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

Trials Real World

What we need i. Prevent restenosis – cost effective Either : - Treat all – at equivalent cost £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 £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.

All or only in higher risk ?

68 yr non-insulin dependant diabetic

Bifurcations ?

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 ?

PACLITAXEL V-Flex Supra - G ELUTES ASPECT De novo <16 mm Dose Density ( µ g/mm 2 ) 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)

PACLITAXEL

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

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

GIUDANT / Cook … paclitaxel

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

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%)

II

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 Q Slow Release Formulation De novo arm 1,000 Patients mm Lesion Lengths Stents: mm, Lengths: mm Multiple Stents Allowed TAXUS V In Stent Restenosis arm 500 Patients TAXUS Stent versus Brachytherapy

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

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)

SIROLIMUS Mean lesion length 14.4mm

21.2 ± ± 6.7 Stented length 14.4 ± ± 5.7 Mean Lesion length Control (%) (n=525) CYPHER (%) (n=533) C B2 B B1 B AHA/ACC A Diabetes Mellitus SIRUS – how like real life was it ??

CYPHER (%)Control (%) Diameter > 2 stents > 2 stents Mean stents per patient (n) 1.4 ± ± 0.6 Patients with overlapping stents

Reference vessel diameter (mm)

CYPHER n=131 Control n=148 P Restenosis In-stent < In-segment TLR (%) < MACE (%) < SIRIUS - Diabetic sub-group

SIRUS – the ‘edge effect ‘

Overall Male Female Diabetes No Diabetes LAD Non-LAD Small Vessel (<2.75) Large Vessel Short Lesion Long Lesion (>13.5) Overlap No Overlap Hazards Ratio 95% CI SirolimusControlP-value CYPHER better SIRIUS:TLR Events

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) Lesion Length (mm) BIFURCATION

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

E-SIRIUS 250 patients De novo single vessel,15mm- 35mm long, mm 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 Web based (2680) ‘ Cypher Registry ‘real life’ cases Web based (2680) ‘

What else is happening ??

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

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

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

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

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 two doses 15 ug and 75 ug cf bare metal Connor

Rapamycin analogues

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

Tacrolimus

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

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

Everolimus and Guidant programme Biosensors Int FUTURE 1

Preliminary data 16 patients !! FUTURE 1 RAVEL TAXUS Late loss 0.08 mm 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 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

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.

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

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

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)

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

In Vitro Inhibition of Human Coronary Artery Smooth Muscle Cell Proliferation ABT-578 Rapamycin % Inhibition Concentration (nM) A

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 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 selected centers, IVUS at index and 8 months Initial Enrolment: March 2003

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

Future developments

2 or more drugs Anti-restenotic Anti-thrombotic Local Simvastatin Delivery After Vascular Injury Neointimal Thickness days 28 days Simvastatin Rapamycin Control * * * P<0.05 vs CON (  m) P = 0.53 P = 0.07 Simvastatin Rapamycin

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

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

Trials Real World TAXUS II +, SIRIUS, DELIVER 2 TAXUS II +, SIRIUS, DELIVER 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

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?