The Pantera Lux Paclitaxel DEB Device Description and Clinical Studies. Christoph Hehrlein, University Clinic Freiburg i.br.

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1 The Pantera Lux Paclitaxel DEB Device Description and Clinical Studies Christoph Hehrlein, University Clinic Freiburg i.br. Germany

2 Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Grant/Research Support Grant/Research Support Grant/Research Support Company Medtronic Cordis BIOTRONIK

3 Introducing the Pantera Lux DEB from BIOTRONIK A combination of known and novel technologies Balloon Pantera (semi-compliant) Excellent deliverability and crossability Paclitaxel (3.0 µg/mm 2 ) Tested thoroughly in animal studies Showed high safety and a trend towards better efficacy compared to competitor products Drug Anti-proliferative, lipophilic and allow fast absorption Pre-clinical show high safety & efficacy Excipient Butyryl-tri-hexyl citrate (BTHC) Keeps paclitaxel in micro-crystalline structure for optimal bioavailability Pantera Lux is a potentially highly efficacious solution for treating in-stent restenosis, available in diameters mm and lengths mm. Product is CE marked. Not for sale in the U.S.

4 Matrix Coating Pure paclitaxel Excipient: Butyryl-tri-hexyl + = citrate (BTHC) Matrix coating Matrix coating: guarantees Guarantees a high bioavailability of paclitaxel on the target side for rapid drug absorption by the vessel wall keeps Keeps the paclitaxel in a microcrystalline structure which is easily absorbable BTHC: degrades Degrades to citric acid and alcohol also Also used as additive in blood bags to keep the crystalline structure of the plastic malleable

5 Overview of comprehensive pre-clinical work with Pantera Lux Model Pharmacokinetic Balloon only First DEB then stent First stent then DEB ISR model Result High starting concentration and decrease over time. In the beginning less drug in tissue compared to Paccocath, later more Subtle drug effect, safe Some drug effect, safe Pronounced drug effect, safe Moderate drug effect, safe Safety was proven in all models Drug effect is seen in most models Comparison to other commercial products revealed similar or improved drug effect Data on file at BIOTRONIK AG

6 Pharmacokinetics of Pantera Lux Paclitaxel µg/g tissue min 2h 8h 1d 2d 7d N = 6 N = 6 N = 8 N = 6 N = 6 N = 6 Time after balloon dilatation (days) Data on file at BIOTRONIK AG

7 QCA values from pig coronary arteries [%] First stent, then balloon Diameter Stenosis at 28 days Median Values POBA n = 11 Pantera Lux n = 11 Elutax n = 11 SeQuent Please n = 10 Data on file at BIOTRONIK AG

8 Clinical Overview

9 Paclitaxel REleasing Balloon in Patients PresEnting with In-Stent Restenosis (PEPPER)- FIM Study Design DESIGN: Prospective, multi-centre, non-randomized, European clinical trial of the Pantera Lux Paclitaxel Releasing Balloon* OBJECTIVE: To evaluate the safety and efficacy of the Pantera Lux in patients with in-stent restenosis in coronary arteries PRINCIPAL INVESTIGATOR: Prof. Hehrlein, University Medical Center Freiburg, Germany 81 patients enrolled between August 2009 and February 2010 in 9 clinical sites in Germany, Poland and Denmark 81 patients treated with the Pantera Lux Paclitaxel Eluting Balloon Clinical follow-up at 1 month Clinical & QCA follow-up at 6 months Clinical follow-up at 12 months * Decice not for sale in the US.

10 Study Endpoints Primary Endpoint Late Lumen Loss (in-stent) at 6 month follow-up Secondary Endpoints In-seg. LLL, % diameter restenosis, binary restenosis at 6 months Cumulative MACE* rate at 1, 6 and 12 months Type of reoccurrence according to Mehran classification Device & technical success * Composite of cardiac death, non-fatal MI, clinically driven TLR, clinically driven TVR

11 Inclusion/Exclusion Major Inclusion Criteria Patients with a single restenotic lesion in a previously stented area of a coronary artery (irrelevant whether BMS or DES related) Target reference vessel diameter (visual estimation): 2-4 mm Target lesion length (visual estimation): 8 28 mm Target lesion stenosis (visual estimation): 50% - < 100% Major Exclusion Criteria Myocardial infarction (STEMI/NSTEMI) within 72 hours of the intended treatment Additional coronary lesions (restenotic or de novo) in the same vessel which requires treatment Totally occluded coronary artery (Mehran classification IV and TIMI flow 0)

