Future directions for CKD anaemia Iain C Macdougall BSc, MD, FRCP

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

4. Lancet, 9th September 2006

5. Outline of presentation • 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

6. Outline of presentation • 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

8. Erythropoiesis in CKD Erythropoietin Iron SCF, IL-1, IL-3, IL-6, IL-11 SCF, GM-CSF, IL-3 About 8 Days PluripotentStem Cell Burst-Forming Unit-Erythroid Cells (BFU-E) Colony-FormingUnit-ErythroidCells (CFU-E) Proerythro-blasts Erythro-blasts Reticulocytes RBCs Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4th ed. 2005;267-288.

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

10. Outline of presentation • 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

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

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

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

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

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

16. Termination of EPO-receptor signalling EPO S S JAK 2 JAK 2 P P Haemopoietic cell phosphatase P P P 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

20. Outline of presentation • 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

21. Lancet 9th September 2006

22. I. EPO-receptor agonists

23. II. Other mechanisms

24. I. EPO-receptor agonists

25. II. Other mechanisms

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

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

28. C.E.R.A. EPO 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

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 HematideTM • HematideTM is about to begin Phase III of clinical development – stable at room temperature – antibodies do not cross-react with EPO, x1/month, ?cheaper

31. 4.0 Starting Dose: 3.5 3.0 2.5 2.0 Mean Hb Change From Baseline (g/dL) (Target Hb Range: 11 – 13 g/dL) 1.5 1.0 0.5 0.025 mg/kg SC 0.050 mg/kg SC 0.075 mg/kg SC 0.050 mg/kg IV 0.0 -0.5 0 4 8 12 16 20 24 Week Injection 1 Injection 5 Injection 4 Injection 3 Injection 2 Injection 6 Hematide in pre-dialysis CKD patients (Phase 2) Macdougall et al., ASN, San Diego, Nov. 2006.

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. 2 3 1 HIF stabilizers(Prolyl hydroxylase inhibitors) O2 PHD proteasomal degradation HIF-1 OH HIF-2 OH HIF  HIF-2 HIF-1 HIF target genes- EPO, etc. HRE Macdougall & Eckardt, Lancet, 2006

34. Placebo Patients FG-2216 Patients Placebo Patients FG-2216 Patients Urquilla P et al.: J Am Soc Nephrol 2004; 15: 546A. BUT Wiecek A. et al. XLII ERA-EDTA Congress, Istanbul 2005. HIF stabilizers • Orally-active inhibitors of HIF prolyl hydroxylase have been synthesized (FG-2216; FG-4592 - FibroGen) • They cause an increase in EPO levels, even in CKD patients • FG-2216 was in phase II of its clinical trial programme • FDA has suspended further development of FG-2216 following the death of a female patient from fulminant hepatic necrosis Urquilla P et al.: J Am Soc Nephrol 2004; 15: 546A

35. Outline of presentation • 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

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

37. New trials

38. 3896* Number of patients 2000 4000 3000 1000 TREAT1 CHOIR2 CREATE3 Besarab4 * IVRS 12 October 2007

39. TREAT vs. CHOIR

40. TREAT vs. 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?