A few days ago, The New York Times broke a story about two doping cases in cycling. On the surface, that may not seem like interesting news. We’re probably not going to spend a lot of time on positive doping cases here at Anabolic.org, as our readers are well aware that performance-enhancing drug (PED) use remains ingrained in many sports, agree with it or not. But the Times story is very interesting given the drug involved. Both cases involved FG-4592, also known as roxadustat, which is a new type of erythropoiesis stimulating agent. This drug is still in the research phases, and not yet available as a prescription anywhere in the world. We’ve been getting a lot of questions about it, and thought a quick introduction was in order.
First, let’s discuss how it works. FG-4592 (roxadustat) targets the hypoxia-sensing pathway (how the body senses low oxygen). This drug specifically acts as a prolyl hydroxylase domain (PHD) enzyme inhibitor. By blocking its targeted PHD enzyme, the drug stabilizes a protein known as HIF-2α (Hypoxia-Inducible Factor 2α), which is largely found in the kidneys. Kidney HIF-2α directly controls the transcription and production of erythropoietin (EPO), a protein that stimulates red blood cell production. Very simply put, FG-4592 (roxadustat) tricks your body into thinking oxygen levels are low. We could possibly call this an “altitude pill” if we wanted, as its effects on HIF-2α mimic some of the changes noted when a person ascends to high altitude.
Another interesting thing about this drug is that it is not a large complex peptide like erythropoietin (EPO) and its analogs, the main doping drugs of this class at present. FG-4592 is a small molecule, with the added benefit of being very stable and orally bioavailable. It can be given by pill instead of injection. This is likely to make it attractive to a much wider number of athletes. EPO drugs have had the reputation of being quite niched thus far. They have not been widely adopted by athletes, except in the most competitive circles. They are tricky to use, potentially dangerous, and carry the discomfort and stigma of injection. While we are unclear on the safety of FG-4592 and other drugs like it, we do see the potential for this class of drugs to be adopted by a much wider body of athletes, given that you simply need to swallow a pill.
But wait… The New York Times quoted AstraZeneca representative Abigail Bozarth as saying, “There is no other drug like FG-4592.” Perhaps there is an accurate statement if you view its chemical structure from a very strict perspective. In reality, FG-4592 is one of many new PHD inhibitors under development, even presently in clinical evaluation for the treatment of anemia. Some other notable agents include Akebia’s AKB-6548, BAY85-3934 from Bayer, FG-2216 and this (FG-4592), developed by FibroGen, and GlaxoSmithKline’s GSK1278863. There have actually been 22 clinical trials registered in the United States on PHD inhibitors thus far. I’ve included a quick chart that highlights them for your review, taken from a recent article in the journal Stem Cells Translational Medicine.
It is still too early to make judgments on FG-4592, or PHD inhibitors in general. There does appear to be ample data suggesting these agents work to support red cell production, as theorized. But again, none of these drugs has yet been fully evaluated for safety. So far, toxic effects have not been noticed. There is still a great deal we still don’t know about them, however, and of course, how they may be optimally used. We must remember that erythropoiesis is a potentially dangerous system to mess with. It can be a fine line between increasing hematocrit (red cell density) to a point that improves performance, and one that greatly endangers the individual with thickened blood and risk of heart attack or stroke. The potential for an easy “EPO pill” raises a lot of questions and concerns. For now, I think it is best not to experiment with black market FG-4592. We’ll likely learn much more about it in the months and years to come. In the meanwhile, this indeed is an interesting topic. I will surely try to keep tabs on it.