110317 PUREMA(R)

PUREMA® - one step closer to physiological sievingDr. Stefan Breiter MEMBRANA GmbH Wuppertal Germany www.membrana.com PUREMA®: Overview Based on breakthrough process innovation (patented) A member of the DIAPES® family, polymer: polyethersulfone • outstanding biocompatibility • renowned clinical records Unique process technology provides sharpest sieving curve (S.E.T.) • new pore forming technology with patent protection • active blood side surface management facilitates toxin removal • highest middle molecular removal (e.g. ß2m) • low albumin loss improved patented bundle makeup P.E.T.® • LMW removal: performing better than any other synthetic membrane The PUREMA® membrane family covers the range from low to super flux PUREMA® : New Technology Unique process technology influences separation profile of membrane formation • thicker separation layer • sharpened sieving profile (S.E.T.) • optimized dialysate side distribution • higher mechanical strength resulting in • low albumin loss • high middle molecule removal • maximum low molecular clearance • Very high CIS retention 5280 PUREMA® - Chemical Structure 0 0 PUREMA®: polyethersulfone S 0 0 0 S 0 conventional polysulfone 4533 CH3 0 C CH3 Polysulfone and Polyethersulfone Polysulfone and Polyethersulfone are given trivial names for substances from the same class (polyethers, polysulfones) chemically, both are very similar minor differences in hydrophilicity, mechanical and thermal stability generally different production principles of the basic polymer both are equally suitable as membrane materials similar production prinicples of the membranes minute, but decisive differences from manufacturer to manufacturer Cross Section of Different Membranes APS Polysulfon PUREMA® Polyflux 1069 . E.T.PUREMA® Production Process Polymer solution Core liquid Cross-section view Polymer spinning solution Core liquid Spinneret S. • washing • drying • winding • cutting 4695 wrapping of capillary bundles make-up membrane formation pre-extraction . E.P.T.® : Performance Enhancing Technology PET (Poly Ethylene Terephthalate) spacer yarns consist of multifilament threads integrated into the fiber bundles Improves dialysate distribution throughout the dialyzer • Increases clearance values • Maintains consistent performance throughout the entire treatment from dialyser to dialyser 0319 . Comparison of Bundle Make Up I Fresenius F-series DIAPES® Gambro Polyflux S-series 0969 . Comparison of Bundle Make Up II Fresenius Optiflux-series PUREMA® Gambro Polyflux L-series 0970 . PUREMA® H 1065 . 2 1.6 1.8 2 2.4 1.2 Surface area [m²] .PUREMA®: highest LMW Clearance in vitro Benchmark 300 290 280 270 260 250 240 230 QB 300 [ml/min] PUREMA® H PUREMA® Fesenius FX-Series FX Optiflux Fresenius Optiflux® Polyflux GambroH Polyflux® H Fresenius F-Series F GambroS Polyflux® S Polyflux APS Asahi Polysulfone Urea clearance [ml/min] 220 1 5270 1. PUREMA®: Stable Low Molecular Clearance 300 30 min. 250 * * Clearance [ ml / min ] 200 QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0. 240 min. March 2005 .05 30 min vs. 240 min 150 100 50 0 Urea 5524 Creatinine Phosphate Clinical Study. 4.E.T. 2. S.S. thicker separation layer unchanged ultrafiltration more uniform pore distribution active surface management steeper sieving curve 5525 more selective removal . stands for Sieving Enhancing Technology unique patented process technology 1.T. 3.E. PUREMA® H: Uniform Pore Size Distribution first generation PES membrane separation layer cross-section outer surface inner surface 1072 PUREMA® . – Sieving Enhancing Technology Pore Size Distribution Vit.60 nm ß2-m: 5.E.28 nm BSA:10.S. B12: 2.94 nm ◊ /  m: 8.88 nm Inulin:4.64 nm PUREMA H Fresenius FX Polyflux S PUREMA® % 5282 pore size Conventional Polysulfone .T. 9 0.8 0.2 