Transcript NOBORI

NOBORI
New Generation Drug Eluting Stent
Clinical Data
Danny Detiege
Clinical Manager - Cardiology
Terumo Europe N.V.
Leuven, Belgium
MY CONFLICTS
OF INTEREST ARE
Employee of Terumo Europe
Nobori DES components
Highly
Flexible
BMS Platform
Polymer - PLA
Biodegradable
Drug – Biolimus A9
Coating
Only abluminal
Lipophilic
Specifically developed
for local applications
Proprietary Hydrophilic Coating
for excellent deliverability
Mechanism of Action Biolimus A9
FKBP-12
mTOR
Everolimus
Biolimus A9
Sirolimus
Biolimus A9
Growth
Factor
Biolimus A9
Receptor
mTOR
mTOR
Biolimus A9
FKBP
FKBP
p34CDC2
S
p27kip
G0
G1
G2
M
In all Nobori trials treatment of more
than one vessel was allowed
NOBORI – Clinical Program
NOBORI PK – 20 Patients
Confirmation of pharmacokinetics
Nobori DES
NOBORI 1 – 363 patients
Nobori DES Randomized versus
Taxus (surrogate endpoint-LL)
NOBORI CORE – 107 patients
Nobori DES similarity versus
Cypher (surrogate endpoint-LL)
NOBORI CORE
endothelial study 43 patients
Comparison endothelial function
at 9 months Nobori vs Cypher
NOBORI Japan – 340 patients
Nobori DES Randomized versus
Cypher (clinical endpoint-TVF)
NOBORI 2 – 3000 patients
Real life registry
COMPARE II 2700 patients
Randomized vs Xience V in all
Comers population
NOBORI Pharmacokinetics Study
BA9 Blood Collection Time Points
TIME POINTS
Trial
Sample
Size (n)
Nobori
PK Study
20
PreProcedure
Mins / Hours / Days / Months
2
15
30
1
2
3
8
24
48
72
7
28
3
6
             
Biochemistry/Haematology Blood Collection Time Points
* t=0 defined as deployment balloon inflation/ stent implantation
Biolimus A9 concentration
26
24
22
28mm
14mm
18
16
14
12
LLOQ
10
8
Minutes
Houres
Days
6
3
28
7
72
48
24
3
2
1
45
30
15
2
fo
re
6
Be
pg/mL
20
Months
Time points
LLOQ = Lowest level of quantification
Ostojic et al. CCI 2008
Systemic concentration of drugs (ng/mL) eluted
from DES
Maximum blood concentration of
Biolimus A9 is 52 times LOWER
than Sirolimus and 87 times
lower than Everolimus
Mean
SD
Minimum*
Maximum
n
Biolimus1 A9
0,020
0,007
0,010
0,032
20
Sirolimus2
0,80
0,37
0,43
1,66
19
Everolimus3
NR
NR
0,14
2.79
37
NR= Not reported
1= Ostojic et al. CCI 2008
2=Vetrovec et al. CCI 2006
3=Wiemer et al. AHJ 2008
NOBORI 1
2:1 randomization, non-inferiority design
Single blind – two vessel – staging allowed
De novo native coronary lesion
Vessel diameter: 2.5-3.5 mm
Lesion length: <25 mm
Predilatation required
Nobori stent
n = 85 phase 1
153 phase 2
PI: Dr B. Chevalier
N = 363 patients
29 sites
Europe, Asia, Australia
Control Taxus stent
n = 35 Express Ph 1
90 Liberte Ph 2
Clinical
endpoints
Clinical/MACE
30d
Angio/IVUS
4mo
9mo
12mo
2yr
3yr
4yr
QCA
IVUS
Primary endpoint: In-stent late lumen loss by QCA at 9 months
Secondary endpoints: MACE (Death, MI, TVR) TLR, TVF at 9 months and ABR at 9
months, Procedure, Lesion success, In-segment late loss
Drug therapy: ASA and clopidogrel 6 months
5yr
Primary Endpoint Result
•
•
Assumed in-stent Late Loss (LL)

0.39 mm for Taxus / 0.34 mm Nobori

Assumed SD: 0.50 mm
Delta non-inferiority margin: 0.20mm
Δ LL (mm)
- 0.21 - 0.12
0
Nobori®
Late Loss result
