HORMONE
ERYTHROPOIETIN
U
NDERSTANDING THE FUNCTION
ceived patent protection and began sell ing the a form of EPO in 1989. The Ge netics Institute also tried to commercial ly develop EPO-a, and the result was one of the largest patent fights in U.S. history, according to the Biotechnology Industry Organization. The case was finally settled in favor of Amgen in 1996, giving the com pany exclusive U.S. rights. Amgen manufactures and sells its Epogen brand of EPO-a in the U.S. for kid ney dialysis patients. Johnson & Johnson has a long-standing licensing agreement with Amgen to sell its Procrit brand, man ufactured by Amgen, for nondialysis uses in the U.S. through J&J's affiliate Ortho Biotech.J&J also sells its Eprex brand, man ufactured by Ortho Biologies, outside the U.S. for all uses throughJanssen-Cilag. The Amgen-J&J relationship has been a rocky one, as the two companies have battled over breaches in the EPO licensing agreement. Amgen's Epogen had 2004 U.S. sales of $2.6 billion, while J&J's Procrit and Eprex
EPOETIN ALFA Name: Erythropoietin (EPO) CAS Registry: 113427-24-0 Other names: Procrit, Epogen> Eprex Introduced: 1989, Amgen Sales: Combined 2004 sales of all EPO products was approximately $11 billion
of endogenous hormones and putting them to good use to treat diseases has been one of the great accomplishments of modern medicine. One natural hormone that has turned out to be a blockbuster generation anemia drug, darbepoetin, drug—but not without some controver which is similar to EPO but contains two sy—is erythropoietin (EPO). additional sialic acid-containing carbohy EPO is a glycoprotein (protein-sugar drate chains. The additional carbohydrate conjugate) that serves as the primary reg groups increase the activity of the hor ulator of red blood cells (erythrocytes) in mone and slow its rate of clearance from mammals. It stimulates bone marrow stem the body; thus a dose is required about half cells to differentiate into red blood cells as often as EPO. Amgen sells darbepoetand controls hemoglobin synthesis and red in-α as the Aranesp brand to treat anemia blood cell concentration. Human EPO is related to cancer chemotherapy and kid a 30,400-dalton molecule containing 165 ney failure. "Wbrldwide, Aranesp sales were amino acids and four carbohydrate chains $2.5 billion in 2004. that incorporate sialic acid residues. There Despite improving the quality oflife for are several forms of EPO, designated by hundreds of thousands of sick people, Greek letters, that differ only in the car EPO has a dark side. Endurance athletes bohydrate content. such as cyclists, distance runners, and cross-country skiers have misused recom In infants, EPO is produced mostly in binant EPO as a performance-enhancing the liver, but the kidneys become the pri drug. Clinical studies have shown mary site of EPO synthesis short that EPO can provide a 5 to 15% ly after birth. EPO production is boost in athletic performance by stimulated by reduced oxygen producing extra red blood cells to content in arterial blood in the improve oxygen uptake and thus kidneys. Circulating EPO binds aerobic power. to receptors on the surface of erythroid progenitor cells that in But EPO used this way can be turn mature into red blood cells. lethal. The additional red blood Human EPO was first isolated cells can cause "hyperviscosity" or and later purified from urine in thickened blood, particularly when the 1970s. Interest in developing athletes are dehydrated, raising the clinical uses for EPO led to the risk for heart attacks and strokes. discovery of the gene encoding The deaths of a few dozen elite ath letes, especially cyclists, have been EPO, and several groups devised linked to EPO use since the 1980s. recombinant D N A methods to A natural way to increase EPO produce EPO by the mid-1980s. production is altitude training, Recombinant EPO quickly OXYGEN BOOSTER David S. Goodsell of Scripps made it to market to treat ane Research Institute created this image of erythropoietin made famous by distance runners. Exercise physiologists have known mia resulting from a host of con (red) bound to its receptor (blue and green) from for some time that the body reditions, primarily kidney failure, coordinates taken from the Protein Data Bank. sponds to the thinner air above H I V infection in patients treat6,000 feet by increasing EPO concen ed with AZT, and cancer chemotherapy had combined 2004 sales of $3.6 billion. tration and red blood cell volume after a Doses of EPO are given by injection one Other versions of EPO include Roche's few weeks. Some studies indicate that just or more times per week to maintain a nor NeoRecormon brand of recombinant over 4 0 % of runners respond to altitude mal hematocrit level, the ratio of red blood ΕΡΟ-β, which had 2004 European sales training. cell volume to total blood volume. Gener of $1.7 billion. Transkaryotic Therapies, Cambridge, Mass., has developed ΕΡΟ-δ, ally EPO might be prescribed for any con Enzyme immunoassays can provide a and the company recently won a patent dition where blood oxygen levels are de measure of serum EPO levels, but the tests fight with Amgen over the right to sell it pressed and to help eliminate the potential can't determine if the EPO is natural or in Europe. Transkaryotic Therapies will produced recombinantly and injected by need for blood transfusions. start offering it as the Dynepo brand in unscrupulous athletes. The World AntiResearchers at Amgen and at the Ge 2006. Some generic versions of EPO are Doping Agency has now developed com netics Institute, which became part of also being marketed outside the U.S. bination urine and blood tests that can de Wyeth, were involved in separate efforts to Amgen also has developed a secondtect EPO abuse by athletes.—STEVE RITTER develop recombinant EPO. Amgen re
