REACT Treatment Rationale and Clinical Evidence. ICI Meeting 5th of December 2017

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1 REACT Treatment Rationale and Clinical Evidence ICI Meeting 5th of December 2017

2 The SFA is a challenging vessel to treat Shortening 23-25%1 Compression > 1kg2 Torsion 60 3 Bending 64 4 SFA, superficial femoral artery.catheter Cardiovasc Interv. 2009;74(5): Jonker et al., Dynamic Forces in SFA/Popliteal Artery During Knee Flexion, Endovascular Today. Buyer s Guide 2009, pp Supinski, G.S. et al. Effect of Diaphragmatic Contraction on Intramuscular Pressure and Vascular Impedance. J Appl Physiol. 1990;68(4): Cheng, C.P. et al. In Vivo MRA Quantification of Axial/Twisting Deformations of the SFA Resulting from Maximum Hip and Knee Flexion. J Vasc Interv Radiol. 2006;17(6): Nikanorov A. et al. Assessment of Self Expanding Nitinol Stent DeformationAfter Chronic Implantation in the SFA. J Vasc Surg. 2008;48(2): Slide modified of K. Deloose

3 Every Lesion is Different. So is the Treatment. POBA is not widely considered as standard of care in treatment of the SFA lesions. The emergence of Drug-Coated Balloons (DCBs) has revolutionized SFA intervention by eliminating or reducing the need for permanent metallic implants. In certain situations stents are also required to support the vessel wall1 e.g. long and/or calcified lesions, flow limiting dissections (FLD) or residual stenosis (RS). What drives treatment choices in daily SFA practice? 1 Scheinert D. Drug-coated balloon treatment for patients with intermittent claudication: new insights from the IN.PACT Global study long lesion ( 15 cm) imaging cohort. EuroPCR 2015.

4 Every Lesion is Different. So is the Treatment. Short/Mid SFA lesion Definitive Treatment DES DCB DCB +/- BMS BMS BMS +/- DCB PTA Covered Stent Other e.g. Atherec

5 Every Lesion is Different. So is the Treatment. Long SFA lesion Definitive Treatment DES DCB DCB +/- BMS BMS BMS +/- DCB PTA Covered Stent Other e.g. Atherec

6 Every Lesion is Different. So is the Treatment. Calcified SFA lesion Definitive Treatment DES DCB DCB +/- BMS BMS BMS +/- DCB PTA Covered Stent Other e.g. Atherec

7 Every Lesion is Different. So is the Treatment. In-stent Restenosis Definitive Treatment DES DCB DCB +/- BMS BMS BMS +/- DCB PTA Covered Stent Other e.g. Atherec

8 There is no treatment consensus for SFA DCB after successful predilation? DES after failed predilatation? DCB + full lesion stenting in case of dissection/elastic recoil? 8 DCB + spot stenting in case of dissection/elastic recoil?

9 REACT to the Vessel Response with Clinically Proven Treatment Options PTA Satisfactory PTA?* Residual stenosis / flow limiting dissection post-pta?* Residual stenosis / flow limiting dissection post-dcb?* Passeo-18 Lux Passeo-18 Lux + Pulsar 18 BIOLUX P-III BIOLUX 4EVER 9 Pulsar-18 BIOFLEX PEACE * Rocha-Singh K, Tepe G, Schneider P, Zeller T. Refining Strategies for the SFA: Consensus Panel SFA Treatment Algorithm, Supplement to Endovascular Today Global, Spring 2014: 11. ** The use of Passeo-18 Lux for post-dilatation is not within the indication for the product. Pulsar-18 + Passeo-18 Lux** DEBAS

