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Aurore Bouvier
Global Product Manager
Biosensors Europe
Taking DES technology from
concept to long term clinical
evidence
My conflicts of interest are:
Full time employee of
Biosensors Europe SA
BA9 shows sustained safety and efficacy
independent from stent platform or method of
drug delivery!
BioMatrixTM
BioMatrixTM
Flex BioFreedom
TM AXXESS
TM Nobori
(Terumo)
Custom
NXTM
(XTENT)
Stainless Steel Balloonexpandable
Abluminal
biodegradable
polymer
Stainless Steel Balloonexpandable
Polymer Free
Nitinol
Self-expandable
Abluminal
biodegradable
polymer
Designed for
Bifurcations
SS
BA9/PLA
Cobalt-Chrome
BA9/PLA
Biosensors’ DES program
Biolimus A9™
PROPRIETARY BA9™ DRUG
• A rapamycin derivative developed specifically for
stent application by Biosensors International
• Effective immunosuppressive and anti-proliferative
properties
• Reduced systemic exposure and more localized
drug effect due to highest lipophilicity and abluminal
coating
LIPOPHILICITY COMPARISON
• Highest lipophilicity of the common limus drugs1
• Minimizes systemic exposure and reduces the
drug circulating in the bloodstream
• Due to high lipophilicity, the drug is rapidly
absorbed by tissue
1 1
1 Data on file at Biosensors Intl
10925-0
00-E
N –
Rev.0
1
• Biolimus is a semi-synthetic sirolimus analogue with 10x higher lipophilicity and similar potency as sirolimus.
• Biolimus is immersed at a concentration of 15.6 g/mm into a biodegradable polymer, polylactic acid, and applied solely to the abluminal stent surface by a fully automated process.
• Biolimus is co-released with polylactic acid and completely desolves into carbon dioxide and water after a 6-9 months period.
• The stainless steel stent platform has a strut thickness of 120 m with a quadrature link design.
The AxxessTM
Stent
Dedicated bifurcation drug-eluting stent
Nitinol self expanding stent
Abluminal biodegradable PLA/BA9™ coating technology
2 models: bifurcation and left main*
4 references for the bifurcation model:
• 3.0 and 3.5 mm in diameter
• 11 and 14 mm in length
Clinical programs
AXXESS Plus and DIVERGE for de novo bifurcations lesions
AXXENT for left main lesions
Axxess™ bifurcation drug-eluting stent is CE approved
* Left main stent in not CE approved
BioFreedom™
Selectively micro-structured surface holds drug
in abluminal surface structures
Proprietary Highly Lipophilic Limus drug
Hypothesis: Polymer-free drug
release via porous-eluting stents
may reduce late events caused by
polymer stent coatings.
Potential advantage
• Avoid long term late adverse
effects that might be attributable
to the polymer
• Improved surface integrity since
there is no polymer to be sheared
or peeled away from the stent
struts
• Possible shorter need of dual
antiplatelet therapy
Biosensors’ DES program
LEADERS ‘all-comers’ Trial Design
