1. Biotronik’s PLLA Biodegradable DES Program
Ron Waksman MD Associate Chief of Cardiology Washington Hospital Center Georgetown University, Washington DC, USA

2. Ron Waksman, MD Consulting Fee Abbott Laboratories Biotronik, Inc.
Boston Scientific Corporation
Medtronic, Inc.
Merck and Company, Inc.

3. Honoraria
Abbott Laboratories
Boston Scientific Corporation
Medtronic, Inc. Consulting Fee
Merck and Company, Inc.

4. Orsiro Hybrid Drug Eluting Stent
PROBIO® passive coating encapsulates the stent and minimizes interaction between the metal stent and the surrounding tissue
BIOlute® active coating contains a highly biocompatible polymer which delivers a Limus drug via a biodegradable matrix
PRO-Kinetic Energy Stent System brings good deliverability for reaching complex lesions
BIOlute® achieves a
controlled drug release
Quick facts
Passive coating
PROBIO® amorphous silicon carbide coating
Active coating
BIOlute® bioabsorbable PLLA eluting Sirolimus
Drug dose
1.4 µg/mm2
Stent material
Cobalt chromium L-605
Strut thickness
60 µm (3.00 mm stent)
Approval status
CE approved
The BIOlute® polymer matrix gently degrades into CO2 and H2O
Only a PROBIO® sealed stent is left in the arterial wall

5. In vivo drug release in mini pig coronary arteries*
BIOlute contains sirolimus with an elution kinetic optimized to release over weeks
Orsiro elutes one of the most proven drugs for a DES
In vivo drug release in mini pig coronary arteries* 10 20 30 40 50 60 70 80 90
100
% Drug Release
Time (days)
In vivo studies show complete sirolimus release between days
Drug load is 1.4 μg/mm2
Elution curve is in-line with other Limus-based stents
* Residual drug remaining of stent after explantation.
Source: Preclinical Orsiro animal studies, data on file, BIOTRONIK AG.

6. BIOlute contains a high molecular PLLA allowing precise control of mechanical and pharmaceutical properties
Orsiro has an asymmetric coating and excellent polymer integrity
60μm
7.4μm
3.5μm
Asymmetric coating allows greater drug dose on abluminal side of stent strut
Release kinetic is controlled by coating and process design (no additional top coatings are needed)
Surface drug load of 1.4 µg/mm2 strut surface
Mechanical properties are good in general due to the mechanical strength of the polymer
No flaking or pealing at expansion areas
Source: SEM images from IIB Test Report 66/2009.

7. BIOlute degrades gently in less than 2 years to avoid increased inflammation
Elimination of the polymer removes the threat for polymer related long-term events
Real-time degradation of sirolimus loaded PLLA
Time (days)
Molecular weight [a.u.]
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0 50
100
150
200
250
300
350
400
450
500
Source: Preclinical Orsiro animal studies, data on file, BIOTRONIK AG.

8. Benign histology beyond polymer degradation shown in mini-pigs
Masterlayout
Benign histology beyond polymer degradation shown in mini-pigs
Minimal or no inflammatory response of vessel tissue upon degrading polymer
12m
24m
36m
Polymer coating visible at one year
Appearance different morphology; however, analysis shows that there is no residual PLLA
Similar to the Absorb platform, there is only a morphometric imprint left
* …
Source: …
© BIOTRONIK

9. Differences among bioabsorbable and permanent polymer DES
Masterlayout
Differences among bioabsorbable and permanent polymer DES
Pre-clinical histology, mean values at 28 day
Intimal area (mm)
Inflammation score
Fibrin score
Orsiro formulation
PEVA/PBMA SES
PUR SES
PEVA/PBMA – permanent cypher-like
PUR – Pellethane, permanent
PLLA SES
PLGA SES
BMS
© BIOTRONIK

