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

Snowmass 2014

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

Snowmass 2014

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