SCABBING NOW A WALK IN THE PARK FOR HEMOPHILIA A SUFFERERS
Imagine tripping over your feet, face-planting on a sidewalk. You are in shorts, your knees scrape, and you are bloody. You clean it off, and soon you are the proud owner of some new scabs. Life goes on.
Let’s say you are the one of the 5,000 men with hemophilia A—a condition preventing scab formation caused by a lack of blood clotting factors. You would need to start replacement therapy right away, obtaining the missing protein factors by donor plasma or recombinant DNA technology. If you do not, the bleeding could last days, weeks, or even cause fatality. Although effective, traditional replacement therapies have been cumbersome in practice, especially for patients with severe hemophilia. This is due to the clotting factors’ instability. After infusion, the factors have a half-life of between 10 and 25 hours.
Thanks to the FDA’s approval of Biogen Idec’s Eloctate that occurred last week, hemophilia A patients have a considerably easier time acquiring scabs. Eloctate is also a type of replacement therapy, but with a twist. It is an “Fc Fusion Protein”—a hybrid protein that consists of the clotting factor fused with the Fc region of an antibody. The Fc region is a structural feature of antibodies that gives them their unusually high stability, enabling them to remain in circulation for as long as several weeks. Fusing the Fc region with clotting factors buys patients a few days of stability—long enough to reduce the frequency of administration to once every four days. Given that most receive factor VIII treatment as an intravenous infusion, this advancement promises significant quality of life improvements for those patients requiring prophylactic treatment for hemophilia.
Back in March of 2014, Biogen won approval for Alprolix, another fusion protein product (Fc-Factor IX) for the treatment of hemophilia B.
OTHER FC-FUSION PROTEINS ON THE MARKET
While Biogen is the first company to use this approach for hemophilia therapeutics, there are several other Fc fusion proteins currently on the market.
For example, rheumatoid arthritis (RA) drug Enbrel (Amgen/Pfizer) is a fusion of the tumor necrosis factor receptor (TNFR) and the Fc region of an antibody. The receptor soaks up immune system-activating tumor necrosis factor before it can fully activate the immune response, relieving the symptoms of RA. Enbrel has also been approved for psoriasis. Eylea (Regeneron) fuses an antibody Fc region with VEGFR, the receptor for vascular endothelial growth factor; Eylea soaks up VEGF, inhibiting blood vessel growth in the treatment of wet macular degeneration.
As with the hemophilia treatments, fusion with the Fc region makes these proteins more stable in the patient’s blood stream.
NATURALLY OCCURRING FUSION PROTEIN
Most fusion proteins are created in the lab for therapeutic purposes. However, one very well characterized fusion protein, Bcr-Abl, occurs in patients with chronic myelogenous leukemia (CML). Bcr-Abl is the result of a chromosomal translocation, an event in which parts of two chromosomes swap places, fusing together the genes “Bcr” and “Abl.” The result of this fusion is the chronic activation of an enzyme that turns on cell division. Gleevec (Novartis) inhibits this mutant protein and is approved for the treatment of CML.
Hemophilia is sometimes referred to as “the royal disease” because of its prevalence in the European royalty of the 19th and early 20th centuries. Those afflicted were all descendants of Queen Victoria—and royal families of Spain, Germany, and Russia were afflicted.
In 2009, scientists at the University of Massachusetts analyzed DNA from bone fragments of the Romanovs (the last Russian royal family) and found a mutation suggesting “the royal disease” was indeed hemophilia B.
TERM OF THE WEEK: DNA LIGASE
Proteins are created from recipes — what we all know as genes.
Fusion proteins are created by combining two different genes (or recipes) to produce one final product. Scientists use the enzyme DNA ligase to make the magic happen. DNA ligase can be thought of as molecular glue.
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.