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Advanced Angioplasty 2008 Hilton London Metropole Hotel January 25, 2008

Overview of the Endeavor Resolute Preclinical and Clinical Programs. Josiah N. Wilcox, Ph.D. Vice President and Resident Scholar Science & Technology Medtronic CardioVascular. Advanced Angioplasty 2008 Hilton London Metropole Hotel January 25, 2008. Unmet Clinical Needs in the DES era.

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Advanced Angioplasty 2008 Hilton London Metropole Hotel January 25, 2008

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  1. Overview of the Endeavor Resolute Preclinical and Clinical Programs Josiah N. Wilcox, Ph.D. Vice President and Resident Scholar Science & TechnologyMedtronic CardioVascular Advanced Angioplasty 2008 Hilton London Metropole Hotel January 25, 2008

  2. Unmet Clinical Needsin the DES era • TLR and MACE rates remain high in patients at the highest clinical risk of TLR • Diabetics • 11.3% MACE @ 9 mo—DIABETES Trial, Sabate, TCT 2004 • 10.9% TLR @ 12 mo—TAXUS V Trial, Ellis, TCT 2005 • Small Vessels • 9.3% MACE @ 8 mo—SES SMART, Ardissino, JAMA, Dec 8, 2004 • 14.2% TLR @ 12 mo—TAXUSV Trial, Ellis, TCT2005 • Multi-Vessel Disease • 14.3% TLR—The Milan DES Experience, Columbo, ACC 2004

  3. Endeavor Resolute™Design Goals • Improve clinical outcomes in more complex lesions • Maintain current safety profile seen with Endeavor™ DES • Extended drug elution to match the potentially delayed healing times of complex lesions • Combat the sustained stimulus to the proliferative response

  4. Stent Delivery System Drug: zotarolimus Driver Cobalt Alloy Stent Endeavor ResoluteIncorporates the BioLinx™ Polymer System Retains three components of the Endeavor Sprint™ Coronary Stent System with a new DES polymer Novel Features of BioLinx Polymer System: • Medtronic proprietary polymer design • Hydrophobic/Hydrophilic polymer blend • Extended release kinetics • Biocompatibility equivalent to PC • Compatible with multiple drug platforms

  5. Hydrophilic vs Hydrophobic Polymers • Polymers can either be hydrophilic or hydrophobic • Hydrophilic = water-loving • Hydrophobic = water-hating A hydrophobic polymer is not compatible with water A hydrophilic polymer is compatible with water Evidence that hydrophilic polymers are more biocompatibile Body is approximately 70% water

  6. θ1 θ2 Hydrophilic Hydrophobic Hydrophilic vs HydrophobicContact Angles are used to determine if a polymer is hydrophilic or hydrophobic • Angle formed when water drop applied to polymer surface • Smaller angle = more hydrophilic Contact Angle Hydrophobic Polymer Hydrophilic Polymer θ1 <θ2 Water-loving Water-hating

  7. C10 Polymer(Hydrophobic) Based primarily on hydrophobic butyl methacrylate to provide adequate hydrophobicity for zotarolimus C19 polymer(Hydrophilic) Manufactured from a mixture of hydrophobic hexyl methacrylate and hydrophilic vinyl pyrrolidinone and vinyl acetate monomers to provide enhanced biocompatibility Polyvinyl pyrrolidinone (PVP) Hydrophilic polymer increases initial drug burst and enhances biocompatibility The BioLinx Polymer SystemComposed of Hydrophilic and Hydrophobic Polymers C10 C19 PVP Overall the BioLinx polymer blend displays a very hydrophilic surface to the body for biocompatibility

  8. Cell Membrane PC Technology BioLinx Hydrophilic outer surface Hydrophobic layer O N O O P O Phosphorylcholine(PC) Headgroup Vinyl pyrrolidinone groups Medtronic Polymer TechnologiesPC and BioLinx Polymers Hydrophilic Surface Chemistry

