Continuous erythropoiesis receptor activator
Encyclopedia
Continuous erythropoietin receptor activator (CERA) is the generic term for drugs in a new class of third-generation erythropoietic-stimulating agents (ESAs). In the media, these agents are commonly referred to as 'EPO', short for erythropoietin
. CERAs have an extended half-life and a mechanism of action that promotes increased stimulation of erythropoietin
receptors compared with other ESAs.
Under the trade name Mircera, Roche Pharmaceuticals received approval from the U.S. FDA in January 2008 to market a continuous erythropoiesis receptor activator (methoxy polyethylene glycol-epoetin beta
) for the treatment of anemia
in patients with chronic kidney disease, including in those undergoing dialysis
. (Patent disputes between Amgen, which owns several patents relating to recombinant EPO
variants, and Roche are blocking distribution of Mircera in the U.S.) Methoxy polyethylene glycol-epoetin beta previously was approved by the European Commission
in August 2007, and was made available in Europe at the start of 2008.
In terms of its structure, Micera is similar to the previous synthetic EPO drugs, except that it is connected to a chemical called polyethylene glycol
(PEG), which makes it last longer in the body. According to Roche, the product has the longest half-life of all FDA-approved erythropoiesis-stimulating agents (ESAs): up to 6 times longer than darbepoetin alfa and up to 20 times longer than epoetin. CERAs thus promise both lower dosing -- significant owing to the high inherent cost of manufacturing recombinant protein drugs -- and less frequent injections for patients. ESAs are administered via subcutaneous injections, often in doctor's offices for patients who lack the skill or dexterity to inject themselves, so the once- or twice-monthly dosing regimen for CERAs promises fewer costly, inconvenient office visits for patients requiring constant hemoglobin
level maintenance for chronic kidney disease.
In clinical trials, CERA dosed every 3 to 4 weeks demonstrated efficacy similar to that of epoetin alfa and darbepoetin alfa in maintaining hemoglobin concentrations within the target hemoglobin range. CERA has generally been well tolerated in clinical trials.
returned a positive A-sample test for Mircera in the 2008 Tour de France
and was ejected from the race by his team and arrested by French police . In September 2008, it was reported that samples of around 30 tour riders would be re-tested using a new, more effective test for CERA and in October 2008, two-time stage winner Stefan Schumacher
, third overall and polka-dot winner Bernhard Kohl
, and Leonardo Piepoli
tested positive for CERA .
Six weeks after the end of the 2008 Olympic Games, the IOC announced they will be retesting all doping samples from the 2008 Beijing Olympics for CERA.
The IOC announced in April 2009 that cyclist Davide Rebellin
had tested positive for CERA use.
In July 2009, the Union Cycliste Internationale
announced that Danilo Di Luca
, who had finished second in the 2009 Giro d'Italia
had samples from two stages test positive.
In the August 2009 issue of the scientific journal Comparative Exercise Physiology, Don Catlin
, M.D. and colleagues at the Los Angeles-based NGO Anti-Doping Research (ADR) reported that they developed an equine test for CERA.
In November 2009, the Olympic 1500 m champion Rashid Ramzi
was stripped of his title by the IOC after testing positive for CERA.
In July 2010 athlete Erik Tysse gave a positive CERA sample and was later banned for 2 years by IAAF.
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
. CERAs have an extended half-life and a mechanism of action that promotes increased stimulation of erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
receptors compared with other ESAs.
Under the trade name Mircera, Roche Pharmaceuticals received approval from the U.S. FDA in January 2008 to market a continuous erythropoiesis receptor activator (methoxy polyethylene glycol-epoetin beta
Methoxy polyethylene glycol-epoetin beta
Methoxy polyethylene glycol-epoetin beta is the active ingredient of a drug marketed by Hoffmann-La Roche under the brand name Mircera. Mircera is a long-acting erythropoietin receptor activator indicated for the treatment of patients with anaemia associated with chronic kidney disease. It is the...
) for the treatment of anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
in patients with chronic kidney disease, including in those undergoing dialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
. (Patent disputes between Amgen, which owns several patents relating to recombinant EPO
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
variants, and Roche are blocking distribution of Mircera in the U.S.) Methoxy polyethylene glycol-epoetin beta previously was approved by the European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
in August 2007, and was made available in Europe at the start of 2008.
In terms of its structure, Micera is similar to the previous synthetic EPO drugs, except that it is connected to a chemical called polyethylene glycol
Polyethylene glycol
Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...
(PEG), which makes it last longer in the body. According to Roche, the product has the longest half-life of all FDA-approved erythropoiesis-stimulating agents (ESAs): up to 6 times longer than darbepoetin alfa and up to 20 times longer than epoetin. CERAs thus promise both lower dosing -- significant owing to the high inherent cost of manufacturing recombinant protein drugs -- and less frequent injections for patients. ESAs are administered via subcutaneous injections, often in doctor's offices for patients who lack the skill or dexterity to inject themselves, so the once- or twice-monthly dosing regimen for CERAs promises fewer costly, inconvenient office visits for patients requiring constant hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
level maintenance for chronic kidney disease.
