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The Science Behind Taxus

The Science Behind Taxus. Advanced Angioplasty 2004. Christian Vander Velde, Boston Scientific Europe, Marketing. TAXUS Technology. Polymer. Paclitaxel. Platform. Binds tubulin Microtubular dynamics Multifunctional. Express ™ Stent Tandem Architecture Flexibility Maverick ™ Balloon

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The Science Behind Taxus

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  1. The Science Behind Taxus Advanced Angioplasty 2004 Christian Vander Velde, Boston Scientific Europe, Marketing

  2. TAXUS Technology Polymer Paclitaxel Platform • Binds tubulin • Microtubular dynamics • Multifunctional • Express™ Stent Tandem Architecture Flexibility • Maverick™ Balloon Deliverability • Uniformity • Durability • Biphasic Controlled Release Kinetics

  3. Restenotic Cascade Platelet Aggregation The IdealPharmaceuticalShould Control Inflammatory Cells SMC Proliferation SMC Migration ECM The IdealPharmaceuticalShould Promote Endothelialization 0–2Days 2–4Days 4–10 Days 10–14 Days 2–4 Weeks TAXUS Technology - Paclitaxel Table adapted from the experimental models by Ferns et al.

  4. 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 effectively: • Inhibits proliferation • Inhibits migration • Inhibits inflammation • Inhibits secretion Restenosis Prevents • Paclitaxel enables healing by selectively impacting the cells that cause restenosis while allowing healthy healing of endothelial cells • TAXUS shows similar healing between control bare metal stent and paclitaxel Endothelialization Promotes Axel et al, AHA 1997, Karsch et al, SIC 1998 Endothelialization of a paclitaxel-eluting stent in a porcine coronary artery

  5. Polymer Carrier ConsiderationsChemical/Physical and Biological Biocompatible Formulate/ process Coating Integrity Sterilization Drug Loading Drug release Vascular compatible

  6. Coating Integrity BSC Carrier- TransluteTM Coated, Loaded, Sterilized, Expanded 40x 200x • Smooth, Uniform Coverage • No Cracking, Flaking or Delaminating

  7. Uniform PTx Content Along Stents of Different Lengths (15, 24, 32 mm stents -- 1ug/mm2)

  8. Uniform PTx Release From ExpressTMStents of Different Lengths 1.0 ug/mm2, Slow release 16 mm 1.0 ug/mm2, Slow Release 24 mm 1.0 ug/mm2, Slow Release 32 mm

  9. Polymer-based Clinical Data TRIAL DOSE OF PTx LATE LOSS mm TAXUS I 1.0ug/mm2 SR 0.36 +/- 0.48 TAXUS II 1.0ug/mm2 SR 0.31 +/- 0.39 TAXUS II 1.0ug/mm2 MR 0.30 +/- 0.39 TAXUS IV 1.0ug/mm2 SR 0.39 +/- 0.50 Confirmed by IVUS analysis (TAXUS II - Circulation January 20, 2004)

  10. In Vivo Studies, #&@% !!!! In Vivo Considerations for Polymers and Drugs • Animal Model • Rat • Rabbit • Swine • Canine • Implant Time • ImplantLocation • Sub Q • IM • Iliac • Coronary • Other

  11. Polymer CarriersVascular Compatibility Failed candidates (normal porcine coronary model) Polyurethane-coated Stent (2 months) Bare Stent Sub-optimal drug carriers can cause severe inflammatory response In Collaboration w/Drs. Rogers and Edelman,MIT

  12. Effect of Animal Model and Implant SiteRat Subcutaneous Implant Model 28 day Implant - H&E Staining Polyurethane-coated Stent Bare Stent

  13. Effect of Animal Model and Implant Site Porcine Coronary 28 day Bare Stent Polyurethane-coated Stent In Collaboration w/Drs. Rogers and Edelman,MIT

  14. 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

  15. Effect of Animal Model and Implant Site Porcine Coronary Artery 35 day PLA/PCL In Collaboration w/Drs. Rogers and Edelman, MIT

  16. Vascular CompatibilityTransluteTM 90D Bare control 180D Bare control 90D polymer coated 180D polymer coated In collaboration with Dr. Rob Schwartz Mayo Clinic and Dr. Greg Wilson Sick Children’s-Toronto

  17. Translute Polymer Long term (180 days) vascular compatibility 180 day • Good safety profile • Polymer similar to control • Reproduced from lot to lot Translute only Express stent In collaboration with Dr. Rob Schwartz Mayo Clinic and Dr. Greg Wilson Sick Children’s-Toronto

  18. Bare Polymer-coated Vascular Compatibility TransluteTM Endothelial coverage (PECAM 1, 0-5) % Luminal Stenosis Inflammation (CD45, 0-4) No significant differences In Collaboration w/Drs. Rogers and Edelman,MIT

  19. 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

  20. 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

  21. Thank You !

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