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Future directions for CKD anaemia Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Renal Unit, King’s College Hospital,

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Presentation on theme: "Future directions for CKD anaemia Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Renal Unit, King’s College Hospital,"— Presentation transcript:

1 Future directions for CKD anaemia Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Renal Unit, King’s College Hospital, London, UK

2 Honoraria, lecture fees, grants from:- Disclosure Amgen Ortho Biotech Roche Affymax Shire

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4 Lancet, 9 th September 2006

5 Overview of erythropoiesis in CKD in 2007 Cellular and molecular mechanisms relevant to anaemia Future therapies for stimulating erythropoiesis Future developments in the management of CKD anaemia Outline of presentation

6 Overview of erythropoiesis in CKD in 2007 Cellular and molecular mechanisms relevant to anaemia Future therapies for stimulating erythropoiesis Future developments in the management of CKD anaemia Outline of presentation

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8 Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4 th ed. 2005; SCF, GM-CSF, IL-3 SCF, IL-1, IL-3, IL-6, IL-11 Pluripotent Stem Cell Burst-Forming Unit-Erythroid Cells (BFU-E) Colony-Forming Unit-Erythroid Cells (CFU-E) ReticulocytesRBCsErythro- blasts Proerythro- blasts About 8 Days Iron Erythropoietin Erythropoiesis in CKD

9 Pro-inflammatory cytokines (IL-1, TNFα, IL-6, IFNγ)  EPO production EPO + + Iron  Fas Ag Apoptosis ─ hepcidin  Fe absorption  Fe transport  Fe availability (EPO-R, Tf, TfR, Ferriportin, DMT-1) ─ Erythropoiesis in CKD

10 Overview of erythropoiesis in CKD in 2007 Cellular and molecular mechanisms relevant to anaemia Future therapies for stimulating erythropoiesis Future developments in the management of CKD anaemia Outline of presentation

11 rHuEPO stimulates erythropoiesis by activating EPO receptors membrane Activation EPO Receptor rHuEPO Signal Transduction Growth and Differentiation

12 Activation of EPO receptors results in initiation of intracellular signalling pathways Conformational change Phosphorylation of JAK2, a tyrosine kinase Phosphorylation of EPO receptor Initiation of intracellular signalling pathways membrane Jak2 P PP PP rHuEPO Jak2 PP PP P

13 EPO receptor activation leads to activation of genes that promote erythropoiesis membrane nucleus Jak2 P Survival, differentiation, proliferation, and maturation of RBC progenitors and precursors Gene Activation P P P STAT 5 P

14 Survival, differentiation, proliferation, and maturation of RBC progenitors and precursors STAT 5 Gene Activation P PI-3-Kinase Jak2 P SCH MAPK SOS GRB P P P membrane nucleus EPO receptor activation leads to activation of genes that promote erythropoiesis

15 Jak2 PP PP EPO, rHuEPO EPO dimerEPO mimetic peptide Darbepoetin alfa membrane C.E.R.A. Peg-rHuEPO Signal Transduction Survival, differentiation, proliferation, and maturation of RBC progenitors and precursors Gene Activation Jak2 PP PP PP PP PP PP PP PP Investigational All ESAs have the same signalling pathway

16 Termination of EPO-receptor signalling JAK 2 SS P P P P EPO P Haemopoietic cell phosphatase Internalisation and degradation

17 All ESAs have the same mechanism of action Activation of the EPO receptor is the common mechanism by which all ESAs stimulate erythropoiesis However, ESAs may differ from one another in: –Biophysical characteristics (e.g. molecular weight) –EPO receptor binding affinity –Pharmacokinetic properties (e.g. serum half-life, clearance)

18 Weiss & Goodnough, NEJM, March 2005

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20 Overview of erythropoiesis in CKD in 2007 Cellular and molecular mechanisms relevant to anaemia Future therapies for stimulating erythropoiesis Future developments in the management of CKD anaemia Outline of presentation

21 Lancet 9 th September 2006

22 I. EPO-receptor agonists Protein-based ESA therapy Epoetin (alfa, beta, delta, omega) Biosimilar EPOs (epoetin zeta) Darbepoetin alfa C.E.R.A. (methoxy polyethylene glycol epoetin beta) Synthetic erythropoiesis protein (SEP) EPO fusion proteins ~ EPO–EPO ~ GM–CSF–EPO ~ Fc–EPO ~ CTNO 528 Small molecule ESAs Peptide-based (e.g. Hematide) Non-peptide based

23 II. Other mechanisms Prolyl hydroxylase inhibitors (HIF stabilisers) GATA inhibitors Haemopoietic cell phosphatase (HCP) inhibitors EPO gene therapy

