Disclosure. I do not have any potential conflict of interest

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1 Disclosure Speaker name: Dr. med. Arne Schwindt... I have the following potential conflicts of interest to report: X Consulting Employment in industry Stockholder of a healthcare company Owner of a healthcare company Other(s) I do not have any potential conflict of interest

2 Drug Coated Balloon outcomes: what part does technology play? Dr. med. Arne Schwindt St. Franziskus-Hospital Münster, Germany

3 Drug Coated Balloons offer physicians an attractive value proposition for the treatment of lower limb disease Encouraging results have been seen in de novo, restenotic lesions, in-stent restenosis, & in A-V access stenosis. Some logical indications might include: no-stent zones e.g. CFA lesions segments prone to restenosis e.g. long AK lesions Benefits Anti-proliferative therapy while leaving nothing behind Broad anatomical applicability Easily repeatable Avoid stent fracture and ISR burden Preserve future options Matches patient s quality of life expectations (improvement in walking capacity, Rutherford class Limitations Not proven in highly calcified lesions majority of RCTs in TASC A and B lesions problem of elastic recoil and dissection is not adressed by DCB When provisional stent is required= higher procedural cost

4 Inhibition of cell proliferation and migration is required for at least 2 weeks after balloon inflation Platelet Aggregation Inflammatory Cells Restenotic Cascade SMC Proliferation SMC Migration ECM Endothelialization 0 2 Days 2 4 Days 4 10 Days Days 2 4 Weeks DCB has to provide PTX effect for at least 14 days to inhibit migration and proliferation Restenotic cascade after DES is prolonged, hence requiring longer drug effect after Ferns et al. Int. J. Exp. Path. 2000; 81: 63 88

5 Passeo-18 Lux delivers sufficient drug to give long lasting therapeutic effect A high tissue concentration is achieved after balloon inflation Drug concentration rapidly declines within 7d Therapeutic effect is sustained beyond 28d Prolonged presence of drug in vessel tissue is important for clinical efficacy Source:. Data on file at BIOTRONIK AG - SFA Porcine model

6 Economic impact of Drug Coated Balloons Per year: DEB c. 90,000 Swiss Fr. less costly than PTA therapy due to lower repeat intervention costs, despite the greater DEB purchase costs 2yr Comparative Budget Impact: German Healthcare Payers. 4'400 4'200 4'000 3'800 3'600 3'400 3'200 PTA BMS DES DEB Reproduced from Zeller T. LINC 2013 DEB dominated all other options by lower lifetime costs and greater effectiveness DEB represents a cost-effective alternative to PTA with bail-out BMS Sources: Zeller. T. LINC 2013, Diehm et al. JEVT 2013;20: , Kearns BC et al. Cost-effectiveness analysis of enhancements to angioplasty for infrainguinal arterial disease. Br J Surg Aug;100(9):1180-8

7 Not all DCBs are equal. Not all DCBs are proven. BIOTRONIK Cook Eurocor Aachen Resonance BARD Medtronic Boston Scientific Cardio novum Device name Passeo-18 LUX Advance PTX Freeway Elutax Lutonix IN.PACT (Admiral, Pacific) Ranger Paclitaxel Drug Concentration 3 µg/mm μg/mm² 2 μg/mm² 3.5 μg/mm² 2 μg/mm² Excipient peel away insertion aid Positive randomized data against PTA 4F compatible * * At least 1 or more sizes Legflow Sources: company web sites Passeo-18 Lux: BIOLUX P-I. Scheinert et al. JEVT Feb In Print Freeway: FREERIDE Schulte KL Poster presentation LINC 2014 Lutonix: LEVANT-I. JACC 2014; 7:10-9 InPact Pacific: PACIFIER 12m data CCI. 2012;5:00-00.

