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1. New Approaches to the Treatment of Hyperphosphataemia Dr. Alastair J. Hutchison MBChB, FRCP, MD Manchester Institute of Nephrology & Transplantation, UK

4. Hyperphosphataemia The Silent Killer Amann K, Gross ML, London GM, Ritz E: Hyperphosphatemia - a silent killer of patients with uremia. NDT , 1999,14,2085-2087 .

5. Young et al. Kidney Int 2005;67:1179-1187

6. Young et al. Kidney Int 2005;67:1179-1187

10. <0.97 mmol >2.90 mmol Block et al. 2005

11. <2.20 mmol >2.75 mmol Block et al. 2005

14. “ If you’re not confused, you’re not paying attention” Tom Peters

17. Phosphate Control in ESRD Average daily intake of phosphorous = 1000mg Approximately 50% absorbed = 500mg Dialysis removes around 300mg Daily net positive balance = +200mg Therefore oral phosphate binder s needed to reduce phosphate absorption by at least 200mg

22. Sponsors of the k/DOQI Bone & Mineral Guidelines Paricalcitol Cinacalcet Renagel

23. USA k/DOQI Guidelines 2004 Serum phosphate 1.13 – 1.78 mmol/L (3.5 – 5.5 mg/dL) Opinion Serum calcium Preferably lower end of normal Opinion (8.4 – 9.5 mg/dl, 2.10 – 2.37 mmol/L) Ca x PO4 product < 4.5 mmol 2 /L 2 (< 55mg 2 /dL 2 ) Evidence Target PTH level 150 – 300 pg/ml (16 – 33 pmol/L) Evidence Calcium dosage Less than 1500mg elemental calcium Opinion Is this good advice?

27. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis Block et al. 2005;68:1815-1824

31. Lanthanum vs Calcium - 301: Design Weeks of treatment – 3 – 1 0 5 25 48 154 Enrolment Washout La treatment group 66% Titration phase Maintenance phase Open-label extension Optional extension phase Ca treatment group 34% Part 1 3 weeks Part 2 5 weeks Part 3 6 months Part 4 6 months Part 5 2 years Hutchison AJ. Nephron Clin Pract 2005;100:c8–19 N=767

32. Mean (± SD) serum phosphate levels Serum phosphate (mmol/L) Titration phase Dose-maintenance phase 3.1 2.6 2.1 1.6 1.1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Hutchison AJ. Nephron Clin Pract 2005;100:c8–19 Time (weeks) La Ca

33. Hypercalcaemic events (>ULN) by Week 26 Hutchison AJ. Nephron Clin Pract 2005;100:c8–19 1 (0.4) 0 6 2 (0.8) 1 (0.2) 5 7 (2.7) 3 (0.6) 4 8 (3.1) 3 (0.6) 3 20 (7.8) 6 (1.2) 2 59 (23.0) 16 (3.1) 1 159 (62.1) 480 (94.3) 0 Ca ( n = 257) n (%) La ( n = 510) n (%) Hypercalcaemic episodes

34. Ca  P Product Reduction Hutchison AJ. Nephron Clin Pract 2005;100:c8–19 P = 0.961 P = 0.009 P = 0.061 1.0 1.2 1.4 1.6 1.8 2.0 End of titration (Week 5) Mid-maintenance (Week 17) End of maintenance (Week 25) Mean Ca x P reduction (mmol 2 /L 2 ) Study phase La Ca

35. 98 patients, age 55 ± 14.3 yr, 59 males Recruited from dialysis centres in 12 countries. In 63 a histomorphometric analysis of baseline and follow-up bone biopsies was performed. C . SWAENEPOEL A . TORRES A . FERREIRA A. HUTCHISON M. DE BROE M. LAVILLE H-H . NEUMAYER W. SULOWICZ S. SULKOVA A. BALDUCCI G. COEN L. DJUKANOVIC M. POPOVIC S. PEJANOVIC A. SIKOLE G. SPASOVSKI Kidney Int 2003;85:s73-78 European One Year Paired Bone Biopsy Study

36. Categorisation of bone histology 2994 Kidney Int 2003;85:s73-78 Lanthanum Calcium

37. Long-term observational population Two year extension LAM-IV-301 LAM-IV-303 LAM-IV-307 LAM-IV-308 SDP405-309 N = 93 total 41 EU, 52 US 40 patients 1 patient 48 patients 4 patients Hutchison AJ & Pratt R. ASN 2005 Provides up to 6 years observation in a small number of patients….