12 Site Investigator Country Patients Herz-Kreislauf Zentrum, Bad Segeberg Prof. G. Richardt Germany 20 Universitätsklinikum, Freiburg Prof. C. Hehrlein Germany 14 Herz-Diabetes Zentrum, Bad Oeynhausen Enrolment completed as of April Dr. M. Wiemer Germany 12 Universitätsklinik, Rostock Dr. H. Schneider Germany 10 University Hospital, Poznan Dr. M. Lesiak Poland 7 Elisabethkrankenhaus, Essen PD Dr. C. Naber Germany 6 Rigshospitalet, Kopenhagen Dr. E. Joergensen Denmark 5 Herzzentrum München-Bogenhausen Prof. E. Hoffmann Germany 5 University Hospital, Bydgoszcz Prof. J. Kubica Poland 2 TOTAL 81 Results presented are from the first 45 German patients

13 First 45 German patients Baseline (n=45) Medical history / risk factors N = 45 Hypercholesterolemia 93.3 % Hypertension 86.7 % History of MI 66.7 % Diabetes 20.0 % Renal disease 17.8 % Respiratory disease 15.6 % Congestive Heart Failure 11.1 % History of stroke / TIA 6.7 % History of smoking 6.7 % Hepatic disease 2.2 % Multiple answers possible % Distribution of ISR according to Mehran by stent type ISR distribution by stent type: BMS DES IA IB IC ID II III IV* BMS 53.3% *IV = Exclusion Criteria DES 46.7%

14 All angiographic data has been evaluated by an independent core lab (Prof. Dietz, Wiesbaden) First 45 German patients Results Procedural success 6-month clinical follow-up N = 45 Device success 100 % N = 39 1 MACE 7.7 % Cardiac death 0.0 % MI (non-fatal) 2.6 % TLR (clinically driven) 2.6 % TVR (clinically driven) 2.6 % 6-month angiographic follow-up DES ISR BMS ISR N = 34 2 N = 16 N = 18 LLL (in-stent) 0.03 ± 0.35 mm 0.15 ± 0.28 mm ± 0.37 mm LLL (in-segment) ± 0.27 mm ± 0.27 mm ± 0.28 mm 1 1 pt. withdrew consent; 1 pt. died; 4 pts. scheduled but late for follow-up 2 3 pts. without angio (refused/not done), 2 pts. with pending angio analysis

15 First 45 German patients Results Comparison of primary endpoint result at 6 months to literature data Late Lumen Loss - in stent (Mean +/- SD) 0.80 PEPPER N = 34 IN.PACT CORO ISR N = 19, Scheller EuroPCR 2010 PACCOCATH ISR I/II N = 47, Scheller et al. Clin Res Cardiol 2008;97:773 PEPCAD II N = 66, Unverdorben et al. Circulation 2009;119:2986 mm

16 Case 1: Procedure 70 year male, previous MI, DES ISR in Cx (Mehran class IC), treated with 3.0/25mm Pantera Lux, symptom-free at 6 month follow-up 90% ISR Pre-dilatation Longer + larger DEB

17 Case 1: Acute result and follow-up 70 year male, previous MI, DES ISR in Cx (Mehran class IC), treated with 3.0/25mm Pantera Lux, symptom-free at 6 month follow-up Acute PCI result 6-month follow-up

18 Drug REleasing Pantera LUX PTCA Balloon Catheter Registry (DELUX) Design DESIGN: Prospective, multi-centre, nonrandomized, international, clinical registry with follow-up at 1, 6 and 12 months PRINCIPAL INVESTIGATOR: Ralph Tölg, Bad Segeberg, Germany Up to 600 patients in sites in Europe, Middle East and North America Patients treated with the Pantera Lux Paclitaxel Eluting Balloon Clinical follow-up at 1 month PRIMARY ENDPOINT: MACE at 6 months (Death, non-fatal MI, clinically driven TVR) SECONDARY ENDPOINTS: MACE at 1 & 12 months; clinically driven TVR at 1, 6 and 12 months and cute success (clinical device & clinical procedure success) Clinical follow-up at 6 months Clinical follow-up at 12 months Patients Enrolled* 228 * As of 20 September 2010.

19 Conclusions The 6-month results of the first 45 German patients from the PEPPER trial show excellent in-stent and in-segment LLL Pantera Lux clinical data shows effective reduction of neointimal hyperplasia for the treatment of ISR, regardless of stent type Final results of all 81 European PEPPER patients to be presented soon Potentially other promising indications for DEB will be studied in DELUX registry