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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


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


Coating Morphology Determines Particle Adhesion and Tissue Pharmacokinetics


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


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


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!


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


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


Inflammation Score

73%

36% 34%29% 28%

0%

20%

40%

60%

80%

100%


% 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


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


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


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


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.


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


• 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


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

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