Disclosures. How many people have heard a talk on DCBs? By show of hands, how many people here have used a DCB?

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1 Disclosures Drug Coated Balloons: How they work and what s the evidence? Christopher D. Owens, MD, MSc UCSF vascular surgery I am paid to talk about peripheral interventional procedures by Medtronic and BARD I am director of a physiology laboratory working on drug delivery I am the PI of drug delivery trials, Mercator MedSystems By show of hands, how many people here have used a DCB? How many people have heard a talk on DCBs? 1

2 SFA IDE Trial Results: K-M Patency 100.0% Reported 12 Month Primary Patency K-M 90.0% 80.0% 70.0% 60.0% 83% Drug-Coated 82% 81% Standard Nitinol Stents 77% 50.0% Zilver PTX Stroll Resilient Durability II Stent Zilver PTX Smart LifeStent EverFlex Patient sample size Diabetics (%) Avg. lesion length (cm) Fracture rate (%) Occlusion (%) PSVR Primary Patency by Duplex Ultrasound of Japan Single Arm Study 84.8% Patency was assessed by ultrasound when it was standard of care and is reported for 58% of patients. There were no significant differences in demographics, lesion characteristics, TLR rate, or thrombosis rate compared to patients without ultrasound. Primary Primary Patency Patency (lesions (lesions remaining remaining at at risk) Months risk) Months Japan Japan PMS PMS (PSVR (PSVR 2.4) 2.4) % 96.7% (535) (535) % 84.8% (469) (469) Primary patency rate is 84.8% through 12 months in the Japan PMS 2

3 Similarity between Zilver PTX and DCB How do we know if drugs do anything on devices? The biologic effect of a DES is measured in the proliferative phase of intimal hyperplasia the steep part of the slope. In the beginning there was balloons: Geometry of Claudication interventional RCTs Zilver PTX Medtronic DCB BARD DCB Tigris How they work? FAST Balloon angioplasty 67% restenosis ASTRON Resilient BASIL SURGERY VIBRANT 3

4 DCB technology overview Inpact Admiral Invatec Admiral PTX 3.5 µg/mm 2 Urea Lutonix Lutonix Balloon PTX 2 µg/mm 2 Polysorbate/sorbitol Anti-Proliferative Agent Review Paclitaxel (Cytotoxic) Interferes with cell division Paclitaxel Rapamycin (Cytostatic) Interferes with cell growth Mitosis Protein synthesis. G0 Sirolimus (rapamycin) Cell prepares Cell for prepares mitosis for mitosis DNA synthesis Growth Factor mtor Replication prep DCB mechanism of action facilitates the transfer of PTX deep into vessel tissue Paclitaxel physicochemical properties Paclitaxel is approximately 200,000 times less water soluble than heparin Partitiions into vessel wall rather than blood stream (Creel CJ Circ Res 2000; 86: Enhances cellular uptake and retention for prolonged anti-restenosis effect (Axel D Circulation 1997; 96:636-45) PTX MW = 853 g/mol; Urea MW = 60 g/mol; Sorbitol C 6 H 14 O 6 MW = 182 g/mol (stereoisomer of Mannitol); Polysorbate >1000 g/mol DCB matrix coating: Paclitaxel Urea - excipient that controls drug release DCB inflation: Matrix coating contact with the blood Urea hydrates causing the release of paclitaxel Paclitaxel binds to the wall due to its hydrophobic and lipophilic properties Paclitaxel penetration: Through vessel wall deep into the media and adventitia Interferes with the causes of restenosis Can remain in the vessel wall for over 60 days at therapeutic levels 1 Drug Water Solubility (µg/ml) Heparin 50, PTX Comparison 200,000 times Lipophilicity (octanol/water partition coefficient 4

