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The TAXUS™ Paclitaxel-Eluting Stent Program

The TAXUS™ Paclitaxel-Eluting Stent Program. The safety and effectiveness of the TAXUS ™ Express 2 ™ Stent has not been established in patients with coronary artery reference vessel diameters less than 2.5 mm or in lesions longer than 28 mm or in patients with diabetes. Table of Contents.

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The TAXUS™ Paclitaxel-Eluting Stent Program

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  1. The TAXUS™ Paclitaxel-Eluting Stent Program

  2. The safety and effectiveness of the TAXUS™ Express2™ Stent has not been established in patients with coronary artery reference vessel diameters less than 2.5 mm or in lesions longer than 28 mm or in patients with diabetes

  3. Table of Contents • Drug-eluting stent overview • Drug-eluting stent benefits In your opinion … Part 1 • Consistently low revascularization rates In your opinion … Part 2 • Excellent safety with desirable healing In your opinion … Part 3 • Ability to treat various patients and lesions • What does the future hold?

  4. Drug-Eluting Stent OverviewFrom Bare Metal to Drug-Eluting Stents Key Drug-Eluting Stent Characteristics Key Bare Metal Stent Characteristics Restenosis Reduction • Binary restenosis • Dramatic TLR/TVR reduction • Consistent performance throughout the target lesion • Predictable results across all patient subsets • Desirable late loss • Complete endothelialization • Wide margin of safety Healing • Large lumens • Various lesion access • Excellent conformability • Minimize incomplete apposition • Deliverability Deliverability and Conformability

  5. Drug-Eluting Stent Benefits • Reduced angiographic restenosis • Reduced clinical restenosis • Comparable safety compared to bare-metal stents • Improved patient outcomes • Positive trends in various lesion subsets • Positive trends in various patient populations

  6. In your opinion ... • Which patients should receive drug-eluting stents? • What factors are critical to consider when trying to minimize repeat revascularizations? • What are the most important components of a drug-eluting stent and why?

  7. TAXUS IV Clinical TrialTLR Overall at 9 Months RR=0.39 [0.26-0.59] P<0.0001 RR=0.27 [0.16-0.43] P<0.0001 Event % P=0.48 *= Express® Control Stent. **= TAXUS™ Express® Stent

  8. TAXUS IV Clinical TrialTLR Overall at 12 Months RR=0.41 [0.29-0.57] P<0.0001 RR=0.29 [0.19-0.43] P<0.0001 P=0.74 Event % *= Express® Control Stent. **= TAXUS™ Express® Stent

  9. TAXUS IV Clinical Trial TLR/TVR Overall at 9 Months P<0.0001 P<0.0001 P=0.0008 P<0.0001 P=0.0001 P=0.005 Event % *= Express® Control Stent. **= TAXUS™ Express® Stent

  10. TAXUS IV Clinical Trial TLR/TVR Overall at 12 Months P<0.0001 P<0.0001 P=0.0003 P<0.0001 P<0.0001 P=0.0120 Event % *= Express® Control Stent. **= TAXUS™ Express® Stent

  11. N=489 N=507 N=109 N=104 N=54 N=51 Impact of Diabetes MellitusTAXUS IV Clinical Trial TLR at 9 Months P=0.004 P=0.32 P<0.0001 *= Express® Control Stent. **= TAXUS™ Express® Stent

  12. N=489 N=507 N=109 N=104 N=54 N=51 Impact of Diabetes MellitusTAXUS IV Clinical Trial TLR at 12 Months P=0.12 P<0.0001 P=0.0063 *= Express® Control Stent. **= TAXUS™ Express® Stent

  13. N=214 N=206 N=241 N=257 N=195 N=197 Impact of Vessel Diameter (QCA)TAXUS IV Clinical Trial TLR at 9 Months P<0.0001 P=0.0004 P=0.057 RVD (mm) *= Express® Control Stent. **= TAXUS™ Express® Stent

  14. N=154 N=150 N=498 N=511 Impact of RVD (visual assessment)TAXUS IV Clinical Trial TLR at 9 Months P=0.0001 P<0.0001 *= Express® Control Stent. **= TAXUS™ Express® Stent

