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Modified Erythropoietin Molecules Under Development

which are known to increase the in vivo potency and circulatory half-life of the molecule. This approach has been used to create an Fc fusion protein (Syntonix Pharmaceuticals, Inc) that can be administered by aerosol inhalation.28

Attempts have been made to fuse EPO with unrelated peptides, such as human chorionic gonadotropin beta (beta HCG)26 an antibody,27

or the Fc part of American Society of Nephrology.36 One hundred and seventeen patients

Albumin is another fusion partner of glycoproteins such as insulin and interferon. Three kinds of albumin–EPO fusion proteins (IALE, AD2LE and AD1LE) have been produced with a similar half-life and in vivo efficacy to that of darbepoetin.29

A non-glycosylated denatured EPO was obtained from Escherichia coli and then refolded and pegylated.30

The final molecule had a lower

bioactivity than rHuEPO but enhanced thermal stability and prolonged circulating half-life in rats. The addition of linear PEGs of increasing size and a branched activated PEG (PEG-2, 40kDa) progressively improves pharmacokinetic performances;31

the two 40k-PEG conjugates

demonstrated comparable in vivo efficacies to that of rHuEPO. However, even if they are effective in correcting anaemia, all these EPO-modified proteins raise some concerns about immunogenicity.32

Sotatercept (ACE-011)

ACE-011 (Acceleron and Celgene Corporation) is a novel drug being developed for the treatment of chemotherapy-induced anaemia. It is a dimeric fusion protein that targets members of the transforming growth factor-β superfamily that signal through the activin receptor type IIA (ActRIIA). The drug, consisting of the extracellular domain of the ActRIIA linked to the Fc portion of human IgG1, binds to activin, preventing activin from binding endogenous receptors and interfering with downstream signalling cascades, in particular the SMAD pathway. This pathway promotes hepcidin transcription in hepatocytes and maintains systemic iron homeostasis.33

In a phase I clinical trial in

post-menopausal females, sotatercept increased haematocrit levels.34 The drug also seems to have antitumour activity and promotes new bone formation.35

ACE-011 is currently being studied in two phase II clinical trials in cancer patients; a phase IIa, study is also ongoing to test anaemia correction in patients with CKD stage V.

Hypoxia-inducible Transcription Factor Stabilisers

The hypoxia-inducible transcription factors (HIFs) mediate the effects of hypoxia on the cell. By regulating the expression of a large array of target genes during hypoxia, these proteins also direct adaptive changes in several systems, including the hematopoietic system. Under normal conditions, the HIFα subunit is prolyl hydroxylated and then degraded. Under hypoxia, HIFα accumulates and together with HIFβ transcriptionally activates genes such as EPO. The HIF-stabilisers prevent HIF inactivation through alpha hydroxylation and thus stimulate erythropoiesis. These agents have the great advantage that they can be administered orally. The clinical development of FG-2216 (FibroGen, Inc.), the first promising molecule in this class, was halted some years ago following a case of fatal hepatitis. In 2008, phase II clinical trials in dialysis and non-dialysis patients were started with a new agent (FG-4592, FibroGen, Inc.). The preliminary findings of one of these phase II trials were presented at the 2010 annual meeting of the


with CKD stage III–IV were randomised to either FG-4592 (n=88, four doses escalating from 0.7 to 2mg/kg administered two or three times weekly) or placebo (n=28) for four weeks. The haemoglobin responder rate was dose dependent and maximal in those receiving the highest dose three times weekly. For responders, median time to haemoglobin response was 22–43 and 15–22 days for twice and three times weekly administration, respectively. Despite the rapid rate of haemoglobin rise with higher doses compared with that observed with other ESAs, a significant increase in blood pressure was observed in only one patient. No liver toxicity was described. GlaxoSmithKline is developing another prolyl hydroxylase inhibitor (GSK1278863). A single-escalating-dose, phase I clinical trial was concluded in 2009 in healthy individuals. A phase IIa clinical trial is underway to evaluate the safety, pharmacokinetics and efficacy of repeat doses in anaemic patients with CKD (both dialysis and pre-dialysis).

Gene Therapy

Several techniques have been tried to release a small but continuous amount of EPO into the circulation through EPO gene therapy.37–42 Unfortunately, these approaches are not yet used in clinical practice because it appears difficult to exactly tune the amount of EPO needed to correct anaemia, maintaining a level of expression that promotes erythropoiesis in the long term and varies according to clinic needs. Moreover, ex vivo transfected implanted cells may give rise to immunological problems.


PBI-1402 (Prometic) is a low-molecular-weight synthetic drug with erythropoiesis-stimulating activity. This compound is orally active and although it mimics the biological activity of EPO, it has a mechanism of action that is distinct from EPO because it does not bind to the same cell surface receptor. In multiple pre-clinical models it has also shown anticancer activity. Phase I studies showed a good safety profile and an increase of reticulocyte counts in healthy volunteers. A phase II trial of PBI-1402 showed a significant increase in haemoglobin levels in patients with chemotherapy-induced anaemia. Recent experiments based on a 5/6 nephrectomised rat model have demonstrated the ability of PBI-1402 to correct anaemia in this setting. These results suggest that this agent could also have a potential use in the treatment of anaemia in patients with CKD, but to date no clinical trials with this compound are under way.

Vitamin E-coated Dialysers

Oxidative stress may have an independent negative role on anaemia and ESA responsiveness; anecdotal data suggest that oral vitamin E supplementation may improve ESA responsiveness.43

Given that

blood–membrane interaction plays a key role in generating oxidative stress, direct free-radical scavenging at the membrane site has been proposed. Some studies tested the role of vitamin E-coated membranes on ESA responsiveness. One study found that a significantly higher proportion of patients achieved the recommended haemoglobin target while receiving a lower ESA dose after being shifted from their previous dialyser to a vitamin E-coated membrane.44 However, improved ESA responsiveness may also have been caused by enhanced membrane biocompatibility. More recently, a pilot, open, controlled, randomised study of 20 haemodialysis patients compared a synthetic polysulphone dialyser with and without vitamin E.45

A clear

trend towards a greater decrease in the ESA resistance index (i.e. the ratio between haemoglobin and ESA dose) was found in the vitamin E


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