New phosphate binders: what do they add?
Jürgen Floege
Division of Nephrology, University Hospital [email protected] Fernández-Martín JL et al. Nephrol Dial Transplant. 2015 Apr 28 Bone mineral markers and mortality in the COSMOS cohort
Baseline PO4 controlled (3.6-5.2 mg/dl) Baseline PO4 too high (>5.2 mg/dl) Chiu YW, et al. Clin J Am Soc Nephrol 2009;4:1089–96 Phosphate binders: approximately 50% of daily pill burden in dialysis patients
The daily tablet load in dialysis patients is one of the highest of all chronic illnesses (~19 tablets/day)
Others N = 233 Phosphate Median number of tablets Antihyper- binders (49%) for phosphate binders: tensive Calcium acetate/carb. = 9 drugs Sevelamer = 9 (18%) Lanthanum = 6 New therapeutic options in the management of phosphate
Tablet Pleiotropic Effective Accumulation Cost volume effects
Aluminum Ø Calcium Ø acetate/carb.
Sevelamer
Lanthanum Ø
Ca-Mg Ø
Colestilan KDIGO 2016 CLINICAL PRACTICE GUIDELINE UPDATE DIAGNOSIS, EVALUATION, PREVENTION AND TREATMENT OF CKD-MBD
2016 2009
In adult patients with CKD stages In patients with CKD stages 3–5D and 3a-5D receiving phosphate- hyperphosphatemia, we suggest lowering treatment, we suggest restricting the dose of calcium-based restricting the dose of calcium- phosphate binders in the presence of based phosphate binders. (2B) arterial calcification (2C) and/or adynamic bone disease (2C) and/or if • Block GA, Wheeler DC, Persky MS, et al. Effects of phosphate binders in moderate serum PTH levels are persistently low CKD. J Am Soc Nephrol 2012; 23: 1407-1415. (2C). • Di Iorio B, Bellasi A, Russo D. Mortality in kidney disease patients treated with phosphate binders: a randomized study. Clin J Am Soc Nephrol 2012; 7: 487-493. • Di Iorio B, Molony D, Bell C, et al. Sevelamer versus calcium carbonate in incident hemodialysis patients: results of an open- label 24-month randomized clinical trial. Am J Kidney Dis 2013; 62: 771-778. Patel L et al, Clin J Am Soc Nephrol online Dec 14, 2015 Meta-Analysis: Sevelamer vs. Calcium-containing PO4-Binders
Sevelamer vs. Calcium Acetate
Sevelamer vs. Calcium Carbonate 2x Di Iorio!
Sevelamer vs. Calcium Acetate and Carbonate combined
0.54 [0.32, 0.93]
Pro Sevelamer Pro Calcium Di Iorio B et al, Clin J Am Soc Nephrol 2012; 7: 487-93 INDEPENDENT trial: Sevelamer vs. Calcium Carbonate in CKD Stage 3-4
Sevelamer
P<0.05 All Cause Mortality Calcium Carbonate New therapeutic options in phosphate management
Pleiotropic Accumu- Effective Pill burden Cost effects lation
Aluminium Ø
Calcium-Ac/Carb Ø
Sevelamer
Lanthan Ø
Ca-Mg Ø
Colestilan
Fe-Citrate Ø ?
Fe-Oxyhydroxide Ø Lewis JB et al, J Am Soc Nephrol 2014 online pub Ferric citrate for phosphate binding
PO4 [mg/dl]* Week 52 Week 56
Iron citrate 5.12 ± 0.12 4.86 ± 0.13 Primary Primary endpoint Placebo 5.44 ± 0.15 7.21 ± 0.19 * Mean ± SEM
Iron citrate
Sevelamer Ca acetate Umanath K et al, J Am Soc Nephrol 2015; 26: online publication Ferric citrate for phosphate binding: Iron
Iron citrate Sevel/Ca acetate
FDA Approval: Sept 05, 2014 Week Sept 14: US regulators warn about danger of iron overload with ferric citrate and that doctors must monitor iron parameters. Block GA et al, Am J Kidney Dis. 2015; 65(5):728-736 Ferric citrate in CKD 3-5 patients
S-Ferritin Hemoglobin
Ferric citrate Ferric citrate Mean 5.1 g/day Mean 5.1 g/day
Placebo Placebo Sucroferric oxyhydroxide binds phosphate by replacing hydroxy groups
O OH
P HO O OH O Phosphate Fe(III) Fe(III)
Composed of: Iron ~21 % Sucrose ~30 % Starch ~30% Water <10% Start