0.5 0.6 SC 0.4 0.7 0.1 0 100 PUREMA(R) H FMC FX Optiflux Human Kidney Polyflux H 1000 10000 100000 Molecular Weight [Dalton] .PUREMA® H sieving curve 1 0.3 0. S. active centres are created on the blood side (patent protected technology) these active centres mediate the electrostatic. polar and hydrophobic interactions of proteins and middle molecular toxins with the membrane wall protein adsorption to the membrane and the pores is reduced (reduced clogging) middle molecular toxins can move more easily through the pores unprecedented removal characteristics .T. – Sieving enhancing technology: active surface management during the production process.E. – Active Surface Management PUREMA® Blood Side Surface red: hydrophobic domains (PES) green: hydrophilic domains (PVP) blue: active centre 1268 .T.E.S. PUREMA®: Visibly Reduced Protein Adsorption Polyamix PUREMA® Polysulfone FX Protein adsorption visualised with fluorescent ß2m 1300 . Polyflux H140 Polysulfon FX60 .PUREMA® H – Reduced Protein Adsorption Adsorption of Radioactive Labelled Albumin 11 10 9 Albumin Adsorption / units 8 7 6 5 4 3 2 1 0 PUREMA H Purema®H 5598 ® H PUREMA Purema H without S.T .E. 5 0.SC Profile of PUREMA® Compared to Other Synthetic Membranes 1 0.3 0.015 Fresenius Optiflux-series Gambro Polyflux H-series 0.01 In vitro testing in minimodules 5% BSA in PBS QB 200 ml/ min m² QF 30 ml/ min m² 5276 0.4 0.9 0.02 PUREMA® Fresenius F-series Fresenius FX-series 0.7 0.6 0.8 sieving coefficient 0.2 0.005 0 BSA .1 0 Cytochrome C sieving coefficient PUREMA® Fresenius F-series Fresenius FX-series Fresenius Optiflux-series Gambro Polyflux H-series 0. 05 PUREMA® H vs. July 2004 / March 2005 .7m² Polyflux 170H.7m² PUREMA * * * * Polyflux 170 H 1.8m² ® Purema H H.ß2M Removal 100 90 80 Polysulfon FX80 Polysulfone FX80. 1. 1. QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0. FX80 and 170H ß2M .removal Ratio [ % ] 70 60 50 40 30 20 10 0 corrected by hematocrit corrected according to Bergström-Wehle 5526 Clinical Studies. 7m² QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.05 PUREMA® H vs.8m² Purema H® H. Polyflux 170 H 1.05 30 min vs.Clearance [ ml / min ] *** Polysulfon FX80 Polysulfone FX80. 240 min 120 100 80 60 40 20 0 30 min 5527 240 min Clinical Studies.7m² PUREMA Polyflux 170H. 1. July 2004 / March 2005 . 1. FX80 and 170H ** p< 0.PUREMA®: Consistently high ß2M Clearance Over Time 160 140 ** * * ** * ** ß2M . Albumin Removal 3 Albumin in dialysate [g / 4h] 2.7m² Polyflux QB = 300 ml/min QD = 500 ml/min 8 patients 2 1. 1.5 0 5528 Clinical Studies.5 1 0.5 Polysulfon FX80 Polysulfone FX80. July 2004 / March 2005 . 1. 1.7m² Polyflux170H 170H.8m² ® PUREMA Purema H H. 7m² Polyflux170 170H.Cystatin C Removal 80 Cystatin C . July 2004 / March 2005 . 1. FX80 and 170H corrected by hematocrit corrected according to Bergström-Wehle 5530 Clinical Studies.7m² QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.Removal Ratio [ % ] 70 60 50 40 30 20 10 0 * * * * Polysulfon FX80 Polysulfone FX80.8m² ® PUREMA Purema H H. Polyflux H 1.05 PUREMA® H vs. 1. 7m² Polyflux 170H.Clearance [ml/min] ** * Polysulfon FX80 Polysulfone FX80. 1.05 vs. FX80 and 170H 100 80 * 60 40 20 0 30 min 5531 240 min Clinical Studies.7m² PUREMA Polyflux 170 H 1. July 2004 / March 2005 . 240 min ** p< 0. 1.Cystatin C Clearance 140 ** 120 * Cystatin C .8m² Purema H ® H. QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.05 30 min vs. Removal Ratio [% 70 60 50 40 30 20 10 0 Polysulfon FX80 Polysulfone FX80. 1.8m² ® PUREMA Purema H H. March 2005 . FX80 corrected by hematocrit corrected according to Bergström-Wehle 5532 Clinical Study. 