Drug eluting stents : clinical trials

1
Drug eluting stents clinical
trials clinical use Tony Gershlick
Glenfield Hospital Leicester
BCIS AA London 2002
2
The size of the clinical problem
Incidence of restenosis 10
Angioplasties per annum (worldwide)
1 500 000 STENTING Number per annum (world
wide 80) 1 200 000 Restenosis repeat
procedures (10-12) 170 000
3
What is the market ? 1 500 000 X 1.2
STENTS/Pt 75 0 000
4
What do we need for local stent based drug
delivery ? Good understanding of the pathology
Effective, potent, agent but not toxic Deals
with re modelling intimal hyperplasia Stent as
user friendly as current stents No effect
(polymer) stent itself Drug delivered when
where needed. Controlled delivery over required
period. Understanding PK /dosing
issues Animal data (safety) Pilot
studies Rollout clinical studies who to use
them in
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Anti- Anti-
Immuno Migration
Endothelial Thrombotic Neoplastic
suppressant ECMatrix
vascular function
Heparin Hirudin/iloprost abciximab
Paclitaxel Actinomycin D Methotrexate Taxane
QP2 Angiopeptin Vincristine Mitomycin BCP 678 AS
c-myc
Sirolimus Tacrolimus Dexamethasone M-prednisilone
Interferon g Leflunomide cyclosporin Tranilast
Halofuginone Batimastat Proylhydroxylase
Inh C-proteinase inh
Oestradiol Statins ABT 578 PGE1 VEGF
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remodelling
Re endothelialisation
Matrix formation
VEGF
VEGF
Injury
Sirolimus
Sirolimus
Thrombus Formation
VSC proliferation
Red and white cell release growth factors
Inflammation
VSC migration
Dexamethasone Sirolimus
Dexamethasone Sirolimus
Batimastat Sirolimus Paclitaxel
Batimastat Sirolimus Paclitaxel
VSC proliferation
Actinomycin Sirolimus Paclitaxel
Actinomycin Sirolimus Paclitaxel
Matrix degradation
7

SMC proliferation matrix production
platelet -rich thrombus
platelet , WBC
Thrombin, PDGF, b FGF
AN II
TG F b NO Heparans
cfos,cmyc
G0 G1 S
8
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Current status clinical
trials Paclitaxel Cook
Corp Boston Scientific Rapamycin
Cordis Batimastat / Dexamethasone
Biocompatibles Actinomycin D Guidant
10
The Medtronic programme AVI Biopharma Inc
Neugenes AS
Stability, specificity, adverse effects
Open studies Stent loaded 2002
11
Histologic Finding (II)
4 Weeks After Antisense Delivery
control
1 mg
5 mg
10 mg
12
Paclitaxel Cook Corp 1 ASPECT
13
Paclitaxel Cook Corp 2 ELUTES
3 ug is the cut off dose
14
6-Month Safety Data (hierarchical analysis)

• Paclitaxel Dose 2.7 1.4 0.7
  0.2 Control
• N 37 39 39 37 38
• Death 1 0 0 0
  0
• Q-wave MI 0 0 0 0 0
• CABG 0 0 0 0 0
• SAT 1 0 0 0 1
• Non-Q-MI 1 0 1
  0 1
• TLR 1 1 1 2 3
• Event-Free 89 97 95
  95 89
• Not significant
• Patient with ISR no TLR

No late stent thromboses
15
The ELUTES Trial
Conclusions I

• Paclitaxel reduced binary in-stent restenosis
  from
• 21 to 3 (p0.055)
• 2. Primary efficacy endpoints were achieved
• Diameter stenosis reduced from 34 to 14 (plt.01)
• Late loss reduced from 0.73 mm to 0.10 mm
  (plt0.005)
• 3. Primary safety endpoint was achieved
• No significant difference in event-free survival
  between 2.7 µg/mm2 and Control at 1 or 6 months

