1. Drug –eluting stents Where are we now and what can we expect in 2003? Tony Gershlick Leicester Drug –eluting stents Where are we now and what can we expect in 2003? Tony Gershlick Leicester

2. Trials Real World

3. What we need i. Prevent restenosis – cost effective Either : - Treat all – at equivalent cost (DES @ £450) - Select those at higher risk - Treat those who develop ISR ii.Trials to reflect the patients undergoing PCI iii.Trials to continue to show benefit ( o late adverse events ) iv.N.I.C.E. What we need i. Prevent restenosis – cost effective Either : - Treat all – at equivalent cost (DES @ £450) - Select those at higher risk - Treat those who develop ISR ii.Trials to reflect the patients undergoing PCI iii.Trials to continue to show benefit ( o late adverse events ) iv.N.I.C.E.

4. All or only in those @ higher risk ?

6. 68 yr non-insulin dependant diabetic

8. Bifurcations ?

9. Are the DES trials moving with the need ? trial update trial evaluation what is new ? Are the DES trials moving with the need ? trial update trial evaluation what is new ?

10. PACLITAXEL V-Flex Supra - G ELUTES ASPECT De novo <16 mm 0.0 1.0 2.0 3.0 4.0 Dose Density ( µ g/mm 2 ) 0 0 10 20 30 40 50 Diameter Stenosis (%) ELUTES ASPECT TLR In-segment 5.9% (NS) TLR In-stent R 2.4% (p=0.02) v 13% control TLR In-segment 5.9% (NS) TLR In-stent R 2.4% (p=0.02) v 13% control TLR 4.6% versus 12% (<0.05)

11. PACLITAXEL

14. Non –polymer Guidant Achieve stent paclitaxel in ELUTES dose Non –polymer Guidant Achieve stent paclitaxel in ELUTES dose

16. 20% 10% 22 In segment BR TVF C treated C treated 17 12

17. GIUDANT / Cook … paclitaxel

18. 1 Single Lesion < 25 mm Plus complicating factor * CTO, Bifurcation, ISR 2 single lesions < 25 mm de novo or * 1 long lesion > 25 mm DELIVER 2 Trial DES Trials and real life

19. DELIVER II – Lesion characteristics (n = 500) Intended treatment One <25mm lesion with complicating factor * 47% Two <25mm lesions 26% One very long lesion (> 25 mm) 27% In-stent restenosis (25%) Bifurcations Chronic total/sub-total occlusions (28%) (19%) PACLITAXEL Death3 (0.6%) TLR (PCI)2 (0.4%) TLR (CABG)None Q-wave MI3 (0.6%) Non Q-wave MI7 (1.4%) Total15 (3.0%)

21. II

22. TAXUS IV To demonstrate safety and performance of TAXUS Express SR compared to uncoated express control Prospective randomised double blinded 10 to 28mm 6 Sites in US 1326 patients presenting with de novo lesions (10 to 28mm) Randomisation was stratified by treated diabetes and vessel diameter Recruitment complete currently in follow up phase Primary endpoint - 9 months TVR rate Recruitment complete currently in follow up phase. TAXUS V 80 U.S. Sites Anticipated Start Q1 2003 Slow Release Formulation De novo arm 1,000 Patients 10 - 40 mm Lesion Lengths Stents: 2.25 - 4.0 mm, Lengths: 8 - 32 mm Multiple Stents Allowed TAXUS V In Stent Restenosis arm 500 Patients TAXUS Stent versus Brachytherapy

23. TAXUS VI European Study designed evaluate safety and efficacy of TAXUS Express MR formulation (1mcg/mm2) De Novo lesions vessel diameter >2.5mm to 18mm and <40mm 448 patients randomised in 2 groups Primary endpoint TVR at 6 months Patients will be followed up for 5 years Enrollment commenced June 2002 will close Jan 2003

26. Non polymer dead in the water ?? Lesion/patient risk & stent risk Await DELIVER 2 ? TAXUS to date some reflection of real life but on-going real test - % events in control group (poor stent, mix of risks) - overall (in-segment effect) Non polymer dead in the water ?? Lesion/patient risk & stent risk Await DELIVER 2 ? TAXUS to date some reflection of real life but on-going real test - % events in control group (poor stent, mix of risks) - overall (in-segment effect)

27. SIROLIMUS Mean lesion length 14.4mm

28. 21.2 ± 5.7 21.6 ± 6.7 Stented length 14.4 ± 5.8 14.4 ± 5.7 Mean Lesion length Control (%) (n=525) CYPHER (%) (n=533)20.626.0 C 33.532.6 B2 B2 38.134.0 B1 B1 7.87.4 AHA/ACC A 28.224.6 Diabetes Mellitus SIRUS – how like real life was it ??

