Comparison of particulate embolization in

different DCB formulations.

Aloke V. Finn, MDCVPath Institute Inc. Gaithersburg, MD.

USA

Conflict of Interest Declaration

• Institution grant/research support– 480 Biomedical, Abbott Vascular, Atrium,

BioSensors International, Biotronik, Boston Scientific, Cook Medical, Cordis J&J, GSK, Kona, Medtronic, MicroPort Medical, CeloNova, OrbusNeich Medical, ReCore, SINO Medical Technology, Terumo Corporation, and W.L. Gore, Spectronics, CSI, Lutonix Bard, Surmodics, Microport, Meril Life Sciences

• Speaking Honoraria

– Abbott, Cook Medical, Lutonix, Boston Scientific

Elements of an Effective DCB Formulation

• Must deliver large quantities of the drug within seconds

• Distribute within the media in the first few days

• Therapeutic drug levels must be maintained for morethan 4 weeks

• Must allow rapid healing as compared to DES

• No need for long-term anti-platelet therapy

• Biologic effects must be observed by histology at 28-days

• Effective drug delivery to target tissue while avoiding non-target effect (i.e. minimize emboli)

• Downstream Panniculitis Secondaryto Drug–Eluting Balloon Angioplasty.Ibrahim T et al, JACC Cardiovasc Interv. 2016;12;9(17):e177-9.

• Vasculitis resulting from a superficial femoral artery angioplasty with a paclitaxel-eluting balloon.Thomas SD et al, J Vasc Surg. 2014;59(2):520-3

• Acute hypersensitivity reaction to femoral drug-coated balloons.

Lake E et al, Vasa. 2017 May;46(3):223-225

Three Case Reports for Downstream Effect of DCB

Use: Particulate Embolization Related?

Device Company CoatingDrug 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, Medtronic Vascular, Santa Clara, CA, USA Paclitaxel–urea 3.5 Yes

Lutonix® 035 DCB BARD, Murray Hill, NJ, USA Paclitaxel–polysorbate/sorbitol 2.0 Yes

Ranger Boston Scientific Paclitaxel–Acetyl Tributyl Citrate 2 2.0 Yes

Passeo-18 Lux® Biotronik, Bülach, Switzerland Paclitaxel–butyryl-tri-hexyl citrate 3.0 Yes

Stellarex® Covidien, Mansfield, MA, USA Paclitaxel-polyethylene glycol 2.0 Yes

SurVeilTMDCB SurModics, MN, USA Paclitaxel-proprietary photolink® 2.0 Yes

IN.PACT

ELUTAX Sequent PleasePantera Lux

SurModicsLutonix

Drug Coated Balloon Devices (Peripheral artery)

IN.PACT™ ADMIRAL™ MAINTAINS GREATER DRUG IN TISSUE

• While there is expected variability across studies, IN.PACT ™ Admiral ™ consistently provides higher PTX tissue concentration than Lutonix ™* DCB through 90 days

• Paclitaxel available for both IN.PACT ™ Admiral ™ and Lutonix ™* DCB post-24 hours, but IN.PAC T ™

Admiral ™ achieves sustained effect through slow release of solid-phase paclitaxel reservoirs

Arterial Tissue Concentration

Note: Data on file with MedtronicGranada, J; JACC INT, 2015

0

10

20

30

40

50

60

70

80

4hours

1 Day 7 Day 21 Day 30 Day 45 Day 60 Day

Dru

g i

n T

issu

e

(ng

/mg

)

Ranger DCB

In.Pact Admiral DCB

Lutonix DCB

BSX Boston Ranger DCB*

MDT IN.PACT Admiral DCB

Bard Lutonix DCB

0 2 0 4 0 6 0 8 0 1 0 0

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

D a y s

Dru

g i

n T

iss

ue

(n

g/m

g) IN .P A C T

L u to n ix

0 2 0 4 0 6 0 8 0 1 0 0

0

1 0

2 0

3 0

D a y s

Dru

g i

n T

iss

ue

(n

g/m

g)

Downstream Sampling for Paclitaxel Analysis and Histopathology Assessment

Coronary band

EFA

IFA

Angiogram of the SFA

• Evaluated skeletal muscle and coronary band for potential embolic changes• Distal paclitaxel concentration • Histology

• Distal embolization• Vascular changes

Gracillis

Rectus

Femoris

SemitendonosisArteries

not shown

GastrocnemiusSemimembranosis

Gluteus Maximus

Left or Right SFA Randomly Treated by

LUTONIX, In.Pact or POBA

LEF 1x or

3x OL

LIF

REF 1x or

3x OL

RIF

Histo only Treatment Scheme: A total of 2

DCB treated sites (1/vessel) in the external

femoral arteries of one leg (left or right).

