This page contains a Flash digital edition of a book.
New Treatment Approaches in Chronic Kidney Disease-associated Anaemia

treated group compared with the control group (37 versus 20%, p = not significant); this difference became statistically significant when analysed using multivariate analysis. Further larger studies need to demonstrate that these membranes have significant positive clinical effects in order to balance high treatment costs.


RHuEPO has been available to treat anaemia in patients with CKD for the past twenty years. More recently, long-acting rHuEPOs with modified molecular structures have also entered the market offering the advantage of less-frequent administration schedules. All these molecules are effective in correcting anaemia and decreasing transfusion needs. However, the treatment of anaemia with rHuEPO or its analogues is quite expensive, given that their synthesis, like that of other biomolecules, is complex. New ESAs are or will be even more expensive than rHuEPO because of the high costs of the pharmacological research, which has not yet been covered by years of selling. Moreover, safety concerns have been raised recently about the use of ESAs that may be associated with increased

1. McClellan WM, Aronoff SL, Bolton WK, The prevalence of anaemia in patients with chronic kidney disease, Curr Med Res Opin, 2004;20:1501–10.

2. Locatelli F, Pisoni RL, Combe C, et al., Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS), Nephrol Dial Transplant, 2004;19:121–32.

3. Storring PL, Tiplady RJ, Gaines Das RE, et al., Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties, Br J Haematol, 1998;100:79–89.

4. Powell JS, Berkner KL, Lebo RV, et al., Human erythropoietin gene: high level expression in stably transfected mammalian cells and chromosome localization, Proc Natl Acad Sci U S A, 1986;83:6465–9.

5. Kwan JT, Pratt RD, The Epoetin Delta Study Group, Epoetin delta, erythropoietin produced in a human cell line, in the management of anaemia in predialysis chronic kidney disease patients, Curr Med Res Opin, 2007;23:307–11.

6. Nimtz M, Martin W, Wray V, et al., Structures of sialylated oligosaccharides of human erythropoietin expressed in recombinant BHK-21 cells, Eur J Biochem, 1993;213:39–56.

7. Egrie JC, Browne KJ, Development and characterisation of novel erythropoiesis stimulating protein (NESP), Nephrol Dial Transplant, 2001;16(Suppl. 3):3–13.

8. Locatelli F, Canaud B, Giacardy F, et al., Treatment of anaemia in dialysis patients with unit dosing of darbepoetin alfa at a reduced dose frequency relative to recombinant human erythropoietin (rHuEpo), Nephrol Dial Transplant, 2003;18:362–9.

9. Chanu P, Gieschke R, Charoin JE, et al., Population pharmacokinetic/pharmacodynamic model for C.E.R.A. in both ESA-naive and ESA-treated chronic kidney disease patients with renal anemia, J Clin Pharmacol, 2010;50:507–20.

10. Livnah O, Stura EA, Johnson DL, et al., Functional mimicry of a protein hormone by a peptide agonist: the EPO receptor complex at 2.8 A, Science, 1996;273:464–71.

11. Wrighton NC, Farrell FX, Chang R, et al., Small peptides as potent mimetics of the protein hormone erythropoietin, Science, 1996;273:458–64.

12. Fan Q, Leuther KK, Holmes CP, et al., Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia, Exp Hematol, 2006;34:1303–11.

13. Woodburn KW, Fan Q, Winslow S, et al., Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model, Exp Hematol, 2007;35:1201–8.

14. Macdougall IC, Rossert J, Casadevall N, et al., A peptide- based erythropoietin-receptor agonist for pure red-cell aplasia, N Engl J Med, 2009;361:1848–55.

15. Stead RB, Lambert J, Wessels D, et al., Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo- controlled, dose-escalation study in healthy volunteers, Blood, 2006;108:1830–4.

