Darbepoetin alfa

Darbepoetin alfa (rINN) is a synthetic form of erythropoietin. It stimulates erythropoiesis (increases red blood cell levels) and is used to treat anemia, commonly associated with chronic renal failure and cancer chemotherapy. Darbepoetin is marketed by Amgen under the trade name Aranesp.

It was approved in September 2001 by the Food and Drug Administration for treatment of anemia in patients with chronic renal failure by intravenous or subcutaneous injection. In June 2001, it had been approved by the European Medicines Agency for this indication as well as the treatment of anemia in cancer patients undergoing chemotherapy.

It is produced by recombinant DNA technology in modified Chinese hamster ovary cells. It differs from endogenous erythropoietin by containing two more N-linked oligosaccharide chains. It is an erythropoiesis stimulating 165-amino acid protein.

Like EPO its use increases the risk of cardiovascular problems, including cardiac arrest, seizures, arrhythmia or strokes, hypertension and hypertensive encephalopathy, congestive heart failure, vascular thrombosis or ischemia, myocardial infarction and edema. A recent study has extended these findings to treatment of patients exhibiting cancer-related anemia (distinct from anemia resulting from chemotherapy). Pre-existing hypertension contra-indicates the use of darbepoetin as does existing a hematologic disease. Adverse reactions can include hypotension, fever, chest pains, nausea and myalgia.

Also like EPO it has the potential to be abused by athletes seeking an advantage. Its use during the 2002 Winter Olympic Games to improve performance led to the disqualification of cross-country skiers Larisa Lazutina and Olga Danilova of Russia and Johann Mühlegg of Spain from their final races.

Safety advisories in anemic cancer patients
Amgen sent a "dear doctor" letter in January, 2007, that highlighted results from a recent anemia of cancer trial, and warned doctors to consider use in that off-label indication with caution.

Amgen advised the United States FDA as to the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).

In response to these advisories, the FDA released a Public Health Advisory on March 9, 2007, and a clinical Alert for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents such as epogen and darbepoeitin. The advisory recommended caution in using these agents in cancer patients receiving chemotherapy or off chemotherapy, and indicated a lack of clinical evidence to support improvements in quality of life or transfusion requirements in these settings.

In addition, on March 9, 2007, drug manufacturers agreed to new "black box" warnings about the safety of these drugs. On November 8, 2007, additional "black box" warnings were included on the aranesp label, at the request of the FDA.

On March 22, 2007, a congressional inquiry into the safety of erythropoeitic growth factors was reported in the news media. Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients.

Business considerations for drug manufacturers
Epogen and Darbepoeitin alfa had more than $6 billion in combined sales in 2006. Procrit sales were about $3.2 billion in 2006.