29. CYPHER (%)Control (%) Diameter 2.5 19.317.2 3.0 3.045.645.8 3.5 3.535.137.0 > 2 stents > 2 stents28.629.5 Mean stents per patient (n) 1.4 ± 0.7 1.4 ± 0.6 Patients with overlapping stents 28.526.9

30. Reference vessel diameter (mm) 2.782.810.347

31. CYPHER n=131 Control n=148 P Restenosis In-stent8.348.5 < 0.001 In-segment17.650.5 TLR (%) 6.922.3 < 0.001 MACE (%) 9.225.0 < 0.001 SIRIUS - Diabetic sub-group

32. SIRUS – the ‘edge effect ‘

33. Overall4.116.60.0001124 Male4.416.60.0001122 Female3.416.50.0007130 Diabetes6.922.30.0006154 No Diabetes3.214.30.0001111 LAD5.119.80.0001147 Non-LAD3.414.30.0001109 Small Vessel (<2.75) 6.318.70.0001125 Large Vessel1.914.80.0001128 Short Lesion3.216.10.0001129 Long Lesion (>13.5) 5.217.40.0001122 Overlap4.517.70.0003131 No Overlap3.916.10.0001121 Hazards Ratio 95% CI 1.00.90.80.70.60.50.40.30.20.100.70.80.9 SirolimusControlP-value CYPHER better SIRIUS:TLR Events

34. T Stenting V Stenting Y Stenting Crush Technique 4 Final subgroups (Per Protocol): –63 patients in the DES + DES arm –22 patients in the DES + PTCA arm Final subgroups (Per Protocol): –63 patients in the DES + DES arm –22 patients in the DES + PTCA arm DES +DES DES +PTCA Main Branch (N = 63) Side Branch (N = 65) Main Branch (N = 23) Side Branch (N = 23) Diabetics, n (%) 13(21) 6 (26) RVD (mm) 2.6 6 6 2.1 1 1 2.6 5 5 2.1 0 0 Lesion Length (mm) 10.8 5.5 12.2 5.1 BIFURCATION

35. DES +DES DES +PTCA Main Branch (N = 63) Side Branch (N = 65) Main Branch (N = 22) Side Branch (N = 22) Overall Stent Thrombosis rate was 3.6% BIFURCATION

36. E-SIRIUS 250 patients De novo single vessel,15mm- 35mm long, 2.5 - 3.5mm diameter : reporting Q4/ACC SIROLIMUS FREEDOM trial: Diabetic MVD randomised - Cypher or CABG RESOLVE ISR ISR VBT versus DES UK … Europe Start.. Spring 03 RESOLVE ISR ISR VBT versus DES UK … Europe Start.. Spring 03 Cypher Registry ‘real life’ cases 10 000 Web based (2680) ‘ Cypher Registry ‘real life’ cases 10 000 Web based (2680) ‘

37. What else is happening ??

38. Conor Stent: Drug delivery from large, discrete, non-deforming reservoirs Ductile Hinges Allow struts to open Without deformation

39. SCEPTER Drug Release: Zero-order, 100% mural release of paclitaxel Through a layered polymer delivery system Cap Layer Drug Layer Barrier Layer

40. The Conor Stent releases all of the stent contents in approximately 2 weeks in- vitro. The TAXUS stent releases about 10% of total loading in 10 days (about 10 ug), the remaining 90% remains on the stent permanently. Cap Layer Drug Layer Barrier Layer

41. Porcine Stent Injury Study Proximal LAD metal metal @ 30d 16 ug @ 30d Proximal LAD 16 ug Clear dose response All p<0.05 vs. metal

42. SCEPTER S tudy of C ontrolled Elution of Paclitaxel for The Elimination of Restenosis S tudy of C ontrolled Elution of Paclitaxel for The Elimination of Restenosis Spring 2003 260 two doses 15 ug and 75 ug cf bare metal Connor

43. Rapamycin analogues

47. Why ? I. Commercial 2. Alter potency.. Modifying affinity for binding proteins 3. Modify physical properties * Lipophilic, tissue penetration, residence time * Stability * Release kinetics 4. Alter metabolic elimination 5. Overcome edge effect 6. Higher risk populations Why ? I. Commercial 2. Alter potency.. Modifying affinity for binding proteins 3. Modify physical properties * Lipophilic, tissue penetration, residence time * Stability * Release kinetics 4. Alter metabolic elimination 5. Overcome edge effect 6. Higher risk populations

49. Tacrolimus

50. Cyclosporin TacrolimusSirolimus Binding protein: Effector protein: Actions: Cyclophilin FKBP 12 Calcineurin TOR Blocks T-cell activation No effect on smooth muscle Toxic to kidneys Blocks T-cell proliferation (anti-inflammatory effect) Blocks SMC proliferation

53. Sirolimus R=H Everolimus R= CH 2 CH 2 OH

55. Everolimus and Guidant programme Biosensors Int FUTURE 1

56. Preliminary data 16 patients !! FUTURE 1 RAVEL TAXUS Late loss 0.08 mm -0.01 mm 0.31 mm control 0.84 mm % Diameter stenosis 3% control 39% Binary restenosis 0% control 20% IVUS % intimal suppression 88% 95% 65% No edge effect Preliminary data 16 patients !! FUTURE 1 RAVEL TAXUS Late loss 0.08 mm -0.01 mm 0.31 mm control 0.84 mm % Diameter stenosis 3% control 39% Binary restenosis 0% control 20% IVUS % intimal suppression 88% 95% 65% No edge effect

57. Everolimus Drug Eluting Stent - GUIDANT  Everolimus was loaded on the Guidant Multi-Link Penta TM in 2 doses using EVAL as drug delivery polymer.  Fast release – 282  g/stent (51.7  g released in 3 days in vivo) (Everolimus 3)  Slow release – 205  g/stent (7.8  g released in 3 days in vivo) (Everolimus 2)  Slow release – 245  g/stent (61.3  g released in 3 days in vivo) (Everolimus 4)  Slow release –337  g/stent (59.9  g released in 3 days in vivo) (Everolimus 5)  The two doses were compared to EVAL alone in a pig coronary artery model of stenting at 28 days.

