Boston Scientific Drug eluting stent program A Scientific Approach Identify therapeutic agent Identify appropriate polymer carrier Evaluate a broad range of doses and release kinetics Evaluate maximum dose Maximum loading capacity Identify the vascular toxic dose Determine the safe and therapeutic range for the artery Establish the minimum effective range Identify therapeutic agent Identify appropriate polymer carrier Evaluate a broad range of doses and release kinetics Evaluate maximum dose Maximum loading capacity Identify the vascular toxic dose Determine the safe and therapeutic range for the artery Establish the minimum effective range Polymer Carrier Considerations Chemical/Physical and Biological Formulate/ process Coating Integrity Sterilization Drug Loading Drug release Biocompatible Vascular compatible PTx Paclitaxel Microtubular dependent steps in restenosis Growth Factors Cytokines SMC Proliferation Stent implant Injury Platelet Activation Inflammation Cell Cycle SMC Migration Extracellular Matrix synthesis & secretion Signal Transduction PTx Wide Dose Range Screening Identifies 1.0 ug/mm 2 for detailed analysis 2 ug/mm 2 4 ug/mm ug/mm 2 1ug/mm 2 Pronounced EC loss Medial thinning Fibrin Drug effect Thrombus Minimal EC loss Medial thining Fibrin Drug Effect No Thrombus 85 ug345 ug 175 ug 50 ug In-vitro release from 1 ug/mm2 formulations Release comparison Safety margin for multiple and/or overlapping stents Cumulative Paclitaxel Release (In Vitro) FormulationAmount released (g) 1 day10 days Slow Moderate Fast fold 3--fold Higher initial peak aids in blunt response to implant injury Margin of >16 fold compared to next dose considered for humans 16-fold 2--fold TAXUS I-III Summary TAXUS I Safety Study Slow Release Formulation Prospective, Randomized, Placebo Controlled, Blinded De novo lesions, 3.0 and 3.5mm Three centers in Germany (PI: Prof Grube) Total 61 patients: 31 drug, 30 bare Primary endpoint: 30 day MACE: 0% Demographic & Lesion characteristics similar (~3.0 mm diameter; ~11 mm length) Caution: Investigational device. Limited +y U.S. law to investigational use. Not available for sale in the US Safety Results 180 Day MACE 0% 30 Day MACE 0% Thrombosis 0%7% Cumulative 180 Day MACE 0%7% TVR 0% Q-Wave MI 0% Death (Death, Q-Wave MI, TVR, & Thrombosis) NIRxNIR Higher TVR rate in NIR control cohort compared with NIRx paclitaxel-eluting stent cohort RIO Post-procedure QCA Patient that Receive the NIRx RIO 6-month follow-up 6 Month Binary Restenosis Rate 0%10% NIRxNIR Reduced restenosis rate in NIRx paclitaxel-eluting stent (statistical significance not expected with this sample size) NIR c ontrol restenosis rate is within expected range 0% 2% 4% 6% 8% 10% 12% 14% (n=30)(n=29) p-value = 6 Month QCA Significant improvements with NIRx MLD (mm) % DS 2.19 0.65 NIR 2.61 0.49 NIRx NIR NIRx (n=29) p-value = (n=30) p-value = (n=29)(n=30) 51% 19% 6 Month QCA Late Lumen Loss (mm) 0.36 0.47 NIRxNIR Significant Improvements with NIRx Late Loss Index 0.2 2 0.29 NIRxNIR p-value = (n=30)(n=26) p-value = (n=30)(n=26) 49% 51% NIRx MLD Edge Effects Analysis No evidence of restenosis or remodeling at the edges in either group No significant differences for proximal and distal edges between both the NIR and NIRx NS P=0.0072NS ProximalLesionDistal IVUS Follow-up Results Neointimal Volume Index 1.02 0.72 NIRxNIR Significant Improvements with NIRx p-value = (n=26) 32 % mm 3 /mm % Neointimal Volume Index 7.19 5.54 NIRxNIR p-value = (n=26) 32 % mm 3 /mm IVUS Patient that Received NIRx Post Procedure 6-Month Follow-up Conclusion Safety results show: low MACE & 0% Stent Thrombosis 0% Binary Restensosis and significant IVUS & QCA improvements suggest great promise in the prevention of restenosis TAXUS II, III & IV will provide additional insight regarding the efficacy of the TAXUS paclitaxel-eluting stent TAXUS II Safety and Efficacy Study Slow and Moderate Release Formulation Safety & Superior Performance De novo lesions (3.0 and 3.5mm) 532 Patients from 16 Countries and up to 40 Centers Two Sequential Dose Cohorts Slow and Moderate Release 266 Patients Randomized in Each Cohort Drug 133: Bare 133 Primary Endpoint: Plaque Volume by IVUS TAXUS 2 study P IAntonio Colombo (It) QCA Core labCardiolysis (NL) IVUS Core LabCardiolysis (NL) 30 centres worldwide (Asia, Canada, Australia, Europe) TAXUS 2 Recruitment complete 7 January 2002 Leading centres Prof Silber (Germany)45 cases Dr Banning/Channon (UK)43 cases Prof Hauptman (Germany)39 cases Dr Drzewiecki (Poland)38 cases Prof Grubbe (Germany)37 cases TAXUS 2 UK Centres Oxford Southampton (Dr Dawkins) St Thomass (Dr Redwood) 54 cases- 10% of total study population Results Expected August 2002