1o endpoint: MACE: Cardiac death, MI, clinically-indicated TVR (9 mo)
2o endpoints: Death, CV death, MI, TLR, TVR
Stent thrombosis according to ARC
Angiographic study: In-stent % diameter stenosis (9 mo)
Late loss, binary restenosis
DAPT recommended for 12 months
BioMatrix Flex™ (BES)*
N=850
Cypher® Select™ (SES)
N=850
Stable and ACS Patients Undergoing PCI
N=1700 Patients
10 European centers
1:3 Randomisation
Clinical F/U
N=640
Angio F/U
N=210
Clinical F/U
N=640
Angio F/U
N=210
Assessor-blind
1:1 Randomisation
MACE
Pnon-inferiority < 0.0001
Psuperiority = 0.050
Number at risk
SES 850 774 738 718 701 676 655 640 616 589 572
BES 857 780 749 733 723 710 697 675 657 635 618
MACE = cardiac death, MI, or clinically-indicated TVR
* p-value for superiority
Serruys et al., oral abstract presentation, TCT 2012
Definite ST
Landmark Analysis @ 1 Year
0
1
2
3
4
5
6
0 6 12 18 24 30 36 42 48 54 60
BES
SES
Months
%
2.0 %
2.0 % 2.5 %
0.66 %
0 to 1 year RR
0.99 (0.51-1.95)
P=0.98*
1 to 5 year RR
0.26 (0.10-0.68)
P=0.003*
P for interaction = 0.022
* p-value for superiority
Serruys et al., oral abstract presentation, TCT 2012
Definite ST in Complex Patients
*P values for superiority
Windecker, S., oral presentation ,TCT 2010
STEMI
1.0
2.0
3.0
%
2.6%
5.1%
0 6 12 18 24 36 30 Months
2.6%
5.1%
4.6%
2.6%
3-year HR
0.50 [0.18 to 1.34]
P = 0.16*
0
4.0
Δ2.0% Δ3.5% Δ3.5%
5.0
6.0
High SYNTAX SCORE (>16)
1.0
2.0
3.0
%
2.0%
4.3%
0 6 12 18 24 36 30 Months
2.0%
3.8%
2.5%
2.0%
3-year HR
0.46 [0.16 to 1.35]
P = 0.15*
0
4.0
Δ0.5% Δ1.8%
Δ2.3%
5.0
6.0
Bifurcation
1.0
2.0
3.0
%
1.5%
5.2%
0 6 12 18 24 36 30
Months
1.5%
5.2%
3.4%
1.5%
3-year HR
0.28 [0.08 to 1.03]
P = 0.04*
0
4.0
Δ1.9% Δ3.7% Δ3.7%
5.0
6.0
Multi Vessel
2.0
4.0
6.0
%
BES
SES
0 6 12 18 24 36 30 Months
3.8%
8.1% 8.1%
3.0%
3-year HR
0.45 [0.16 to 1.31]
P = 0.14*
0
8.0
Δ 5.1% Δ 4.3%
10.0
3.8%
8.1%
Δ 4.3%
GLOBAL LEADERS
Primary endpoint: Study Treatment strategy superior to reference treatment strategy on cumulative 2
year composite of all cause mortality and new Q-wave MI
Study Treatment Strategy Reference Treatment Strategy
All-Comers PCI Population
ACS and Elective/Stable Patients
N =16’000
1:1 Randomization, Open-Label Design
Biolimus-eluting stent (BES)
BioMatrix Flex™
1 month ASA + Ticagrelor
23-months monotherapy
Ticagrelor
12 months DAPT ACS pts (ASA + Ticagrelor)
Elective pts (ASA + Clopidogrel)
12-months monotherapy ASA
Tic
agre
lor
AS
A
Tic
agre
lor
AS
A
Clo
pid
ogre
l
9 Month Restenosis in DIVERGE
1. Verheye S. et al, J Am Coll Cardiol, 2009
2. Verheye S. et al, oral presentation, TCT 2009
Any In-segment bifurcation restenosis:
6.4% (9/140 at 9 months)1,2
Side Branch RS
3 pts 2 pts
4 pts
Parent Vessel RS
Both
Proximal edge:
2.8%2 SB stent:
4.8%1,2
(105 SB stents)
Distal PV Cypher:
2.1%2
AXXESS:
0.7%1,2
Location Analysis:
Very low restenosis rate in bifurcation
lesions.