8 DCB clinical study results illustrate performance differences 100% 80% 60% 40% Passeo-18 Lux (3 µg/mm²) 97% 88.5% 84.3% 77% Lutonix (2 µg/mm²) 72% 65.2% 91.4% In.Pact (3.5 µg/mm²) 82.2% 83.7% 59% 20% 0% Study Name BIOLUX P-I Vessels SFA Time-Point 6m BR BIOLUX P-II BTK 6m TLP Myers NSW SFA-ISR 27m PP LEVANT I SFA 6m PP LEVANT II SFA 12m PP PACIFIER SFA 6m BR In.PACT I SFA 12m PP In.PACT Deep BTK 12m PP In.PACT SFA-IT SFA 12m PP What coating technology factors could influence clinical results? Drug Concentration: µg/mm² vs. 2 µg/mm² Excipient: Hydrophobic vs. hydrophilic

9 Passeo-18 Lux DCB combines proven technologies Coating: PTX Drug 3 µg/ mm² Butyryl-Tri Hexcyl Citrate (BTHC) Platform SafeGuard Insertion aid Improves ease of handling Protects the user and balloon from contact and damage Passeo-18 Balloon Ø: 3-7mm L: mm

10 Excipients improve tissue uptake of Paclitaxel Tissue Concentration PTX Only PTX + Iopromide (SeQuent) Blood Concentration ng/ml ng/ml min 30 min 1 hr 3 hrs 24 hrs hr 24 hrs 72 hrs 5 min 30 min 1 hr 3 hrs 24hrs Non-atherosclerotic Rabbit Iliac Model 28 days PTX only PTX + Iopromide D Source: Virmani, presented at Linc 2012

11 Lux coating technology uses BTHC excipient Biocompatible, safe and effective Excipient Butyryl-Trihexyl Citrate (BTHC) Characteristics BTHC is hydrophobic and less dissolvable in blood and saline/water used during interventional procedures compared to other common hydrophilic excipients Common uses of BTHC Metabolism Used in medical devices & cosmetics Additive in blood bags to keep the crystalline structure of the plastic malleable Safe: it is approved to be dissolved into the blood and used in the body Quickly metabolized by the body and excreted via urine, bile and expired air¹ Degrades to citric acid and alcohol (n-hexanol¹) 1 European Commission SCENIHR Report Feb 2008

12 BTHC fulfills the requirements of an ideal excipient for DCB applications BTHC in the Lux formulation allows to balance good coating adhesion to the balloon surface and rapid drug delivery upon vessel contact BTHC assures micro-crystalline Paclitaxel structure in Lux formulation for optimal tissue absorption and retention Lux formulation with BTHC is safe and biocompatible

13 Coating technology: PTX concentration strongly influences total drug load Drug Concentration Label Claim Drug Content Normalized Surface of a 5x40mm balloon 4,0 3000,0 μg/mm 2 3,0 2,0 1,0 μg 2000,0 1000,0 0,0 Passeo-18 Lux Lutonix 035 In.Pact Admiral 0,0 Passeo-18 Lux Lutonix 035 In.Pact Admiral 3 μg/mm 2 2 μg/mm μg/mm 2 3 μg/mm 2 2 μg/mm μg/mm 2 PTX concentration of 3 μg/mm 2 may result in more drug available at the lesion site Safety profile was assessed in animal studies 1 and is confirmed in human clinical trials 2 Safety and efficacy of 3 μg/mm 2 technologies is also supported by long term evidence in coronary and peripheral applications 3 Source: 1. Data on file at BIOTRONIK AG 2. BIOLUX P-I 12m Scheinert D. presented at TCT 2013; InPact Pacific: PACIFIER 12m data CCI. 2012;5: Tepe et al. THUNDER N Engl J Med 2008; Werk et al. FEMPAC Circulation. 2008; Paccocath 5y Scheller B. J. Am. Coll. Cardiol. Intv. 2012;5;

14 Coating Technology: Excipient behaviour Simulated use of a 5mm x 40mm DCB in physiological solution at 37 C 97.1% 74.2% 88.4% Device Excipient Type Solubility * Passeo-18 Lux Butyryl-tri-hexyl citrate (BTHC) Hydrophobic Very low IN.PACT Urea Hydrophilic * In water Fast dissolving Lutonix Polysorbate/sorbitol Hydrophilic/hydrophobic Fast dissolving Coating characteristics are modified when surface is wetted Hydrophilic excipients are more soluble and degrade faster Hydrophobic excipients are less soluble and have reduced drug loss in physiological environments Source: Data on file at BIOTRONIK AG

15 Coating technology: Drug loss Simulated use of a 5mm x 40mm DCB in physiological solution at 37 C 51.5% 87.9% 46.2% 1130 µg 148 µg 1438 µg Drug loss during track is normal and expected. Drug release at the lesion site mandates coating fragility to ensure coating leaves the balloon surface. However, remaining PTX quantity should be sufficient to have a therapeutic effect. DCBs with 3 μg/mm 2 appear to retain higher quantities of PTX after track and inflation Source: Data on file at BIOTRONIK AG

