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

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

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

4. – Paclitaxel is a multi-functional drug which effectively: Inhibits proliferation Inhibits migration Inhibits inflammation Inhibits secretion – Paclitaxel is a multi-functional drug which effectively: Inhibits proliferation Inhibits migration Inhibits inflammation Inhibits secretion TAXUS Technology - Paclitaxel Promotes Endothelialization Restenosis Prevents Paclitaxel selectively impacts smooth muscle cells, platelets, and white blood cell activity without affecting endothelial cells – 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 of a paclitaxel-eluting stent in a porcine coronary artery Axel et al, AHA 1997, Karsch et al, SIC 1998

5. Polymer Carrier Considerations Chemical/Physical and Biological Formulate/process CoatingIntegrity Sterilization Drug Loading Drug release Biocompatible Vascularcompatible

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

7. Uniform PTx Content Along Stents of Different Lengths (15, 24, 32 mm stents -- 1ug/mm 2 )

8. Uniform PTx Release From Express TM Stents of Different Lengths 1.0 ug/mm 2, Slow release 16 mm 1.0 ug/mm 2, Slow Release 24 mm 1.0 ug/mm 2, 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) 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 Considerations for Polymers and Drugs Animal Model Animal Model – Rat – Rabbit – Swine – Canine Implant Time Implant Time Implant Location Implant Location – Sub Q – IM – Iliac – Coronary Other Other In Vivo Studies, #&@% !!!!

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

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

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

14. 28 day PLA/PCL coated stent 56 day PLA/PCL coated stent In Collaboration w/Drs. Rogers and Edelman, MIT Rabbit Iliac Artery Effect of Animal Model and Implant Site

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

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

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

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

19. TAXUS Technology - Translute™ Polymer Polymer-based matrices provide: ease of handling ease of handling uniform dose along stent and dosing in a controlled manner = consistency 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 a matrix by which drug release can be manipulated to achieve a desired biological response Polymer-based matrices provide: ease of handling ease of handling uniform dose along stent and dosing in a controlled manner = consistency 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 a matrix by which drug release can be manipulated to achieve a desired biological response With greater opportunities come greater challenges

20. Translute TM Polymer stability  Translute TM coating integrity was maintained in 10-year equivalency tests*  The Translute TM 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 !