1. Current Results of Drug Coated Balloons
William A. Gray MD
Director of Endovascular Services
Associate Professor of Clinical Medicine

2. I have no real or apparent conflicts of interest to report.
William A. Gray, MD
I have no real or apparent conflicts of interest to report.

3. The paradox and challenge of the ideal DCB
Simply stated: To fully maintain an antiproliferative agent on a balloon until it is positioned at the lesion and then have all of the intended (metered?) dose leave the balloon and reside completely within the targeted tissue with little if any systemic loss

4. Transfer and maintenance of drug in vessel wall: an order of magnitude
POBA Day 7
Following 60-sec dilatation approximately 10%-15% of the drug is in the vessel wall 40–60 min later.
24 hours later ~10% of drug delivered still resides in vessel wall (1/100 of original dose)
Drug-balloon Day 7
Microtubule staining confirms
sustained presence of paclitaxel
at 1 week
JACC Vol. 35, No. 7, June 2000:1969–76
J Am Coll Cardiol 2003;42:1415–1420.

5. Cotavance™ proposed mechanism of action
Localized vascular retention of Paclitaxel acting as micro “depots” producing sustained local drug delivery.
Source: Biological Concepts and Lessons Learned From the PACCOCATH Technology in Pre-Clinical Animal Models. Juan Granada, EuroPCR May 2010. 4 4

6. DCB inhibits vessel recoil/remodeling
Improved lumen due to:
-Less neoimtima
-Less negative remodeling
7-day histology
A. POBA
B. Drug balloon
JACC Vol. 35, No. 7, June 2000:1969–76

7. Elements of drug-coated balloon systems
Standard
Wrapped configuration
Surface modified
Anti-proliferative
Paclitaxil
‘limus family
Others?
Excipient
iopromide
urea
polymers
nanoparticles

8. Choice of antiproliferative agent for DCB
Ideal properties include:
High lipophilicity resulting in rapid/high absorption
Long-term antiproliferative effects
No local or systemic toxicity
Easily applied to balloon surface
Uniform distribution
Minimal loss with packing, sterilization, shipping, and handling prior to use
Minimal loss on transition through catheter/body and on initial inflation
While most of the data for DEB currently exists with paclitaxel, the ‘limus family of agents possess many of these qualities and may also be suitable

9. Paclitaxel and rapamycin tissue kinetics
PNAS June 22, 2004 vol. 101 no

10. Current DCB paclitaxel dosing
DCBs Balloon Surface Dosing
Product
Paclitaxel (μg/mm2)
Dose on Balloon Surface
Lutonix 2
Paccocath®
(Medrad Interventional) 3
IN.PACT ™ (Invatec/Medtronic)
Dior® -Gen II (EuroCor)

11. First-generation DCB vary by formulation of paclitaxil and excipient
Excipient affects:
Total drug load possible/required on balloon for efficacy
Peak drug dose and drug half-life in arterial wall
Downstream drug loss during balloon transit and inflation
Coating durability and dose uniformity
Paclitaxel is generally preferred in a crystalline form

12. Excipient determines coating characteristics
DCBs may differ in the uniformity of their drug coating
Differences in formulations and manufacturing methods can result in an uneven coating and a less uniform dose delivery

13. Sub-Optimal Excipient
Excipient controls drug release rate
Paclitaxel Arterial
Tissue Levels
Rate of Coating Release
No Excipient
Sub-Optimal Excipient
No Excipient: Release rate too slow resulting in insufficient drug uptake in the vessel. Sub-Optimal Release rate too fast resulting in excessive Excipient: transit drug loss and insufficient drug uptake in tissue

14. Excipient effects drug loss during transit to treatment site
Additive determines drug release during arterial transit:
No release with no additive (far right), but sub- therapeutic tissue uptake (see next slide)
Overly fast release occurs with certain additives (left two), resulting in insufficient drug delivery to the target site
Lutonix formulation optimizes rate of drug release during transit and therapeutic drug levels in target tissue

15. Excipient determines tissue level for any given dose of paclitaxil
Supra-therapeutic, potentially toxic
Sub-therapeutic
Additive is an independent determinant of drug level in target vascular wall tissue
Sub-therapeutic tissue levels in treated arterial segment with no additive (far left)
Levels high with others (far right)

16. Excipient relates to efficacy in pre-clinical non-atherosclerotic coronary overstretch models
Additive is an independent determinant of efficacy in animal models, despite the same dose of drug on balloon surface
Restenosis quantified by late lumen loss at 1 month, normalized by restenosis of plain balloon angioplasty control; i.e., calculated by 1 - [(Late Loss of Control) – (Late Loss of Drug Coated Balloon Formulation)]/(Late Loss of Control).