38. Expected remaining lifetimes (years) of the general U.S. population & of dialysis & transplant patients ESRD patients, 2003 General US population, 2002 Transplant Dialysis 15.9 14.6 15.1 5.4 5.6 5.5 26.6 23.4 25.2 Overall 1.8 1.7 1.8 4.5 3.8 4.3 85+ 2.2 2.2 2.2 8.3 6.9 7.8 80 –84 7.7 6.2 6.7 2.7 2.6 2.6 11.1 9.3 10.4 75 –79 8.9 7.4 7.9 3.1 3.1 3.1 14.4 12.0 13.4 70 –74 10.6 9.1 9.6 3.7 3.6 3.7 18.0 15.2 16.8 65 –69 12.5 11.0 11.5 4.4 4.3 4.3 21.9 18.7 20.4 60 –64 14.7 13.2 13.8 5.0 5.0 5.0 26.0 22.5 24.4 55 –59 17.2 15.7 16.3 5.9 6.0 5.9 30.4 26.6 28.6 50 –54 19.8 18.5 19.0 6.7 7.0 6.8 34.9 30.8 33.0 45 –49 22.7 21.5 21.9 7.6 8.0 7.8 39.5 35.2 37.5 40 –44 25.8 24.8 25.2 8.7 9.2 9.0 44.2 39.8 42.1 35 –39 28.9 28.3 28.5 10.0 10.8 10.5 49.0 44.4 46.8 30 –34 Female Male All Female Male All Female Male All Age

39. Demographics 24 (25.8%) 0 24 (46.2%) Black 61 (65.6%) 40 (97.6%) 21 (40.4%) Caucasian 64 (68.8%) 28 (68.3%) 36 (69.2%) Male 1 (1.1%) 1 (2.4%) 0 Other 7 (7.5%) 0 7 (13.5%) Hispanic 29 (31.2%) 13 (31.7%) 16 (30.8%) Female 53.2  14.3 51.7  13.0 54.5  15.2 Mean Age Total N = 93 EU N = 41 US N = 52

40. Lanthanum Exposure by Total Daily Dose 17 (18.3%) 3 (3.2%) 5 (5.4%) 8 (8.6%) 1 (1.1%) ≥ 6 93 (100%) 25 (26.9%) 36 (38.7%) 27 (29.0%) 5 (5.4%) Total Total 3000 mg 2250 mg 1500 mg 750 mg Year 11 (11.8%) 6 (6.5%) 4 (4.3%) 1 (1.1%) 0 5 – <6 28 (30.1%) 5 (5.4%) 12 (12.9%) 8 (8.6%) 3 (3.2%) 4 – <5 22 (23.7%) 9 (9.7%) 8 (8.6%) 5 (5.4%) 0 3 – <4 15 (16.1%) 2 (2.2%) 7 (7.5%) 5 (5.4%) 1 (1.1%) 1 – <3

41. Serum Phosphate Levels Throughout Treatment With Lanthanum Carbonate

42. Serum PTH Levels Throughout Treatment With Lanthanum Carbonate kDOQI target

43. Liver enzymes – ALT/AST Levels (U/L)

44. Plasma Lanthanum Levels During Overall Lanthanum Exposure Mean  SD (ng/mL) Year 0.75  0.31 6 0.97  0.69 5 0.63  0.75 4 0.67  0.64 3 0.63  0.53 2 0.52  0.60 1 0.01  0.05 Baseline

51. 56% vs 10% 65% vs 36% 46% vs 33% 49% vs 24%

52. Our futures are entirely predictable by a quick retrospective cross-sectional study of our past

53. “ I wanted a perfect ending…now I've learned, the hard way, that some poems don't rhyme, and some stories don't have a clear beginning, middle, and end. Life is about not knowing, having to change, taking the moment and making the best of it, without knowing what's going to happen next” Gilda Radner