2. Disclosure Statement Consultant for ThermopeutiX, Inc. Stockholder of ThermopeutiX, Inc. Snowmass 2014

3. Local Vascular Drug Delivery  Drug Eluting Stents  Drug Coated Balloons  Catheter-directed fluid delivery Snowmass 2014

4. “This will certainly be a major area of continuous discussion throughout the course. Clearly with the evolution of drug-eluting balloon technology and all the related endovascular techniques, it’s a really important concept that we try to bring into practice.” ‘Leaving nothing behind’ marks a new mantra for intervention Dierk Scheinert (Park Hospital and Heart Center, Leipzig, Germany) in LINC TODAY Jan.24, 2013 Snowmass 2014

5. Drug Coated Balloons German Consensus Group recommendations for coronary applications* −BMS ISR (Class IIa, Level B), small vessels, bifurcations THUNDER**, FEMPAC***, and many other subsequent trials positive for PVD *Kleber, et al, EuroIntervention 2011;7(Suppl. K):125-28 **G. Tepe, et al. NEJM 2008;358:689-99 ***M. Werk, et al, Circulation 2008;118:1358-1365 Snowmass 2014

6. Only one drug available Only one dose available Drug remains in systemic circulation Fixed length and diameter Very expensive— multiple catheters required Coatings present multiple technological and regulatory challenges and concerns Limitations of Coated Balloons Snowmass 2014

7. Only one drug available Only one dose available Drug remains in systemic circulation Fixed length and diameter Very expensive— multiple catheters required Coatings present multiple technological and regulatory challenges and concerns Limitations of Coated Balloons Snowmass 2014

8. Techniques using may be as (more?) effective, and overcome the limitations of DES and DCB Techniques using Local Fluid Drug Delivery may be as (more?) effective, and overcome the limitations of DES and DCB Snowmass 2014

9. Why Fluid Rx Delivery Atlas of interventional radiology. - C. Cope et al, Gower Medical Publishing, New York, 1990 Snowmass 2014

10. DEB Image from M.Takano, et al, International Journal of Cardiology 2010;141(3): e51–e53 Snowmass 2014

12. G. Tepe, et al. NEJM 2008;358:689-99

13. Genie Catheter Vessel segment sizes treated with single use: 2.5-3.5 mm diameter; 20-28 mm long Snowmass 2014

14. LOCAL TAX vs THUNDER Different vessels — coronary vs. fem-pop Similar exposure times — 2 vs. 1 min. Much lower PTX dose —.0082 vs 4.7 mg Similar LLL and RR 2 CM G. Tepe, et al. NEJM 2008;358:689-99 Herdeg,et al., CIRC CARDIOVASC INTERV 2009;2:294- 301 Herdeg, EUROINTERVENTION 2011;7:K11-K16 Snowmass 2014

15. G. Tepe, et al. NEJM 2008;358:689-99 Herdeg,et al., CIRC CARDIOVASC INTERV 2009;2:294- 301 Herdeg, EUROINTERVENTION 2011;7:K11-K16 Snowmass 2014

16. Vessel segment sizes treated with single use: 1-4 mm diameter; 10-50 mm long Snowmass 2014

17. Latif F, Hennebry TA, Successful revascularization of re- stenosis of lower extremity arteries with localized delivery of paclitaxel. Cathet Cardiovasc Intervent. 2008;72:294-298 Local Paclitaxel Delivery for SFA Disease (IRRITAX). www.clinicaltrials.gov; Identifier: NCT00821028;updated Aug.2, 2011 ClearWay Catheter Snowmass 2014

18. TAPAS Targeted Adjustable Pharmaceutical Administration System RED: Infusion lumen Radiopaque markers

19. TAPAS Targeted Adjustable Pharmaceutical Administration System

20. Dual catheter system incorporating occlusion balloons Adjustable treatment length, up to 300mm Removal of drug post treatment — “Infuse and Remove” Allows sequential treatment of multiple vascular segments and vessels — only 1 device/patient Drug choices upon discretion of physician; variety of applications — restenosis, thrombus management, chemotherapy, etc. FDA cleared, CE Mark TAPAS Targeted Adjustable Pharmaceutical Administration System Snowmass 2014

