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The Science Behind Taxus Advanced Angioplasty 2004 Christian Vander Velde, Boston Scientific Europe, Marketing TAXUS Technology Paclitaxel • • • Binds tubulin Microtubular dynamics Multifunctional Polymer • • Uniformity • Durability • Biphasic Controlled Release • Kinetics Platform Express™ Stent Tandem Architecture Flexibility Maverick™ Balloon Deliverability TAXUS Technology - Paclitaxel Restenotic Cascade Platelet Aggregation The Ideal Pharmaceutical Should Control Inflammatory Cells SMC Proliferation SMC Migration ECM The Ideal Pharmaceutical Should Promote Endothelialization 0–2 2–4 4–10 Days Days Days Table adapted from the experimental models by Ferns et al. 10–14 Days 2–4 Weeks TAXUS Technology - Paclitaxel Paclitaxel selectively impacts smooth muscle cells, platelets, and white blood cell activity without affecting endothelial cells – Paclitaxel is a multi-functional drug which Restenosis effectively: • • • • Inhibits proliferation Inhibits migration Inhibits inflammation Inhibits secretion Prevents – Paclitaxel enables healing by selectively impacting the cells that cause restenosis while allowing healthy healing of endothelial cells • TAXUS shows similar healing between Endothelialization Promotes control bare metal stent and paclitaxel Axel et al, AHA 1997, Karsch et al, SIC 1998 Endothelialization of a paclitaxel-eluting stent in a porcine coronary artery Polymer Carrier Considerations Chemical/Physical and Biological Biocompatible Formulate/ process Coating Integrity Sterilization Drug Loading Drug release Vascular compatible Coating Integrity BSC Carrier- TransluteTM Coated, Loaded, Sterilized, Expanded 40x 200x • Smooth, Uniform Coverage • No Cracking, Flaking or Delaminating Uniform PTx Content Along Stents of Different Lengths (15, 24, 32 mm stents -- 1ug/mm2) Uniformity of Paclitaxel Distribution Along Stent Comparison of % Paclitaxel Recovery from Consecutive 4cm Segments Along Stent 140 15mm NIR (85ug) 24 mm Express WH (151ug) 32 mm Express WH (209ug) Paclitaxel % Recovery ( [HPLC/gravimetric] x 100%) 120 100 80 60 40 20 0 1 2 3 4 5 6 Stent Segment (Approximately 4cm length per each segment) 7 8 Uniform PTx Release From ExpressTM Stents of Different Lengths % Cumulative Paclitaxel Release % Cumulative Paclitaxel Release 4.0% 4.0% 1.0 ug/mm2, Slow release 16 mm 1.0 ug/mm2, Slow Release 24 mm % Paclitaxel Released 3.0% 2.0% 1.0% 0.0% 2.0% 1.0% 0.0% 0 2 4 6 8 10 12 0 2 4 TIME (Days) 6 TIME (Days) % Cumulative Paclitaxel Release 4.0% 1.0 ug/mm2, Slow Release 32 mm 3.0% % Paclitaxel Released % Paclitaxel Released 3.0% 2.0% 1.0% 0.0% 0 2 4 6 TIME (Days) 8 10 12 8 10 12 Polymer-based Clinical Data TRIAL TAXUS I TAXUS II TAXUS II TAXUS IV DOSE OF PTx 1.0ug/mm2 SR 1.0ug/mm2 SR 1.0ug/mm2 MR 1.0ug/mm2 SR LATE LOSS mm 0.36 +/- 0.48 0.31 +/- 0.39 0.30 +/- 0.39 0.39 +/- 0.50 Confirmed by IVUS analysis (TAXUS II - Circulation January 20, 2004) In Vivo Considerations for Polymers and Drugs • Animal Model – In Vivo Studies, #&@% !!!! – – – Rat Rabbit Swine Canine • Implant Time • Implant Location – – – – Sub Q IM Iliac Coronary • Other Polymer Carriers Vascular Compatibility Failed candidates (normal porcine coronary model) Bare Stent Polyurethane-coated Stent (2 months) Sub-optimal drug carriers can cause severe inflammatory response In Collaboration w/Drs. Rogers and Edelman,MIT Effect of Animal Model and Implant Site Rat Subcutaneous Implant Model 28 day Implant - H&E Staining Bare Stent Polyurethane-coated Stent Effect of Animal Model and Implant Site Porcine Coronary 28 day Bare Stent Polyurethane-coated Stent In Collaboration w/Drs. Rogers and Edelman,MIT Effect of Animal Model and Implant Site Rabbit Iliac Artery 28 day PLA/PCL coated stent 56 day PLA/PCL coated stent In Collaboration w/Drs. Rogers and Edelman, MIT Effect of Animal Model and Implant Site Porcine Coronary Artery 35 day PLA/PCL In Collaboration w/Drs. Rogers and Edelman, MIT Vascular Compatibility TransluteTM 90D Bare control 180D Bare control 90D polymer 180D polymer coated coated In collaboration with Dr. Rob Schwartz Mayo Clinic and Dr. Greg Wilson Sick Children’s-Toronto Translute Polymer Long term (180 days) vascular compatibility Lumen Area 180 day 12 10 8 2 mm 6 4 2 0 Bare Control Translute only Express stent Translute Coated • Good safety profile • Polymer similar to control • Reproduced from lot to lot In collaboration with Dr. Rob Schwartz Mayo Clinic and Dr. Greg Wilson Sick Children’s-Toronto 28 Days 90 Days Vascular Compatibility TransluteTM Endothelial coverage (PECAM 1, 0-5) % Luminal Stenosis 100 80 60 40 20 0 5 4 3 2 1 0 0 60 120 180 0 60 120 180 Inflammation (CD45, 0-4) Bare Polymer-coated 4 3 2 No significant differences 1 0 0 60 120 180 In Collaboration w/Drs. Rogers and Edelman,MIT TAXUS Technology - Translute™ Polymer Polymer-based matrices provide: • ease of handling • uniform dose along stent and dosing in a controlled manner = • consistency a matrix by which drug release can be manipulated to achieve a desired biological response With greater opportunities come greater challenges TransluteTM Polymer stability TransluteTM coating integrity was maintained in 10-year equivalency tests* The TransluteTM polymer has shown remarkable stability out to two years in an animal model* Harsh conditions (alcohol storage, mild heat, agitation) fail to degrade the polymer* Tests have shown that following physical abrasion of the polymer, the release is not markedly increased* * data on file Thank You !