Drug

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Drug eluting stents Where are
we now and what can we expect in 2003?
Tony Gershlick Leicester
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Trials
Real World
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What we need i. Prevent restenosis cost
effective Either - Treat all
at equivalent cost (DES _at_ 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.
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All or only in those _at_ higher risk ?
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68 yr non-insulin dependant diabetic
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Are the DES trials moving with the need ? trial
update trial evaluation what is new ?
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PACLITAXEL
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PACLITAXEL
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Non polymer Guidant Achieve stent paclitaxel in
ELUTES dose
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In segment BR TVF
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12
12
10
C treated
C treated
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GIUDANT / Cook paclitaxel
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DES Trials and real life
1 Single Lesion lt 25 mm Plus complicating
factor CTO, Bifurcation, ISR 2
single lesions lt 25 mm de novo or
1 long lesion gt 25
mm
DELIVER 2 Trial
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DELIVER II Lesion characteristics(n 500)
PACLITAXEL
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II
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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)
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SIROLIMUS
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SIRUS how like real life was it ??
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SIRIUS - Diabetic sub-group
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SIRUS the edge effect
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SIRIUS TLR Events
Sirolimus
Control
P-value
Overall
4.1
16.6
0.0001
124
M
ale
4.4
16.6
0.0001
122
Female
3.4
16.5
0.0007
130
Diabetes
6.9
22.3
0.0006
154
No Diabetes
3.2
14.3
0.0001
111
LAD
5.1
19.8
0.0001
147
Non-LAD
3.4
14.3
0.0001
109
Small Vessel (lt2.75)
6.3
18.7
0.0001
125
Large Vessel
1.9
14.8
0.0001
128
Short Lesion
3.2
16.1
0.0001
129
Long Lesion (gt13.5)
5.2
17.4
0.0001
122
Overlap
4.5
17.7
0.0003
131
No Overlap
3.9
16.1
0.0001
121
Hazards Ratio 95 CI
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0.7
0.8
0.9
CYPHER better
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BIFURCATION
T Stenting V Stenting


Y Stenting Crush Technique4

• Final subgroups (Per Protocol)
• 63 patients in the DES DES arm
• 22 patients in the DES PTCA arm

DES
DES

DES
PTCA



Main Branch

Side Branch

Main Branch

Side Branch

(N 63)

(N 65)

(N 23)

(N 23)

Diabetics, n ()

13(21)

6 (26)



RVD (mm)

2.6
6

2.1
1

2.6
5

2.1
0

Lesion Length
10.8

5.5

12.2

5.1

(mm)




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BIFURCATION

DES
DES

DES
PTCA



Main Branch

Side Branch

Main Branch

Side Branch

(N 63)

(N 65)

(N 22)

(N 22)

Overall Stent Thrombosis rate was 3.6
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SIROLIMUS
FREEDOM trial  Diabetic MVD randomised - Cypher
or CABG
E-SIRIUS 250 patients De novo single
vessel,15mm-35mm long, 2.5 - 3.5mm diameter
reporting Q4/ACC
Cypher Registry real life cases 10 000
Web based (2680)
RESOLVE ISR ISR VBT versus DES UK Europe
Start .. Spring 03
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What else is happening ??
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Conor StentDrug delivery from large,
discrete,non-deforming reservoirs
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SCEPTER Drug ReleaseZero-order, 100 mural
release of paclitaxelThrough a layered polymer
delivery system
Cap Layer
Drug Layer
Barrier Layer
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• 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.

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Porcine Stent Injury Study
Clear dose response All plt0.05 vs. metal
16 ug _at_ 30d
Proximal LAD 16 ug
Proximal LAD metal
metal _at_ 30d
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SCEPTER

• Study of
• Controlled
• Elution of
• Paclitaxel for
• The
• Elimination of
• Restenosis

Spring 2003 260 two doses 15 ug and 75 ug cf
bare metal Connor
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Rapamycin analogues
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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
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Tacrolimus
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Cyclosporin
Tacrolimus
Sirolimus
FKBP12
Cyclophilin
Binding protein
TOR
Calcineurin
Effector protein

• Blocks T-cell activation
• No effect on smooth muscle
• Toxic to kidneys

• Blocks T-cell proliferation
• (anti-inflammatory effect)
• Blocks SMC proliferation

Actions
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Everolimus R CH2CH2OH
Sirolimus RH
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Everolimus and Guidant programme
Biosensors Int FUTURE 1
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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
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Everolimus Drug Eluting Stent -GUIDANT

• Everolimus was loaded on the Guidant Multi-Link
  PentaTM in 2 doses using EVAL as drug delivery
  polymer.
• Fast release 282 mg/stent (51.7 mg released in
  3 days in vivo) (Everolimus 3)
• Slow release 205 mg/stent (7.8 mg released in 3
  days in vivo) (Everolimus 2)
• Slow release 245 mg/stent (61.3 mg released in
  3 days in vivo) (Everolimus 4)
• Slow release 337 mg/stent (59.9 mg 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.

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Everolimus Drug Eluting Stent -GUIDANT
Everolimus 2
SS EVAL
Everolimus 3
Pig at 28 Days Everolimus 3
Everolimus 2 fast release 282 mg/stent
slow release 205 mg/stent
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Percent stenosis at 28 and 90 Days Following
Everolimus-Eluting Stent Implanation in Pig
Coronary Arteries
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Stenosis
Everolimus 4 - 245 mg 104 mg top coat
Everolimus 5 - 337 mg 169 mg top coat
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Everolimus and Guidant programme
VISION E studies SPIRIT 1 (etc etc) dosing,
CE marking US pivotal n.b. no UK !!!
(regulatory)
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Structural Domains Binding to FKBP-12 and mTOR
Similarities of ABT-578 and Rapamycin
Rapamycin
ABT-578
FKBP Binding
mTOR Effector
Domain
Domain
MEDTRONIC
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• In Vitro Inhibition of Human Coronary Artery
  Smooth Muscle Cell Proliferation

100
A
80
60
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Inhibition
ABT-578
Rapamycin
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0
-20
0.01
0.1
1
10
100
Concentration (nM)
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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

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Everolimus plus
Everolimus R CH2CH2OH
Sirolimus RH
Everolimus plus R CH2CH2R
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Future developments
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Paclitaxel Small vessels , edge effect 40ug
/balloon . Vessel wall
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First
Steps
Properties
Degradation
Kinetic
vs.
Composition

Structure
rel.
Mass
Loss
/

100
Alloy
1 1
st
batch
90
Alloy
2 fine
80
Alloy
3
Alloy
2
coarse
70
Alloy
1 2
batch
nd
60
50
0
14
28
42
56
70
84
98
Time / Days
C
ontinuous
Immersion
Test in 0,9
NaCl
37C
pH
7,0.
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Trials
TAXUS II , SIRIUS , DELIVER 2
Real World
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D.E.S. (current or
improved ) are likely to impact on restenosis
in the real world
the Limus effectLyticitis
Qs . Can we afford them ?
Will N.I.C.E approve them?