IN.PACT 1x

or 3x Tx site

LEF 1x or

REF

RIF

PK and histo Treatment Scheme: A

total of 2 treated sites in the external

femoral arteries of one leg (left or right).

1x or 3x LUTONIX

or IN.PACT Tx site POBA 1x or

3x Tx site

LUTONIX1x or 3x Tx site

LEF:1x

or 3x

POBA

Downstream Incidence of Distal Embolization (%)

SurvivalTreatment & Arteries

Lutonix 035 IN.PACT P-value

Paclitaxel concentration in downstream tissues (ng/g)

Skeletalmuscle

Coronaryband

Skeletalmuscle

Coronaryband

Skeletalmuscle

Coronaryband

28-day (1x, n=5) 1.3

(0.6-2.3)1.5

(1.1-65.8)60.8

(32.6-118.1)189.0

(134.0-700.0)0.009 0.02

28-day (3x, n=5)3.7

(1.3-10.9)31.5

(5.9-54.1)170.9

(19.7-221.5)871.0

(567.5-1315.0)0.08 0.009

90-day (3x, n=4)0.6

(0.5-6.4)2.7

(0.0-25.5)16.1

(12.8-319.2)158.0

(6.3-1178.0)0.009 0.05

SurvivalTreatment & Arteries

Lutonix 035 IN.PACT P-value

Number of micro-vessels with paclitaxel-associated findings

28-day (1x, n=5) 1 (0-2) 4 (2-12) 0.03

28-day (3x, n=5) 1 (0-12) 26 (11-34) 0.07

90-day (3x, n=4) 0 (0-3) 11 (5-15) 0.02

0

25

50

75

100

Lutonix 035 IN.PACT

0

25

50

75

100

Lutonix 035 IN.PACT

0

25

50

75

100

Lutonix 035 IN.PACT

A

B

C

15.4% (11.5-30.8)

n=5

7.7% (0-11.5)n=5

38.5% (15.4-42.3)n=5

7.7% (0-15.4)n=5

46.2% (19.2-57.7)N=5

0% (0-11.5)N=5

P=0.04

P=0.07

P=0.01

Single Balloon (1x) Overlapping Balloons (3x) Overlapping Balloons (3x)

90-Day Survival28-Day Survival

Dis

tal

Em

bo

lizati

on

(%

)

Downstream Findings in Porcine Skeletal Muscle (28-Day)

High (20x and 40x) power images

of vascular changes in skeletal

muscle at 28 days.

Vascular changes include pyknotic

nuclei embedded in homogenous

pink material (yellow arrow),

representing fibrinoid necrosis

(black arrows), with surrounding

inflammatory cells (blue arrows).

Lutonix (1x) Vascular Change IN.PACT (1x) Vascular Change

High (40x) power images of

crystalline material (red

arrows) at 28d

IN.PACT (1x) Crystalline Material IN.PACT (3x) Crystalline Material

In. Pact DCB vs. Stellarex vs. Ranger The Second Comparative Study

LEF 1x orREF

RIF

Treatment Scheme: A total of 2 treated

sites in the external femoral arteries (left

or right) in each pig

3x IN.PACT Tx site 3x Ranger or

Stellarex Tx

site

LEF

LIF

• Same swine model - 28 day study

• 3x dose, same size DCB

• DCB inflated for 60 secs

• Blinded-device ID

• Same sampling method and evaluation endpoints as the first Lutonix vs. IN.PACT comparative study

Downstream Incidence of Distal Embolization (%)

SurvivalTreatment

Second Comparative Study

IN.PACT Ranger Stellarex

Paclitaxel concentration in downstream tissues (ng/g)

28-day (3x)

Skeletalmuscle

Coronaryband

Skeletalmuscle

Coronaryband

Skeletalmuscle

Coronaryband

216.5(326.1-146.2)

911.3(691.3-1773.8)

91.5(44.8-116.9)

822.5 (347.9-1450.6)

101.9(44.6-163.8)

962.3 (149.9-1160)

SurvivalTreatment

Second Comparative Study

IN.PACT (n=12) Ranger (n=6) Stellarex (n=6)

Percentage of sections with vascular changes in downstream nontargettissues (%)

28-day (3x) 42.9 25 30

Overlapping Balloons (3x), 28-Day Survival

First Comparative Study

Lutonix (n= 5) IN.PACT (n=5)

7.7 38.5

First Comparative Study

Lutonix IN.PACT

Skeletalmuscle

Coronaryband

Skeletalmuscle

Coronaryband

3.7(1.3-10.9)

31.5(5.9-54.1)

170.9(19.7-221.5)

