Absorbable Metal Stent, Clinical Update and DREAMS Drug Eluting Absorbable Metal Stent, Concept and pre-clinical data

1. Absorbable Metal Stent, Clinical Update and DREAMS – Drug Eluting Absorbable Metal Stent, Concept and pre-clinical data Ron Waksman, MD Professor of Medicine (Cardiology) Georgetown University, Associate Director Division of Cardiology Washington Hospital Center Washington DC ICI Tel-Aviv Israel

2. 2 Potential Advantages of a Bioabsorbable Non-polymer Based Coronary Stent Provides metal stent scaffolding and radial strength properties Leaves no stent behind (no chronic inflammation, no long-term impact on local vasomotion) No “Full metal jacket” ? easier surgical bypass connection No Stent Thrombosis No Need for Prolonged antiplatelet therapy MRI / CT compatibility ? provides non-invasive F/U

3. 3 Absorbable Magnesium Stent*

4. 4 Performs like a bare metal stent (BMS) Radial strength, recoil parameters similar to BMS Naturally bioabsorbs Absorbable Magnesium Stent

5. 5 Minipigs - 8 weeks after implantation* Magnesium Alloy & Biocompatibility

6. 6 Magnesium alloy absorption 56 days after implantation in domestic pigs Magnesium Alloy & Absorption

7. 7 Complete occlusion of the left pulmonary artery after de-banding and closure of the arterial duct with a clip (the device with three markers is for calibration purposes)

8. 8 Crossing the stenosis with a guide wire angiography revealed reperfusion

9. 9 Implantation procedure of Mg Stent 3.0/10mm with a contrast filled balloon catheter

10. 10 At one week follow up after Mg Stent the left lung was reperfused

11. 11 Clinical Results BEST-BTK First in Man experience with the Biotronik absorbablE metal StenT Below The Knee

12. 12 Male 10 50% Female 10 50% Average age 76 yrs (59 - 96) Clinical vascular status Rutherford Class IV 9 45% Rutherford Class V 11 55% Patient demographics (N=20)

13. 13 Lesion description (N=20) Average lesion length 11 mm (2 mm – 20 mm) Average vessel diameter 2.7mm (2.5 mm 3 mm) Average stenosis 84 % (75% – 95%) Dissection 0 0% Ulceration 1 5% Thrombus 3 15% Calcification 14 70%

14. 14 Procedure description Cross-over (11/20) Inflow improving R/ Long sheath in popliteal Lesion crossing wire .014”

15. 15 Procedure description Post-PTA control Flow restricitive residual stenosis

16. 16 Procedure description Post operative control Satisfactory outflow

17. 17 94.7% Limb Salvage After One Year 3M 100.0% 6M 94.7% 9M 94.7% 12M 94.7%

18. 18 High Patency Rate Below The Knee 3M 89.5% 6M 84.2% 9M 78.9% 12M 72.4%

19. 19 Early Prototypes for “big AMS”

20. First in Man Coronary: PROGRESS-AMS Study Clinical Performance and Angiographic Results of the Coronary Stenting with Absorbable Metal Stents

21. 21 Australia M. Horrigan, Melbourne Belgium B. de Bruyne & W. Wijns, Aalst Germany R. Erbel & M. Haude, Essen The Netherlands JJRM. Bonnier & J. Koolen, Eindhoven Switzerland F. Eberli & T. Luescher, Zurich P. Erne, Luzern UK C. Di Mario & C. Ilsley, London USA R. Waksman, Washington PROGRESS AMSCenters & Investigators

22. 22 Primary Hypothesis Demonstrate feasibility and safety in the range of currently available bare metal stent systems with a MACE rate after 4 months < 30%. Primary Endpoint MACE at 4 months defined as: Cardiac death Nonfatal myocardial infarction Ischemia driven TLR PROGRESS AMS Hypothesis & Study Endpoint

23. 23 PROGRESS AMSSecondary Endpoints Device success (defined as final diameter stenosis by QCA) Procedure success (defined as final diameter stenosis without in hospital MACE) Process of degradation Late in lesion lumen loss at 4 months (QCA/IVUS) Percent diameter stenosis at 4 months (QCA/IVUS) Binary restenosis at 4 months (QCA/IVUS) MACE at 6 and 12 months TLR at 4, 6, and 12 months TVR at 4, 6, and 12 months

24. 24 PROGRESS AMS Major Inclusion Criteria Patient = 18 years of age Evidence of ischemia (stable or unstable angina, or a positive functional ischemia study) Planned single de novo lesion treatment in a native coronary artery Target vessel 3.0 to 3.5 mm in diameter by visual estimate Lesion length < 15 mm in length Target lesion in a native coronary artery with = 50% and < 100% diameter stenosis Patient has normal baseline CK / CK-MB / Troponin I values

25. 25 PROGRESS AMSDemographics

26. 26 PROGRESS AMSLesion Location/Characteristics

27. 27 PROGRESS AMS Angioplasty Procedure

28. 28 PROGRESS AMSIn Hospital, 30d and 4m events

29. 29 C.R. ? 39 years – RCA

30. 30 AMS: 16-row MSCT Compatible

31. 31 PROGRESS AMSIVUS

32. 32 Results IVUS-analysis PROGRESS AMS

33. 33 PROGRESS AMSTLR rates

34. 34 PROGRESS AMSStudy Conclusions The FIM coronary study showed: Feasibility: High technical and procedural success Safety: no death, no MI, no stent thrombosis The study met the primary endpoint (MACE <30%) Further improvement in stent design, coating and combination with antiproliferative drugs are the focus of the present R&D efforts to further improve efficacy for coronary use  The Absorbable Metal Stent (AMS): The AMS technology platform is proven MRI / CT compatible Absorption was documented with IVUS during FU

35. 35 The Problems: Early recoil Fast degradation Neointima formation The Solutions: Change stent Design Modify the Alloy Load a drug with Bioabsorbable Polymer DREAMS – Drug Eluting Absorbable Metal Stent (AMS)

36. 36 BIOTRONIK DREAMS Pimecrolimus-Eluting Stent System This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)

37. 37 Next generation coronary AMS

38. 38

39. 39 Dose Finding Angiography: Percent Area Stenosis

40. 40 Pimecrolimus Preliminary Results from Pre clinical Studies

41. 41 Future DevelopmentsDrug Eluting Absorbable Metal Stent DREAMS Absorbable Metal Stent Platform Fully absorbable platform Proven biocompatibility throughout the entire absorption process* Effective scaffolding properties** Controlled Drug Eluting Stent Design Precise drug release kinetic and direction Resorbable polymer

42. 42 Safe in human coronaries Safe in peripheral arteries (tibial) Absorbed as intended < 90 days Long term animal studies available No distal embolization, No inflammation Fully compatible with CT or MRI angiography Restenosis mainly due to early recoil and neointima formation New Generations AMS under preclinical testing Status of AMS 2006

43. 43 Thank You