What is the Data for DCB in BTK & What Next? Prof. Thomas Zeller Department Angiology University Heart-Center Freiburg - Bad Krozingen Bad Krozingen , Germany

Faculty Disclosure Thomas Zeller, MD For the 12 months preceding this presentation, I disclose the following types of financial relationships: Honoraria received from: Abbott Vascular, Bard Peripheral Vascular, Veryan, Biotronik, Boston Scientific Corp., Cook Medical, Cordis Corp., Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme Consulted for: Abbott Vascular, Bard Peripheral Vascular, Boston Scientific Corp., Cook Medical, Gore & Associates, Medtronic, Spectranetics Research, clinical trial, or drug study funds received from: 480 biomedical, Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Cordis Corp., Gore & Associates, Abbott Vascular, Medtronic, Spectranetics, Terumo, TriReme, Volcano

Most DCBs have shown a biologic effect in femoro-popliteal lesions 6-month Late Lumen Loss from 8 DCB Technologies Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwälder U, Beregi JP, Claussen CD, Oldenburg A, Scheller B, Speck U. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008 Feb 14;358(7):689-99 Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hosten N, Hamm B, Speck U, Ricke J. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation. 2008 Sep 23;118(13):1358-65 Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, Tepe G, Naisbitt S, Rosenfield K. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014 Jan;7(1):10-9 Scheinert D, Schulte KL, Zeller T, Lammer J, Tepe G. Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient: twelve-month results from the BIOLUX P-I randomized trial. J Endovasc Ther. 2015 Feb;22(1):14-21 Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, Eschenbach G, Hartmann H, Lange C, Schnorr B, Stiepani H, Zoccai GB, Hänninen EL. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv. 2012 Dec;5(6):831-40 D.Scheinert - Advance 18 PTX Study - LINC 2013 oral presentation Schroeder H, Meyer DR, Lux B, Ruecker F, Martorana M, Duda S. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study. Catheter Cardiovasc Interv. 2015 Aug;86(2):278-86 T.Albrecht – Preliminary angiographic and clinical 6-month results of the CONSEQUENT trial - LINC 2016 oral presentation W.Guo - AcoArt I First Prospective, Randomized, Multicenter Clinical Trial for the Use of the Orchid DCB in Femoropopliteal Artery Disease - LINC 2016 oral presentation

Evidence from DEB Trials Long-term Freedom from TLR Significant and sustained TLR reduction up to 5 years FEMPAC 2Y THUNDER 5Y

Context view: 4 RCTs, 3 DCBs 1-year Primary Patency Complex Patient Population similar patient characteristics p=0.002 p<0.001 p<0.001 p<0.001 PTA PTA PTA PTA Stellarex (ptx 2 µg/mm2) In.Pact (ptx 3.5 µg/mm2) Lutonix (ptx 2 µg/mm2) * Corelab adjudicated (VascCore Core laboratory - Boston, MA, USA) Duplex derived Primary Patency based on 2.5 PSVR threshold. ‡ evaluated @ day 365; † evaluated @ day 360 S.Lyden - ILLUMENATE Pivotal Stellarex DCB IDE Study 12-month Results - oral presentation, TCT 2016 M.Brodmann - ILLUMENATE European Randomized Clinical Trial: 12-month Final Results from the Stellarex DCB – oral presentation, AMP 2016 Tepe G et al. IN.PACT SFA Trial Investigators.. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015 + G.Tepe, Charing Cross 2014 oral presentation + P. Krishnan, DCB show superior 3-year outcomes vs. PTA: results from In.Pact SFA randomized trial - oral presentation, VIVA 2016 K.Rosenfield et al. Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. N Engl J Med 2015

DCB are not yet indicated in clinical routine in BTK lesions Further Research needed! Why?

Conflicting Evidence DEBATE BTK vs. IN.PACT Deep Journal of the American College of Cardiology 2014. 64;15:1568-76 Drug-Eluting Balloon Versus Standard Balloon Angioplasty for Infrapopliteal Arterial Revascularization in Critical Limb Ischemia 12 Month Results From the IN.PACT DEEP Randomized Trial Thomas Zeller, Iris Baumgartner, Dierk Scheinert, Marianne Brodmann, Marc Bosiers, Antonio Micari, Patrick Peeters, Frank Vermassen, Mario Landini, David B. Snead, K. Craig Kent, Krishna J. Rocha-Singh, IN.PACT DEEP Trial Investigators Circulation Drug-Eluting Balloon in peripherAl inTErvention for Below The Knee Angioplasty Evaluation (DEBATE-BTK): A Randomized Trial in Diabetic Patients with Critical Limb Ischemia Single-Center Randomized Trial 132 Patients CLI: 100%, Diabetes: 100% Average lesion length: 13 cm CTO: 80% IN.PACT™ Amphirion™ vs. PTA ™ Liistro F et al. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation. 2013 Aug 6;128(6):615-21 T. Zeller LINC 2014 & Zeller et al. JACC 2014