16. Besarab A, Zeig S, Geronemus R, et al., Hematide, a synthetic peptide-based erythropoiesis stimulating agent, maintains hemoglobin in hemodialysis patients previously treated epoetin alfa (erythropoietin). Presented at the National Kidney Foundation Spring Clinical Meeting, Orlando, FL, 10–14 April 2007.

cardiovascular risks following targeting to high haemoglobin levels and/or exposure to excessive doses46 tumour control in the oncology setting.47

and reduced survival and This will entail additional

requirements to be fulfilled by the drugs under development before clinical approval, which will further increase costs. However, the synthesis of simpler molecules not related to ESA structure may lead to the creation of cheaper ESAs that would revolutionise the market. In this respect, peginesatide seems to be the most promising in the near future. CNTO 530 and CNTO 528, two non-erythropoietin derived EPO-receptor agonists, are also under clinical development. Given their long half-life, they are likely to be administered less frequently than peginesatide. In the meantime, biosimilars of rHuEPO have entered the market in many European countries and compete economically with the originator or long-acting ESAs.

New approaches to stimulate erythropoiesis will not only need to be effective and safe, but will also need to be a substantial improvement on rHuEPO or other available ESAs, or be cheaper thanks to the development of simpler manufacturing processes. n

17. Pickering LM, Cwiertka K, Jassem J, et al., Hematide, a synthetic peptide-based erythropoiesis stimulating agent (ESA), assessed for correction of anemia in oncology patients receiving chemotherapy, Blood, 2006;108:378a.

18. Affymax and Takeda announce phase 3 trials meet primary endpoints for investigational drug, Hematide™/peginesatide, to treat anemia in chronic renal failure with some differences noted in secondary analyses. Available at: www.investors (accessed 5 November 2010).

19. Bugelski PJ, Capocasale RJ, Makropoulos D, et al., CNTO 530: molecular pharmacology in human UT-7EPO cells and pharmacokinetics and pharmacodynamics in mice, J Biotechnol, 2008;134:171–80.

20. Sathyanarayana P, Houde E, Marshall D, et al., CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools, Blood, 2009;113:4955–62.

21. Pérez-Ruixo JJ, Krzyzanski W, Bouman-Thio E, et al., Pharmacokinetics and pharmacodynamics of the erythropoietin Mimetibody construct CNTO 528 in healthy subjects, Clin Pharmacokinet, 2009;48:601–13.

22. Bouman-Thio E, Franson K, Miller B, et al., A phase I, single and fractionated, ascending-dose study evaluating the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of an erythropoietin mimetic antibody fusion protein (CNTO 528) in healthy male subjects, J Clin Pharmacol, 2008;48:1197–207.

23. Schneider H, Chaovapong W, Matthews DJ, et al., Homodimerization of erythropoietin receptor by a bivalent monoclonal antibody triggers cell proliferation and differentiation of erythroid precursors, Blood, 1997;89:473–82.

24. Elliott S, Lorenzini T, Yanagihara D, et al., Activation of the erythropoietin (EPO) receptor by bivalent anti-EPO receptor antibodies, J Biol Chem, 1996;271:24691–7.

25. Liu Z, Stoll VS, Devries PJ, et al., A potent erythropoietin- mimicking human antibody interacts through a novel binding site, Blood, 2007;110:2408–13.

26. Fares F, Ganem S, Hajouj T, Agai E, Development of a long- acting erythropoietin by fusing the carboxyl-terminal peptide of human chorionic gonadotropin beta-subunit to the coding sequence of human erythropoietin, Endocrinology, 2007;148:5081–7.

27. Schriebl K, Trummer E, Lattenmayer C, et al., Biochemical characterization of rhEpo-Fc fusion protein expressed in CHO cells, Protein Expr Purif, 2006;49:265–75.

28. Dumont JA, Bitonti AJ, Clark D, et al., Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway, J Aerosol Med, 2005;18:294–303.

29. Joung CH, Shin JY, Koo JK, et al., Production and characterization of long-acting recombinant human albumin- EPO fusion protein expressed in CHO cell, Protein Expr Purif, 2009;68:137–45.

