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TCT | October 2017 | The Science Behind the Outcomes | DC00074047
DCB From a Pre-Clinical Perspective: The Relevance of
Paclitaxel Dose and Coating Integrity
Juan Granada, MDPresident and CEO
Cardiovascular Research Foundation
Columbia University Medical Center, New York
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
Disclosure Statement of Financial Interest
Within the past 12 months, the Skirball Center for Innovation have
received grants and research support with the organization(s) listed
below:
Grant/Research Support: Abbott Vascular, Amaranth Medical, Amber
Medical, Amgen, Baylis, BIO2 Medical, Bristol-Myers, Boston Scientific,
Cagent Vascular, Caliber Therapeutics, Cephea, Columbia Medical,
Corindus Vascular, Celyad, Freudenberg Medical, Intact Vascular,
JenaValve, Keystone Heart, LimFlow Medical, LoneStar Heart, Marvel
Medical, Medtronic, Meril Life Sciences, MicroVention, Motus GI,
Navigate Cardiac Structures, New York University, OrbusNeich Medical,
SoundBite Medical, Spectranetics, Toray Industries, Vetex Medical,
Volcano (Philips), Zimmer Biomet
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
Coating Morphology Determines Particle Adhesion and Tissue Pharmacokinetics
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
Paclitaxel Particle Microstructure Affects Drug Tissue Residence
0
100
200
300
400
500
0 50 100 150 200Cum
ula
tive
PT
x R
ele
ase
(µ
g)
Time (min)
Crystalline Transpax™
Amorphous Transpax™
Particle Micro-Structure and In Vitro Dissolution Rates
0 8 1 6 2 4
0
2 5
5 0
7 5
1 0 0
H o u r s
% D
ru
g D
iss
olu
tio
n*
I N . P A C T
L u t o n i x
* D e r i v e d p e r c e n t a g e v a lu e s c o n s t r a in e d b y 0 a n d 1 0 0
Granada JF, et al. Open Heart 2014
Crystalline
Amorphous
Particle Micro-Structure and Paclitaxel Tissue Levels
Gongora CA. JACC Cardiovasc Interv. 2015
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
Paclitaxel Tissue Levels Variations in
Drug Coated Balloon Technologies
0
10
20
30
40
50
60
70
80
4 hours 1 Day 7 Day 21 Day 30 Day 45 Day 60 Day
Paclit
axel Levels
(ng/m
g)
Ranger DCB
In.Pact Admiral DCB
Lutonix DCB
0
5
10
15
20
25
30
35
4 hours 1 Day 7 Day 21 Day30 Day45 Day60 Day
Paclit
axel Levels
(ng/m
g)
Ranger DCB
In.Pact Admiral DCB
Lutonix DCB
∆ T
issu
e L
evels
Gongora CA. JACC Cardiov. Interv. 2015 Jul;8(8):1115-23
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
Impact of Paclitaxel Balloon Dose in Neointimal Proliferation and Restenosis
Granada JF. JACC Cardiovascular Interventions Oct 2012
COTAVANCE-MEDRAD
Dose Response Study
Reduction in %AS
• SFA, ISR-model
• High-cholesterol swine
• 1-µg/mm2: 13.2% (p=0.5) vs. PTA
• 3-µg/mm2: 26% (p<0.04) vs. PTA
50%
Biological efficacy of DCB depends on both
Paclitaxel concentration and particle solubility profile!
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
Comparative Impact of Dosing on
Neointimal Proliferation and Restenosis
SHORT TERM Effect (28-Days)
Gongora CA et al. J Am Coll Cardiol Intv. 2015;8:1115-23.