10 BIOTRONIK Passeo-18 Lux LUX Coating Technology Passeo-18 Lux SafeGuard Insertion Aid Clinically Proven

11 BIOLUX P-III all-comers global registry to confirm safety and effectiveness for Passeo-18 Lux DCB DESIGN: Prospective, international, multi-center, postmarket all-comers registry to further investigate Passeo-18 Lux paclitaxel releasing balloon catheter Efficacy and Safety in the treatment of atherosclerotic disease of the infrainguinal arteries, with pre-defined subgroups in 700+ patients. PRINCIPAL INVESTIGATOR: Prof. G. Tepe, Klinikum Rosenheim, Germany PRIMARY ENDPOINT: Clinical: Freedom from Major Adverse Events (MAE)1 at 6 months 882 subjects enrolled with de novo or restenotic lesions in the infra-inguinal arteries 700 patients All-Comers Population 6-month Follow-up Death Withdrawals Lost to follow-up Missed Visits N= 555 N= 22 N= 10 N= 9 N= month Follow-up Death Withdrawals Lost to follow-up Missed Visits N= 552 N= 42 N= 24 N= 24 N= months Follow Up Performance: Freedom from clinically-driven TLR2 at 12 months 11 Tepe G., Presented at CIRSE 2017, 12-month All-comers SFA subset 1 MAE Major Adverse Events: 2 TLR Target Lesion Revascularization

12 BIOLUX P-III all-comers SFA Baseline and Lesion Characteristics Baseline Characteristics N = 441 Male (%) 267 (63.1) Age (±SD) 69.3±10.2 Nicotine abuse (%) 325 (76.8) Hypertension (%) 352 (83.2) Diabetes (%) 185 (43.7) Previous PVI / surgeries (%) 234 (55.3) Lesion Characteristics All-Comers SFA N= 494 Lesion length, mm (mean ± SD) 94.2 ± 76.8 BIOLUX P-III is the only Infra-inguinal arteries Real -World Registry : No patient characteristic limitations No lesion characteristic limitations Use of additional devices allowed 47 sites, 16 countries (EU, Australia, Asia) 47.8% 50% 45% 40% 35% 30% Mean ref. vessel diameter mm (mean ± SD) 5.1 ± % 85.8 ± % TASC C lesion (n, %) 80 (16.2) 10% TASC D lesion (n, %) 40 (8.1) 5% Diameter stenosis (%) 30.6% CLI 25% 17.4% 15% 9.5% Calcified lesions moderate and severe (n, %) (41.7) 3.7% 0.5% 1.3% 0%

13 BIOLUX P-III all-comers global registry confirms safety and effectiveness of Passeo-18 Lux DCB in SFA Freedom from clinically driven Target Lesion Revascularization3 84.9% [ ] (365 days) Freedom From cd-tlr (%) Primary Patency Rate Primary Patency1 94.5% [ ] (365 days) Time (days) # Lesions at risk # Events 494 Time (days) # Lesions at risk # Events 494 Key Baseline Characteristics (1) 13 (2) (3) TASC C/D 24.3% CLI 30.6% Calcification 76.5% (41.7% moderate/heavy) Defined as freedom from >50% restenosis in the target lesion as indicated by a duplex ultrasound peak systolic velocity ratio (PSVR) >2.5 or by visual assessment of an angiogram with no clinically driven reintervention DUS not mandated _ KM curve based on last contact date Any re-intervention performed for 50% diameter stenosis (visual estimate) at the target lesion after documentation of recurrent clinical symptoms of the patient adjudicated by an independent CEC Presented by G. Tepe at CIRSE

14 Passeo-18 Lux performs well in perspective with other global registries, even in more complex patients 94.5% 93.9% 87.3% % ftlr [%] Primary Patency[%] % 81.4% 85.4% 30.6% % % 20 20% % 30 11% 8.6% % BIOLUX PIII AllILLUMENATE Interim comers SFA Passeo-18 Global Stellarex Lux 3µg/mm² 2µg/mm² ftlr Bailout Stenting A.L.L. (cm) 94.5% 20.0% % 15.0% 7.2 LUTONIX Global SFA Stellarex 2µg/mm² 94.3% 25.2% 10.1 In.Pact GLOBAL In.Pact Admiral 3.5µg/mm² 91.3% 24.7% Krishnan P. 12-Month Interim Results of ILLUMENATE Global Study with the Stellarex DCB. Oral presentation. NCHV, June Thieme M. Lutonix Global SFA Real-World Registry: 12 Month Outcomes. Oral presentation. TCT, October 11-15, Ansel G. The IN.PACT Global Registry: One-Year Outcomes Using the IN.PACT DCB in an Unrestricted, Real-World Environment. Oral presentation. TCT, October 11-15, 2015 CLI [%] Bailout Stenting [%] 100

