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