 0.33 ± 0.51 mm Taxus
 0.11 ± 0.30 mm Nobori
0.20
Taxus better
Result:
Nobori = NON-INFERIOR p<0.001
Nobori = SUPERIOR*
p=0.001
*The SUPERIORITY was a secondary objective
Key Angiographic Results
Late Loss
0.40
64% Reduction
p < 0.001
Binary Restenosis
53% Reduction
p < 0.05
10%
91% Reduction
p = 0.01
91% Reduction
p = 0.01
0.33
8%
0.30
mm
6%
0.17
0.20
0.12
4.6%
4.6%
4%
0.09
0.10
2%
0.00
In-stent
Nobori N=269
In-segment
Taxus N=139
0%
0.4%
In-stent
0.4%
In-segment
Intravascular Ultrasound Results
Nobori®
101 lesions
Taxus®
53 lesions
Pvalue
Mean Lumen Area (mm² SD)
Post procedure
9 Month follow-up
7.4  1.6
7.5  1.8
7.9  2.3
7.2  2.3
0.16
0.48
Minimum Lumen Area (mm² SD)
Post procedure
9 Month follow-up
6.1  1.4
5.9  1.7
6.5  2.0
5.6  2.2
0.23
0.40
Mean Plaque Area (mm² SD) *
0.1  0.5
0.5  0.6
<0.001
Neointima volume (mm³ SD) *
3.1  8.8
13.5  20.4
0.003
1.9  5.5
6.8  8.0
0.001
In-stent Volume Obstruction
(% SD) *
MACE Rate at 1 Year
10
Nobori
Taxus
8
8,0
6
5,4
%
4,8
3,8
4
3,2
2,1
1,6
2
0,4
2,4
0,8
0
Cardiac death
0
Q-Wave MI
0
Non-Q-Wave
MI
TVR
MACE
Stent
Thrombosis
Stent Thrombosis up to 2 years
Definite and Probable Stent
Thrombosis According to ARC*
Stent thrombosis Per Protocol
Nobori
Stent
N=238
Taxus
Stent
N=125
Acute
0.0
2.4
Subacute
0.0
1.6
Late
0.0
0.8
Nobori
Stent
N=238
Taxus
Stent
N=125
Early
0.0
1.6
Late
0.0
0.0
Very Late
0.0
0.8
0.0
2.4
0.0
2.4
Total up to 1 year
0.0
3.2
Definite and
probable
Total up to 2
years**
0.0
4.0
Total up to 2
years**
*ARC = Academic Research Consortium – Procedural MIs not counted as ST
**Only patients from Phase 1 were followed up to 2 Years
NOBORI CORE
NOBORI CORE Study Design
Prospective, Multicentre, Comparative
Non-randomized
De novo native coronary lesion
Vessel diameter: 2.5-3.5 mm
Predilatation required
Antiplatelet therapy: ASA and clopidogrel 6 months
N = 107 patients (6 sites)
Co-PI – M. Ostojic
W. Wijns
Nobori stent
n = 54
Control Cypher stent
n = 53
Clinical
endpoints
Clinical/MACE
30d
9mo
12mo
2yr
3yr
4yr
Angio/Atrial Pacing
QCA
Endothelial Function Assessment
Primary endpoint: In-stent late lumen loss by QCA at 9 months
Secondary endpoints: Endothelial functionality, MACE (Death, MI, TVR) TLR, TVF at 9
months and restenosis at 9 months, Procedure, Lesion success
5yr
QCA Findings at 9 Months
RVD (mm)
MLD – stent (mm)
MLD – lesion (mm)
DS (%)
Late loss – stent (mm)
Late loss – lesion (mm)
Binary Restenosis %
Nobori®
Cypher®
P
72 Lesions
74 Lesions
Value
3.00 ± 0.36
2.59 ± 0.42
2.27 ± 0.48
13 ± 10
0.10 ± 0.26
0.12 ± 0.35
2.84 ± 0.40
2.28 ± 0.49
2.13 ± 0.48
20 ± 12
0.12 ± 0.43
0.18 ± 0.40
0.09
<0.001
0.15
0.001
0.70
0.43
1.7 (1/60)
4.2 (2/48)
0.18
Ostojic et all EuroIntervention 2008
NOBORI CORE
Endotelial Function Assessments
Protocol of atrial pacing for
Endothelial Function Assessment
Pacing
2 min
HR 70-90
2 min
HR 90-110
2 min
HR 110-130
STOP
Pacing
HR 130-150
2 min
Ntg IC bolus
Angio
Angio
Angio
Angio
Angio
Angio
Angio
METHODS
1. Baseline conditions were established and angiography performed
2. Rapid Atrial pacing with 20 bpm higher than baseline for 2 min
3. Angiographic images acquisition followed by 2 minutes rest