15 REACT to the Vessel Response with Clinically Proven Treatment Options with Pulsar-18 PTA Satisfactory PTA?* Residual stenosis / flow limiting dissection post-pta?* Residual stenosis / flow limiting dissection post-dcb?* Passeo-18 Lux Passeo-18 Lux + Pulsar 18 BIOLUX P-III BIOLUX 4EVER 15 Pulsar-18 BIOFLEX PEACE * Rocha-Singh K, Tepe G, Schneider P, Zeller T. Refining Strategies for the SFA: Consensus Panel SFA Treatment Algorithm, Supplement to Endovascular Today Global, Spring 2014: 11. ** The use of Passeo-18 Lux for post-dilatation is not within the indication for the product. Pulsar-18 + Passeo-18 Lux** DEBAS

16 BIOTRONIK Pulsar-18 Thin Struts Pulsar-18 Low COF (Chronic Outward Force) Clinically Proven 16

17 BIOFLEX PEACE all-comers global registry to confirm safety and effectiveness for Pulsar-18 BMS DESIGN: All-Comers registry. Prospective, multicenter, for the treatment of stenosis and occlusion of the superficial femoral artery using the 4F PULSAR 18 stent. PRINCIPAL INVESTIGATOR: Dr. M. Lichtenberg (Arnsberg,DE) PRIMARY ENDPOINT: 6m Major Adverse Event (MAE) rate 12m primary patency SECONDARY ENDPOINT: Primary patency at 6 & 24m FTLR at 6, 12 & 24m 17 BIOFLEX PEACE Nolte-Ernsting C. Presented at CIRSE 2017 * Not for all subjects all measures are available All-Comers Registry 189 Subjects screened BMS (per protocol) Pulsar-18 6-month Follow-up Primary Patency Freedom from TLR MAE Clinical Success N= month Follow-up Primary Patency Freedom from TLR Clinical Success N= 139* 24-months Follow Up N=79*

18 BIOFLEX PEACE all-comers registry Baseline and Lesion Characteristics Baseline Characteristics Male (%) 99 (61.9%) Age (±SD) 69.7 (10.46) Nicotine abuse (%) 115 (71.9%) Hypertension (%) 141 (88.1%) Diabetes (%) 53 (33.1%) Renal insufficiency (%) 31 (19.4%) Lesion Characteristics Lesion length, (cm) (mean ± SD) 18 N = 160 N= ± 10.3 Mean ref. vessel diameter (mm ) (mean ± SD) 4.97 Mean implanted stent diameter (mm) 5.77 TASC C lesion (n, %) 34 (18.3%) TASC D lesion (n, %) 40 (21.5%) Calcified lesions moderate and severe (n, %) 78 (41.9%) BIOFLEX PEACE Nolte-Ernsting C. Presented at CIRSE 2017 * Not for all subjects all measures are available Mean stent oversizing 0.8mm TASC C/D lesions 39.8% Calcified lesions 41.9%

19 BIOFLEX PEACE all-comers global registry confirms safety and effectiveness of Pulsar-18 BMS in SFA Freedom from clinically driven Target Lesion Revascularization 86.2% (365 days) Freedom from cd-tlr (%) Primary Patency Rate Primary Patency* 97.1% (365 days) Time (months) # Patients at risk (n) Survival (%) Time (months) Presented C. Nolte-Ernsting at CIRSE 2017 * Imaging cohort of 127 subject, where duplex data was available # Patients at risk (n) Survival (%)

20 BIOFLEX PEACE 12-months data confirms safety and effectiveness data from previous Pulsar studies ftlr [%] Primary Patency[%] Primary Patency BIOFLEX PEACE 4EVER TASC D TASCD II PEACE BERN 4F Intervention 86.2% 73.4% 77.0% 85.4% 79.5% 61.1% 80.0% 2.9% % % % % % % 8.1 BIOFLEX PEACE Nolte-Ernsting C., Presented at CIRSE 2017, 12-month data; 4EVER Bosiers et al. J Endovasc Ther. 2013;20: ; PEACE Lichtenberg M. JEVT, 2014, 21:373380; BERN Baumann F. JCS 2012:52;475-80; TASC D Lichtenberg M. JCS 2013: 54; 433-9; TASC D II Lichtenberg M. Clin Med Insights 2014: 8; 37-42; 4F Interventions Sarkadi H. et al. Safety, Clinical Outcome and Fracture Rate of Femoropopliteal Stenting Using a 4F Compatible Delivery System. Eur J Vasc Endovasc Surg (2015) 49, TLR A.L.L. (cm) Average Lesion Length [cm]

