Hemoglobin target in CKD-related anemia
Achieving "sweet spot" level depends on what epoetin is used
Among patients with kidney disease the ideal hemoglobin should be between 11 and 12 g/dL. A hemoglobin level above or below this so-called "sweet spot" may lead to certain risks, according to Dr. Ajay Singh, associate professor of medicine at Harvard University and clinical director of the renal division at the Brigham Women's Hospital in Boston, Massachusetts. On the other hand, achieving the "sweet spot" leads to better outcome, he said in a symposium on anemia management in chronic kidney disease (CKD) organized by Janssen Pharmaceutica. In the same symposium, Dr. Suresh Aravind, executive director at Johnson & Johnson's Pharmaceutical Services in New Jersey, discussed the issue of biopharmaceuticals and the guidelines on biosimilars issued by the European Agency for the Evaluation of Medicinal Products (EMEA).
Singh said these targets were validated in two large studies-the Normal Hematocrit Study and the Correction of Hemoglobin and Outcomes in Renal Insufficiency study-which showed that higher hemoglobin levels increased the risk of death by 30 to 34 percent. More recently, a metaanalysis of nine randomized controlled trials published in The Lancet in February 2007 (Phrommintikul et al.) concluded that when treating CKD patients with recombinant human erythropoietin for anemia, targeting higher hemoglobin concentrations puts them at increased risk of death.
Still, Singh pointed out that there are risks associated with having very low hemoglobin concentrations. Symptoms include tiredness and exhaustion, poor quality of life, high transfusion rate, and a higher rate of cardiovascular complications.
Gaining precision
Managing a patient's hemoglobin level is like balancing on a tightrope, and achieving the desired hemoglobin requires precision in treatment. But how does one achieve this? Said Singh: "We must use agents that have consistent precision … because we have a very narrow range that we need to get into." Unfortunately, the availability of biosimilars-agents that have similar activity to the innovator epoetin but not necessarily meeting its specifications-may make it difficult to reach the sweet spot.
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"Up to this point, there have been limited data on the efficacy and safety of biosimilar epoetin. They are prescribed under the assumption that they have similar safety and efficacy profiles as the innovator product," warned Singh, whose team analyzed the efficacy and safety of biosimilars. Their study of 31 samples showed that seven exceeded the pH specification, 16 exceeded osmolality specifications, one failed to meet the specification for total protein, and two exceeded the epoetin content specification.
In terms of activity, potency, and safety, one sample failed to meet the specification while 11 samples exceeded the specification in in vitro bioassays. In vivo potency tested in mice ranged from 48 percent to 163 percent, with seven samples not meeting the specification and one sample exceeding it.
Singh explained that it may be difficult to hit the hemoglobin sweet spot if "you are given molecules that are not powerful enough or too much." Another finding that should make doctors very concerned is the presence of bacterial endotoxins in two samples-something that may cause sepsis in patients, if given in large quantities.
The real deal
Epoetins fall under biopharmaceuticals, complex proteins that are complicated to produce for several reasons. For one, they are big molecules with multilevel structures and are made by living cells.
"If your cells are not in a good mood, they will die," said Aravind. "You have to make sure that the cells in your container are very happy with their living conditions." Since biosimilars are proteins, they are also more likely to induce an immune response in patients than simple, low-molecular-weight drugs. Temperature is likewise important because it can affect the structure of the protein. Both can affect the quality of the final product.
Manufacturing biopharmaceuticals begins with developing the host cell, the cell that will produce the particular protein. The host cell is multiplied and placed in special containers where they can make epoetin. Once produced, the epoetin molecules are extracted and purified. Each batch is analyzed after purification to make sure that the protein matches the given specifications. If the epoetin does not meet even one of the specifications, the entire batch is disposed of, and the process has to start again. After production, equal care goes into handling and storage of the product.
Biosimilars commonly do not meet the specifications and they usually cost less because "the purification process is very expensive, but extremely important to make sure the product is safe," pointed out Aravind. In effect, "the process is the product," as many in the biopharmaceutical industry say.
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