible for EPO expression. Shire and sanofi-aventis believed that this technology would circumvent patents held by Amgen.

Similarly, Roche believed that its pharmaceutical compositions and processes for making Mircera were sufficiently different from those claimed under Amgen patents. Methoxy polyethylene glycol-epoetin beta is a continuous EPO receptor activator that is produced by recombinant DNA technology in CHO cells. This is a second generation epoetin beta product and was the first agent to directly convert dialysis patients to a monthly dosing schedule.

While Dynepo and Mircera were cleared by the courts for launch in Europe, production and commercialisation of these products in the US is prohibited until Amgen patents have expired.

Safety issues
Safety concerns arose in 2007 over the possibility that ESA therapy is associated with increased tumour growth and decreased survival in some patients with cancer. A randomised controlled study of Epogen among women with metastatic breast cancer was terminated prematurely when interim results demonstrated higher rates of mortality and fatal thrombotic events at four months, compared with placebo. The study was designed to evaluate survival when haemoglobin levels were maintained between 12 and 14g/dL.

Another phase II trial of Mircera in Europe for the treatment of chemotherapy-induced anaemia in patients with non-small cell lung cancer (NSCLC) was terminated because of an imbalance in the number of deaths. These are just two examples from an increasing number of studies that were terminated or reported negative safety results.

To address these concerns, the FDA has updated warnings and product labels for all ESAs. Modifications made to the prescribing information for Epogen, NeoRecormon and Aranesp in November 2007 include a specified haemoglobin target range of 10-12g/dL for patients with chronic kidney disease, and an upper limit of 12g/dL for patients with chemotherapy-induced anaemia.

For patients with cancer, the warnings also emphasise that ESAs may cause tumour growth and shorten survival at doses that attempt to achieve a haemoglobin level of 12g/dL or greater. An additional warning clarifies that ESAs should only be used in patients with cancer when anaemia is specifically caused by chemotherapy. Similar updates were adopted in the EU during March 2008 after a review of clinical data by the EMEA.

Policy change
In response to the labelling changes, the Center for Medicare and Medicaid Services (CMS) in the US has introduced a new policy to reimburse for ESAs only when the blood haemoglobin of a patient with cancer falls below 10g/dL; it will also stop paying when haemoglobin rises above this level. Considering this policy could threaten nearly $1bn worth of sales, it is not surprising that Amgen and other distributers of EPO products are lobbying for modifications to CMS policy and product warnings. The companies are also working with the US Food and Drug Administration (FDA)  and conducting additional clinical trials to determine the most appropriate target haemoglobin range.

Due to the reduced commercial prospects and limited opportunities for collaboration, Neose discontinued development of its glycoPEGylated erythropoietin product in January 2008. The agent was at the phase II stage of development and had not displayed any safety or efficacy concerns. Similarly, the future development of Mirecera is also uncertain.

Treatment with recombinant EPO undoubtedly spares some patients with cancer from blood transfusions and provides a more effective and convenient alternative to other therapies, such as androgenic hormones. However, until more comprehensive data on the risks of ESAs becomes available, safety concerns will remain.

The Author
Lauren Donely - Managing Editor, R&D Insight

19th May 2008


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