The management of anemia associated with kidney disease is undergoing a revolution as the safety of erythropoietin analogs is being challenged by newly recognized dangers including cardiovascular disease, strokes, access failures and malignancy. Anemia protocols have been adjusted by changes in FDA labeling and conflicts between high quality observational data and a few well done randomized controlled trials. Dr. Iain Macdougall (IM), Department of Renal Medicine, King’s College Hospital, London UK, discusses newer anemia therapies with Dr. Joel Topf, eAJKD web advisory board member. Dr. Macdougall reviews various strategies and highlights the promising agents that will hopefully be available to safely help patients in the future.

His review covers:

• Peginesatide: a small peptide that activates erythropoietin receptors despite not sharing structural homology with native erythropoietin.
• Hypoxia inducible factor (HIF) stabilization: stimulates endogenous erythropoietin by altering the signals that regulate gene transcription. The fact that these agents are pills rather than injections make these agents particularly interesting.
• Hepcidin modulation: a novel approach to anemia that switches the focus from erythropoietin to iron utilization. Drugs that lower hepcidin activity increase iron availability.
• GATA-2 inhibitors: enhance erythropoietin transcription.
• Gene therapy: human trials have shown the effectiveness of splicing the erythropoietin gene into skin cells and then transferring the cells back into the patient. This procedure increased erythropoietin production and resulted in correction of anemia in CKD.

eAJKD: What is the role of non-erythropoietin anemia agents after publication of the TREAT and Normalization of Hematocrit studies?

IM: We have had erythropoietic agents for over 20 years now. We have used them extensively. There have been a number of trials that have raised some concerns, such as the studies you mentioned and additionally CHOIR and CREATE. The hypothesis that has been generated from post-hoc analysis of some of these studies is that high doses of the erythropoietin may be harmful. There are additional effects to their anti-apoptotic actions on red cells, and these pleiotropic actions on endothelium, platelet function, and possibly tumor growth, amongst other things, are probably dose-related and perhaps due to high exposure to erythropoietin. Hence, there is a need for alternative substances that may avoid exposing patients to very high levels of erythropoietin.

eAJKD:  Do you think that peginesatide might have a more narrow range of activity or fewer of these pleiotropic effects?

IM: There was a very good editorial review written by Dr. Franklin Bunn from Harvard University in the New England Journal Medicine in November 2009 concurrent with publication of the paper on peginesatide treatment for pure red cell aplasia.  Bunn postulated that peginesatide, being unique from erythropoietin, might have distinct biologic effects to epoetin and may be safer. Of course the proof is still pending. The PEARL studies did have a safety signal in the nondialysis patient population (increased harm from peginesatide) versus a comparator ESA. That safety signal was not seen in a study in the dialysis population.

eAJKD: Can you please comment more on the safety concerns from PEARL?

IM: Based on the data that has been presented at the ASN Congress in 2010 and the European Renal Association Congress earlier this year, the line was a hazard ratio of 1.32 for the composite safety end-point for peginesatide compared with the darbepoietin.

eAJKD:  What about stroke or malignancy risk?

IM: PEARL was not powered to show a difference in stroke. There was no stroke or malignancy safety signal at all. While both of these were concerns with TREAT, neither was shown in the peginesatide studies.

eAJKD: There was an intriguing paragraph in which you describe a theory that endogenous erythropoietin may be safer then exogenous erythropoietin. Can you comment on that?

IM: There is circumstantial data that high circulating concentrations of erythropoietin may be harmful. The HIF stabilizers are able to continuously drive EPO gene transcription and evoke a more continuous erythropoietin response without reaching the erythropoietin levels seen with intermittent erythropoietin injections.

The hope is that lower levels of erythropoietin will allow effective erythropoiesis and a better safety profile. However it is possible that they will bring with them separate and novel safety concerns. Also, they are oral tablets.

There are several HIF stabilizers in clinical trials. At least 3 companies are developing HIF stabilizers. It may end up resembling the ACE inhibitor field rather than the ESA market with multiple molecules competing in the class with similar activities but individual variations in potency and effectiveness. There was some concern with the initial FG2216 molecule regarding hepatic toxicity but no toxicity concerns have been raised in the second generation of molecules.

eAJKD: It was intriguing that FG4592 was associated with decreases in hepcidin levels, is that true?

IM: Yes, that is true. There is an upside and a downside to these products. The upside is that it makes the bone marrow more sensitive to erythropoietic stimulation. It will up-regulate iron transporter genes and proteins, increase iron availability, and promote erythropoiesis. The downside is that there are other actions and genes that one might not want activated.

eAJKD:  Is this effect on hepcidin a general property of HIF stabilizers or specific to FG4592?

IM: The molecules are different and I don’t think it can be assumed that every HIF stabilizer will have a similar effect profile. They may not all lower hepcidin. I think it is likely, but the only way to be sure is to do a trial.  The only HIF stabilizer that has been shown to lower hepcidin at this point is FG4592.

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