24 I. EPO-receptor agonists Protein-based ESA therapy Epoetin (alfa, beta, delta, omega) Biosimilar EPOs (epoetin alfa, epoetin zeta) Darbepoetin alfa C.E.R.A. (methoxy polyethylene glycol epoetin beta) Synthetic erythropoiesis protein (SEP) EPO fusion proteins ~ EPO–EPO ~ GM–CSF–EPO ~ Fc–EPO ~ CTNO 528 Small molecule ESAs Peptide-based (e.g. Hematide) Non-peptide based

25 II. Other mechanisms Prolyl hydroxylase inhibitors (HIF stabilisers) GATA inhibitors Haemopoietic cell phosphatase (HCP) inhibitors EPO gene therapy

26 Multiple generic epoetin alfas are being marketed worldwide – variable quality – variable biological activity – inaccurate labelling –? immunogenicity PERU China

27 The “generic” epoetin alfas differ from approved epoetin alfas Isoelectric Focusing* The first biosimilar epoetin alfa was approved in Europe in June 2007 (Sandoz) – others pending

28 C.E.R.A. Continuous Erythropoietin Receptor Activator Methoxy polyethylene glycol epoetin beta long-acting ESA IV half-life = SC half-life = 130 hrs ?once–monthly dosing C.E.R.A. EPO

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30 EPO mimetic peptides Family of peptides discovered with erythropoietin-mimetic activity Amino acid sequences completely unrelated to native EPO Same functional / biological properties as EPO First one described was EMP-1 A similar EMP pegylated and dimerised to produce Hematide TM Hematide TM is about to begin Phase III of clinical development – stable at room temperature – antibodies do not cross-react with EPO, x1/month, ?cheaper

31 Injection 1Injection 2Injection 3Injection 4Injection 5Injection 6 (Target Hb Range: 11 – 13 g/dL) Week Mean Hb Change From Baseline (g/dL) Starting Dose: Hematide in pre-dialysis CKD patients (Phase 2) mg/kg SC mg/kg SC mg/kg SC mg/kg IV Macdougall et al., ASN, San Diego, Nov

32 10 CKD patients with Ab+PRCA (Germany, France, UK) Treated with once-monthly SC Hematide 0.05mg/kg End-point – Hb > 11 g/dL without RBC transfusions

33 O2O2 OH proteasomal degradation OH HRE HIF-1  HIF-2  HIF  HIF-2HIF-1 PHD HIF target genes - EPO, etc. HIF stabilizers (Prolyl hydroxylase inhibitors) Macdougall & Eckardt, Lancet, 2006

34 HIF stabilizers FDA has suspended further development of FG-2216 following the death of a female patient from fulminant hepatic necrosis BUT Urquilla P et al.: J Am Soc Nephrol 2004; 15: 546A FG-2216 was in phase II of its clinical trial programme Orally-active inhibitors of HIF prolyl hydroxylase have been synthesized (FG-2216; FG FibroGen) They cause an increase in EPO levels, even in CKD patients Urquilla P et al.: J Am Soc Nephrol 2004; 15: 546A. FG-2216 Patients Placebo Patients Wiecek A. et al. XLII ERA-EDTA Congress, Istanbul FG-2216 Patients Placebo Patients

35 Overview of erythropoiesis in CKD in 2007 Cellular and molecular mechanisms relevant to anaemia Future therapies for stimulating erythropoiesis Future developments in the management of CKD anaemia Outline of presentation

36 New iron preparations – ferrumoxytol, Ferrinject, etc. New trials Further initiatives

37 Study design Study pop. n Follow- up GoalsEnd- points RCT -db Type 2 DM CKD years Hb 13 vs 9 CVS RCT -sb > 70 yrs CKD wks Hb 13 vs 9.5 QoL SF36 vit EXTEND Observ.CKD pts 4000 q2wk vs q4wk DA PREFERENCE Prospective cohort CKD pts Several hundred Compare diff.mode of admin. ESA mode of admin. MIRCERA in Renal Tx Open- label Renal Tx Several hundred 1 year  Hb QoL New trials

38 TREAT 1 CHOIR 2 CREATE 3 Besarab Number of patients 3896* * IVRS 12 October 2007

39 TREAT vs. CHOIR No. of centres Median (pt-mths) Total follow- up (pt-yrs) Events (n) CHOIR

40 TREAT vs. CHOIR No. of centres Median (pt-mths) Total follow- up (pt-yrs) Events (n) CHOIR TREAT (already) (already) > double that of CHOIR

41 Questions we don’t have answers to Are high doses of EPO bad or is it just that “being hyporesponsive” is bad? Is giving EPO to “hyporesponsive” patients bad? Is a Hb of 11–12 g/dl appropriate for all CKD patients? Does Hb variability/instability/cycling impact on mortality/morbidity, or is it just a marker of outcome?


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