  15. N=133 N=131 N=304 N=323 N=206 N=197 Impact of Stent DiameterTAXUS IV Clinical Trial TLR at 9 Months P=0.0001 P=0.0002 P=0.002 Stent diameter (mm) *= Express® Control Stent. **= TAXUS™ Express® Stent

  16. N=226 N=214 N=325 N=351 N=97 N=91 Impact of Lesion Length (QCA)TAXUS IV Clinical Trial TLR at 9 Months P=0.0009 P=0.0001 P=0.01 Lesion length (mm) *= Express® Control Stent. **= TAXUS™ Express® Stent

  17. N=382 N=372 N=127 N=134 N=153 N=126 Impact of Total Stent LengthTAXUS IV Clinical Trial TLR at 9 Months P<0.0001 P=0.0004 P=0.002 Stent length (mm) *= Express® Control Stent. **= TAXUS™ Express® Stent

  18. Lesion Length Response (tertile analysis)TAXUS IV Clinical Trial TLR at 9 Months Control TAXUS™ Stent TLR (%) < 2.5 2.5-3.0 > 3.0 RVD (mm) Lesion Length (mm)

  19. TAXUS IV Clinical Trial Restenosis at 9 Months RR=0.30 [0.19, 0.46] P<0.0001 RR=0.23 [0.13, 0.38] P<0.0001 Restenosis (%) *= Express® Control Stent. **= TAXUS™ Express® Stent

  20. N=78 N=98 N=97 N=105 N=92 N=88 TAXUS IV Clinical Trial RestenosisImpact of Vessel Diameter (QCA) P<0.0001 P=0.0001 In-Segment Restenosis (%) P=0.10 RVD (mm) *= Express® Control Stent. **= TAXUS™ Express® Stent

  21. N=49 N=57 N=125 N=143 N=93 N=91 TAXUS IV Clinical Trial RestenosisImpact of Stent Diameter P=0.0002 P<0.0001 In-Segment Restenosis (%) P=0.13 Stent diameter (mm) *= Express® Control Stent. **= TAXUS™ Express® Stent

  22. Reduced In-Stent Binary Restenosis No Edge Effect in TAXUS IV Clinical Trial P<0.001 P<0.001 26.6 24.4 % of patients P=0.81 P=0.27 7.9 5.5 3.4 2.7 1.9 0.7 Intent-to-treat, angiographic subset (n=732) *= Express® Control Stent. **= TAXUS™ Express® Stent

  23. 9-Month % Diameter Stenosis Improved In-Stent and at Both Edges in TAXUS IV Clinical Trial P<0.0001 P<0.0001 39.8 37.2 % Diameter Stenosis 26.3 P=0.0167 P=0.0001 17.4 16.1 13.2 11.8 7.6 Intent-to-treat, angiographic subset (n=732) *= Express® Control Stent. **= TAXUS™ Express® Stent

  24. 9-12mm 9-12mm 0-3mm 0-3mm 3-6mm 3-6mm 6-9mm 6-9mm 12-15mm 12-15mm TAXUS II Clinical TrialUniform Suppression of Neointima at 6 Months IVUS analysis of TAXUS II clinical trial patients showed uniform neointimal suppression throughout the entire stent Control* 3.0 P=ns TAXUS™ Stent** 2.0 Neointimal hyperplasia area [mm2] P=ns 1.0 distal proximal proximal 0.0 distal *= Express® Control Stent. **= TAXUS™ Express® Stent

  25. 9-12mm 9-12mm 0-3mm 0-3mm 3-6mm 3-6mm 6-9mm 6-9mm 12-15mm 12-15mm TAXUS IV Clinical Trial Uniform Suppression of Neointima at 9 Months IVUS analysis of TAXUS IV clinical trial patients showed uniform neointimal suppression throughout the entire stent 4 Control* 3 P=ns TAXUS™ Stent** Neointimal area (mm2) 2 P=ns 1 0 distal distal proximal proximal *= Express® Control Stent. **= TAXUS™ Express® Stent

