The Relevance of Paclitaxel Dose and Coating for Efficacy and Safety

Renu Virmani, MD

CVPath Institute, Inc.

Gaithersburg, Maryland, USA

Potential conflicts of interest

Speaker's name: Renu Virmani, MD I have the following potential conflicts of interest to report: Consultant: 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. Employment in industry: No Honorarium: 480 Biomedical, Abbott Vascular, Boston Scientific, Cordis J&J, Lutonix, Medtronic, Merck, Terumo Corporation, and W.L. Gore. Institutional grant/research support: 480 Biomedical, Abbott Vascular, Atrium, BioSensors International, Biotronik, Boston Scientific, Cordis J&J, GSK, Kona, Medtronic, MicroPort Medical, CeloNova, OrbusNeich Medical, ReCore, SINO Medical Technology, Terumo Corporation, and W.L. Gore. Owner of a healthcare company: No Stockholder of a healthcare company: No

Requirements For DCB

• Must deliver large quantities of the drug within seconds

• Must distribute within the media in the first few days

• Therapeutic drug levels must be maintained for at least several weeks

• Must allow rapid healing as compared to DES

• No need for long-term anticoagulation

• Light microscopy must show biologic effects at 28-days at least

Device Company Coating Drug dose (µg/mm2)

CE mark*

Advance 18 PTX™ Cook Medical, Bloomington, IN, USA Paclitaxel 3.0 Yes

Cotavance® Bayer Schering Pharma AG, Berlin, Germany Paclitaxel–iopromide 3.0 Yes

Freeway™ Eurocor, Bonn, Germany Paclitaxel–shellac 3.0 Yes

IN.PACT™ Admiral, Amphirion, Pacific

Medtronic Vascular, Santa Clara, CA, USA Paclitaxel–urea 3.0 Yes

Lutonix DCB® (Moxy) BARD, Murray Hill, NJ, USA Paclitaxel–polysorbate/sorbitol 2.0 Yes

Legflow® Cardionovum, Warsaw, Poland Paclitaxel–shellac 3.0 Yes

Passeo-18 Lux® Biotronik, Bülach, Switzerland Paclitaxel–butyryl-tri-hexyl citrate 3.0 No → Yes

Stellarex® Covidien, Mansfield, MA, USA Paclitaxel 2.0 No → Yes

* Lutonix DCB® and IN.PACT™ are currently approved by the FDA for clinical use in USA.

In.Pact

ELUTAX

Sequent Please

Pantera Lux

SurModics

Moxy

Drug coated balloon devices (Peripheral artery)

Byrne RA, Joner M. et al. Nat Rev Cardiol. 2014;11:13-23

Immunofluorescence micrographs showing the

effect of 1.0 μmol/L paclitaxel on cytoplasmic

microtubule distribution.

Immunofluorescence micrographs demonstrating the

effect of 1.0 μmol/L paclitaxel on the distribution of the

contractile filament smooth muscle α-actin and the

intermediate filament vimentin in haSMCs.

a-actin

vimentin

Anti-b-tubulin

The effect of nonstop incubation

with 1.0 μmol/L paclitaxel

on haSMC morphology.

Paclitaxel

Control

Paclitaxel-treated cultures, cell numbers are reduced.

haSMCs are smaller and discoid with a loss of tail .

Axel D I et al. Circulation 1997;96:636-645

disarrangement of α-actin bundles with

partial circumferential orientation α-actin filaments predominantly orientated

along the cell axis

changes of cell shape and size

Cells smaller, ellipsoid, and show an unorganized, decentralized

tubulin distribution

Parameters that distinguish DCB from DES

DES DCB

Drug concentration on the device

Low 5-10 μg/mm

Very High 2-3 μg/mm2 (≒20-30 μg/mm)

Drug transfer at the time of deployment

Slow Rapid, all at once

Reservoir of drug Polymer No (excipient important)

Drug retention in tissues Short term Need a drug which binds to cell membranes and is easily transferable to adjacent cells

Diffusion Good Excellent

Lipophilic yes Even better

Active ingridient Not necessary Should be active immediately

DES

DCB

Histologic Parameters for Evaluation of DCB Safety/Efficacy

• Key parameters include:

– Endothelial Loss

– Fibrin/Platelets

– Inflammation

– Injury

– Medial Smooth Muscle Cell Loss

– Matrix Replacement:

• Proteoglycan

• Collagen

– Adventitial Fibrosis

Fibrin

SMC loss

Proteoglycan

Drug deliver of DEB

Unpublished Data; Pharmakokinetic and Histologic Response to a Paclitaxel Eluting Balloon (Sponsor: Kaneka Corporation) in 2009