17. Sample of testing required for DCB’s
Final
Optimized
Formulation
In Vitro Studies
Coating performance
Formulation stability
Manufacturability
In Vivo Studies
Peak drug levels in tissue
Drug half-life in tissue
Transit/Inflation time: dose impact
Particulate analysis
Serum, myocardial and organ
drug levels
Histopathology
Potential Excipients > 225 analyzed
Down-Select
> 250 Formulations
Testing
> 120 Coatings
> 3000 Devices
Lutonix was the first company founded to systematically screen excipients & optimize coating formulation
Theoretical basis for prospective screening:
-- Identification of the best additive formulation is critical to optimizing DCB efficacy and safety
-- Knowledge of mechanism of action should allow improvement over previously studied DCBs
Proprietary Excipient Selected
Very hydrophilic and water soluble, but still has affinity for drug
Upon balloon contact with vessel wall, facilitates tissue uptake by increasing exposure and accelerating drug release and transfer to tissue
Is stable, non-reactive, and safe in humans
41 Pre-Clinical Studies 10 GLP Studies 634 Animals
Courtesy of Lutonix, Inc.
Investigational - CE Mark Pending

18. The following involved with PAD clinical trials using DCB technology will be discussed
Medrad Interventional/Possis
Invatec/Medtronic
Lutonix
EuroCor
Cook
Aachen Resonance Elutax
Biotronik Passeo-18 Lux/Pheron
Caliber Theraputics TADD

19. TLR in patients without prior TLR, amputation or death
DCB (Medrad) clinical trial: femoral-popliteal THUNDER
Long-term follow-up 35
6 months 30
>6-12 months
>12-24 months 25 20 % 15 10 5
TLR in patients without prior TLR, amputation or death
Uncoated BA
Uncoated BA / Paclitaxel contrast
Paccocath

20. DCB (Medrad) clinical trial: femoral-popliteal THUNDER 6 month outcomes

21. Cotavance™/Paccocath® technology Planned Studies
Trial
Design
(all multicenter)
Primary Endpoint
Principle
Investigators
RIVER (US)
Femoral-popliteal (de novo)
Randomized
POBA vs. DCB
12 month binary
restenosis
William Gray
Gary Ansel
CANAL (US)
Infra-popliteal
(de novo)
TBD
COPA CABANA (EU) Femoral-popliteal
(ISR)
12 month LLL
Gunnar Tepe
Euro CANAL (EU)
6 month LLL
12 month AFS
Clinically-driven TLR
Nicolas Diehm
DEFINITIVE AR EU)
atherectomy +DCB
vs. DCB alone
12 month target lesion patency
Thomas Zeller

22. DEFINITIVE AR study: Rationale for Plaque Excision
Incorporation of drug delivery technology as an anti-restenotic treatment while maintaining the unique biomechanical properties of the femoropopliteal tract.
Mechanically re-canalize artery without overstretch
Remove diffusion barrier  better and more effective and homogenous drug uptake
Reduce likelihood of bail-out stenting and preserve native artery architecture

23. Paccocath and DA Pilot Study Histology
Control:
PTX Balloon + stent
Test:
SilverHawk + PTX Balloon
In areas of directional atherectomy, minimal neointimal hyperplasia was noted. The healing response was similar to what has been observed in sirolimus and paclitaxel coated stents pre-clinical work
Source: ev3 internal data; Histology performed by CVPath.

24. Lutonix clinical trials
3 studies fully enrolled: 6 month angiographic follow-up available late 2010
US peripheral IDE beginning near-term
LEVANT I SFA-Popliteal
100-patient prospective randomized study
DCB vs. PTA
PI: Dierk Scheinert
PERVIDEO I Coronary ISR
40-patient prospective single arm
PI: Detlef Mathey and Laura Mauri
De Novo Trial
Coronary
De Novo
24-patient prospective single arm
PI: Patrick Serruys
Completed Studies
Investigational - CE Mark Pending