4. Repeat procedure with increasing pacing rate by 20 bpm up to 150
5. Intra-arterial nitroglycerin injection
6. Angiographic image acquisition
7. Off line QCA analysis of proximal, in-stent, distal segments and reference
vessel
Distal vessel: change in diameter after pacing
3,2
3,0
mm
2,8
X
Nobori reference
Cypher reference
Nobori stented vessel
Cypher stented vessel
*
2,6
X
2,4
*X
2,2
2,0
Baseline
Highest pacing step
Nitroglycerin
*p=0.001 for percentage change
Hamilos et al JACC 2008
Hamilos et al Circulation CI 2008
NOBORI CLINICAL TRIALS
Summary
MACE Rate in NOBORI Trials
16
14,3
Nobori
12
%
Comparator
8
6,7
5,9
5
5,6
4,6
4,1
4,2
4
1,9
NA
0
20 Pts
107 Pts
120 Pats
243 Pts
490 Pts
NOBORI PK
NOBORI CORE
NOBORI 1-Phase 1
NOBORI 1-Phase 2
Total Nobori Trials
3 Years
2 Years
1 Year
MACE = Cardiac Death, Myocardial Infarction, Clinically Driven TLR
Key Angiographic Findings in NOBORI Trials
NOBORI 1 Phase 1
N=120
Nobori
n=85
Follow-up
Late loss mm
Taxus
n=35
9 months
NOBORI CORE
N=107
NOBORI Phase 2
N=243
Nobori
n=54
Nobori
n=153
Cypher
n=53
9 months
Taxus
n=90
9 months
0.15±0.27
0.33±0.34
0.10±0.26
0.12±0.43
0.11±0.30
0.32±0.50
Diameter stenosis
14±8
19±10
13±10
20±12
14±8
21±15
Restenosis - stent
0.0%
0.0%
1.7%
6.3%
0.7%
6.2%
Restenosis lesion
0.0%
0.0%
3.3%
6.3%
0.7%
6.2%
0.0%
2.9
0.0%
4.1%
0.0%
1.1%
TLR
TLR = Clinically driven target lesion revascularization
DES Efficacy
Clinically Driven TLR Rate in DES Pivotal Trials
7,0
6,0
5,0
Sirius=N=533
Taxus IV-N=662
Endeavor II-N=600
Spirit II-N=225
NOBORI 1=N=363
4,0
5,9
4,6
4,9
4,4
3,8
%
4,1
3,0
Nobori Upper Limit of
95%CI =1.2%
6,5
6,5
6,3
3,1
2,0
1,8
1,8
0,0
0,0
1,0
0,0
0,0
0 Months
9 months
1 Year
0,0
2 Years
*Nobori 2 years N=85
Holmes et al Circulation 2004; Stone et al Circulation 2004; Leon – ACC 2004; Stone, TCT 2004;
Fajadet, Circulation 2006; Fajadet PCR-2006; Chevalier et al; Eurointervention 2007; PCR 2008
DES Safety
Stent Thrombosis in Pivotal DES Trials
1,2
Sirius=N=533
1,0
1,0
Taxus IV-N=662
0,9
Endeavor II-N=600
Spirit II-N=225
0,8
NOBORI 1=N=363
%
0,7
0,6
0,4
Nobori
Upper Limit of
95%CI =1.2%
0,5
0,3
0,3
0,3
0,0
1 Months
0,0
1 Year
0,0
2 Years
0,2
0,0
0,0
0 Months
Holmes et al Circulation 2004; Stone et al Circulations 2004; Leon – ACC 2004; Stone, TCT 2004;
Fajadet, Circulation 2006; Fajadet PCR-2006; Chevalier et al; Eurointervention 2007; PCR 2008
CONCLUSIONS - Nobori DES clinical results
Nobori stent showed non-inferiority vs Taxus and Cypher DES with respect
to in-stent late loss
Endothelial function showed better recovery in Nobori- than in Cyphertreated vessels at 9m
 could be related to drug release kinetics, biodegradable polymer or abluminal
coating
•
•
•
The clinical evidence available to date for Nobori stent shows excellent safety
and efficacy confirmed by:
Very low rate of MACE, Restenosis and TLR
No late stent thrombosis
Long term follow-up results awaited to confirm current trends and to further
explore the potential positive impact of biodegradable polymer on long term
safety of this innovative DES
Initial excellent results to be confirmed in ‘real-life’ setting