In clinical trials, CERA dosed every 3 to 4 weeks demonstrated efficacy similar to that of epoetin alfa and darbepoetin alfa in maintaining hemoglobin concentrations within the target hemoglobin range. CERA has generally been well tolerated in clinical trials.
Illegal use in sports
Like all previous generations of EPO, the drug has made its appearance as a doping agent in endurance sport. It was rumoured to be blocked from the kidneys due to its size and therefore undetectable by urine-based doping controls. However, professional cyclist Riccardo RiccoRiccardo Riccò
Riccardo Riccò is a professional road bicycle racer from Italy, currently under contract to UCI Continental team Meridiana-Kamen, and suspended from competition. He was ejected from the 2008 Tour de France for doping violations and suspended...
returned a positive A-sample test for Mircera in the 2008 Tour de France
2008 Tour de France
The 2008 Tour de France was the 95th Tour de France. The event took place from 5–27 July 2008. Starting in the French city of Brest, the tour entered Italy on the 15th stage and returned to France during the 16th, heading for Paris, its regular final destination, which was reached in the 21st stage...
and was ejected from the race by his team and arrested by French police . In September 2008, it was reported that samples of around 30 tour riders would be re-tested using a new, more effective test for CERA and in October 2008, two-time stage winner Stefan Schumacher
Stefan Schumacher
Stefan Schumacher is a German professional road racing cyclist.-Career:First professionally employed with Team Telekom in 2002, he was released the following year...
, third overall and polka-dot winner Bernhard Kohl
Bernhard Kohl
thumb|Bernhard Kohl wears the polka dot jersey of theTour the France at the city centre criterium inWels on 30 July 2008Bernhard Kohl is an Austrian former professional road bicycle racer and recognized climbing specialist...
, and Leonardo Piepoli
Leonardo Piepoli
Leonardo Piepoli is an Italian professional road racing cyclist. He most recently rode for on the UCI ProTour, but had his contract suspended in July 2008 during the Tour de France amid allegations of the use of the blood boosting drug EPO in the team.-Career:He is a record four-time winner of the...
tested positive for CERA .
Six weeks after the end of the 2008 Olympic Games, the IOC announced they will be retesting all doping samples from the 2008 Beijing Olympics for CERA.
The IOC announced in April 2009 that cyclist Davide Rebellin
Davide Rebellin
Davide Rebellin is an Italian road bicycle racer, currently riding for the Italian Miche-Guerciotti team. He served a 2-year suspension for testing positive for Mircera at the 2008 Olympic Games...
had tested positive for CERA use.
In July 2009, the Union Cycliste Internationale
Union Cycliste Internationale
Union Cycliste Internationale is the world governing body for sports cycling and oversees international competitive cycling events. The UCI is based in Aigle, Switzerland....
announced that Danilo Di Luca
Danilo Di Luca
Danilo Di Luca is an Italian professional road racing cyclist who rode for numerous UCI Professional Continental teams throughout his career including Liquigas-Bianchi and . He holds victories in the Giro di Lombardia in 2001, the 2005 UCI ProTour and won both the Giro d'Italia and the spring...
, who had finished second in the 2009 Giro d'Italia
Giro d'Italia
The Giro d'Italia , also simply known as The Giro, is a long distance road bicycle racing stage race for professional cyclists held over three weeks in May/early June in and around Italy. The Giro is one of the three Grand Tours , and is part of the UCI World Ranking calendar...
had samples from two stages test positive.
In the August 2009 issue of the scientific journal Comparative Exercise Physiology, Don Catlin
Don Catlin
Don H. Catlin, M.D. is an anti-doping scientist and one of the founders of modern drug-testing in sport. -Career:Catlin has overseen testing for performance-enhancing drugs at the three most recent Olympics held in the United States since the 1984 Summer Games in Los Angeles, as well as testing...
, M.D. and colleagues at the Los Angeles-based NGO Anti-Doping Research (ADR) reported that they developed an equine test for CERA.
In November 2009, the Olympic 1500 m champion Rashid Ramzi
Rashid Ramzi
Rashid Ramzi is a Moroccan-Bahraini track and field athlete competing internationally for Bahrain in the 800 metres and 1500 metres. Ramzi was investigated by the IAAF after the 2008 Summer Games and was stripped of his gold medal for doping.Ramzi was born in Asfi, Morocco...
was stripped of his title by the IOC after testing positive for CERA.
In July 2010 athlete Erik Tysse gave a positive CERA sample and was later banned for 2 years by IAAF.