Binary Restenosis (BR) and Clinically Driven TLR (CD-TLR) IN.PACT Deep 12-month Freedom from Major Amputation, Binary Restenosis Rate, TLR Rate & LLL 12-month Binary Restenosis (BR) and Clinically Driven TLR (CD-TLR) 12-month Late Lumen Loss 0.605 ± 0.775 0.616 ± 0.781 Zeller T. et al. JACC 2014

DCB-BTK - Negative Evidence: BIOLUX P II 72-patients (CLI + IC) RCT of Passeo-18 Lux vs. PTA 12-month CD-TLR Rates: 30.1% (DCB) vs. 30.6% (PTA) (p=0.805) 12-month Loss of Primary Patency 49.2% (DCB) vs. 45.6% (PTA) (p=0.908) Event Rate: TLR Lesions 0.0% 20% 40% 60% 80% 100% Time to Event (days) 365 uncoated DRB Event Rate: Patency loss 0.0% 20% 40% 60% 80% 100% Time to Event (days) 365 uncoated DCB Amputation target extremity Major 8/ 23.7 [12.6,42.0] 1/ 3.3[0.5,21.4] 9/ 25.8 [ 14.3, 43.9] 2/ 5.6 [1.4,20.7] 0.975 0.631 Zeller T et al., JACC CCI 2015

DCB-BTK Evidence: DCB vs. DES 50-patients (CLI + IC) RCT of IN.PACT Amphirion vs. DES Lesion length: 14.8 (DCB) vs. 12.7 (DES) (p=0.330) Key findings (DCB vs. DES) at 6-month: Binary restenosis: 58% vs. 28% (p=0.0457) LLL: 1.35±0.2 vs. 1.15±0.3 (p=0.62) >50% restenosis length (cm): 4.3±1.6 vs. 3.6±1.5 (p=0.16) TLR: 14.3% vs. 7.4 (p=0.21) (P.M. Kitrou, MD, PhD – CIRSE 2013, LINC 2014)

Why do we need dCb in btk interventions?

In CLI most BTK lesions are longer than 10cm Bare metal stents did fail to show a benefit over PTA

Ferraresi R, LINC 2016

In CLI most BTK lesions are longer than 10cm Bare metal stents did fail to show a benefit over PTA No dedicated DES for BTK use are yet commercially available and clinically tested Appropriate length, at least 8cm for balloon expandable stents Drug eluting nitinol stents not yet tested below the knee Are stents the right choice for long distant BTK lesions extending to the foot? DCB are the optimal treatment tool for long BTK lesions an din particular foot arteries

NO DCB Class Effect?! results awaited IN.PACT DEEP failure applies to IN.PACT Amphirion only. Each DCB stands on the merits of its own data 480-patient RCT of Lutonix DCB vs. PTA in BTK-CLI results awaited Marianne Brodmann LINC 2014

DCB in BTK Interventions What next? Is paclitaxel the right drug for BTK interventions?

Paclitaxel Eluting DES vs PTA/BMS Below the knee Paclitaxel Eluting DES vs PTA/BMS PADI CLI: PTA±BMS vs DES for infrapopliteal lesions Multi-center randomized two-arm study 136 patients with 144 limbs CLI, Rutherford 4-6 De novo stenoses or occlusions below knee joint Vessel diameter 2-6 mm, length ≤ 90 mm PTA±BMS or paclitaxel-DES (Taxus Liberté) Heparin, Aspirin, Clopidogrel Overhagen et al. Circ Cardiovasc Interv 2016

DCB in BTK Interventions What next? Is paclitaxel the right drug for BTK interventions? “Limus” eluting DCB might become the appropriate solution for long BTK lesions.