21. Paclitaxel Uptake in Arterial Wall Non-atherosclerotic Virmani R. LINC 2012 Snowmass 2014

22. Paclitaxel Uptake in Arterial Wall Non-atherosclerotic Virmani R. LINC 2012 Shishehbor M. JACC 2012;60:B51 Snowmass 2014

23. Ptx Concentration in Blood nanograms/ml 5 min30 min1 hr3 hr24 hr Sequent DEB 712.87.65.13.41.8 TAPAS + Ptx2.360.55 Virmani R. LINC 2012 Shishehbor M. JACC 2012;60:B51 Snowmass 2014

24. Proximal SFA Proximal Balloon Distal Balloon Drug solution infusion Distal SFA Proximal Balloon Distal Balloon Drug solution infusion Mid SFA Proximal Balloon Distal Balloon Drug solution infusion CASE 1: 79-year-old male presented with rest pain in the left leg, and a history of diabetes, hypertension and smoking. A single TAPAS Catheter delivered paclitaxel to 3 discrete segments of the left superficial femoral artery following atherectomy. Paclitaxel was mixed with a 50% solution of contrast media and saline to a final drug concentration of 3mg/ml. Drug dwell time at each segment was 1 minute. After each infusion, the paclitaxel was aspirated from the vessel. Images courtesy of Dr. Luigi Steffanon, Hesperia Hospital, Modena, Italy.

25. Proximal occlusion balloon Distal occlusion balloon Proximal radiopaqu e marker Distal radiopaqu e marker 5 minute infusion of paclitaxel + contrast in a 150 mm segment of fem-pop in-stent restenosis Courtesy of Dr. Eric Dippel, Bettendorf, IA

26. TAPAS Clinical Experience Post-market surveillance analysis —87 cases 9 drugs in 5 different clinical applications -Thrombus management (glycoprotein IIb/IIIa inhibitors and lytics) -Sclerotherapy (Atossisclerol) -Prostrate cancer (Abraxane) -Restenosis prevention (paclitaxel and tacrolimus) Snowmass 2014

27. Images courtesy of Dr. Paolo Gazzo, Hospital Santa Corona, Pietra Ligure, Italy Sclerosing agent + contrast media is introduced TAPAS ® positioned in spermatic vein from femoral vein access After removing drug from first site, TAPAS ® is repositioned at a second treatment site TAPAS ® in Venous Disease — delivery of Atossisclerol 2% + contrast Snowmass 2014

28. Future Directions Renu Virmani (CVPath Institute, Gaithersburg, Maryland) in LINC TODAY Jan.24, 2013 “I don’t think there’s going to be one perfect solution for everyone because it just never works that way. We are quite different from one another, so we all need different kinds of treatments, and I think that’s what’s going to continue.” Snowmass 2014

29. Future Directions with Local (Fluid) Drug Delivery Targeted Rx selection and dosing -Patient/subset specific; DM, ISR, “frequent fliers” New drugs and applications -TAPAS as a tool to facilitate investigation; can study just the drug Drug combos Snowmass 2014

30. Cilostazol + Paclitaxel Comparison of Dual Drug-Eluting Cilotax Stent and Paclitaxel-Eluting Taxus Liberte Stent in Native Coronary Artery Lesions; Whan Lee C, Park DW, Seung KB, Kim PJ, Park HJ, Kim WJ, Lee JY, Kang SJ, Lee SH, Kim YH, Park SW, Park SJ; American Journal of Cardiology (Feb 2011) “…..In-stent late loss was significantly lower in the Cilotax than in the Taxus Liberte group (0.22 ± 0.31 vs 0.50 ± 0.55 mm, p = 0.002). Although in- segment restenosis rate did not differ significantly between the 2 groups (3.8% vs 10.9%, respectively, p = 0.271), in-stent restenosis rate was significantly lower in the Cilotax stent group (0% vs 10.9%, p = 0.027).” Snowmass 2014

31. Techniques using may be as (more?) effective, and overcome the limitations of DES and DCB Techniques using Local Fluid Drug Delivery may be as (more?) effective, and overcome the limitations of DES and DCB Snowmass 2014