Histology images: Nakano M, et al. Cardiology Today's Intervention 2012;1:10-11

Coating Integrity is Variable

Lutonix Catheter

PTX PTX in coating

after aqueous exposure

PTX Adherence to Balloon: iopromide versus urea coating

Kelsch et al. Invest Radiol. 2011;46:255-263

* p=0.002 ** through a blood-filled hemostatic valve and guiding catheter and 1min in stirred blood *** not released during expansion in a coronary artery

Split-off during dry inflation

Loss during

passage**

Remnant on balloon after deflation ***

Paclitaxel uptake in the Arterial Wall

600 500 400 300 200 100 0

Iopromide matrix coating

Urea matrix coating

Paclitaxel uptake in arterial wall 15-25 minutes Post stent implantation (n= 6 arteries each)

Kellsch B, et al. Investigative Radiology 2011;46(4):255-63

Yazdani SK, et al. Catheter Cardiovasc Interv. 2014;83(1):132-40

μg

58.8±54.2

60 min

Lutonix, 2mg/mm2

Polysorbate+sorbitol

Lutonix , 2 mg/mm2 deployed in Swine

Femoral Artery model at 1x

Vascular, downstream, and pharmacokinetic responses to treatment with a low dose drug‐coated balloon

in a swine femoral artery model

Yazdani SK, et al. Catheter Cardiovasc Interv. 2014;83(1):132-40

Vascular changes following Lutonix DCB treatment in Porcine Iliac arteries

28-days 90-days 180-days 1x dose

Yazdani SK, et al. Catheter Cardiovasc Interv. 2014;83(1):132-40

*Medtronic data on file

Paclitaxel concentrations post-treatment support long-term efficacy*

• Detectable levels of drug up to 180 days in both arms (therapy dose and safety margin)

• At 320 no quantifiable drug is identified in the targeted tissue area

Drug in Tissue

0 5 0 1 0 0 1 5 0 2 0 0

0

2 0

4 0

6 0

8 0

D a y s

Pa

clita

xe

l c

on

ce

ntra

tio

n (n

g/m

g)

N o m in a l D o s e

3 X S a fe ty M a rg in D o s e

Porcine IleoFemoral Artery

6 0 9 0 1 2 0 1 5 0 1 8 0

0 .0 0 1

0 .0 1

0 .1

1

1 0

D a y s

Pa

clita

xe

l c

on

ce

ntra

tio

n (n

g/m

g)

N o m in a l D o s e

S a fe ty M a rg in D o s e

N = 6 / t im e p o in t

E C 5 0 P a c lita xe l

IN.PACT Drug Eluting Balloon: Medtronic

•Very mild neointimal / medial inflammation resolved by 180 days

•SMC loss at indicating pharmacological activity of paclitaxel

Preclinical Response

Neointimal / Medial Inflammation Score

Day post-Treatment

Sco

re

28 90 180 28 90 1800

1

2

3

4

*

Control

DEB

*

Neointimal Proteoglycan / Collagen Score

Day post-Treatment

Sco

re

28 90 180 28 90 1800

1

2

3

4

5Control

DEB*

Medial SMC Loss (Depth)

Day post-Treatment

Sco

re

28 90 180 28 90 1800

1

2

3

4

5

*

*Control

DEB* *

Medial SMC Loss (Circumf)

Day post-Treatment

Sco

re

28 90 180 28 90 1800

1

2

3

4

**

Control

DEB

*

Paclitaxel action

Histomorphometry of Treated Porcine Arteries*

*Medtronic data on file

IN.PACT Drug Eluting Balloon: Medtronic

1X Inflation 4X Inflations 6X Inflations Controls

Dose-dependent Changes in Iliofemoral Arteries Following SeQuent DEB treatment at 14 days

X6 inflations

Vascular Changes in Downstream Skeletal Muscle

4x Dose

1x Dose

90 Days 180 Days 28 Days

90 Days 28 Days

(None observed for 1x dose at 180 days)

(None of physiological significance observed for Moxy DCB at any time)

Safety Profile All about Balancing Safety, Efficacy and Biologic

Response Not all balloons are created equal

Effic

acy

Safe

ty

Drug Load

Use of Carrier/Excipient

Drug Retention

Repeat Inflations

More

Less

less

more

Rapid Vascular Healing

Good Re-Endothelialization

No distal Emboli

Less neointima Absence of restenosis No, early or late thrombosis

Acknowledgments

CVPath Institute

Hiroyoshi Mori, MD Kazuyuki Yahagi, MD Oscar D. Sanchez, MD Tobias R. Koppara, MD Erica Pacheco, MS Robert Kutz, MS Russ Jones Ed Acampado, DVM Youhui Liang, MD Abebe Atiso, HT Jinky Beyer Hedwig Avallone, HT Lila Adams, HT Hengying Ouyang, MD Elena Ladich, MD Frank D Kolodgie, PhD Michael Joner, MD

Washington DC

The Relevance of Paclitaxel Dose and Coating for Efficacy and Safety

Renu Virmani, MD

CVPath Institute, Inc.

Gaithersburg, Maryland, USA