Long Term Clinical FU available
MACE*
AXXESS PLUS – 5 Years DIVERGE – 4 Years
0
5
10
15
20
0 12 24 36 48 60
%
Months
13.9 13.9
15.6 17.3 17.3
*(Cardiac death, MI, bypass, ci-TLR)
Grube, TCT 2011
*(all death, MI, id-TLR)
Ormiston, EuroPCR 2012
9.3
14.0
16.0
18.0
0
5
10
15
20
%
Months
Randomized (1:1), multi-center physician initiated trial
True bifurcation with involvement of a
significant side branch requiring a stent
9 mo 12 mo 2 yr 3 yr 4 yr 5 yr
Clinical follow-Up
Xience PRIME using
culotte technique
n=20
Axxess™ (prox. MB) +
BioMatrix™
n=20
2 sites in Belgium
(Leuven and Genk)
P.I: C. Dubois Dr. C.Dubois and Prof. J.Dens are previous investigator of the DIVERGE trial
Angiographic / OCT follow-Up
1° Endpoint: stent strut coverage assessed with OCT at 9 months.
2° Endpoints: stent strut apposition and neointimal hyperplasia assessed with OCT at 9 months,
angiographic restenosis, Major Adverse Cardiac Events (MACE) and components, stent thrombosis, etc
COBRA Study
BioFreedom FIM Design
BioFreedom FIM 182 patients
12 Month Angio FU 107 patients
BioFreedom
standard
dose
(BFD SD)
N=35
BioFreedom
low
dose
(BFD LD)
N=36
TAXUS®
Liberté ®
N=36
Second Cohort
Enrollment Period
Jan 2009 – Jun 2009
BioFreedom
standard
dose
(BFD SD)
N=25
BioFreedom
low
dose
(BFD LD)
N=26
TAXUS®
Liberté ®
N=24
4 Month Angio FU 75 patients
First Cohort
Enrollment Period
Sept 2008 – Jan 2009
Angio FU 92% Angio FU 92%
2nd Cohort – PRIMARY ENDPOINT
0.17 [0.09, 0.39]
0.22 [0.17, 0.66]
0.35 [0.22, 0.57]
0.0
0.1
0.2
0.3
0.4
BFD SD BFD LD TAXUS
P = 0.001* (p=0.11**)
P = 0.21* (p=0.55**)
(m
m)
N = 31 N = 31 N = 35
In-Stent LLL at 12 Months FU
*Non-inferiority tests based on the mean. **Superiority tests.
All values are presented as median [IQR].
Grube E., oral presentation, TCT 2010
All patients – 1st and 2nd Cohorts (96.1%)
36-Month Outcomes
EVENT BFD SD
N = 60
BFD LD
N = 62
TAXUS
N = 60
MACE
(All Death, MI, Emergent Bypass
or TLR)
7(11.9%) 11(18.1%) 6(10.0%)
All Death 3(5.1%) 2(3.3%) 1(1.7%)
MI 1(1.7%) 2(3.4%) 1(1.7%)
Q Wave MI 0(0.0%) 0(0.0%) 0(0.0%)
Non-Q Wave MI 1(1.7%) 2(3.4%) 1(1.7%)
Emergent Bypass 0(0.0%) 0(0.0%) 0(0.0%)
TLR 3(5.2%) 8(13.2%) 4(6.7%)
Definite/probable stent
thrombosis (ARC) 0(0.0%) 0(0.0%) 0(0.0%)
All P values are non-significant.
Tests were performed for BFD SD vs. TAXUS and BFD LD vs. TAXUS.
Grube TCT 2012
Clinical Follow-Up
Primary safety endpoint: Composite of cardiac death, MI, definite/probable stent thrombosis at 1 year
(Non-inferiority)
Primary efficacy endpoint: Clinically driven TLR at 1 year
(Superiority)
DAPT mandated for 1 month only, followed by long term SAPT
BioFreedom™
DCS
Gazelle™
BMS
Prospective, multi-center, multi-national, double blinded randomized trial
High Bleeding Risk PCI population
(ACS + Elective stable patients)
LEADERS FREE Trial Design
1:1 randomization
1 mo 2 mo 4 mo 1 yr 2 yr
2500 patients in 60 centers worldwide