10. PLLA is our best choice for BIOLute
Masterlayout
PLLA is our best choice for BIOLute
Key requirements and performance goals of degradable polymers
Assure stability of properties of DES over time (drug stability, release stability,…)
Safe transport the drug to the target lesion
Controlled release of the drug
After those jobs are done, the polymer isn‘t needed any more, that means: Don‘t interact with the body: Either it is completely inert (not feasible) or it goes away without interaction = slow and without provoking inflammation
PLLA
PDLLA
PLGA
Mechanical strength and performance ++ +
Drug release control (done by diffusion control, NOT by degradation of carrier)
Biocompatibility = no inflammation before/during/after degradation
Stability against humidity (for polymer AND drug) -
Processability
© BIOTRONIK

11. The PK Energy platform offer exceptional deliverability, conformability in a thin-strut device
Deliverability is crucial for treatment of complex lesions
PK Energy Features
… translates into performance
Expect PK Energy-like performance with the Orsiro stent
PK Energy stent design is optimal for a drug coating and allows for maximum coating integrity during expansion
Optimized delivery system allows for higher pressure inflations, as seen with DES (RBP 16 atm, Mean Burst Pressure [MBP] atm depending on diameter)
Double helical design gives excellent flexibility without compromising scaffolding or fatigue resistance
Cobalt chromium alloy allows for thinner struts (60 μm) resulting in flexibility and better results
Advanced stent crimping technology ensure a low crossing profile (0.99 mm)
Optimized delivery system with Pantera-based catheter design customized for DES usage

12. Compared to other drug eluting stents, Orsiro has among the thinnest struts
Orsiro Hybrid DES
SEM images
Strut thickness
140 μm
91 μm
81 μm
60 μm
Polymer thickness*
12.6 μm
4.8 μm
7.8 μm
7.4 μm
Total thickness
153 μm
99 μm
95 μm
71 μm
* Only abluminal coating thickness represented.

13. BIOlute® coating integrity is superior to what is commonly seen for other DES
Selection of Orsiro pictures
ESEM images of Orsiro as provided by IIB

14. First in Man Experience With a Drug Eluting Stent in De Novo Coronary Artery Lesions (BIOFLOW-I)
Study Design
DESIGN: Prospective, multi-centre, non-randomized, first in man trial
OBJECTIVE: To assess the safety and clinical performance of the ORSIRO hybrid drug eluting stent in patients with single de-novo coronary artery lesions
CLINICAL COORDINATING INVESTIGATOR: Prof. Martial Hamon, University Hospital of Caen, France
PRINCIPAL INVESTIGATORS: Dr. Rodica Niculescu, MD, PhD, FESC Dr. Dan Deleanu, MD, FESC
30 patients enrolled July 2009 in 2 clinical sites in Romania
Clinical follow-up at 1 month
Clinical & angiographic
follow-up at 4 months
Clinical & angiographic
follow-up at 9 months
Clinical follow-up at 12, 24 & 36 months
Primary Endpoint
In-stent late lumen loss at 9 months by QCA

15. Baseline clinical characteristics
Patient demographics show multiple co-morbidities and moderate level of diabetics
N=30
Age, years
58.10 yrs ± 9.80
Male sex
60.0%
18/30
Hyperlipidemia
93.3%
28/30
History of MI
73.3%
22/30
Hypertension
66.6%
20/30
Smoker
53.3%
16/30
Diabetes
23.3%
7/30
CHF
20.0%
6/30

16. Baseline lesion characteristics
Lesion characteristic show 1/3 of complex lesions with high device success
Pre-Procedure
N=30
RVD (mm)
2.75 ± 0.34
MLD (mm)
0.95 ± 0.29
% Diameter stenosis
65.52 ± 9.47
Mean Lesion length (mm)
11.71 ± 4.40
Procedural
Stent length per lesion (mm)
19.93 ± 5.33
Stent diameter per lesion (mm)
3.08 ± 0.37
Direct stenting
20.0%
Device success*
100.0%
* Defined as In-Stent < 30% residual stenosis by offline QCA

