4/17/2015 Disclosures • I am paid to talk about peripheral interventional procedures by Medtronic and BARD Drug Coated Balloons: • I am director of a physiology laboratory How they work and what’s working on drug delivery the evidence? • I am the PI of drug delivery trials, Mercator MedSystems Christopher D. Owens, MD, MSc UCSF vascular surgery By show of hands, how many How many people have heard a people here have used a DCB? talk on DCBs? 1
4/17/2015 SFA IDE Trial Results: K-M Patency 100.0% Reported 12 Month Primary Patency K-M 90.0% 83% 82% 81% 77% 80.0% Drug-Coated 70.0% Standard Nitinol Stents 60.0% 50.0% Stent Zilver PTX Zilver PTX Smart Stroll LifeStent Resilient EverFlex Durability II Patient sample size 236 250 134 287 Diabetics (%) 49 47 38 43 Avg. lesion length 5.4 7.7 7.1 8.9 (cm) Fracture rate (%) 0.9 1.8 3.1 0.4 Occlusion (%) 27 24 17 48 PSVR 2.0 2.5 2.5 2.0 6 6 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 Patency Primary Patency (lesions remaining at risk) (lesions remaining at risk) Months Months Japan PMS Japan PMS (PSVR 2.4) (PSVR 2.4) 6 96.7% (535) 6 96.7% (535) 12 84.8% (469) 12 84.8% (469) Primary patency rate is 84.8% through 12 months in the Japan PMS 2
4/17/2015 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 How they work? Medtronic Zilver BARD DCB PTX DCB Tigris FAST Balloon angioplasty ASTRON 67% restenosis Resilient BASIL VIBRANT SURGERY 3
4/17/2015 Anti-Proliferative Agent DCB technology overview Review Inpact Admiral Lutonix • Invatec Admiral • Lutonix Balloon Rapamycin (Cytostatic) Paclitaxel (Cytotoxic) Interferes with cell division Interferes with cell growth • PTX 2 µ g/mm 2 • PTX 3.5 µ g/mm 2 • Polysorbate/sorbitol • Urea G 0 Paclitaxel Mitosis Protein Mitosis Protein synthesis synthesis. Sirolimus (rapamycin) Growth mTOR Cell prepares Cell DNA DNA Replication prep Factor for mitosis prepares synthesis synthesis for mitosis DCB mechanism of action facilitates Paclitaxel physicochemical properties the transfer of PTX deep into vessel • Paclitaxel is approximately 200,000 times less water soluble than tissue heparin • Partitiions into vessel wall rather than blood stream (Creel CJ Circ Res 2000; 86:879-84 • 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 Drug Water Solubility Lipophilicity ( µ g/mL) (octanol/water partition coefficient DCB inflation: DCB matrix coating: Paclitaxel penetration: Heparin 50,000 10 -13 • • • Paclitaxel Matrix coating contact Through vessel wall deep into • PTX 0.25 10 3 Urea - excipient that with the blood the media and adventitia • • controls drug release Urea hydrates causing the Interferes with the causes of Comparison 200,000 times 10 16 release of paclitaxel restenosis • • Paclitaxel binds to the wall Can remain in the vessel wall due to its hydrophobic and for over 60 days at lipophilic properties therapeutic levels 1 4
4/17/2015 Histology images show sustained Can a single balloon inflatation produced sustained drug retention of low drug levels for extended concentrations. Preclinical data supporting safety and long-term neointimal inhibition 10 Paclitaxel Concentration (ng/mg) PTX Concentration 80 1 (ng/mg) Crystals are 60 Embedded crystals embedded into 0.1 Paclitaxel crystals are provide extended released as excipients arterial wall and drug release to 0.01 hydrates 40 sequestered by EC Paclitaxel surrounding tissue 50 tissue 0.001 60 90 120 150 180 20 Time [Days] Nominal Dose Porcine IleoFemoral Artery 0 3X Safety Margin Dose 0 50 100 150 200 Sections shown are stained by Days Hematoxylin & Eosin (H&E) • Detectable levels of drug in tissue over 180 days in both arms (therapy dose and safety margin) • 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 