disclosure statement consultant for thermopeutix, inc. stockholder of thermopeutix, inc. snowmass...
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Local Drug Delivery —Beyond RestenosisRonald Jay Solar, Ph.D.
San Diego, CA
29th Annual Snowmass Symposium March 9 - 14, 2014
Disclosure Statement
Consultant for ThermopeutiX, Inc.
Stockholder of ThermopeutiX, Inc.
Snowmass 2014
Local Vascular Drug DeliveryDrug Eluting Stents
Drug Coated Balloons
Catheter-directed fluid delivery
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“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
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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
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• 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
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• 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
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Techniques using Local Fluid Drug Delivery may be as (more?) effective,
and overcome the limitations of DES and
DCBSnowmass 2014
Why Fluid Rx Delivery
Atlas of interventional radiology. - C. Cope et al, Gower Medical Publishing, New York, 1990
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DEB
Image from M.Takano, et al, International Journal of Cardiology 2010;141(3): e51–e53Snowmass 2014
G. Tepe, et al. NEJM 2008;358:689-99
Genie Catheter
Vessel segment sizes treated with single use:2.5-3.5 mm diameter; 20-28 mm long
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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;358:689-99Herdeg,et al., CIRC CARDIOVASC INTERV 2009;2:294-301Herdeg, EUROINTERVENTION 2011;7:K11-K16Snowmass 2014
THUNDER-DEB LOCAL TAX-Fluid0
5
10
15
20
25
30
35
40
45
6-Month Binary In-Stent Restenosis
PTXControl
G. Tepe, et al. NEJM 2008;358:689-99Herdeg,et al., CIRC CARDIOVASC INTERV 2009;2:294-301Herdeg, EUROINTERVENTION 2011;7:K11-K16Snowmass 2014
Vessel segment sizes treated with single use:1-4 mm diameter; 10-50 mm long
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• 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
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TAPASTargeted Adjustable Pharmaceutical Administration System
RED: Infusion lumen
Infusion lumen
Radiopaque markers
TAPASTargeted Adjustable Pharmaceutical Administration System
• 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
TAPASTargeted Adjustable Pharmaceutical Administration System
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Paclitaxel Uptake in Arterial Wall
1 hr 3 hr 24 hr 72 hr0
0.5
1
1.5
2
2.5
SeQuent DEB
Tiss
ue C
once
ntra
tion
µg/m
gNon-atherosclerotic
Virmani R. LINC 2012Snowmass 2014
Paclitaxel Uptake in Arterial Wall
1 hr 3 hr 24 hr 72 hr0
0.5
1
1.5
2
2.5
SeQuent DEBTAPAS + Ptx
Tis
sue C
once
ntr
ati
on
µg/m
gNon-atherosclerotic
Virmani R. LINC 2012Shishehbor M. JACC 2012;60:B51Snowmass 2014
Ptx Concentration in Bloodnanograms/ml
5 min 30 min 1 hr 3 hr 24 hrSequent DEB
712.8 7.6 5.1 3.4 1.8
TAPAS + Ptx 2.36 0.55
Virmani R. LINC 2012Shishehbor M. JACC 2012;60:B51Snowmass 2014
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.
Proximalocclusion balloon
Distalocclusion balloon
Proximal radiopaque marker
Distal radiopaque 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
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)
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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
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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.”
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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
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Cilostazol + PaclitaxelComparison 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
Techniques using Local Fluid Drug Delivery may be as (more?) effective,
and overcome the limitations of DES and
DCBSnowmass 2014