5 Can a single balloon inflatation produced sustained drug concentrations. Preclinical data supporting safety and long-term Paclitaxel Concentration (ng/mg) Days 200 PTX Concentration (ng/mg) EC Paclitaxel Time [Days] Nominal Dose 3X Safety Margin Dose Porcine IleoFemoral Artery Histology images show sustained retention of low drug levels for extended neointimal inhibition Paclitaxel crystals are released as excipients hydrates Crystals are embedded into arterial wall and sequestered by tissue Sections shown are stained by Hematoxylin & Eosin (H&E) Embedded crystals provide extended drug release to surrounding tissue Detectable levels of drug in tissue over 180 days in both arms (therapy dose and safety margin) SAFETY At 320 days, no quantifiable drug is identified in the targeted tissue area in nominal dose Drug concentration levels in plasma are < 1/10 of that in tissue, drop 50% in 30 minutes, and not detectable after 48 hours Paclitaxel offers a wide therapeutic window % Inhibition of Neointimal Area µg Paclitaxel/mm2 Balloon Surface Therapeutic range 2-4 µg/mm 2 IN.PACT Admiral: 3.5 µg/mm 2 Dose-dependent response up to 2-4 µg/mm 2 Wide, stable therapeutic window with no statistically significant differences in neointimal inhibition or local toxic effects from 4 up to 10 µg/mm 2 Clinically effective drug levels transfer within 60 seconds, with no negative clinical effects from longer inflation time In comparison to PTX doses for oncolological treatment, maximum plasma concentration for IN.PACT is under 1/100th Paclitaxel therapy / disease Dosing (per course) Duration C max (plasma) IV / Ovarian 1ǂ 135 mg/m 2 3 hours 2170 ng/ml IV / Ovarian 1ǂ 175 mg/m 2 3 hours 3650 ng/ml IV / NSCLC mg/m 2 24 hours 195 ng/ml DEB 2 /PAD mg/m 2 60 sec (DEB inflation) 1.6 ng/ml 1. Scheller B, et al. PTX Balloon Coating, a Novel Method for Prevention and Therapy of Restenosis. Circulation. 2004;110: Speck U, Scheller B, Abramjuk C, et al. Neointima inhibition: comparison of effectiveness of nonstent-based local drug delivery and a DES in porcine coronary arteries. Radiology. 2006;240: Cremers B, et al. Comparison of two different PTX-coated balloon catheters in the porcine coronary restenosis model. Clin Res Cardiol. 2009;98: Cremers B, et al DEB: Very short-term exposure and overlapping. Thromb Haemost. 2009; 101: Rowinsky EK, Donehower RC. Paclitaxel (Taxol). N EnglJ Med. 1995;332: Margolis J, McDonald J, Heuser R, et al. Systemic nanoparticle PTX (nab-ptx) for ISR I (SNAPIST-I): A first-inhuman safety and dose-finding study. Clin Cardiol. 2007;30: TAXOL Package Insert BMS Princeton, NJ Rev April IN.PACT Admiral 6x120mm (data on file at Medtronic) 3. Based upon animal studies (data on file at Medtronic) ǂ administered q 3 wks. with a median of six courses 5

6 What is the evidence? DCB clinical evidence INPACT ADMIRAL RCT PTA comparator Single blinded Randomized following successful predil. 78% primary patency Appears safe in claudication Core labs appropriate LUTONIX RCT PTA comparator Double blinded Randomized following successful predil. 74% primary patency Appears safe in claudication Core labs appropriate LEVANT 2 In.Pact SFA LEVANT 2 DCB Data Follow up 30d- 12 mos Treatment assignment Blinded Non - Blinded DCB control DCB control 73.5% Lesion length (mm)* Ca++ (%)** %% Restenosis(%) Provisional stenting (%) B. Restenosis (%) TLR(%)

7 Primary Patency Through 390 Days 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% IN.PACT SFA 12-Month Efficacy Outcomes Primary Patency Kaplan Meier (All ITT) 1 IN.PACT Admiral DCB PTA (P<0.001 by log-rank test) Days After Index Procedure 89.8% Clinically-Driven Target Lesion Revascularization (CD-TL % CD-TLR at 12 Months 15% 66.8% % % 5% 0% P< % IN.PACT Admiral DCB 20.6% PTA Summary of current SFA local drug delivery Cook, Medtronic, and BARD are to be congratulated for advancing the science of drug delivery Each has made clinically meaningful improvements for our patients Our collective consciousness of how to do angioplasty has been raised We are getting better results in our control arms with low bail out stenting 1. Primary patency is defined as freedom from clinically-driven TLR and freedom from restenosis as determined by DUS PSVR Clinically-driven TLR defined as any re-intervention due to symptoms or drop of ABI/TBI of >20% or >0.15 compared to post-procedure ABI/TBI Summary of DCB technology It is difficult to compare the 2 programs BARD has an excellent safety profile still, there is embolization with both devices. My opinion Medtronic has more particles released during transit and BARD may have fewer but larger ones. Both programs provided consistent improvement over PTA. Differences in CD-TLR may be, in part, due to bias inherent in the Medtronic trial design. 7