  9. Endeavor ResoluteBioLinx Polymer In Vivo Drug Elution 100 80 60 % Remaining % Zotarolimus Loading % Eluted 40 20 <2% (LOQ) 0 0 50 100 150 200 Days Greater than 85% of zotarolimus is eluted at 60 daysComplete drug content exhausted by 180 days

  10. A Robust Durable Coating BioLinx is the first polymer system designed specifically for DES applications The BioLinx Polymer System provides a durable and robust coating The stent surface is primed to improve adhesion of the BioLinx Polymer System A deployed stent after tracking 3 times in a 5 Fr guide catheter BioLinx Polymer System Primer Atomic Force Microscopy (AFM) studies indicate that the interface between the BioLinx Polymer System and the primer is very strong

  11. Endeavor ResoluteInhibition of Neointimal Development at 28 Days 28 day porcine study results Driver Control Endeavor Resolute Endeavor Resolute Significant inhibition of neointimal development compared to Driver controls

  12. Endeavor ResoluteExtended Efficacy out to 90 days 60 50 40 Driver (bare) Stenosis 30 Endeavor Resolute 20 10 0 Day 28 Day 90 Significant inhibition of neointimal development at both 28 and 90 days in porcine coronary arteries

  13. Developing a New Understanding of the Science of DES Polymer Biocompatibility

  14. Monocytic Adhesion Correlates With Polymer Hydrophobicity Fluoro Polymer Negative Control Positive Control PC BioLinx SIBS PBMA ContactAngle: 83° 94° 115° 129° 118° Hydrophilic Hydrophobic

  15. Endeavor Resolute with BioLinxBest in Class biocompatibility equivalent to Endeavor with PC Comparison of Inflammation Scores 5 4.5 4 3.5 Endeavor* 3 Endeavor Resolute* 2.5 Inflammation Score Fluro Polymer DES 2 PBMA DES 1.5 1 0.5 0 28 days 90 days 180 days 365 days Time after stenting *Data on File Medtronic CardioVascular **Data from Abbott US Physician presentation SE2924433D Endeavor not tested at 365 days Low inflammatory scores seen with Endeavor and Endeavor RESOLUTE stents compared to DES containing hydrophobic polymers platforms in porcine coronary arteries

  16. The Design of DES PolymersHydrophobic vs. Hydrophilic • First generation drug eluting stent (DES) coatings have been based on hydrophobic polymers to hold and elute hydrophobic drugs • SIBS • PBMA • Fluoro Polymer • Hydrophobic polymers may stimulate inflammatory reactions • Hydrophilic polymers may be more biocompatible in the aqueous body environment • The phosphorylcholine (PC) based polymer used in the second generation Endeavor DES, is a hydrophilic polymer that shows good biocompatibility • The next generation Endeavor Resolute DES coating based on the BioLinx Polymer System, is a unique blend of hydrophilic and hydrophobic polymers, that offers both biocompatibility and extended drug elution • Hydrophobic polymers may contribute to the problem of Late Stent Thrombosis by increasing inflammation, endothelial dysfunction and/or expression of procoagulant proteins in the vessel wall

  17. Endeavor RESOLUTE Clinical Update Caution: Endeavor and Endeavor Resolute are investigational devices with an investigational drug, not approved for sale or commercial use.

  18. RESOLUTEClinical Trial Design Single De Novo Native Coronary Artery Lesions Lesion Length: 14-27mm Stent Diameters: 2.5, 3.0, 3.5mm Stent Lengths: 18, 24, 30mm (8/9mm bailout) Drug Dose: 1.6 g/mm2 stent surface area Antiplatelet therapy for 6 months Pre-dilatation required 130 Patients (9 additional PK Sub-Study Patients enrolled after original 130 patients) 12 Sites (New Zealand and Australia) Endeavor Resolute Stent Clinical/MACE 30d 4mo 6mo 9mo 12mo 2yr 3yr 4 yr 5 yr Angio/IVUS N=30 N=100 Primary Endpoint: Late lumen loss (in-stent) at 9 mths by QCA Secondary Endpoints: MACE at 30 days, 6, 9 and 12mths and IVUS and angiographic parameters at 9mths 30 pt Subset: 4mth MACE and angiographic, IVUS parameters* *Meredith et al: EuroInterv 2007; 3:50-53