after 48 hours Paclitaxel offers a wide therapeutic window In comparison to PTX doses for oncolological treatment, maximum plasma concentration for IN.PACT is under 1/100th • Dose-dependent response up to 2-4 100 µg/mm 2 % Inhibition of Neointimal Area 90 80 70 Paclitaxel Dosing • Wide, stable therapeutic window with no Duration C max (plasma) 60 therapy / disease (per course) 50 statistically significant differences in 40 neointimal inhibition or local toxic effects IV / Ovarian 1 ǂ 135 mg/m 2 3 hours 2170 ng/mL 30 from 4 up to 10 µg/mm 2 20 IV / Ovarian 1 ǂ 175 mg/m 2 3 hours 3650 ng/mL 10 0 IV / NSCLC 1 135 mg/m 2 • Clinically effective drug levels transfer 24 hours 195 ng/mL 0 2 4 6 8 10 within 60 seconds, with no negative µ g Paclitaxel/mm2 Balloon Surface DEB 2 /PAD 3 4.8 mg/m 2 60 sec (DEB inflation) 1.6 ng/mL clinical effects from longer inflation time Therapeutic range 2-4 µ g/mm 2 IN.PACT Admiral: 3.5 µ g/mm 2 1. Scheller B, et al. PTX Balloon Coating, a Novel Method for Prevention and Therapy of Restenosis. Circulation . 2004;110:810-814. 2. Speck U, Scheller B, Abramjuk C, 1. TAXOL Package Insert BMS Princeton, NJ Rev April 2011 et al. Neointima inhibition: comparison of effectiveness of nonstent-based local drug delivery and a DES in porcine coronary arteries. Radiology . 2006;240:411– 418. 2. IN.PACT Admiral 6x120mm (data on file at Medtronic) 3. Cremers B, et al. Comparison of two different PTX-coated balloon catheters in the porcine coronary restenosis model. Clin Res Cardiol . 2009;98:325– 3. Based upon animal studies (data on file at Medtronic) 330. 4. Cremers B, et al DEB: Very short-term exposure and overlapping. Thromb Haemost . 2009; 101: 201–206. 5. Rowinsky EK, Donehower RC. Paclitaxel ǂ administered q 3 wks. with a median of six courses (Taxol). N Engl J Med . 1995;332:1004-1014. 6. Margolis J, McDonald J, Heuser R, et al. Systemic nanoparticle PTX (nab-PTX) for ISR I (SNAPIST-I): A first-in- human safety and dose-finding study. Clin Cardiol. 2007;30:165-170 5
4/17/2015 What is the evidence? DCB clinical evidence INPACT ADMIRAL LUTONIX • RCT • RCT • PTA comparator • PTA comparator • Single blinded • Double blinded • Randomized following • Randomized following successful predil. successful predil. • 78% primary patency • 74% primary patency • Appears safe in • Appears safe in claudication claudication • Core labs appropriate • Core labs appropriate LEVANT 2 DCB Data LEVANT 2 In.Pact SFA Follow up 30d- Blinded Non - Blinded 12 mos Treatment DCB control DCB control 73.5% assignment 56.8%% Lesion length 6.3 6.4 8.9 8.8 (mm)* Ca++ (%)** 10.4 8.1 8.1 6.2 Restenosis(%) 16 12 5 5.4 Provisional 2.5 6.9 7.3 12.6 stenting (%) B. Restenosis 26 43 18 48 (%) TLR(%) 11 15 2.4 21 6
4/17/2015 IN.PACT SFA 12-Month Efficacy Summary of current SFA local drug delivery Outcomes • Cook, Medtronic, and BARD are to be Primary Patency Kaplan Meier (All ITT) 1 Clinically-Driven Target Lesion Revascularization (CD-TL congratulated for advancing the science of drug 100% 89.8% 25% P <0.001 90% 20.6% delivery Primary Patency Through 390 Days 78.4 20% 80% CD-TLR at 12 Months 70% • Each has made clinically meaningful 60% 15% improvements for our patients 50% 66.8% ( P< 0.001 by log-rank test) 49.5 40% 10% 30% • Our collective consciousness of how to do 20% 5% IN.PACT Admiral DCB 2.4% angioplasty has been raised 10% PTA 0% 0% – We are getting better results in our control 0 30 60 90 120 150 180 210 240 270 300 330 360 390 IN.PACT Admiral DCB PTA 360 Days After Index Procedure 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 ≤2.4 2. 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
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