Compared to the ASPECT Trial
16
ELUTES ASPECT QCA Results
Percent Diameter Stenosis
50
ELUTES
40
ASPECT
30
Diameter Stenosis ()
20
10
0
0.0
1.0
2.0
3.0
4.0
Dose Density (µg/mm2)
17
ELUTES ASPECT QCA Results
ELUTES
Binary Restenosis
30
ASPECT
20
Binary Restenosis Rate ()
10
0
0.0
1.0
2.0
3.0
4.0
Dose Density (µg/mm2)
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Conclusions II
4. A near linear relationship exists between the
dose density of paclitaxel (µg/mm2) and the rate
of restenosis, the percent diameter stenosis, and
the late loss. 5. Based on the results of the
ELUTES and ASPECT studies, a minimum effective
dose density of approximately 3 µg/mm2 has been
identified. 6. The dose was effectively
delivered without a polymer
what other trials are planned ?
19
Planned Paclitaxel studies
1.In-stent ELUTES (Europe) PI Ivan de Scheerder
the ELUTES Group 2. PATENCY (3.0ug/mm2)
v Control (USA) PI Alan Heldman 3. In-stent
PATENCY (USA) 4. DELIVER Trial (USA) 3
ug/mm 2 Bill ONeill William Knopf
20
DELIVER Clinical Trial Status

• Conditional IDE Approval received Nov. 8, 2001

• First patient enrolled on Nov. 9, 2001
• Louis Cannon, M.D., FACC
• President of the Michigan Cardiac and Vascular
  Research Center at St. Marys Medical Center,
  Saginaw, Michigan

21
Paclitaxel Coating

• Based on Cooks paclitaxel coating applications
  (ELUTES and ASPECT)
• Coating applied to abluminal surface of stent
  only using Cooks proprietary coating technology
• Paclitaxel Dose Information
• 3 mg/mm2 (Nominal) Metal Surface Area
• No carriers, polymers, binding agents,
  excipients, or overcoats

• Based on Guidants MULTI-LINK RX PENTATM CSS

22
SCORES Trial Rule 1. Use an established device
and do some pre-clinical studies
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Taxus II de novo, Antonio Colombo
24
TAXUS IV Pivotal Study 1100 de novo lesions
Taxol impregnated polymer coated EXPRESS stent
Un-coated EXPRESS stent
Taxol impregnated polymer coated EXPRESS stent
550 patients ISR
Vascular brachytherapy
25
Rapamycin
26
Mechanism of Action of Sirolimus

• Binds to intracellular receptor protein (FKBP12)
  in target cells
• Elevates p27Kip1 levels inhibits cyclin/cyclin
  dependent kinase complexes
• Reduces protein RB phosphorylation
• Induces cell-cycle arrest in late G1 phase

SIROLIMUS
S
X
CELLCYCLE
G1
G2
G0
M
CELL DIVISION
27
RAVEL A RAndomised, double-blind study with the
Sirolimus-eluting Bx VElocity balloon expandable
stent in the treatment of patients with de novo
native coronary artery Lesions
Authors M.C. Morice, P.W. Serruys, J.E. Sousa,
J. Fajadet, M. Perin, E. Ban Hayashi, A.
Colombo, G. Schuler, P. Barragan, C. Bode
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Key Components of the Sirolimus-Eluting Stent

• Bx VELOCITY balloon-expandable stainless steel
  (316L) stent

• Blend of components (2 polymers sirolimus) in
  a fixed ratio
• Thin uniform coating (5-10mm thick)

Only 3 (180µg) of a Rapamune (sirolimus) oral
daily dose is applied to a coronary stent
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RAVEL Endpoints

• Primary endpoint 0.25mm reduction in 6m late
  loss.
• Secondary endpoints
• Angiographic restenosis rate
• In-stent diameter stenosis
• In-stent MLD
• MACE _at_ 1m, 6m, 1,2,3,4,5 years
• 6m TLR
• 6m TVR
• volume obstruction (IVUS)
• Resource use _at_ 1m, 6m, 1,2,3,4,5 years.