2.0 μg/mm23.5 μg/mm22.0 μg/mm2
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
SHORT TERM (28-Days) Restenosis Rates
of Different Clinically Available DCB
0,00
1,00
2,00
3,00
4,00
PTA Stellarex Lutonix Passeo IN.PACT
Injury Score
0,00
1,00
2,00
3,00
4,00
PTA Stellarex Lutonix Passeo IN.PACT
Inflammation Score
73%
36% 34%29% 28%
0%
20%
40%
60%
80%
100%
PTA Stellarex Lutonix Passeo IN.PACT
% Area Stenosis
Ste
llare
xP
TA
L
uto
nix
Passeo
-Lu
x
IN.P
AC
T
0,54
2,20 2,23 2,342,50
0,00
1,00
2,00
3,00
4,00
PTA Stellarex Lutonix Passeo IN.PACT
Fibrin Score
P<0.001P=0.01
P<0.001
P= NSP= NS
Data Courtesy of Cheng YP. Skirball Center for Innovation 2017
During the first year, the anti-restenotic effect of most
DCB technologies is expected to be comparable
ISR Model in the Familial Hypercholesterolemic Swine
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
Impact of Dose in Long-Term Paclitaxel
Tissue Levels (Sustained Drug Availability)
1,2Data on file with Medtronic; Study PS767
Healthy Porcine Arterial Model1
Higher input drug concentration facilitates
higher long-term tissue concentrations
In-Stent Restenosis Porcine Arterial Model2
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
Ste
llare
xIN
.PA
CT
Ste
llare
xIN
.PA
CT
Pre-DCB 60 Days 90 Days
8,03 8,4012,84 14,82
11,25 13,85
0
5
10
15
20
25
Stellarex IN.PACTA
rea
(m
m²)
Lumen Area by OCT
Pre-DCB Post-DCB 60 Days Post-DCB 90 Days
61% 58%51% 42%56% 46%
0%
20%
40%
60%
80%
100%
Stellarex IN.PACT
Area Stenosis by OCT
Δ= 1.59 (12%)Δ = 0.97 (7%)
P=0.03
90-Days Restenosis Prevention Following
DCB Treatment in Swine Model of SFA-ISR
Δ +5% Δ +4%
Data Courtesy of Cheng YP. Skirball Center for Innovation 2017
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
DCB Coating Integrity and Particulate
Coating Stability
Particulate Formation
Acute Drug Transfer
Acute Drug Transfer
In.Pact Pacific™ 6X40
(3μg/mm²)
Ranger™ 6X40
(2μg/mm²)
Lutonix Moxy™ 6X40
(2μg/mm²)
DCBs were delivered in a peripheral track model with fluid recirculation. Particulates lost downstream were
collected with a 5µm polycarbonate filter and are shown as green dots. Fluid recirculation ~320 ml/min; Fluid temp 37°C
Gongora CA, et al. JACC Cardiovasc Intv. July 2015.
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
Major Adverse Clinical Events
In FDA-Approved DCBs
1. Rosenfield K, et al. N Engl J Med 2015;373:145-53.
2. Presented by Laurich C, SVS, Chicago, USA 2015.
3. Tepe G, et al. Circ 2015;131:495-502.
4. Presented by Jaff MR, VIVA, Las Vegas, USA 2016..
5. Presented by Brodmann M, AMP, Chicago, USA 2016.
6. Stellarex Instructions for Use; IFU No. P011966-C Rev 07/2017.
7. Presented by Zeller T, LINC, Leipzig, Germany 2017. One major amputation reported, but
total number of subjects evaluated at 12 months for this endpoint is unavailable.
LEVANT II1 Global2 IN.PACT SFA3
Global
Clinical
Cohort4 EU RCT5 US Pivotal6 Global7
PTA Lutonix 035 PTA IN.PACT Admiral PTA Stellarex PTA Stellarex Stellarex
Subjects 160 316 691 111 220 1406 72 222 100 200 371
All Thrombosis 3.7% (4/107) 1.4%
(3/207)
2.9%
(38/1311)
0.0%
(0/95)
1.1%
(2/189)
Revasc. due to
Thrombosis
0.7%
(1/140)
0.4%
(1/285)
1.3% (8/634)
Major Amputation 0.0%
(0/140)
0.3%
(1/286)
0.5% (3/635) 0.0% (0/107) 0.0%
(0/207)
0.2%
(3/1311)
0.0%
(0/60)
0.0%
(0/204)
0.0%
(0/95)
0.0%
(0/189)
17
12-Month Reported Thrombosis and Major Amputation Rates
Distal downstream particle embolization does not seem
to impact thrombosis or amputation rates in RCT
TCT | October 2017 | The Science Behind the Outcomes | DC00074047
• RCTs have proven the clinical performance and the
mechanisms of action (and failure) of DCBs in the SFA
territory
• Not only paclitaxel dosing but also particle solubility are
important technological drivers to achieve long-term
suppression of restenosis
• In lower-dose DCBs, paclitaxel particle solubility is
particularly key to achieve long term-clinical success
• Particulate embolization does not seem to affect
thrombosis or amputation rates in RCT
• The ability to maintain a sustained biological response
over time (restenosis prevention) will be the main driver
of clinical success in the field of DCBs
Conclusions
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