30. Wang YJ, Liu YD, Chen J, et al., Efficient preparation and PEGylation of recombinant human non-glycosylated erythropoietin expressed as inclusion body in E. coli, Int J Pharm, 2010;386:156–64.

31. Wang YJ, Hao SJ, Liu YD, et al., PEGylation markedly enhances the in vivo potency of recombinant human non- glycosylated erythropoietin: a comparison with glycosylated

erythropoietin, J Control Release, 2010;145:306–13.

32. Coscarella A, Liddi R, Di Loreto M, et al., The rhGM-CSF-EPO hybrid protein MEN 11300 induces anti-EPO antibodies and severe anaemia in rhesus monkeys, Cytokine, 1998;10:964–9.

33. Finberg KE, Whittlesey RL, Fleming MD, Andrews NC, Down- regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis, Blood, 2010;115:3817–26.

34. Ruckle J, Jacobs M, Kramer W, et al., Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women, J Bone Miner Res, 2009;24:744–52.

35. Raje N, Vallet S. Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss, Curr Opin Mol Ther, 2010;12:586–97.

36. Besarab A, Hulter HN, Klaus S, et al., FG-4592, a novel oral HIF prolyl hydroxylase inhibitor, elevates hemoglobin in anemic stage 3/4 CKD patients. American Society of Nephrology Renal Week 2010; Denver, CO, USA, 16–21 November 2010. Abstract SA-FC416.

37. Sebestyén MG, Hegge JO, Noble MA, et al., Progress toward a nonviral gene therapy protocol for the treatment of anemia, Hum Gene Ther, 2007;18:269–85.

38. Fattori E, Cappelletti M, Zampaglione I, et al., Gene electro- transfer on an improved erythropoietin plasmid in mice and non-human primates, J Gene Med, 2005;7:228–36.

39. Eliopoulos N, Gagnon RF, Francois M, Galipeau J, Erythropoietin delivery by genetically engineered bone marrow stromal cells for correction of anemia in mice with chronic renal failure, J Am Soc Nephrol, 2006;17:1576–84.

40. Oh TK, Quan GH, Kim HY, et al., Correction of anemia in uremic rats by intramuscular injection of lentivirus carrying an erythropoietin gene, Am J Nephrol, 2006;26:326–34.

41. Kakeda M, Hiratsuka M, Nagata K, et al., Human artificial chromosome (HAC) vector provides long-term therapeutic transgene expression in normal human primary fibroblasts, Gene Ther, 2005;12:852–6.

42. Gothelf A, Hojman P, Gehl J, Therapeutic levels of erythropoietin (EPO) achieved after gene electrotransfer to skin in mice, Gene Ther, 2010;17:1077–84.

43. Cristol JP, Bosc JY, Badiou S, et al., Erythropoietin and oxidative stress in haemodialysis: beneficial effects of vitamin E supplementation, Nephrol Dial Transplant, 1997;12:2312–7.

44. Cruz DN, De Cal M, Garzotto F, et al., Effect of vitamin E-coated dialysis membranes on anemia in patients with chronic kidney disease: an Italian multicenter study, Int J Artif Organ, 2008;31:545–52.

45. Andrulli S, Di Filippo S, Manzoni C, et al., Effect of synthetic vitamin E-bonded membrane on responsiveness to erythropoiesis-stimulating agents in hemodialysis patients: a pilot study, Nephron Clin Pract, 2010;115:c82–9.

46. Locatelli F, Aljama P, Canaud B, et al., Target haemoglobin to aim for with erythropoiesis-stimulating agents: a position statement by ERBP following publication of the trial to reduce cardiovascular events with Aranesp therapy (TREAT) study, Nephrol Dial Transplant, 2010;25:2846–50.

47. Bohlius J, Schmidlin K, Brillant C, et al., Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials, Lancet, 2009;373:1532–42.



Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68