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QCA In-stent Analysis
Sirolimus Control N120 N118

• Lesion length (mm) 9.56 9.61 NS
• Ref. Vessel Diameter (mm) 2.60 2.64 NS
• MLD (mm) Pre 0.94 0.95 NS
• Post 2.43 2.41 NS
• FU 2.42 1.64 lt .0001
• Late loss (mm) - 0.01 0.33 0.80 0.53 lt
  .0001
• Late loss index - 0.02 0.57 lt .0001
• DS () FU 15 37 lt .0001
• Restenosis rate () 0 26 lt .0001

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Diameter Stenosis at Follow-up
31.5
POST
PRE

Control
Sirolimus
32
RAVEL
Event free survival Death, MI, CABG, Re-PTCA

33
RAVEL Control Group TLR
26 Procedures in 26 patients 26
100 Non clinically driven TLR 11
42 Clinically driven TLR 15
(8) 58 Based on (non mutually excl.) -
Anginal status 7 27 - Positive stress
test 8 31 - Positive invasive diagn. test 2
8 - ECG changes 1 4 - Angiographic
stenosis gt70 2 8
34
RAVEL Diabetic Sub-group
P lt 0.0001
35
RAVEL IVUS in-stent analysis at 6-months
follow-up Sirolimus Control N48
N46 EEM volume(mm3)
280 280 NS Stent
volume(mm3) 131
132 NS Neointimal volume (mm3)
2 37 lt0.001 Lumen volume
(mm3) 129 95
lt0.001 volume obstruction 1.4
28.6 lt0.001
Incomplete apposition 20 4
lt0.015
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ESIRIUS - Sirolimus European Trial

• DESIGN
• Multicenter, randomized, trial
• Two treatments uncoated vs 1XTC-coated Bx
  Velocity (RX)
• 250 patients (175 patients/arm), 25 clinical
  sites
• De novo native coronary lesions
• - single vessel,15mm-35mm long, 2.5 - 3.5mm
  diameter
• ENDPOINTS
• Primary QCA _at_ 8months
• Secondary endpoints. Target vessel failure at 9
  months
• Composite MACE _at_ 30d, 6m, 9m, 12m, 36m.
• European based Cost effectiveness, systemic
  release
• 3 UK centres Glenfield, London Chest, Guys
  StThomass

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SIRIUS - Sirolimus US Pivotal Trial

• DESIGN
• Multicenter, randomized, pivotal trial
• Two treatments uncoated vs 1XTC-coated Bx
  Velocity (OTW)
• 1,100 patients (550 patients/arm), 55 clinical
  sites
• De novo native coronary lesions
• - single vessel,15mm-35mm long, 2.5 - 3.5mm
  diameter
• ENDPOINTS
• Primary Target vessel failure at 9 months
• Secondary endpoints QCA _at_ 8months in 850 pts.
• Composite MACE _at_ 30d, 6m, 9m, 12m, 36m.
• completed

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Sao Paulo QCA Results (FIM)
70
3.5
65
2.89
2.89
2.79
60
3
2.72
50
2.5
40
2
Diameter Stenosis
DS
MLD/mm
MLD
30
1.5
1.04
20
1
15.8
8.1
10
0.5
4.7
4.8
0
0
Pre-procedure
Post-procedure
4 months
12 months
24 months
n 30
n 27
n 12
n 30
40
Drug Coated Comparison Percent Diameter
Stenosis Drug Arm Control Arm ELUTES 14
34 ASPECT 14 39 RAVEL 15 37
Restenosis rates lt 5 can be anticipated
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Actinomycin D Guidant
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Effect on Neointimal Formation
Percent Stenosis at 28 Days with Actinomycin D
35
Control
Polymer only
30
2.5 ?g/cm2
10 ?g/cm2
40 ?g/cm2
25
70 ?g/cm2
Lumen
20
15
Stent Strut
10
Miniature Yucatan Swine
43
Actinomycin
D GUIDANT Chemotherapeutic
antineoplastic and antibiotic properties Polymer
T.R.U.E Coat TM on a
standard Tetra stent Pre clinical
10 ug/cm2 20-30 release _at_ 24 hours 90 28
days (40ug/cm2 70 ug/cm2 incomplete
healing ve remodelling) Clinical trials
1. ACTION n 360
uncoated v 2.5 ug/cm2 v 10ug/cm2
10 end point MACE / DS 2. OPEN
(US) control versus dose from ACTION
44
Drug eluting stents clinical
trials clinical use Tony Gershlick
Glenfield Hospital Leicester
BCIS AA London 2002
45
Biocompatibles Inflammation
Dexamethasone Migration Batimistat Proliferati
on ABT 578 Healing TBD  
46
Dexamethasone STRIDE
47
Study Design