10 minutes after adding water Floege J J. Nephrol 2016 Floege J et al, Kidney Int 2014 PA-CL-05: Phosphate reduction over 52 weeks
Weeks of Treatment in PA-CL-05A & -05B
0 -0,07 -0,5 -0,17 -0,27 -1 -0,37
-1,5 -0,47 Sucroferric oxyhydroxide
Sevelamer -0,57 (mmol/L) -2 -0,67 -0,77 -2,5
PA-CL-05A PA-CL-05B -0,87 Change in Serum Phosphorus
-3 -0,97 Change Change in Serum Phosphorus (mg/dL)
Sevelamer is always sevelamer carbonate in the sucroferric oxyhydroxide Phase III programme FAS (N=1041) Floege J et al, Kidney Int 2014 PA-CL-05: Ferritin (N=1055)
300 600 250 500 200 Sucroferric oxyhydroxide 400 150
300 (ng/mL)
100 (pmol/L) 200 50 Sevelamer 100
Mean Mean Change in Serum Ferritin 0 0 Mean Mean Change in Serum Ferritin
Weeks on Study Treatment
US EU Other countries Mean change S-Oxyh. Sevelamer S-Oxyh. Sevelamer S-Oxyh. Sevelamer ng/mL 200 100 98 2 61 -36 Floege J et al, Kidney Int 2014 PA-CL-05: Ferritin (N=1055)
300 600 250 500 200 Sucroferric oxyhydroxide 400 150
300 (ng/mL)
100 (pmol/L) 200 50 Sevelamer 100
Mean Mean Change in Serum Ferritin 0 0 Mean Mean Change in Serum Ferritin
Weeks on Study Treatment
US EU Other countries Mean change S-Oxyh. Sevelamer S-Oxyh. Sevelamer S-Oxyh. Sevelamer ng/mL 200 100 98 2 61 -36 Week 0 Average daily
Mean daily number of tablets taken - 24 PA - CL Therapy dose - 05A: Tablets 05A: 1) (Stage quantity start (g/day), Sucroferric oxyhydroxide Oxyhydroxide Sucroferric 1.5 ± 0.6 Floege J et J al, Sevelamer 6.5 ± Kidney 2.5 Int 2014 New therapeutic options in the management of phosphate
Tablet Pleiotropic Accumulati Effective Cost volume effects on
Aluminum Ø Calcium Ø acetate/carb.
Sevelamer
Lanthanum Ø
Ca-Mg Ø
Colestilan
Iron citrate Ø ?
Fe-Oxyhydroxide Ø Tamura MK et al, Kidney Int. 2012;82:261-9 Neglected in guidelines and discussions: Life expectancy of dialysis patients after dialysis onset (USA 2012) Lenglet A et al, Nephrol Dial Transplant 2016
Nicotinamide to control phosphate? The NICOREN trial
N=49 Nicotinamide 0.5-2g/day (= 1-4 tbl)
HD-Patients 4 weeks titration „Wash-out“ Phase 24 week trial duration (up to 24 weeks) until (without active vit-D/cinacalcet) Primary endpoint: Non-inferiority S-PO4 ≥1.6 mmol/l N=51 Sevelamer HCl 3-10g/day (= 4-12 tbl) Lenglet A et al, Nephrol Dial Transplant 2016
Nicotinamide to control phosphate? The NICOREN trial
Nicotinamide 3 Tbl/day 11 Tbl/day Sevelamer HCl Lenglet A et al, Nephrol Dial Transplant 2016
Nicotinamide to control phosphate? The NICOREN trial
Drop-out patients: 7x GI-side effects 4x thrombocytopenia N=49 N=27 2x death Nicotinamide 3x transplant 6x others HD-patients „wash-out“ Week 24 phase 2x GI-side effects N=51 1x death N=46 Sevelamer 1x transplant 1x others Nicotinamide as Add-On Therapy Compared to NOPHOS Placebo in HD-Patients with HyperPHOSphatemia MEDICE
Screening n=1079
Randomization 3:1 n=738
PO4-Binder + Nicotinamid PO4-Binder + Placebo Once daily 2-6 capsules Once daily 2-6 capsules (max. 1.500 mg/d) placebo
• 100 dialysis centers in Germany, Poland, Austria • Last patient in: February 2016 Last patient out: March 2017
23 What did Floege say….?
• Phosphate: control is beneficial
• Calcium-containing PO4-Binders: calcium-free is better but consider your patient!
• Ferric citrate: effective PO4-binding, significant iron- uptake with possibility of overload, high pill burden
• Sucroferric oxyhydroxide: effective PO4-binding, low iron-uptake, low pill burden • Nicotinamide: no good as monotherapy, add-on? KDIGO 2016 Draft Guideline Update on CKD-MBD Likely final in early 2017