1.05 vs.7m² * * QB = 300 ml/min QD = 500 ml/min 8 patients * p< 0.Myoglobin Removal 80 Myoglobin . Myoglobin Clearance 80 Polysulfon FX80 Polysulfone FX80. July 2004 / March 2005 .7m² Purema H PUREMA Myoglobin .Clearance [ml/ min] 70 60 50 40 30 20 10 0 Polyflux 170H 170H Polyflux QB = 300 ml/min QD = 500 ml/min 8 patients 30 min 5533 240 min Clinical Studies. 1.8m² ® H. 1. 8m² Purema H ® H. 80 Polysulfone 1. July 2004 / March 2005 .7m² PUREMA Polyflux 170H Polyflux 170H 100 75 50 25 0 -25 -50 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000 QB = 300 ml/min QD = 500 ml/min 8 patients Molecular weight [Da] 5534 Clinical Studies. 1.PUREMA® H „Separation Profile“ 150 125 30 min Clearance [ml/min] Polysulfon FX FX80. 1.8m² Polyflux 170H Polyflux 170H. 1. 1. July 2004 / March 2005 .PUREMA® Biocompatibility: White Blood Cell Count 110 Polysulfon FX80 Polysulfone FX80.7m² QB = 300 ml/min QD = 500 ml/min 8 patients 100 90 WBC [ % ] 80 70 60 50 0 30 60 90 120 Time [ min ] 5535 150 180 210 240 Clinical Studies.7m² Purema H PUREMA® H. PUREMA® Biocompatibility: Complement Activation 7 6 5 C5a [ µg/l ] 4 3 2 1 0 0 5536 Polysulfon FX80 Polysulfone FX80. 1.7m² Purema H® H. 1.7m² PUREMA QB = 300 ml/min QD = 500 ml/min 8 patients 30 60 90 120 Time [ min ] 150 180 210 240 Clinical Studies. 1. July 2004 / March 2005 .8m² Polyflux 170H Polyflux 170H. 1.PUREMA® Biocompatibility: Platelet Count 120 110 100 90 80 70 60 50 0 5537 Polysulfon FX80 Polysulfone FX80. July 2004 / March 2005 . 1.7m² PUREMA QB = 300 ml/min QD = 500 ml/min 8 patients Platelet Count [ % ] 30 60 90 120 Time [ min ] 150 180 210 240 Clinical Studies. 1.7m² Purema H® H.8m² Polyflux 170H Polyflux 170H. 7m² Purema H ® H.8m² Polyflux Polyflux170H 170H. 1. 1. 1. July 2004 / March 2005 .7m² PUREMA QB = 300 ml/min QD = 500 ml/min 8 patients TAT [ µg/l ] 8 6 4 2 0 0 30 60 90 120 150 180 210 240 Time [ min ] 5538 Clinical Studies.PUREMA® Biocompatibility: Activation of Coagulation 14 12 10 Polysulfon FX80 Polysulfone FX80. . 69: 2087-2093. Kidney Int. 2006 5638 .Reduced Mortality Risk in High-efficiency Hemodiafiltration Canaud B et al. PUREMA® proved its outstanding performance the ß2m clearance and removal found with PUREMA® in HD corresponds to HDF with replacement volumes exceeding 60ml/min with conventional polysulfone membranes .e. in particular middle molecules (low molecular weight proteins) in the first clinical studies.high efficiency (i. high volume) HDF has a significant survival benefit over HD it is common sense that this is due to the superior removal of toxins. 15 (Suppl.β2 -Microglobulin Removal in Online Post-dilution HDF with Conventional High-flux Polysulfone orange line represents performance of PUREMA® in HD in first clinical trials 5663 Lornoy W et al (2000) Nephrol Dial Transplant. 1): 49-55 . β2 -Microglobulin Removal in Online Post-dilution HDF with Conventional High-flux Polysulfone orange line represents performance of PUREMA® in HD in first clinical trials 5663 Lornoy W et al (2000) Nephrol Dial Transplant. 15 (Suppl. 1): 49-55 . 8 patients.7 m²) in HD Fresenius HF80S (1. 1. 240 min 3 treatments (1 week) with each dialyser Determination of dialyser efficiency • Instantaneous clearances and reduction rates of low-molecular weight proteins • Albumin loss . PUREMA® H (Bellco "Phylther".7 m²) in postdilution HDF: QS=60ml/min QB=300 ml/min.Clinical study PUREMA® H in HD vs.8 m²) in postdilution HDF: QS=60ml/min Gambro Polyflux 170H (1. competitors in HDF Prospective. cross-over design. QD=500-QS ml/min. 7 PUREMA PUREMA H1.Low Molecular Clearances (Plasma) 30 Minutes 250 ns p<0.05 ns ns ® H1. QS= 60ml/min Polyflux Polyflux170H 170H HDF.7 HD 200 30 min Clearance [ml/min] Polysulfone PolysulfoneHF80S HF80S HDF. QS= 60ml/min 150 100 n= 8 corrected for surface area 50 0 5743 Urea Creatinine Phosphate Clinical Study KSPU0603 October 2006 .05 p<0. PUREMA H1.s.7 PUREMA® H1.s.7 HD Polysulfone Polysulfone HF80S HF80S HDF. QS= 60ml/min ß2M .Clearance [ml/min] 60 40 n= 8 corrected for surface area 20 0 HD HDF 30 min HDF HD HDF 180 min HDF Clinical Study KSPU0603 October 2006 .