21 Pulsar-18 performs well in perspective with other BMS and DES global SFA studies ftlr [%] Primary Patency[%] MAJESTIC PP ftlr A.L.L. (cm) ZILVER PTX RCT ZILVER PTX Japan RESILIENT DURABILITY ABSOLUTE 96.1% 96.1% 84.46% 91.6% 84.8% 91.4% 81.3% 87.3% 72.2% 79.1% 63% N/A 86.2% 97.1% BIOFLEX PEACE Nolte-Ernsting C., Presented at CIRSE 2017, 12-month data; MAJESTIC ; ZILVER RCT Dake M, et al JACC 2013; 61: n=236 ZILVER PTX JAPAN Yokoi H, et al JACC 2016 Feb 8 ; 9(3) : RESILIENT Data obtained from product SSED found on n=213 DURABILITY Bosiers M et al J. Endovascular Ther 2009 Jun ; 16(3) : n=151 ABSOLUTE Schillinger et al New England J. Med 2006 May 4 ; 354(18) ; 354(18) : BIOFLEX PEACE Average Lesion Length [cm] 100

22 REACT to the Vessel Response with Clinically Proven Treatment Options with Passe-18 Lux and Pulsar-18 PTA Satisfactory PTA?* Residual stenosis / flow limiting dissection post-pta?* Residual stenosis / flow limiting dissection post-dcb?* Passeo-18 Lux Passeo-18 Lux + Pulsar 18 BIOLUX P-III BIOLUX 4EVER 22 Pulsar-18 BIOFLEX PEACE * Rocha-Singh K, Tepe G, Schneider P, Zeller T. Refining Strategies for the SFA: Consensus Panel SFA Treatment Algorithm, Supplement to Endovascular Today Global, Spring 2014: 11. ** The use of Passeo-18 Lux for post-dilatation is not within the indication for the product. Pulsar-18 + Passeo-18 Lux** DEBAS

23 BIOLUX 4EVER investigated performance of Passeo-18 Lux and Pulsar DESIGN: Physician-Initiated, prospective, multi-center (5), controlled trial Investigating the Efficacy of EV Treatment of Fempop Arterial Stenotic Disease with BIOTRONIK Passeo-18 Lux Drug Releasing Balloon & BIOTRONIK Pulsar-18 Stent. PRINCIPAL INVESTIGATOR: Dr. Marc Bosiers, AZ Sint-Blasius, Dendermonde, Belgium PRIMARY ENDPOINT: Primary patency at 12 months, defined as freedom from >50% restenosis as indicated by an independently verified duplex ultrasound peak systolic velocity ratio (PSVR) <2.5 in the target vessel with no reintervention. SECONDARY ENDPOINT: Primary patency at 6 and 24 months follow-up Freedom from TLR at 6, 12 and 24 months follow-up Changes in ABI measurements at 12 and 24 months follow-up 23 Deloose K., Presented at CX 2017, 12-month data (365 days) 120 Patients, 5 centers in Belgium Passeo-18 Lux & Pulsar-18 per protocol 6-month Follow-up Primary Patency Freedom from TLR N= month Follow-up Primary Patency Freedom from TLR N= months Follow Up N=60

24 BIOLUX 4EVER Baseline and Lesion Characteristics Baseline Characteristics N = 120 Male (%) 79 (65.83) 70.8 ( ±10.5) Age (±SD) Nicotine abuse (%) 73 (60.83) Hypertension (%) 76 (63.33) Diabetes (%) 23 (19.17) Renal insufficiency (%) 15 (12.50) Lesion Characteristics Lesion length, mm (min-max ± SD) N= mm ( ; ±49.49) Ref. vessel diameter mm (min-max ± SD) 5.26 mm ( ; ±0.59) Mean DCB diameter (min max; ±SD) 5.15 mm ( ; ±0.57) Mean stent diameter (min max; ±SD) 5.78 mm ( ; ±0.53) Occlusions (n, %) Calcified lesions (n, %) 24 Deloose K., Presented at CX 2017, 12-month data (365 days) 40 (33.33) 60 (50) Mean stent oversizing 0.5mm Calcified lesions 41.9%

