1. BioFreedom – the world’s first coronary stent system coated with BA9
BioFreedom – the world’s first coronary stent system coated with BA9. No polymer just stent and drug – no carriers, no permanent polymers or biodegradable polymers. The next natural progression in the development of the BioMatrix family of stents.

2. What is BioFreedom ?

3. BioFreedom™: The First BA9 DCS that combines the advantages of both DES and BMS
Stent Platform
316 L Stainless Steel
Strut thickness
0.0044”
Crimped profile
0.043” (3.0mm)
Polymer
No polymeric drug carrier
Drug
Biolimus A9™
Dose
Standard Dose: 15.6µg of BA9/mm stent length
Release kinetics
50 hours/90% release
Product Approval
CE mark granted
BioFreedom – the same stainless steel platform as BioMatrix Flex / Neo Flex which is 96%-98% free of drug at 28 days and as such becomes BMS stent-like around 28 days. The safety of a BMS with the effectiveness of a DES – giving you options for all your patients not just those who can take long DAPT regimens.
I LIKE!

4. BioFreedom
BioFreedom BA9 and no polymer – a combination that works, and offers the clinician the opportunity to tailor DAPT to reduce the bleeding risk

5. Polymer Inflammation has a potential impact on long-term safety and efficacy
Evidence has been accumulating over recent years demonstrating that durable polymer coatings on DES can lead to chronic inflammation and impaired healing. Biosensors developed the successful BioMatrix Flex / NeoFlex system, which addressed this issue and now we come to the market with a drug only coated stent – completely polymer free, a system we attest offers new options when it comes to selecting the right DAPT regime for all your patients.
Inflammatory polymers have been shown to cause endothelial dysfunction in pre-clinical and clinical models1, 2, 3, 4
Dysfunctional endothelium can lead to vasoconstriction, increased inflammation, increase potential for thrombosis and delayed healing 5, 6, 7
The hypothesis is that an inflammatory polymer increases the potential for dysfunctional endothelium which may increase the potential for TLR and VLAST
1) Data from Abbott XIENCEV US Physician presentation SE D
2) Data on File at MDT - In vitro data verifying biocompatibility of BioLinx. Ref. Lab Notebooks 1813LAB (Carol Sullivan), 1816LAB & 1715LAB (Jennifer Wong). Ref. slides 15, 16 & 17 of TCTMD ) 3) Poster by Kishore Udipi: Development of a Novel Biocompatible Co-Polymer System for Extended Drug Release in a Second Generation Drug Eluting Stent Coverage
4) Awata et al. ACC
5) JW Kim et al. ACC 2008.
6) Data on File at MDT - Haraguchi et al. TCT ACH Challenge for Driver, Endeavor, Cypher, Taxus
7) PS 406 (ACH Challenge for Endeavor Resolute and Xience V)

6. From BioMatrix™ to BioMatrix Flex™ BMS-like Level of Re-Endothelialization in the Animal Model
In animal models,
the BioMatrix Flex™ stent
achieves a similar level of
re-endothelialization
compared to its bare metal
stent platform1
BA9 allows strut coverage similar to a BMS at 28days. BioFreedom with no polymer should allow healing at the same level and time ?
Animal modelling shows that the BA9 eluting Biomatrix Flex/Neoflex achieves re-endothilesiation similar to a BMS at 28 days. This supports the hypothesis that shorter DAPT can be considered for the BioFreedom stent - as it is free of drug at 28 days and as BA9 allows re-endothelisation similar to a BMS at 28 days, there is good healing and strut coverage therefore reducing the need for prolonged DAPT.
BioFreedom potentially offers options as to the length of DAPT clinicians choose to suit the requirements of any individual patient.
Further discussion ...
It is widely recognised that improved techniques and technologies have helped drive the reduction in ST and postulated that long term DAPT is more likely to drive bleeding episodes and the adverse events that accompany them. A minor bleeding episode has a 7-10 fold increase in adverse events associated with it.
The trade off for reduction in ST events with DAPT has always been an increase in bleeding episodes.
1 Data on file at Biosensors Intl

7. With BioFreedom 98% of drug is off the stent after 1 month
BA9 is proven to deliver BMS-like reendothilisation at 28 days.
The Biofreedom stent is 98% free of drug at 28days.
Biosensors conclude there is a high possibility that BioFreedom is the first stent with the efficacy of a DES and the safety of a BMS