β2-Microglobulin Plasma Clearance 100 n. QS= 60ml/min Polyflux Polyflux 170H 170H HDF. 80 n. Removal Rate 100 90 ns p< 0.7 PUREMA® H1. QS= 60ml/min ß2M . QS= 60ml/min n= 8 HD HDF HDF Removalby Ratio Removal Rate corrected Bergström-Wehle 5687 Clinical Study KSPU0603 October 2006 .Removal Rate [%] 80 70 60 50 40 30 20 10 0 170H Polyflux 170H HDF.ß2-Microglobulin .7 HD Polysulfone HF80S HF80S HDF.05 PUREMA H1. for comparison: β2-Microglobulin Plasma Clearance for all membranes in HD mode 100 p< 0.05 p< 0.05 p< 0.05 p< 0.05 p< 0. QS= 0ml/min n= 8 corrected for surface area 60 40 20 HD 0 HD 30 min HD HD HD 180 min HD Clinical Study KSPU0603 October 2006 .05 ® H1.Clearance [ml/min] 80 PolysulfoneHF80S HF80S Polysulfone HD. QS= 0ml/min Polyflux170H 170H Polyflux HD.7 HD ß2M .7 PUREMA PUREMA H1. 7 HD Polysulfone Polysulfone HF80S HF80S HDF. Cystatin C . QS= 60ml/min Polyflux Polyflux 170H 170H HDF.Removal Rate 80 n.s.Cystatin C . QS= 60ml/min n= 8 HD 0 HDF HDF RR by BW Removal Rate corrected by Bergström-Wehle 5697 Clinical Study KSPU0603 October 2006 .Removal Rate [%] 70 60 50 40 30 20 10 PUREMA H1.7 PUREMA® H1. 7 HD p< 0. QS= 60ml/min n= 8 HD HDF HDF Removal Rate corrected by Bergström-Wehle RR by BW 5707 Clinical Study KSPU0603 October 2006 .7 PUREMA® H1. QS= 60ml/min Polyflux 170H HDF.05 Polysulfone HF80S HDF.Removal Rate 80 Myoglobin Removal Ratio [%] p< 0.Myoglobin .05 70 60 50 40 30 20 10 0 H1. QS= 60ml/min n= 8 HD 0 -10 -20 HDF HDF RR by BW Removal Rate corrected by Bergström-Wehle 5726 Clinical Study KSPU0603 October 2006 .Removal Rate 70 60 ns ns RbP Removal Rate [%] 50 40 30 20 10 PUREMA ® H1.Retinol Binding Protein .7 HD Polysulfone HF80S HF80S Polysulfone HDF.7 PUREMA H1. QS= 60ml/min Polyflux 170H 170H Polyflux HDF. 30 min Clearance of Middle Molecules 100 30 m in Clearance [m l/m in] PUREMA ® H1. QS= 60ml/min Polyflux 170H 170H HDF. QS= 60ml/min ß2m CyC n= 8 75 50 25 0 -25 RbP Myo -50 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000 Molecular weight [Da] 5735 Clinical Study KSPU0603 October 2006 .7 HD Polysulfone HF80S HF80S HDF.Plasma .7 PUREMA H1. 7 PUREMA ® H1. QS= 60ml/min Polyflux 170H Polyflux 170H HDF.180 min Clearance of Middle Molecules 150 180 min Clearance [ml/min] 125 100 75 50 25 0 -25 -50 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000 PUREMA H1. QS= 60ml/min n= 8 ß2m CyC Myo RbP Molecular weight [Da] 5739 Clinical Study KSPU0603 October 2006 .7 HD Polysulfone HF80S Polysulfone HF80S HDF.Plasma . 0 ns ns PUREMA H1. QS= 60ml/min Polyflux Polyflux 170H 170H Albumin in dalysate [g/4h] 1.7 HD Polysulfone Polysulfone HF80S HF80S HDF.5 HDF.5 0.0 0. QS= 60ml/min n= 8 1.Albumin in Dialysate 2.7 PUREMA® H1.0 HD HDF HDF Albumin in dialysate 5709 Clinical Study KSPU0603 October 2006 . Summary of PUREMA® H Characteristics in Haemodialysis Improved biocompatibility with significantly lower complement generation Significantly enhanced LMW protein removal Low albumin loss Steeper sieving profile PUREMA® in HD provides LMW protein removal comparable to online post-dilution HDF with conventional high-flux membranes . .Conclusion Simple haemodialysis with PUREMA® H may have beneficial effects on the outcome of maintenance dialysis patients similar to high-efficiency HDF with conventional synthetic high-flux membranes. Summary of PUREMA® H a member of the DIAPES(R) family: proven clinical record. renowned biocompatibility Significantly enhanced LMW protein removal Low albumin loss Steeper sieving profile stable clearance throughout the treatment . breiter@membrana. Healthcare Membrana GmbH Öhder Strasse 28 42289 Wuppertal +49 (202) 6099 786 stefan.de .Dr. Stefan Breiter Scientific Marketing Manager.