  26. Restenosis ReductionFormula for Fighting Restenosis Several drug-eluting stent characteristics may contribute to restenosis reduction. Multifunctional Effects • The multifunctional effects of a drug may contribute to reducing restenosis Uniform Drug Delivery • Polymeric coatings may provide uniform drug delivery across the stent Rapid Drug Absorption • High degrees of lipophilicity may increase vascular absorption in the tissue surrounding the stent Balloon Overhang • Minimal overhang may potentially reduce trauma at the edges

  27. Restenosis ReductionMultifunctional Activity The TAXUSTM Stent elutes paclitaxel, a multifunctional microtubular inhibitor. • Paclitaxel is believed to have multifunctional effects which reduce: • Inflammation • Proliferation and migration of smooth muscle cells • Extra-cellular matrix secretion Microtubule Network: Paclitaxel promotes the formation of stable microtubules, thereby inhibiting multiple cellular functions Note: Image Courtesy of Dr. Vladimir Rodionov

  28. Paclitaxel Taxol Paclitaxel + Composition 100% Paclitaxel Cremophor EL + Dehydrated alcohol Delivery Elution from stent Intravenous 3,280 µg/kg ovarian CA Dose 1. 5 µg/kg* - 4,250 µg/kg in breast CA Indication Restenosis Cancer Restenosis ReductionPaclitaxel andTaxol are Different * Based on Implantation of a Single 3.5mm X 16mm TAXUS™ Express2™Stent with Total Loaded Dose of 108 g. Dose in g/kg Calculated Using Average Body Surface Area of 1.7m2 and 70kg Body Weight. Note: Taxol is a registered trademark of Bristol Meyers Squibb.

  29. PaclitaxelWide Safety Window Paclitaxel’s broad safety window inhibits smooth muscle cell proliferation & migration while allowing the vessel to heal.

  30. HealingPaclitaxel Endothelial cells are less sensitive than smooth muscle cells to the effects of paclitaxel. • Paclitaxel is a multi-functional drug which appears to: • Inhibit proliferation • Inhibit migration • Inhibit inflammation • Inhibit secretion Restenosis Prevents Endothelialization Promotes • The TAXUS™ paclitaxel-eluting stent appears not to delay endothelialization Complete endothelialization of a paclitaxel-eluting stent in a porcine coronary artery.

  31. Restenosis ReductionUniform Drug Distribution The TransluteTM Polymer provides protection and controlled release of paclitaxel. Translute Polymer is intended to protect the drug during crimping, packaging, distribution, preparation, sterilization, delivery to the lesion, and stent expansion Translute Polymer is intended to control the release of the drug during the critical period of the restenotic cascade

  32. Restenosis ReductionLipophilicity Paclitaxel is highly lipophilic which may increase vascular absorption in tissue surrounding the stent. Outside the cell Paclitaxel (green) Lipid Bi-Layer Inside the cell

  33. In controlled clinical studies, use of the TAXUS™ Stent resulted in consistently low revascularization rates across a broad range of patient and lesion types

  34. In your opinion ... • How do you define “safety” as it relates to drug-eluting stents? • Do you believe that late loss is an indication of efficacy, safety or both? • How important is late loss? • What affects vascular healing after stent implantation?

  35. TAXUS IV Clinical Trial9-Month MACE and TVF P=0.80 P=0.88 P<0.0001 P<0.0001 P=0.0002 P=0.0001 Event (%) *= Express® Control Stent. **= TAXUS™ Express® Stent

  36. TAXUS IV Clinical Trial12-Month MACE and TVF P=1.00 P=0.33 P<0.0001 P<0.0001 P<0.0001 P<0.0001 Event (%) *= Express® Control Stent. **= TAXUS™ Express® Stent

  37. TAXUS IV Clinical TrialStent Thrombosis at 12 Months In-hospital Discharge - 30 days 31 days - 6 months 12 months TAXUS™ Stent** 0.6% (n=4) 0.3 0.3 P=0.75 (n=662) Control* 0.3 0.3 0.2 0.8% (n=5) (n=652) 0 0.2 0.4 0.6 0.8 1 Stent thrombosis, % Note: There were no additional stent thrombosis between 6 and 9 months in either the TAXUS Stent or Control. *= Express® Control Stent. **= TAXUS™ Express® Stent

  38. HealingLate Loss Late loss provides evidence of healing • A drug-eluting stent should not completely eliminate the body’s healing response • Neointima indicates healing after drug-eluting stent implantation • Consistently low but positive late loss values across studies may indicate healing Image Courtesy of Dr. Robert Schwartz

  39. MLD follow-up MLD post-procedure HealingLate Loss in Bare Metal Stents • Late loss in bare metal stents is typically 1.0mm • Late loss is thought to be largely comprised of neointima • Late loss is nearly always a positive number, indicating the lumen decreases in size 0.50mm Late Loss 1.0mm + 0.50mm Illustrations by Boston Scientific. Images not to scale.

