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Experts are thrilled about the development of a new iron chelation drug that could be taken orally, changing the lives of patients who need chronic blood transfusions.
A new therapy for patients with too much iron in their systems, Exjade (deferasirox), received positive reviews from FDA’s Blood Products Advisory Committee on September 29. If approved, Exjade would be the first oral drug available in the United States to help patients eliminate excess iron.
An alternative to an older drug that is administered over many hours through a needle under the skin. Exjade is eagerly anticipated by specialist physicians and patients with blood disorders.
Exjade won unanimous committee support even though its trials did not demonstrate “non-inferiority” to Desferal (deferoxamine), the only other drug available in the United States. Novartis manufactures both drugs.
The company claimed that Exjade is just as effective as Desferal but that the doses of the new drug for patients in the trials were too low. Exjade performed as well as its predecessor among a smaller subset of trial patients who were given higher doses, according to Novartis’ presentation to the committee.
What it Treats
Iron chelation therapy is an unusual treatment designed to help patients with too much iron in their blood and livers. In most cases it does not treat a disease. Iron overload is usually a byproduct of prolonging a patient’s life with blood transfusions, explained Bryan Mackenzie, an assistant professor of cellular and molecular physiology at the University of Cincinnati.
Most patients in the Exjade trials suffered from thalassemia major, a genetic blood disorder that decreases people’s ability to make all of the components of hemoglobin, the part of the red blood cell that transports oxygen throughout the body. Iron is an essential part of hemoglobin and is necessary for binding oxygen.
As a result of low hemoglobin, thalassemia patients need regular blood transfusions, said Kenneth Bridges an assistant professor at Harvard Medical School and doctor at Brigham and Women’s Hospital.
The transfusions add hemoglobin, Bridges explained. But because patients already have the iron-component of hemoglobin, the additional iron in the transfused blood creates a toxic build-up in their organs, especially the liver, heart and pancreas.
“The overload of iron is a byproduct of medical advances,” Bridges said.
Thalassemia patients’ bodies also absorb more than the normal amount of iron from food, Mackenzie explained, enhancing the overabundance. Their bodies are trying to generate more red blood cells in response to the lack of hemoglobin. As a result, they increase the uptake of iron in the intestines.
Although iron is necessary for normal functioning, it is difficult for the body to get rid of excess, according to Thomas Coates, an associate research professor at the Los Angeles Children’s Hospital. Most people lose about 1 milligram of iron each day through their intestines and menstrual blood, Coates said. The body recycles the rest.
“The body has no mechanism to protect itself when it exceeds its ability to eliminate iron,” he explained.
How Chelation Therapy Works
Iron chelation drugs bind excess iron, and take it with them when they are eliminated from he body as waste. The existing therapy, Desferal, uses a large water-soluble molecule to bind iron. Water-solubility allows it to be eliminated from the body easily, Mackenzie said. But it also makes it difficult for the drug pass through the water-repellant membranes surrounding a cell, which it must do to reach the iron.
Because of its structure, it is absorbed into the intestines too slowly for oral ingestion to be effective. And it passes through cell membranes so slowly that it must be administered over 10 to 12 hours, usually via a needle pumping the drug under the skin while the patient sleeps, Coates said.
How it is Different
But Exjade has a lower molecular weight and is fat soluble, which helps it pass through cell membranes to reach iron, according to Novartis spokeswoman Kim Fox.
“It’s a completely different chemical entity from Desferal,” she said, noting that Ciba-Geigy, which merged with Sandoz to form Novartis in 1996, began the research on the delivery technology.
This change in structure allows the drug to be delivered orally once a day and absorbed in the intestines, Coates explained. Eighteen of his patients participated in clinical trials for Exjade.
“It really has changed a lot of lives,” he said. “This is a huge thing.”
Coates and Bridges both noted that compliance can be a problem for patients on Desferal because of the time commitment and discomfort of taking the drug.
Even though Exjade does not bind iron better than Desferal, the improvement in patients’ quality of life would be a major benefit, Mackenzie said. He noted that bad compliance can lead to heart damage and the need for cardiac drugs later in life.
Other Diseases it Treats
Although Exjade was primarily tested on patients with thalassemia, it is also indicated for others who need frequent transfusions. Patients with sickle cell disease and hemochromatosis, a hereditary disease in which the body absorbs too much iron from food, also need iron chelation therapy, Mackenzie said. It could also be used after transfusions following bone-marrow transplants, Bridges added.