25 BIOLUX 4EVER 12-months data confirms performance of Passeo-18 Lux and Pulsar 25 Freedom from Target Lesion Revascularization Primary Patency 89.9% Time (days) Deloose K., Presented at CX 2017, 12-month data (365 days) Cumulative Freedom From TLR (%) Cumulative Primary Patency Rate Primary Patency (PP) and Target Lesion Revascularization (TLR), 12-month data 93.6% Time (days)

26 REACT to the Vessel Response with Clinically Proven Treatment Options with Pulsar-18 and Passeo-18 Lux PTA Satisfactory PTA?* Residual stenosis / flow limiting dissection post-pta?* Residual stenosis / flow limiting dissection post-dcb?* Passeo-18 Lux Passeo-18 Lux + Pulsar 18 BIOLUX P-III BIOLUX 4EVER 26 Pulsar-18 BIOFLEX PEACE * Rocha-Singh K, Tepe G, Schneider P, Zeller T. Refining Strategies for the SFA: Consensus Panel SFA Treatment Algorithm, Supplement to Endovascular Today Global, Spring 2014: 11. ** The use of Passeo-18 Lux for post-dilatation is not within the indication for the product. Pulsar-18 + Passeo-18 Lux** DEBAS

27 DEBAS investigated if the intentional use of Pulsar and Passeo-18 Lux is safe and effective DESIGN: Physician-Initiated, prospective, multi-center (3), controlled trial Investigating safety and efficacy of BIOTRONIK Pulsar-18/35 Stents combined with BIOTRONIK Passeo-18 Lux Drug Coated Balloon in severe Femoropopliteal Arterial Occlusive Disease. 64 Patients, 3 centers in Perth, Australia Pulsar-18 & Passeo-18 Lux per protocol PRINCIPAL INVESTIGATOR: Dr. Patrice Mwipatayi, Perth, Australia 12-month Follow-up Primary Patency Freedom from TLR PRIMARY ENDPOINT: Primary patency at 12 and 24 months, defined as a PSVR at DUS < 2.5 at the stented target lesion with no clinically-driven reintervention within the stented segment. 24-month Follow-up Primary Patency Freedom from TLR N= 44 N= 44 SECONDARY ENDPOINT: Freedom from stent occlusion at 12 and 24 months Freedom from TLR at 12, 18 and 24 months DEBAS: Mwipatayi P. et al. First-in-man experience of self-expanding nitinol stents combined with drug-coated balloon for the treatment of femoropopliteal occlusive disease. Vascular, Jan 2017 [Epub ahead of print] The use of Passeo-18 Lux for post-dilatation is not within the indication for the product. 27

28 DEBAS Baseline and Lesion Characteristics Baseline Characteristics Male (%) Age (±SD) N = (72.7) / Nicotine abuse (%) 17 (38.6) Hypertension (%) 31 (70.4) Diabetes (%) 24 (54.6) Hyperlipidemia (n,%) 23 (52.3) Lesion Characteristics Lesion length, mm (IQR) Ref. vessel diameter mm (min-max ± SD) TASC C (n,%) N= mm ( ) 6.02 mm +/ (45.1) Complex Lesions 96.1% TASC D (n,%) 26 (51) Calcified lesion, moderate (n, %) 22 (43.1) Calcified lesions, severe (n, %) 12 (23.5) Calcified lesions 66.6% DEBAS: Mwipatayi P. et al. First-in-man experience of self-expanding nitinol stents combined with drug-coated balloon for the treatment of femoropopliteal occlusive disease. 28 Vascular, Jan 2017 [Epub ahead of print] The use of Passeo-18 Lux for post-dilatation is not within the indication for the product.