  19. RESOLUTE Patient Flowchart 130 Patients Enrolled 4 MonthFollow-Up 9MonthFollow-Up 12 MonthFollow-Up Clinical F/U 30/30 Clinical F/U 130/130 Clinical F/U 129/130 99.2% 100% 100% Angiographic F/U 30/30 Angiographic F/U 95/100 100% 95%

  20. RESOLUTE Patient Demographics N=130 Meredith et al: EuroInterv 2007; 3:50-53

  21. RESOLUTE Procedural Characteristics N=130 patients, 131 lesions Device success <50% residual in-stent % ds with assigned stent Procedure success <50% residual in-stent % ds & without in-hospital MACE Meredith et al: EuroInterv 2007; 3:50-53

  22. RESOLUTE: 9 Month Follow Up Angiographic Results n=96

  23. RESOLUTEClinical Events to 12 months

  24. RESOLUTENQMI to 12 months

  25. RESOLUTE: DAPTPatients with a Surgical Procedure • 15 Patients discontinued AP Therapy and had surgical procedures • 5 females • 10 males • 1 diabetic • 2 MACE Events by 12 months • Both deaths due to Cancer • Melanoma • Mesothelioma

  26. RESOLUTE Clinical ProgramCurrent Outline US Studies OUS Study Angiographic/IVUS Studies Pivotal Study All Comers (CE Mark) Randomized to Taxus n = ~430 RESOLUTE II Randomized to Taxus n = ~1500 RESOLUTE IV Randomized to Xience n = 2300 RESOLUTE III 2.25 mm n=~150 RESOLUTE Small 38 mm n=~100 RESOLUTE Long 4.0 mm n=~100 RESOLUTE Large

  27. RESOLUTE IIIInternational RCT vs Xience: PI: Patrick Serruys All Comer Dual APT ≥ 6 months N = 2300 15-20 International Sites Randomization 1:1 Endeavor Resolute N=1150 Xience N=1150 Clinical Follow-up 30d 6mo 1yr 2yr 3yr 4 yr 5 yr 13 mo Angiographic Follow-up Primary Endpoint:Non-inferiority TLF (Cardiac Death, TLR, MI) at 12 months Secondary Clinical Endpoints: Cardiac death/MI or TLR Secondary Angiographic Endpoints: (n=460) In-stent and In-segmentDS%, In-stent and In-segment LL at 13 months Secondary OCT Endpoints: (n=~50) Stent Strut Tissue Coverage, Stent Apposition at 13 months

  28. Thank You

  29. Mauri et al. N Engl J Med 2007;356:1020-9. Endeavor: Mauri et al. TCT. 2007 Xience: FDA Panel Meeting Nov. 29, 2007 No. at Risk Pooled Data 1 Year 2 Years 3 Years Cypher863 848 823 Endeavor1301 1287 675 Taxus1351 1300 1117 *Xience 397 377 n/a DES In Perspective ARC Definite and Probable to 3 years 3.0% 2.5% 2.0% 1.5% ARC ST % 1.0% 0.5% 0.0% 0 360 720 1080 1440 Days *Represents “SPIRIT II and III 2-year Complete Analysis” from Panel

  30. Mauri et al. N Engl J Med 2007;356:1020-9. Endeavor: Mauri et al. TCT. 2007 Xience: FDA Panel Meeting Nov. 29, 2007 Pooled Data 1 Year 2 Years 3 Years Cypher863 848 823 Endeavor1301 1287 675 Taxus1351 1300 1117 *Xience 397 377 n/a DES In Perspective Cardiac Death and MI to 3 years 9% 6% Cardiac Death and MI % 3% 0% 0 360 720 1080 1440 Days *Represents “SPIRIT II and III 2-year Complete Analysis” from Panel

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