Kenneth  GrahamVP  Sales  EMEA  &  Managing  Director

Biosensors  Europe  

Taking  DES  technology  from  concept  to  clinical  proof

My  Conflicts  of  interest  are:Full  time  employee  ofBiosensors  Europe  SA

BA9  shows  sustained  Safety  and  Efficacy  –Independent  from  stent  platform  or  method  of  drug  delivery!

Take-­home  message  – ACI  2011

BioMatrixTMBioMatrixTM Flex BioFreedomTM AXXESSTM Plus Nobori

(Terumo)

Custom  NXTM    (XTENT)

Stainless  SteelBalloonexpandableAbluminalbiodegradable  polymer

Stainless  SteelBalloonexpandablePolymer  Free

NitinolSelf-­expandableAbluminalbiodegradable  polymer

Designed  for  Bifurcations

SSBA9/PLA

Cobalt-­ChromeBA9/PLA

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  

11

1 Data on file at Biosensors Intl

10925-­000-­EN  –Rev.01

Biosensors’  DES  program

• 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  µg/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  µm  with  a  quadrature  link  design.

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  restenosisDAPT  recommended  for  12  months

BioMatrix  Flex™  (BES)*  N=850

Cypher® Select™  (SES)  N=850

Stable  and  ACS  Patients  Undergoing  PCIN=1700  Patients

10  European  centers

1:3  Randomisation

Clinical  F/UN=640

Angio F/UN=210

Clinical  F/UN=640

Angio F/UN=210

Assessor-­blind  1:1  Randomisation

MACE

0

5

10

15

20

25

0 6 12 18 24 30 36 42 48

%

Months

BES SES

10.7%

13%15.6%

19.1%12.1%

15.5%

19.3%

23.1%

Δ  1.4

Δ  2.5

Δ  3.7

Δ  4.0

3-­year  RR0.80    (0.63    -­1.01)

2-­year  RR0.83    (0.64    -­1.07)

4-­year  RR0.81    (0.66    -­1.00)

1-­year  RR0.88  (0.66    -­1.17)

Numbers  at  risk

SES 850 775 738 718 702 676 656 639 614

BES 857 781 749 733 723 710 697 677 659

Pnon-­inferiority    <  0.0001

Psuperiority =    0.050

MACE  =  Cardiac  death,  MI,  or  Clinically-­indicated  TVRStefanini  G.  et  al.,  The  Lancet,  2011Ischinger et  al.,  oral  presentation,  TCT  2011

0

1

2

3

4

5

6

%

0 6 12 18 24 30 36 42 48

Months after  index PCI

0  to  1  year  RR  0.99  (0.51-­1.95)P=0.98*    

1  to  4  year  RR  0.20  (0.06-­0.67)  P=0.004*

BESSES

857 821 804 792 787 780 774 757 746BES

850 817 801 787 776 759 750 730 714SES

No.  at risk

2.0%

0.4%

2.0%

2.0%

P  for  interaction=0.017 *  P  values  for  superiorityStefanini  G.  et  al.,  The  Lancet,  2011Ischinger et  al.,  oral  presentation,  TCT  2011

Definite  STLandmark  Analysis  @  1  Year

Definite  ST  in  Complex  Patients

*P  values  for  superiorityWindecker,  S.,  oral  presentation  ,TCT  2010

STEMI

1.0

2.0

3.0

%

2.6%

5.1%

0 6 12 18 24 3630Months

2.6%

5.1%4.6%

2.6%

3-­year  HR0.50  [0.18  to  1.34]

P  =  0.16*

0

4.0Δ2.0% 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 3630Months

2.0%

3.8%

2.5%

2.0%

3-­year  HR0.46  [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 3630Months

1.5%

5.2%

3.4%

1.5%

3-­year  HR0.28  [0.08  to  1.03]

P  =  0.04*

0

4.0

Δ1.9%Δ3.7% Δ3.7%

5.0

6.0Multi  Vessel

2.0

4.0

6.0

%

BESSES

0 6 12 18 24 3630Months

3.8%

8.1%8.1%

3.0%

3-­year  HR0.45  [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%

0

2

4

6

8

10

12

Syntax  Score  High    (>16)

SES

BES

0

2

4

6

8

10

STEMI

SES

BES

Cardiac  death  rate  at  3  years  %

Psup =  0.02 Psup =  0.03

10.5%

4.7%

Post-­hoc  analysisKM  estimates

Post-­hoc  analysisKM  estimates

The  Biolimus A9™ eluting stent shows  a  significantcardiac mortality  benefit

-­57% -­69%

1Serruys,  P.,  oral  presentation,  TCT  2010

9.5%

3.1%Cardiac  death  rate  at  3  years  %

12

2 Windecker,  S.,  oral  presentation,  TCT  2010  

n  =222 n  =239 n  =140 n  =135

GLOBAL  LEADERS  study

• 16,000  patient  study• ACS  +  Elective  PCI  patients• All  patients  receive  BioMatrix  Flex  stent• Randomisation between  two  innovative  DAPT  regimes.

