Monday, June 5, 2023
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Editor's Note:
The first oral therapy for the treatment of anemia in chronic kidney disease is in phase 2 of clinical development. This oral agent is a hypoxia-inducible factor (HIF) stabilizer. HIF is a transcription factor that activates erythropoietin during hypoxic conditions and regulates iron absorption, metabolic response, and vasculogenesis. It is a possibility that the HIF stabilizer may surpass the effectiveness of recombinant erythropoietin because of its ability to stimulate iron absorption and suppress the negative effects of proinflammatory cytokines on red blood cell production. Kimberly Fricke, PharmD, interviewed John W. Adamson, MD, at the 2006 American Society of Nephrology meeting in San Diego, California, on the potential advantages of HIF stabilizers in the treatment of anemia of chronic kidney disease. Dr. Adamson is a Professor of Medicine and Head of the Division of Hematology at the Medical College of Wisconsin in Milwaukee, Wisconsin.
Medscape: Transcription of the erythropoietin gene and eventual production of erythropoietin is regulated by hypoxia-inducible factor (HIF). Can you tell us more about the role that HIF and HIF-stabilizing agents play in regulating erythropoietin production?
Dr. John W. Adamson: Erythropoietin production is regulated by oxygen availability, and in the past few years we've learned that oxygen availability is recognized by a gene product called hypoxia-inducible factor, which is found in the cells that make erythropoietin.[1] The way that HIF-1 alpha works is that, when it's stabilized, it goes to the nucleus and acts as a transcription factor. When it's destabilized, it's broken down within the cell. The new erythropoietin which targets HIF-1 alpha for stabilization actually blocks 1 of the biochemical reactions that leads to destabilization of the molecule, and consequently, HIF-1 alpha is stabilized, it goes to the nucleus, and activates erythropoietin gene production. It's a novel form of therapy to activate endogenous erythropoietin production. All of the other drugs to date have been essentially drugs that have been targeted to give erythropoietin rather than find a way to physiologically stimulate the endogenous production of the hormone.
Medscape: Can you tell us for which disease areas HIF-stabilizing agents are being studied and their significance?
Dr. John W. Adamson: HIF-stabilizing agents should be effective in virtually all of the indications that we currently recognize and perhaps even some more. For instance, the anemia of chronic renal failure is perhaps one of the largest patient populations that requires erythropoietin replacement therapy, patients with the anemia of chemotherapy, patients with cancer who are getting chemotherapy, and patients with other chronic inflammatory diseases. One of the really interesting areas that's being explored now is the field of gerontology and the anemia that's associated with advanced age. The population in the country is getting older. When you're above the age of 80, you have approximately a 20% likelihood of having anemia, often without a recognizable cause. So there's a real need for physiologic agents that can stimulate red cell production or result in the increased production of red cells in the clinic.
The other areas that this particular drug or a drug of this class has going for it is the fact that it acts across multiple genes. It's not just erythropoietin. There are several genes that are involved in hemoglobin synthesis and red cell production that are in fact activated through HIF-1 alpha. And very importantly, we've recently learned that a drug called, or a molecule called, hepcidin, which is a negative regulator of iron absorption and iron release, itself is downregulated by HIF-1 alpha stabilizers, and this opens up a whole new field for improving iron balance in patients who heretofore have had iron restricted red cell production because of inflammation.
Medscape: What are the potential advantages of an HIF-stabilizing treatment strategy for chronic kidney disease patients?
Dr. John W. Adamson: The advantages of an HIF-1 alpha-stabilizing agent, even in patients with chronic renal failure, is that it's still an endogenous source of erythropoietin as opposed to erythropoietin that has to be given by injection. That seems to me to be an advantage just in terms of being able to regulate your own gene. Now the other interesting piece of this, and this was a question that just came up at the symposium today at noon, if patients don't have kidneys how can an HIF-1 alpha-stabilizing agent work. The clear answer to that is that there are other organs, particularly the liver, that can be targeted for erythropoietin production through this mechanism that will respond very well. So I think that there are clear opportunities even in the chronic kidney disease population of patients to use an agent like this to stimulate endogenous erythropoietin production.
I think there are other advantages that HIF-1 alpha-stabilizing agents have. This, the one that's under development, of course, works orally. It would be the first agent that did not have to be injected and that has an enormous amount of convenience. The fact that you can take a pill every 2 or 3 days instead of either self-injecting or undergoing an injection of a drug seems to me to have a real advantage in terms of convenience. And, of course, injecting a drug is not the same as having your own body make the drug. It's just not quite comparable.
Medscape: What might you see as presenting disadvantages to this approach?
Dr. John W. Adamson: The disadvantages lie in the unknown. Hypoxia-inducible factor-regulated genes are genes that affect a lot of bodily functions from glucose metabolism to angiogenesis. We know that, for instance, vascular endothelial growth factor and platelet-derived growth factor are HIF-1 alpha-regulated genes, but the people who are making this drug have taken that into consideration. And so, although the information that I have is relatively sketchy, the information that has come out is that these compounds that are under study are very, very, very specifically targeted so that you don't have a lot of side effects in other oxygen-dependent or oxygen-sensitive cellular systems. How that plays out over time I think is the big question. Of course, whether this drug will work in patients who have an inability to absorb other kinds of medicines that we know about also needs to be taken into consideration. But in terms of convenience, in terms of safety, I think these are real advantages. I think that it's the nonhematopoietic effects that may crop up that I think people are sort of waiting for and might be concerned about, but so far the way the drug or the compound has been created, it's probably not fair to say it's a drug yet. The way the compound has been created and the specificity of the targets are really pretty impressive.