  40. MLD follow up HealingLate Loss in Bare Metal Stents • The Express2™ Stent strut thickness is 0.0052”, which converts to 0.13mm • This is well within the amount of late loss of a bare metal stent, suggesting complete stent strut coverage Lumen Neointima 0.50mm 0.13mm 0.0052”= 0.13mm Illustrations by Boston Scientific. Images not to scale.

  41. MLD follow up HealingTAXUS IV Clinical Trial Late Loss to Strut Thickness Relationship • The Express2™ Stent strut thickness is 0.0052”, which converts to 0.13mm • Based on the TAXUS IV trial late loss values, neointima would be sufficient to completely cover the stent struts. Lumen Neointima 0.195mm 0.130mm 0.0052”= 0.13mm Illustrations by Boston Scientific. Images not to scale.

  42. Low but positive late loss provides evidence that vessel healing has occurred. Late loss =~0.30mm 0.15 mm 0.15 mm 0.30 mm HealingPaclitaxel Selective Impact Paclitaxel allows healing to occur within the vessel, as evidenced by low but positive late loss. • Endothelial cells are less sensitive than smooth muscle cells to the effects of Paclitaxel. Paclitaxel IC50 (nM) Note: Image courtesy of Dr. Robert Schwartz; In vitro cell culture study performed by Dr. Luszher

  43. Late loss <0.6 mm weak predictor of TLR Late loss >0.6mm increasing probability of TLR TAXUS IV Clinical TrialLate loss as a Predictor of TLR Logistic regression combining all patients 100 Probability for TLR (%) 50 0 0.00 0.50 1.00 1.50 2.00 2.50 Late Loss (mm)

  44. TAXUS IV Clinical TrialLate loss as a Predictor of Restenosis Logistic regression combining all patients 100 Late loss >0.6 increasing probability of restenosis Probability for Restenosis (%) 50 0 0.00 0.50 1.00 1.50 2.00 2.50 Late Loss (mm)

  45. In animal and controlled human clinical studies, the TAXUS™ stent consistently demonstrated excellent safety with desirable healing

  46. In your opinion ... • What role does the stent platform play in terms of drug-eluting stent safety and efficacy? • Why is conformability important with drug-eluting stents? • What tradeoffs are you willing to make as it relates to stent designs?

  47. Deliverability and Conformability Excellent deliverability and conformability will continue to be important features with drug-eluting technology… Bare Metal Stents (Desired Features) Drug-Eluting Stents (Desired Features) • Deliverability: - access lesions • Conformability • Deliverability: - access more lesions with longer stents when necessary • Conformability: - provide strut apposition to the vessel for uniform coverage and drug absorption

  48. A broad working range and high RBP combine to provide excellent sizing flexibility. 3.0 mm System Express2™ Stent Nominal 9 atm Quarter Size 14 atm Rated Burst Pressure 18 atm 1.1:1 15 atm Working Range* 9 atm Stent apposition contributes to efficacy and safety • The Express2 Stent platform was designed for excellent deployment with excellent stent to vessel conformability. • A conformable stent provides uniform strut apposition to the vessel wall.

  49. Importance of Stent Apposition Contact between the vessel wall and the stent strut may be essential for drug absorption. Uniform stent apposition allows for uniform drug absorption and uniform restenosis reduction. Incomplete stent apposition / under-deployment may increase the risk of thrombus formation & SAT’s. Achieving proper stent strut apposition may be a key contributor to both efficacy and safety of drug eluting stents, specifically SATs. Efficacy (Restenosis Reduction) Safety (Healing)

  50. HealingIncomplete Apposition Nomenclature

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