• Planned  start  in  2012

The  AxxessTM StentDedicated  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

9  Month  Restenosis in  DIVERGE

1. Verheye  S.  et  al,  J  Am  Coll Cardiol,  20092. Verheye  S.  et  al,  oral  presentation,  TCT  2009

Any  In-­segment  bifurcation  restenosis:  6.4%  (9/140  at  9  months)1,2

Side Branch RS3  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  availableMACE*

AXXESS  PLUS  – 5  Years DIVERGE  -­ 3  Years

0

5

10

15

20

25

0 12 24 36 48 60

%

Months

13.9 13.915.6

17.3 17.3

*(Cardiac  death,  MI,  bypass,  ci-­TLR)Grube,  TCT  2011

9.3

14.016.0

0

5

10

15

20

25

0 12 24 36

%

Month*(all  death,  MI,  ci-­TLR)Agostoni,  EuroPCR 2011

COBRA  Study  • OCT  Study  comparing  Axxess bifurcation  stent  and  Biomatrix  Flex  vs  Xience  Prime  with  cullottetechnique  – P.I.  Prof.  Dubois  -­Leuven

• 20  patients  in  each  arm

• 1° Endpoint:  stent  strut  coverage  assessed  with  OCT  at  9  months.

• Enrollment  started  in  November  2011.

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

BioFreedom  FIM  DesignBioFreedom  FIM

182    patients

12  Month  Angio  FU107  patients

BioFreedom  standarddose

(BFD  SD)N=35

BioFreedom  lowdose

(BFD  LD)N=36

TAXUS®  Liberté ®N=36

Second  Cohort

Enrollment  PeriodJan  2009  – Jun  2009

BioFreedom  standarddose

(BFD  SD)N=25

BioFreedom  lowdose

(BFD  LD)N=26

TAXUS®  Liberté ®N=24

4  Month  Angio  FU75  patients

First  Cohort

Enrollment  PeriodSept   2008  – Jan  2009

Angio  FU  92%

12  Month  Clinical  FU  99%

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**)

(mm)

N    =  31   N    =  31N    =  35

*Non-­inferiority  tests.  **Superiority  tests.Grube E.,  oral  presentation,  TCT  2010

In-­Stent  LLL  at  12  Months  FU

EVENT BFD  SD  N  =  60

BFD  LDN  =  61

TAXUSN  =  59

MACE(All  Death,  MI,  Emergent  Bypass  or  TLR)

4  (6.8%) 9  (14.7%) 6  (10.0%)

All  Death 1  (1.7%) 1  (1.6%) 1  (1.7%)MI 1  (1.7%) 1 (1.6%) 1  (1.7%)

Q  Wave  MI 0  (0.0%) 0  (0.0%) 0  (0.0%)Non-­Q  Wave  MI 1  (1.7%) 1  (1.6%) 1  (1.7%)

Emergent  Bypass 0 (0.0%) 0  (0.0%) 0  (0.0%)TLR 2  (3.4%) 7  (11.5%) 4  (6.7%)Stent  thrombosis  (ARC) 0  (0.0%) 0  (0.0%) 0  (0.0%)

All  patients  – 1st and  2nd Cohorts  (98.9%)

All  P  values  are  non-­significant.Tests  were  performed  for  BFD  SD  vs.  TAXUS  and  BFD  LD  vs.  TAXUS.  

Grube E.,  oral  presentation,  TCT  2010

24-­Month  Outcomes

LEADERS  Free¡ A  randomized  double  blind  trial  of  the  

BioFreedom    (  DCS)  vs.  Gazelle  (BMS)  in  patients  at  high  risk  for  bleeding

¡ 2630  patients  at  up  to  60  sites  in  Europe/Asia/S  America.  2  year  follow-­‐up.  14  month  enrollment.  

¡ Antiplatelet regimen  – 1  mo  DAPT,  ASA  indefinitely

¡ Primary  Endpoints

• Non-­‐inferiority  of  BF  vs BMS  at  one  year  for  cardiac  death  +  MI  +  ST  +  urgent  TLR

• Superiority  of  BF  vs BMS  at  one  year  for  TLR

Where  do  we  go?

• Axxess    controlled  launch  as  of  November  2011

• BioFreedom  planned  to  launch  in  2012

• Taking  a  LEAD  in  evidence  based  medicineo GLOBAL  LEADERSo LEADERS  Free