25. LEVANT I Late Lumen Loss at 6 Months ITT Analysis
Moxy
PTA
Moxy
PTA
Moxy
PTA

26. Levant I Angiographic-based Primary patency Freedom from TLR and > 50% DS
Moxy
PTA
Moxy
PTA
Moxy
PTA

27. Medtronic IN.PACT Drug Eluting Balloon with FreePac™ Coating
Urea ‘Spacer’ Molecule
Paclitaxel Molecule
biocompatible | hydrophilic | naturally-occurring high degree of transfer efficiency
3 Approved Peripheral DEBs
Used to safely & effectively treat thousands of patients since 2009
IN.PACT Amphirion - BtK
IN.PACT Admiral - SFA/Pop
IN.PACT Pacific - SFA/Pop
FreePac ™ Coating
Delivery to vessel wall within seconds
Antirestenotic protection for 28 days
Clinical Program
11 peripheral clinical studies underway

28. (PaccoCath): Porcine Coronary Overstretch Model
FreePAC Technology
Bioequivalence Data
(PaccoCath): Porcine Coronary Overstretch Model

29. (PaccoCath): Porcine Coronary Overstretch Model
FreePAC Technology
Bioequivalence Data
(PaccoCath): Porcine Coronary Overstretch Model

30. Medtronic/IN.PACT PAD Clinical Program
Study PI
Territory
Trial design
1° Endpoint
Status
IN.PACT DEEP
I.Baumgarner
T.Zeller
D.Scheinert
BTK
(CLI)
RCT multicenter EU DEB vs PTA (357 pts)
12m LLL
12m TLR
Enrolling
IN.PACT BTK
Registry Leipzig
(CLI, Claudic.)
Single-arm single center IT(107 pts)
3m Angio Rest. Rate
Completed
DEB BTK IT
Registry
G.Biamino
Single-arm multicenter IT (100 pts)
6m Rest. Rate
DEB SFA IT
SFA
(Claudic, CLI)
Single-arm multicenter IT (108 pts)
6m Patency
Enrollment completed
PACIFIER
M. Werk
(de-novo)
RCT multicenter EU
DEB vs PTA (90 pts)
6m LLL
IN.PACT SFA I
G.Tepe
DEB vs PTA (150 pts)
12m MAE + Primary Patency
ISAR STATH
Ilka Ott,
Max Fusaro
RCT multicenter DE
Stent vs DEB+Stent vs Atherectomy (150 pts)
6m %DS
FAIR
H.Krankenberg
(ISR)
RCT multicenter EU DEB vs PTA (118 pts)
6m DUS Rest. Rate
ISAR PEBIS
RCT multicenter DE DEB vs PTA (60 pts)
IN.PACT SHUNT
P.Pattynama
Hemodialysis Shunts
RCT multicenter EU DEB vs PTA (136 pts)
12m Prim. Patency
upcoming

31. Medtronic: DCB-SFA IT Registry
Preliminary Results 3m 6m
12m
Nr of Patients 89 60
Death
Amputation
TLR
TER 0%
1.1%
2.2%
3.3% 5%

32. N = 91
Werk M et al

34. Eurocor: Iterating the DCB: Artery tissue paclitaxel concentration
µM/L
Dior DEB previous coating
Dior DEB current coating
µM/L

35. Eurocor PAD EU clinical trial plan
Study
Design
Location
Principle Investigator
Freeway Stent Study
Randomized POBA vs. DCB post-stent
SFA-popliteal
Professor Tacke
Freeride
Randomized POBA vs. DEB
Professor Schulte
PACUBA I
SFA-ISR
Professor Lammer

36. Cook DCB: Advance 18PTX Advance 18PTX Balloon Catheter
Nylon balloon/catheter with drug applied directly (no carrier, no polymer).
Drug-coated PTA Balloon Study
Prospective, randomized trial in SFA/popliteal:
Lesions up to 19cm in length
Enrolling up to 150 patients (Germany and Russia)
Primary endpoint
Late lumen loss at 6 months

37. Conclusion
A single-exposure of paclitaxel during balloon angioplasty can be demonstrated to result in both instantaneous and long term drug retention
Via this mechanism, non-stent drug delivery has shown effectiveness in both pre-clinical and clinical settings in peripheral circulation
Delivery mechanisms for antiproliferative agents appear to be important to the biologic efficacy of this therapy, and differ by device/excipient
Current and future clinical trials of DCB in PAD will test both proprietary formulations and adjunct therapies

38. Thank you