8. The price of DAPT : Bleeding ?
As all of the studies have shown, DAPT brings not only increased efficacy but also an increase in major bleeding. Not all of these bleeding episodes need to be fatal but all will bring with them some form of mortality
No significant p-values

9. Is BioFreedom safe ?

10. Pre-Clinical Safety Evaluation
Pre-clinical safety evaluation was conducted comparing two doses of Biolimus and demonstrated the following - we compared high (225µg BA9) and low (112µg BA9) dose Bio-Freedom (HD,LD) to a polymer-coated sirolimus eluting Cypher stent (SES) and a bare metal stent (BMS) at 28 and 180 days in an overstretch coronary mini-swine model.  Endpoints were histomorphometry and histology.
At 28 days, there was a reduction in percent area stenosis by HD, LD and SES compared to BMS (% area stenosis: HD 17.67±4.01, LD 17.45±5.08, SES 16.40±3.89, BMS 26.74±12.37 %, BMS > HD, LD & SES, p=0.001). At 180 days, both Bio-Freedom stents were associated with reduced neointimal hyperplasia, whereas SES exhibited increased neointima (% area stenosis: HD 21.07±4.42, LD 20.00±5.44, SES 33.83±11.15, BMS 28.57±9.28 %, SES > HD & LD, BMS > HD & LD, p<0.001). At 180 days, SES showed increased fibrin and giant cells as well as a trend to more granulomas than the other groups.

11. Pre-Clinical Safety Evaluation
Pre-clinical safety evaluation was conducted comparing two doses of Biolimus and demonstrated the following - we compared high (225µg BA9) and low (112µg BA9) dose Bio-Freedom (HD,LD) to a polymer-coated sirolimus eluting Cypher stent (SES) and a bare metal stent (BMS) at 28 and 180 days in an overstretch coronary mini-swine model.  Endpoints were histomorphometry and histology.
At 28 days, there was a reduction in percent area stenosis by HD, LD and SES compared to BMS (% area stenosis: HD 17.67±4.01, LD 17.45±5.08, SES 16.40±3.89, BMS 26.74±12.37 %, BMS > HD, LD & SES, p=0.001). At 180 days, both Bio-Freedom stents were associated with reduced neointimal hyperplasia, whereas SES exhibited increased neointima (% area stenosis: HD 21.07±4.42, LD 20.00±5.44, SES 33.83±11.15, BMS 28.57±9.28 %, SES > HD & LD, BMS > HD & LD, p<0.001). At 180 days, SES showed increased fibrin and giant cells as well as a trend to more granulomas than the other groups.

12. 48-month Outcomes All Patients – 1st and 2nd Cohorts (93.5%)
EVENT
BFD SD
N = 60
BFD LD
N = 62
TAXUS
MACE
(All Death, MI, Emergent Bypass or TLR)
8(13.6%)
14(23.4%)
8(13.3%)
All Death
3(5.1%)
5(8.6%)
2(3.4%) MI
2(3.5%)
2(3.3%)
1(1.7%)
Q Wave MI
0(0.0%)
Non-Q Wave MI
Emergent Bypass
TLR
3(5.2%)
8(13.2%)
6(10.2%)
Definite / Probable Stent Thrombosis (ARC)
At 48 months there was no  significant difference in MACE and TLR between the 3 studied groups and neither group had any ST events (reinforcing that techniques drive a reduction in ST even with old technology)
All p-values are non-significant.
Tests were performed for BFD SD vs. TAXUS and BFD LD vs. TAXUS.

13. Is BioFreedom effective ?

14. Pre-clinical Efficacy Evaluation
There was no significant difference between either high dose or low dose, however, at 28 days both doses demonstrated significantly reduced neointimal thickness at 28 days vs BMS
Tada et al., Circ Cardiovasc Interv 2010;3;

15. Pre-clinical Efficacy Evaluation
There was no significant difference between either high dose or low dose, however, at 28 days both doses demonstrated significantly reduced neointimal thickness at 28 days vs BMS
Tada et al., Circ Cardiovasc Interv 2010;3;