16 Coating Technology: influencing clinical outcomes 6m Binary Restenosis rates (%) 1130 µg 148 µg 1438 µg *Study device in Pacifier was Medtronic In.Pact Pacific, which uses the same coating technology as the In.Pact Admiral A correlation between drug availability seen in vitro testing 1 and reported clinical data 2,3,4 can be observed DCBs with higher PTX concentration (3-3.5 µg/mm 2) may create higher drug availability at the lesion site, despite coating losses during track/inflation.. Source: 1. Data on file at BIOTRONIK AG 2. BIOLUX P-I 12m Scheinert D. presented at TCT 2013; 3, InPact Pacific: PACIFIER 12m data CCI. 2012;5: LEVANT-I: Scheinert et al.: JACC: Cardiovasc Interv. 2014; 7(1): 10-19

17 Lux in-vivo testing : The quantity of Paclitaxel reaching the lesion was optimal to have a therapeutic effect. Additional drug quantity had no additional effect. IN-VIVO RESULTS: 6m Follow Up PTA Passeo-18 Lux x 1 Single dose: Therapeutic effect evidence- reduced Neointimal-Hyperplasia vs. PTA control Passeo-18 Lux x 2 Double-dosing with second DCB had no additional therapeutic or toxic effect. Source: Data on file at BIOTRONIK AG

18 Passeo-18 Lux Clinical Program Evidence Collection Study Study Design Safety Performance Core lab. All-Comers SFA Popliteal BTK AV Access Calc. Long lesions ISR Vessel Prep. TASC C& D PROs Scheinert DE FIM RCT: SFA Passeo-18 Lux vs. PTA 60 subjects JEVT to be published Feb 2015 Zeller DE FIM RCT: Infrapopliteal Passeo-18 Lux vs. PTA 72 subjects JEVT planned submission Jan 2015 Tepe DE All-Comers Registry Passeo-18 Lux 700 subjects Satellites Bosiers BE Registries Passeo-18 Lux per Satellite Single-arm, SFA Passeo-18 Lux+Pulsar subjects Terasse CA RCT, AV Fistula Passeo-18 Lux vs. PTA 120 subjects Mwipatayi AU Single-centre Pulsar-18 +Passeo-18 Lux 100 subjects Myers AU Robertson AU Retrospective Registries Passeo-18 Lux in ISR 55 & 29 subjects

19 BIOLUX P-III All-comers registry Study Design DESIGN: Prospective, international, multi-centre, open label, all-comers registry to expand and understand the safety and efficacy data on the Passeo-18 Lux DRB in a real world population with infrainguinal artery disease. PRINCIPAL INVESTIGATOR: Prof. Gunnar Tepe, Rosenheim (DE) PRIMARY ENDPOINT: Freedom from clinically-driven TLR within 12 months post-index procedure. SECONDARY ENDPOINTS: (selected) Freedom from clinically-driven TLR within 24 months post-index procedure Primary patency at 12 and 24 months MAE at 6, 12 and 24 months Quality of Life (QOL) assessment: Pain scale, SF-12, WIQ at 6, 12 and 24 months. 600 patients at ca. 55 clinical sites EU & APAC First patient inclusion: Q4/2014 Passeo-18 Lux 6 months: MAE, change in ABI, RC 12 months: freedom from TLR, primary patency, MAE, change in ABI 24 months: freedom from TLR, primary patency, MAE, change in ABI

20 CONCLUSIONS Drug loss during in-vitro testing seems to correlate with reported clinical data DCBs with higher PTX concentration (3-3.5 µg/mm 2) may create higher drug availability at the lesion site, despite coating losses during track/inflation. Coating characteristics are modified when DCBs are exposed to aqueous environments Therefore, due to differences coating technology all DCBs should be evaluated based on clinical evidence- no class effect can be concluded

21 CONCLUSIONS Drug loss during in-vitro testing seems to correlate with reported clinical data DCBs with higher PTX concentration (3-3.5 µg/mm 2) may create higher drug availability at the lesion site, despite coating losses during track/inflation. Coating characteristics are modified when DCBs are exposed to aqueous environments Therefore, due to differences coating technology all DCBs should be evaluated based on clinical evidence- no class effect can be concluded