58. Everolimus 2 Everolimus 3 SS + EVAL Pig at 28 Days Pig at 28 Days Everolimus 3 = Everolimus 2 = fast release 282  g/stent slow release 205  g/stent Everolimus Drug Eluting Stent - GUIDANT

59. Percent stenosis at 28 and 90 Days Following Everolimus-Eluting Stent Implanation in Pig Coronary Arteries 41% 18% Everolimus 4 - 245  g +104  g top coat Everolimus 5 - 337  g +169  g top coat % Stenosis

60. Everolimus and Guidant programme VISION –E studies SPIRIT 1 (etc etc) dosing, CE marking US pivotal n.b. no UK !!! (regulatory) VISION –E studies SPIRIT 1 (etc etc) dosing, CE marking US pivotal n.b. no UK !!! (regulatory)

61. Structural Domains Binding to FKBP-12 and mTOR FKBP Binding Domain mTOR Effector Domain Rapamycin ABT-578 Similarities of ABT-578 and Rapamycin Similarities of ABT-578 and Rapamycin MEDTRONIC

62. In Vitro Inhibition of Human Coronary Artery Smooth Muscle Cell Proliferation -20 0 20 40 60 80 100 0.010.1110100 ABT-578 Rapamycin % Inhibition Concentration (nM) A

64. A Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Coated Driver Coronary Stent in De Novo Native Coronary Artery Lesions Approx 70 Sites in Europe, Canada, Asian Pacific, Australia Approx 1100 subjects Double blind, two arm, randomized controlled trial of ABT-578 coated Driver stent vs. bare Driver stent Follow-up at 30 days, 6, 9, 12 months, yearly to 5 years First 400 (approx) subjects enrolled also participate in subset with angiographic follow-up at 8 months IVUS sub-study at 15-20 selected centers, IVUS at index and 8 months Initial Enrolment: March 2003 Approx 70 Sites in Europe, Canada, Asian Pacific, Australia Approx 1100 subjects Double blind, two arm, randomized controlled trial of ABT-578 coated Driver stent vs. bare Driver stent Follow-up at 30 days, 6, 9, 12 months, yearly to 5 years First 400 (approx) subjects enrolled also participate in subset with angiographic follow-up at 8 months IVUS sub-study at 15-20 selected centers, IVUS at index and 8 months Initial Enrolment: March 2003

65. Sirolimus R=H Everolimus R= CH 2 CH 2 OH Everolimus plus R= CH 2 CH 2 R Everolimus plus

70. 4 5 6 7 8 9

71. Future developments

72. 2 or more drugs Anti-restenotic Anti-thrombotic Local Simvastatin Delivery After Vascular Injury Neointimal Thickness 0 20 40 60 80 100 120 140 0 20 40 60 80 100 120 140 14 days 28 days Simvastatin Rapamycin Control * * * P<0.05 vs CON (  m) 32 45 33 87 106 P = 0.53 P = 0.07 Simvastatin Rapamycin

73. Paclitaxel Small vessels, edge effect 40ug /balloon …. Vessel wall Paclitaxel Small vessels, edge effect 40ug /balloon …. Vessel wall

74. FirstSteps Properties Alloy1 st batch Alloy2 fine Alloy2coarse Alloy3 1 2 nd batch DegradationKineticvs.Composition&Structure ContinuousImmersionTest in 0,9%NaCl; 37°C;pH7,0. 014284256708498 50 60 70 80 90 100 rel.MassLoss/% Time / Days

75. Trials Real World TAXUS II +, SIRIUS, DELIVER 2 TAXUS II +, SIRIUS, DELIVER 2 2003 RAPAMYCIN ANALOGUES JOMED TACROLIMUS GUIDANT EVEROLIMUS MEDTRONIC ABT 578 EVEROLIMUS PLUS MPA 2003 RAPAMYCIN ANALOGUES JOMED TACROLIMUS GUIDANT EVEROLIMUS MEDTRONIC ABT 578 EVEROLIMUS PLUS MPA

76. D.E.S. (current or ‘ improved’ ) are likely to impact on restenosis in the real world ‘the Limus effect’“Lyticitis” Qs. Can we afford them ? Will N.I.C.E approve them? D.E.S. (current or ‘ improved’ ) are likely to impact on restenosis in the real world ‘the Limus effect’“Lyticitis” Qs. Can we afford them ? Will N.I.C.E approve them?