16. In-Stent LLL at 12-month Follow-up 2nd Cohort – Primary Endpoint
P = 0.001* (p=0.11**)
P = 0.21* (p=0.55**)
As the SD BioFreedom significantly reduced LLL versus Taxus at 12 months it became the standard dose for BioFreedom
N = 31
N = 35
N = 31
*Non-inferiority tests based on the mean. **Superiority tests.
All values are presented as median [IQR].
Grube E., oral presentation, TCT 2010

17. BioFreedom Comparable LLL Efficacy
BioFreedom LLL compared to Taxus ( LLL) FIM trial
Xience - Stone GW. ACC2007 Spirit III
Nevo – Ormiston et al. Circ Cadiovasc Interv 2010;3:556-64
BioMatrix Flex - The Lancet, Volume 372, Issue 9644, Pages , 27 September 2008

18. Target Lesion Revascularization at 4 years
- 49%

19. What’s the message ?

20. BioFreedom
BioFreedom: first and only polymer-free drug coated stent with BA9
No polymer offers reduced dysfunctional endothelium
BioFreedom FIM demonstrated the excellent efficacy profile of BioFreedom with 49% RRR in TLR compared to Taxus at 12 months and non-inferiority (with trend towards superiority) in terms of In-Stent LLL
There was no incidence of definite / probable stent thrombosis (ARC) up to 4 years for the patients treated with BioFreedom
Due to drug elution profile, and absence of polymer, at 1 month BioFreedom is effectively BMS-like and therefore a shorter DAPT recommendation may be appropriate
This hypothesis is currently being tested in a large RCT – LEADERS-Free
BioFreedom is the  first polymer-free drug coated stent with BA9 (Biolimus), BioFreedom FIM demonstrated the excellent efficacy profile of BioFreedom with 49% RRR in TLR compared to Taxus at 12 months and non-inferiority (with a numerical improvement and trend towards superiority) in terms of In-Stent LLL. There was no incidence of definite / probable stent thrombosis (ARC) up to 4 years for the patients treated with BioFreedom. Due to drug elution profile, and absence of polymer, at 1 month BioFreedom is effectively a BMS and therefore a shorter DAPT recommendation may be appropriate, this hypothesis is currently being tested in a large RCT – LEADERS-Free. A drug coated stent that allows shorter DAPT with the benefit of a limus drug to regulate the healing process, could also demonstrate a significant reduction in bleeding episodes, if as in the FIM Leaders Free shows no ST events associated with BioFreedom and shorter DAPT is shown to reduce bleeding episodes, then we have a product here that can change the world of PCI with metal stents!

21. More data ?

22. You can talk about it now !
Biosensors believe in BioFreedom and we have invested heavily to get the answers everyone is asking about optimal DAPT. The data from this study will be available in 2015.
You can talk about it now !

23. LEADERS Free trial, a unique design
Double blinded design in a DES trial
PI: Philip Urban
Prospective, multi-center, multi-national, double blinded randomized trial
High Bleeding Risk PCI population
(ACS + Elective stable patients)
Non-comers population
2500 patients in 65 centers worldwide
BioFreedom™
DCS
1:1 randomization
Gazelle™
BMS
Clinical Follow-Up
1 mo 2 mo 4 mo yr yr
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
Leaders Free will answer this question.
It is double blinded, randomized, looking at high bleeding risk forgotten patients in 65 centres worldwide – 2500 recruited April 2014
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)
Two primary endpoints- safety and efficacy
1 month planned DAPT – distinguishing this from post-hoc studies only looking at interruptions at the judgment of the physicians (patients at low risk)
Urban et al., Am Heart J. 2013; 165:

24. Importance of Study
First large scale trial of a DCS using clinical endpoints
First prospective, randomized, double-blinded trial to evaluate the use of an active stent with only one month DAPT
First prospective, randomized, double blinded trial to evaluate outcomes in PCI patients considered at high risk for bleeding

25. How Might Leaders Free impact on clinical practice ?
It will define the relative risks of stent thrombosis and bleeding in a challenging patient subset
It may help “disconnect” active stent implantation and prolonged uninterrupted DAPT
It has the potential to bring the known benefits of a low TLR rate to patients at high risk of bleeding
Read the slide !

26. What else are we planning ?

27. BioFreedom EGO Biofreedom Pre-IDE Study in the US
OCT Study Hong Kong last patient in the next weeks
Pre-IDE Study in the US
Starting in June 2014
BioFreedom Japan registration study
Others ?????