29 DEBAS data shows that the intentional use of Pulsar and Passeo-18 Lux is safe and effective 94.0% 88.0% 94.0% F Time (months) 12 Months Patients at Risk (n) PP (%) 95% CI (%) % ftlr Primary Patency Primary Patency (PP) and Target Lesion Revascularization (TLR), 12 and 24-month data % Time (months) 24 Months % Months Patients at Risk (n) PP (%) 95% CI (%) % Months % DEBAS: Mwipatayi P. et al. First-in-man experience of self-expanding nitinol stents combined with drug-coated balloon for the treatment of femoropopliteal occlusive disease. Vascular, Jan 2017 [Epub ahead of print] The use of Passeo-18 Lux for post-dilatation is not within the indication for the product.

30 Passeo-18 Lux and Pulsar show excellent clinical outcomes: Individually and in Combination Primary Patency and Freedom from Target Lesion Revascularization (ftlr), 12-month data LL (cm) PSVR (<) ftlr [%] Primary Patency [%] BIOFLEX PEACE SE BMS 4EVER SE BMS 5 BIOLUX P-III² DCB * Data overview for informational purposes only and not for head-to head comparison 1 Deloose K., Presented at CX 2017, 12-month data (365 days) 2 Tepe G., Presented at CIRSE 2017, Primary Patency at 12-months All-Comers SFA subset, (not all patients have 12-month DUS or angio) Freedom from cdtlr, Any re-intervention performed for 50% diameter stenosis (visual estimate) at the target lesion after documentation of recurrent clinical symptoms of the patient 3 BIOLUX4EVER¹ DEBAS Comb Tx 12-Month PP 3 Mwipatayi P. et al. First-in-man experience of self-expanding nitinol stents combined with drug-coated balloon for the treatment of femoropopliteal occlusive disease. Vascular, Jan 2017 [Epub ahead of print]. The use of Passeo18 Lux for post-dilatation is not within the indication for the product. 4 Nolte Ernsting C, Presented at CIRSE 2017, 12-month data 5 Bosiers M. J Endovasc Ther. 2013; 20: Month FTLR

31 Passeo-18 Lux and Pulsar show excellent clinical outcomes when compared to DES Primary Patency and Freedom from Target Lesion Revascularization (ftlr), 12-month data PSVR (<) ftlr [%] < DES SE BMS * Data overview for informational purposes only and not for head-to head comparison 1.Deloose K., Presented at CX 2017, 12-month data (365 days) 2 Tepe G., Presented at CIRSE 2017, Primary Patency at 12-months All-Comers SFA subset, (not all patients have 12-month DUS or angio) 3 Mwipatayi P. et al. First-in-man experience of self-expanding nitinol stents combined with drug-coated balloon for the treatment of femoropopliteal occlusive disease. Vascular, Jan 2017 [Epub ahead of print]. The use of Passeo-18 Lux for post-dilatation is not within the indication for the product. 4 Bosiers M. J Endovasc Ther. 2013; 20: DCB Primary Patency [%] LL (cm) Comb Tx 12-Month PP 5 Nolte-Ernsting C., Presented CIRSE 2017, 12month data 6 PMA P100022: FDA Summary of Safety and Effectiveness Data 7 Hiroyoshi Yokoi, JACC, Volume 9, Issue 3, February Mueller-Huellbeck. S. Presented CIRSE Month FTLR

32 Every Lesion is Different. So is the Treatment. Adding Paclitaxel to BMS is definitely improving primary patency & TLR* BIOLUX P-III and BIOFLEX PEACE confirm safety and efficacy for both Passeo-18 Lux and Pulsar-18 as stand-alone therapy approaches * Combined use of Passeo-18 Lux & Pulsar-18 as shown in BIOLUX 4EVER and DEBAS studies offers similar efficacy outcomes compared to DES data * REACT is more than a combined treatment with Passeo-18 Lux and Pulsar. It is a dynamic therapy approach providing a range of clinically proven treatment options * * REACT approach allows physicians to treat SFA with full-lesion paclitaxel coverage offered by a DCB and either spot or full-lesion stenting, depending on the vessel response to an initial angioplasty, potentially reducing metal burden * * BIOTRONIK clinical evidence does not provide a class effect. Only Passeo-18 Lux and Pulsar Stents have the evidence to support all REACT options * * * BIOLUX 4EVER, presented by K. Deloose at CIRSE 2017 ** REACT CSD 32