Below the knee DES vs PTA/BMS Systematic Review of infrapopliteal DES: A meta-analysis of randomized controlled trials 3 RCTs with 501 patients Achilles: DES vs PTA in CLI & IC, n=200 Destiny: DES vs BMS in CLI, n=140 Yukon-BTX: DES vs BMS in CLI & IC, n=161 Relatively short and focal infrapopliteal lesions InfraPop: Meta-Analysis of RCT Results at 1 year DES PTA/BMS P= Primary Patency 80.0% 58.8% <0.0001 Rutherford class improvement 79.0% 69.6% 0.045 Wound healing 76.8% 59.7% 0.04 TLR 9.9% 22.0% 0.001 Event-free survival 72.2% 57.3% Survival 85.5% 86.6% 0.75 Amputation 6.4% 10.8% 0.11 Katsanos K et al, Cardiovasc Intervent Radiol 2013

Sirolimus Coated Balloon – Selution Use of micro-reservoirs made out of biodegradable polymer intermixed with Sirolimus Controlled and sustained drug release Long-term distribution of Sirolimus into tissue to maintain therapeutic levels Novel Cell Adherent Technology – CAT™ Minimizes wash-off during insertion, tracking and lesion crossing Optimizes drug transfer to tissue during short-term balloon dilatation © M.A. Med Alliance – 2016

Med Alliance SELUTION™ – PK Study Source: Med Alliance – PK Study (2014-004) / Bard – Catheterization and Cardiovascular Interventions 83:132–140 (2014) / Medtronic – Presentation Melder (LINC 2012).

DCB in BTK Interventions What next? Is paclitaxel the right drug for BTK interventions? “Limus” eluting DCB might become the appropriate solution for long BTK lesions. The vessel preparation prior to DCB angioplasty might solve the problem of early recoil as one potential failure mode of paclitaxel releasing DCB

Early Recoil After Balloon Angioplasty of Tibial Artery Obstructions in Patients With Critical Limb Ischemia Frederic Baumann, MD; Jacqueline Fust; Rolf Peter Engelberger, MD; Ulrike Hügel, MD; Do-Dai Do, MD; Torsten Willenberg, MD; Iris Baumgartner, MD; Nicolas Diehm, MD. 1Department of Clinical and Interventional Angiology, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, Switzerland. 2Department of Internal Medicine, Inselspital, University Hospital of Bern, Switzerland. 3Department of General and Orthopedic Surgery, Hospital of Münsterlingen, Switzerland. Baumann et al. J Endovasc Ther February 2014 vol. 21 no. 1 44-51

Results: Author’s Conclusions: Elastic recoil: 29/30 patients (97%) Mean luminal compromise: 29% Acute lumen gain: 1.77 mm (2.00 mm - 0.23 mm) Subacute lumen loss (15 min.): 0.53 mm (2.00 mm - 1.47 mm) Author’s Conclusions: Early recoil is frequently observed in CLI patients undergoing tibial angioplasty and may significantly contribute to restenosis. These findings support the role of dedicated mechanical scaffolding approaches for the prevention of restenosis in tibial arteries. Baumann et al. J Endovasc Ther February 2014 vol. 21 no. 1 44-51

Prospective, randomized, multicentric study Atherectomy and Drug-Coated Balloon Angioplasty in Treatment of Long Infrapopliteal Lesions (ADCAT-Study) Atherectomy (Turbohawk, Medtronic) and paclitaxel-coated balloon angioplasty (Lutonix14, Bard) for treatment of long atherosclerotic BTK lesions   Prospective, randomized, multicentric study

Combination Therapy OPTIMIZE BTK1 Multicenter, randomized (atherectomy+DCB vs. DCB) Target N = 50 at up to 10 EU sites RCC 3-5, BTK lesions Diamondback (CSI) + 0.014” DCB Primary Endpoints: Technical success (< 50% residual stenosis without significant angiographic complications Procedural success (achievement of technical success for all target lesions treated during the index procedure) Device success (successful delivery and deployment of the DCB to the target lesion as described IFU) Treatment success (percentage of target lesions meeting technical success with <30% residual stenosis post DCB angioplasty without the use post-adjunctive treatments) Estimated target completion date: June 2018 Clinicaltrials.gov record NCT02561299. https://www.clinicaltrials.gov/ct2/show/NCT02561299?term=cardiovascular+systems+atherectomy&rank=11

We Know… Not all lesions are the same Above the Knee1 Below the Knee1 Mixed morphology (multiple plaque types & thrombus) Medium to large vessels (4 - 9 mm) Lesions more commonly calcified Tortuous, challenging anatomy Small vessels (1.5 - 3.5 mm) 1. VIVA 2011 survey – 100 physicians surveyed. 2. Bishop et al. Ann Vasc Surg. 2008;22:799-805

DCB in BTK Interventions Summary The combination of atherectomy and DCB should be considered in calcified BTK lesions To reduce friction To reduce recoil To potentially improve drug uptake / wall persistence Alternative antiproliferative drugs such as “limus” drugs should be explored Alternative ways of applying the drug to the adventia (Bullfrog, LIMBO study, dexamethasone)