17. Angiographic follow-up results
Primary Endpoint
Late Lumen Loss
@ 9 Months
4-month FUP
9-month FUP
RVD (mm)
2.81 ± 0.28
2.81 ± 0.30
Minimal Lumen Diameter
In-stent (mm)
2.50 ± 0.36
2.56 ± 0.38
In-segment (mm)
2.20 ± 0.35
2.21 ± 0.31
Diameter Stenosis
In-stent (%)
15.19 ± 4.55
13.60 ± 4.27
In-segment (%)
23.66 ± 9.80
23.55 ± 8.06
Late Loss
0.12 ± 0.19
0.05 ± 0.22
0.06 ± 0.23
0.05 ± 0.26
Binary Restenosis 0%
0.05±0.22
0.05±0.26

18. Cumulative frequency of Diameter Stenosis
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19. Cumulative Frequency of Minimum Lumen Diameter
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20. Cumulative Frequency of In-Stent Late Lumen Loss
Mean In-Stent LLL:
4 Months ± 0.21
9 Months ± 0.22
lkjlökj 20 20

21. Clinical outcomes at 9 months
9-month clinical results N %
MACE 2
6.7
Cardiac Death
0.0 MI
Stent thrombosis
TLR (clinically driven)
MACE defined as:
Composite of cardiac death, MI attributed to the target vessel, stent thrombosis and clinically driven target lesion revascularization 21

22. BIOFLOW-I conclusions
In this FIM study the Orsiro Hybrid DES showed promising results in a mixed and atypical population for a FIM study, with relatively high rates of diabetic patients and complex lesions
At 9 months follow-up, no late catch-up was seen in the LLL values and a narrow standard deviation suggests that these study results are quite robust
A larger randomized, comparative study is currently running to prove the safety and effectiveness of this promising device

23. Clinical strategy for the Orsiro will collect comparative and long-term data
Imperative: prove equivalence to the market leader and long-term safety
Study design
A prospective, multi-centre, single treatment clinical trial
Endpoint: LLL 9 months, N=30
A prospective, multi-center, non-inferiority, randomized study, Orsiro vs. Xience Prime
Endpoint: LLL at 9 months, N=440
Clinical strategy
FIM study, results submitted to TÜV in the CE-mark approval process
Comparative, non-inferiority trial testing safety and effectiveness
Study design
A prospective, multi-centre, single treatment clinical registry
Endpoint: LLL at 9 months, N=120
A prospective, multi-centre, single treatment clinical registry
Endpoint: TLF at 12 months, N=1,000+
Clinical strategy
Pivotal trial for market approval in India, testing safety and effectiveness
All comers open label real world evaluation

24. Study Design Primary Endpoint
BIOTRONIK-Safety and Clinical Performance of the Drug Eluting Orsiro Stent in the Treatment of Subjects With single de novo Coronary Artery Lesions (BIOFLOW-II)
Study Design
DESIGN: A prospective, multicenter, international, two-arm, non-inferiority,
randomized controlled clinical study enrolling up to 440 subjects. All subjects will be randomized 2:1 to receive the BIOTRONIK
Orsiro or the Abbott Xience Prime™
OBJECTIVE: To compare the BIOTRONIK Orsiro with the Abbott Xience Prime™ with respect to in-stent Late Lumen Loss (LLL) in a non-inferiority study in de novo coronary lesions at 9 months.
COORDINATING INVESTIGATORS: Prof. Stephan Windecker
Head of Interventional Cardiology
University Hospital Bern, Switzerland
Dr. Thierry Lefevre
Hospital Jacques Cartier, Massy, France
Clinical follow-up at 12 months
Clinical follow-up at 1 month
440 patients
Enrollment started July 2011
Clinical, angiographic, IVUS* and OCT* follow-up at 9 months
Orsiro
Xience PrimeTM
2:1
* Pre specified sub groups with 60 patients in each
Clinical follow-up annually out to 5 years
Primary Endpoint
In-stent late lumen loss at 9 months post procedure by QCA analysis

25. Conclusions
Biodegradable polymer technology has shown to improve outcomes compared with the previous gold-standard of durable polymer SES
Orsiro Hybrid DES applies biodegradable polymer based drug elution with an attractive platform, and has shown promising results in a FIM study, with high rates of diabetic patients and complex lesions
BIOFLOW-II will provide further data on this novel device by directly comparing angiographic outcomes with durable polymer EES (Xience PrimeTM)