Jerry Powell © UC Regents
The recombinant protein fuses clotting factor IX with an immunoglobulin (antibody) molecule, which prevents the body from rapidly metabolizing the hybrid protein. As a result, rFIXFc can be administered once a week, or even every two weeks, rather than every other (or every third) day. This extended half-life could have an enormous impact on hemophilia treatment. The findings appeared in today’s New England Journal of Medicine.
“The major challenge is spontaneous bleeding, either in weight-bearing joints or internally,” said lead investigator Jerry Powell, who directs the UC Davis Hemophilia and Thrombosis Center. “These events can be painful, life-threatening or both. To compound matters, teenage boys often drop off infusing, increasing their risk. Fewer injections should improve compliance.”
Hemophilia B is a congenital disorder caused by reduced levels of clotting factor IX, a protein that helps blood coagulate. By contrast, hemophilia A, the most common form of the disease, is caused by a loss of factor VIII. These conditions almost always affect men.
The trial enrolled 123 patients, 12 or older, who had been treated previously for hemophilia B and was divided into four groups: the first received weekly injections; the second received higher doses every 10 days; the third was only treated for specific bleeding episodes; and the fourth focused on how patients fared while undergoing surgery. An additional subgroup compared rFIXFc’s half-life in the body to that of recombinant factor IX.
The median treatment time was 51.6 weeks, during which compliance was excellent: 95.1 percent in group 1 and 100 percent in group 2. But most importantly, the annualized bleeding rate was reduced by 83 percent in group 1 and 87 percent in group 2, compared to patients receiving episodic treatment in group 3.
In addition, 23 percent of patients in group 1 and 42.3 percent in group 2 experienced no bleeding at all. In group 4, there were 14 surgeries, during which bleeding was well-controlled.
Before the study, more than 80 percent of participants in the first two groups injected at least twice a week. However, with rFIXFc, they only needed to infuse once a week, or every two weeks, to effectively control their bleeding.
While recombinant clotting factors have dramatically extended lifespans for hemophiliacs, the proteins’ short half-lives have been a limiting factor. The problem stemmed from lysosomes, cellular “chop shops” that break down proteins and other molecules. However, fusing an immunoglobulin molecule to factor IX allows the hybrid protein to temporarily escape the lysosomes, providing coagulation protection for a much longer period.
“This is a major innovation,” said Powell. “The body handles rFIXFc like an immunoglobulin molecule, but the factor retains its ability to stop bleeding.”
Some issues still need to be resolved. For example, as many as 3 percent of patients have an immune reaction to factor IX. Because the study was narrowly focused on whether the combined factor would effectively control bleeding, and all participants had successfully used factor IX, researchers did not address whether previously untreated hemophiliacs would develop an immune response to rFIXFc. This question will be addressed in future research. However, none of the study participants had an immune reaction to rFIXFc.
In addition, although the new factor is designed to treat only hemophilia B, the trial’s success outlines an effective strategy to develop long-lasting factors for other forms of the disease.
“This is the first modification to coagulation factors to increase the half-life,” Powell said. “My hope is that other pharmaceutical companies will focus on developing additional long-lasting factors to treat other types of hemophilia.”
The recombinant protein rFIXFc was created by Biogen-Idec. The company paid for extra staff to coordinate the study and lab tests and provided rFIXFc for the trial. In addition, some patients were reimbursed for travel expenses. Powell did not receive any compensation from Biogen-Idec to conduct the research.