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New Treatment Approaches in Chronic Kidney Disease-associated Anaemia


Table 1: New Erythropoiesis-stimulating Agents Under Clinical Development in Patients with Chronic Kidney Disease According to the Development Phase


Drug


Peginesatide (Hematide™) ACE-011


FG-2216 FG-4592


GSK1278863 CNTO 530


CNTO 528 Company


Affymax and Takeda


Acceleron and


Celgene Corporation FibroGen


FibroGen


GlaxoSmithKline Ortho Biotech


Ortho Biotech Structure


Small dimeric peptide + PEG moiety


Dimeric fusion protein


targeting the TGF-β superfamily Prolyl hydroxylase inhibitor


Prolyl hydroxylase inhibitor Prolyl hydroxylase inhibitor Two 20-amino acid peptides + human IgG4 Fc


Two 20-amino acid peptides + human IgG4 Fc human IgG4 Fc


Mechanism of Action EPO receptor activation


Blocking of the SMAD pathway


EPO gene transcription


EPO gene transcription EPO gene transcription EPO receptor activation


EPO receptor activation


Administration Development Route


SC and IV SC and IV PO


PO PO


SC and IV SC and IV EPO = erythropoietin; Ig = immunoglobulin; IV = intravenous; PEG = polyethylene glycol; PO = oral; SC = subcutaneous; TGF = transforming growth factor.


polyethylene glycol (PEG) moiety. The molecular weight of CERA is nearly double that of EPO and it has a much longer half-life (~130 hours).9


Like darbepoetin alpha, the binding affinity of CERA for the erythropoietin receptor is also reduced but to a far greater extent. This peculiarity may contribute to distinct pharmacological characteristics (it has been hypothesised that the same CERA molecule may activate the EPO receptor several times without being internalised). The dose does not need to be modified according to the administration route.


Erythropoietin Mimetic Peptides


In 1996, peptides with no sequence homology to EPO but with EPO receptor specificity were identified.10,11


However, because of their


low molecular mass they were rapidly excreted in urine. A small dimeric peptide was then conjugated to a polyethylene glycol moiety to form a new drug, peginesatide (Hematide™, Affymax and Takeda), which has a highly specific binding to the EPO receptor, with five-times less binding potency than epoetin or darbepoetin alpha.12


Two other non-erythropoietin-derived EPO-receptor agonists have been recently developed by Ortho Biotech Inc. and are undergoing clinical evaluation. Two sequences of a 20-amino acid peptide with weak EPO-like bioactivity (EMP1) were coupled with a human immunoglobulin (Ig) G4 Fc. The molecule obtained, CNTO 530, selectively binds the EPO-receptor.19


In animal studies, it is a more


Unlike rHuEPO and its analogues, and similar to the first peptides, peginesatide is partially cleared by the kidney. Accordingly, CKD patients needed half the dose of healthy volunteers to achieve similar efficacy. Like other long-acting ESAs, peginesatide pharmacodynamics and dose requirement are irrespective of the administration route. Owing to the fact that peginesatide has a molecular structure unrelated to that of EPO, it was used to correct anaemia in a rat model of antibody-mediated pure red-cell aplasia (PRCA)13


out of 14 patients with CKD and PRCA.14 or cancer17


and then found to be effective in 13 Phase I and II trials showed


a good efficacy and safety profile for the drug in healthy volunteers15 and in patients with CKD16


when given once a month


either intravenously or subcutaneously. In June 2010, Affymax and Takeda announced preliminary results of phase III clinical trials in CKD patients.18


The four studies (EMERALD 1, EMERALD 2, PEARL 1 and PEARL 2), which enrolled more than 2,000 patients for a median follow-up of 1.3 years, showed non-inferiority in the mean change in haemoglobin from baseline compared with epoetin and darbepoetin in correcting and/or maintaining haemoglobin in the target range.


Although the combined four studies showed that peginesatide was not inferior to the other ESAs in the risk of cardiovascular composite safety end-points, subgroup analysis of patients not on dialysis found a higher frequency of cardiovascular events in the peginesatide


EUROPEAN ONCOLOGY & HAEMATOLOGY


potent stimulator of erythropoiesis than epoetin-alpha or darbepoetin alpha.20


phase I clinical development.21


A similar molecule, CNTO 528, has undergone Single intravenous administration of


CNTO 528 at ascending doses (from 0.03 to 0.9mg/kg) stimulated the production of reticulocytes, red blood cells and haemoglobin in 24 healthy volunteers. Similar findings were obtained in another single and fractional ascending dose study of 44 healthy adult volunteers.22 Of the ESAs developed to date, CNTO 528 has the longest half-life (four to seven days).


Agonistic Antibodies Targeting the Erythropoietin Receptor


Mouse monoclonal antibodies against the soluble extracellular domain of the human EPO receptor were developed some years ago.23,24


These antibodies mimic EPO activity but activate the EPO receptor poorly. More recently, ABT-007 (Abbott Bioresearch Center) has been developed.25


According to data obtained using a


transgenic mouse model expressing the human EPO receptor (ABT-007 does not recognise the rodent EPO receptor), this is a potent in vivo stimulator of erythropoiesis requiring less-frequent dosing than darbepoetin alpha. In addition, ABT-007 dosing in transgenic mice resulted in less fluctuation of haematocrit than that observed following darbepoetin dosing. Like other long-acting ESAs, increases in haematocrit were similar following either subcutaneous or intravenous administration of ABT-007.


133


group compared with the other ESAs (21.6 and 17.1%, respectively; hazard ratio [HR] 1.34, 90% confidence interval [CI] 1.03–1.73). The clinical meaning of this finding is unclear because it is unlikely that a single ESA would increase cardiovascular risk independently from the haemoglobin target, particularly in non-dialysis patients where doses are much lower than in those receiving dialysis. The HR in the non-dialysis patients was primarily driven by higher rates of death, unstable angina and arrhythmia events in the peginesatide group, but these comorbidities are usually more frequent in dialysis than in non-dialysis patients.


Phase III


IIa


II, not actively recruiting II I I


I


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