• A pilot Phase II trial
• Multi-centre, prospective, non-randomised study
• A total of 70 patients with 6-month angiographic
  follow-up
• 8 Belgian centres

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STRIDE Clinical Follow-Up (30 day)

• MACE not yet completely adjudicated.
• Death not related to DD stent

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Batimastat

• A broad spectrum matrix metalloproteinase
  inhibitor (MMPi)

Batimastat is a proprietary product of British
Biotech Pharmaceuticals Lovdahl D, et al, J Vasc
Res, 2000, 37, 345.
50
Batimastat (BB-94) 4-(N-Hydroxyamino)-2R-Isobu
tyl-3S-(Thienylthiomethyl)- succinyl-L-Phenylalan
ine-n-Methylamide
developed as a broad spectrum matrix
metalloproteinase inhibitor (MMPI) for the
treatment of cancer.
Extra cellular matrix degradation
MMP
51
Lovedahl C. et al 2000 J. of Vascular
Research. 2000 37 5 345-354
Rat aortic smooth muscle cells in
primary and secondary cultures. Batimastat -
restrained phenotypic modulation of v SMCs in
primary cultures -
suppressed injury-induced DNA synthesis and
migration - up-regulation of
ERK1/ERK2 phosphorylation in injured secondary
cultures and in cells treated with basic
fibroblast growth factor was
markedly reduced by batimastat
52
Batimastat anti-Restenosis trIaL utiLizIng the
BiodivYsio locAl drug Delivery PC-steNT
(BRILLIANT) 150 patient prospective
non-randomised study France and Belgium and
Holland
53
Angiopeptin Pilot Trial

• Outline
• 1 site (Hong Kong), 50pts
• De novo lesions
• Six month angiographic and IVUS follow-up
• Primary Endpoint
• Binary restenosis
• Secondary Endpoints
• MACE, IVUS

54
17 b-Estradiol

• Estradiol may have multiple modes of action
• Inhibition of SMC migration and proliferation1
• Inhibits myointimal cell proliferation in
  response to balloon injury2
• Promotes re-endothelialistion of vessel wall
  after injury3
• Inhibits adventitial fibroblast cell migration-
  process involved in negative remodelling4

1 Dai-Do, et al., 1996 2 Chen et al, 1996, Levine
et al, 1996, Oparil et al, 1997 3 White et al,
1997 4 Li et al, 1999
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EASTEREstrogen And Stents To Eliminate Restenosis

• Outline
• 3 sites (30 pts each)
• De novo lesions
• Six month angiographic and IVUS follow-up
• Primary Endpoint
• Binary restenosis
• Secondary Endpoints
• MACE, IVUS

56
Drug eluting stents appear to work But
1. Patients type the real world 2.
Complications seen with VBT 3. High risk
lesions 4. Long term efficacy risk
57
The Glenfield database Jan Dec 2001 Patients
1224 Stented patients
1015 Repeat PCI for ISR 98
9.6 risk factors for ISR DM, lt2.5 mm,
CTO, bifurcation None of these 47
50 50 ISR restenosis predicted
according to standard criteria
58
1224 total PTCA year 2001
167 small vessel 2.5 or less
13.6
209 Diabetics 17.0
178 chronic occlusion 14.5
130 with bifurcation 10.6
 
 
59
Taxol eluting stent
ISR post
ISR pre
ISR follow -up
Patients with ISR (n16) 6M control angiogram. 2
pts (12.5) significant target vessel restenosis
60
ISR Pilot Cypher stent

• Open-label safety study.
• 40 patients.
• 2.5-3.5mm diameter, ? 18mm length.
• 1 or more stents.
• IVUS guided deployment after pre-dilatation.
• 325mg Aspirin 75mg Clopidogrel for 60 days.

61
QCA Results
Late loss 0.09mm
n 17
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Drug eluting stents inhibit the restenotic
process Expand repertoire PCI Probably equally
efficacioustested All comers ? 55 through
the process Currently too expensive for all
patients Prevent high risk (no data).treat
recurrences PCI will replace CABG for most
lesions In 3 4 years all patients will be
treated with drug eluting stents !