871.0(567.5-1315.0)

IN .P AC T R a n g e r S te lla r e x

0

2 0

4 0

6 0

8 0

1 0 0 p=0.2

IN .P AC T R a n g e r S te lla r e x

0

2 0 0

4 0 0

6 0 0

8 0 0

IN .P A C T R a n g e r S te lla re x

0

1 0 0 0

2 0 0 0

3 0 0 0

4 0 0 0

5 0 0 0p=0.01 p=0.5

Paclitaxel concentration in downstream Skeletal muscle

Paclitaxel concentrationin downstream Coronary band

(ng/g) (ng/g)(%)

Histologic sections showingDistal Embolization

Dis

tal E

mb

oliz

atio

n

Pacl

itax

el c

on

cen

trat

ion

Pacl

itax

el c

on

cen

trat

ion

Ranger StellarexIN.PACT

Downstream changes followingIN.PACT vs. Ranger vs. Stellarex, dose 3X, at 28 days

CV38011 L SEMM1_20x

CV38007 Left GracilisCV38007 Right Gracilis

CV38010 R GASTRO1_20x CV38012 L SEMM2_20x

CV38010 Left Gastrocnemius

DCB Design: All About Balancing Safety,

Efficacy, and Biologic Response

Not all balloons are created equal.

Effic

acy S

afe

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

Biologic changes, but no emboli

No Restenosis

Goal of Efficacy

No Aneurysms No Emboli

Goal of Safety

Acknowledgments

CVPath Institute

Sho Torii, MDKazuyuki Yahagi, MDHiroyoshi Mori, MDEmanuel Harari, MDElena Ladich, MDRobert Kutz, MSEd Acampado, DVMYouhui Liang, MDAbebe Atiso, HTJinky BeyerLila Adams, HTFrank D Kolodgie, PhDLiang Guo, PhDRenu Virmani, MD Washington DC

Funding

CVPath Institute Inc.

My email: afinn@cvpath.org

Clinical Relevance

• In the absence of randomized clinical data, preclinical studies can provide excellent information about the relative performance of different technologies

Randomized studies generally exclude high risk patients who probably would be affected most by downstream adverse events

• DCBs which obtain effective drug transfer into the arterial wall while minimizing downstream embolic effects are the goal

Lutonix® 035 vs. In.Pact™ Admiral First Comparative Study in Swine

• Blinded study – Side-by-side

• 1x and 3x dose

• Evaluated skeletal muscle and coronary band at 28 and 90 days

Distal drug concentration

Histology

• Distal embolization

• Vascular changes

Different test methods may yield different results. Pre-clinical test data on file. Pre-clinical results may not be indicative of clinical performance.

Histologic Parameters for

Evaluation of DCB Efficacy

Key parameters include:

• Endothelial loss

• Fibrin / Platelets

• Inflammation

• Injury

• Medial smooth muscle cell loss

• Matrix replacement

• Proteoglycan

• Collagen

• Adventitial fibrosis

Fibrin

SMC loss

Proeoglycan

H&E

α-SMA

Movat

Left or Right SFA Randomly Treated by

LUTONIX, or In.Pact

LEF 3x OL

LIF

REF 3x OL

RIF

Histo only Treatment Scheme: A total of 2

DCB treated sites (1/vessel) in the external

femoral arteries of one leg (left or right).

IN.PACT 3x

Tx site

LUTONIX 3x Tx site

Kolodgie, FD et al. J Vasc Interv Radiol. 2016 Sep 15. pii: S1051-0443(16)30338-4.

Histologic Vascular Changes following

Lutonix vs. In.Pact DCB Treatment (3x)

Lutonix 3x-28d In.Pact 3X-28d POBA-28d

Lutonix 3x-90d In.Pact 3x-90d POBA-90d

0

10

20

30

40

50

Lutonix035

IN.PACT POBA Lutonix035

IN.PACT POBA

28 days 90 days

0

1

2

3

4

Lutonix035

IN.PACT POBA Lutonix035

IN.PACT POBA

28 days 90 days

Luminal Stenosis, %P=0.02 P=.044

Neointimal Area, mm2

P=0.02 P=.030

Kolodgie, FD et al. J Vasc Interv Radiol. 2016 Sep 15. pii: S1051-0443(16)30338-4.

0

1

2

3

4

Lutonix 035 IN.PACT POBA Lutonix 035 IN.PACT POBA

28 days 90 days

Histologic Vascular Changes following

Lutonix 035 vs. IN.PACT DCB Treatment (3x) at 28 and 90 days

SMC loss score (Depth) SMC loss score (Circumference)

Medial proteoglycan score Fibrin/thrombus score

Lutonix 035: n=5, In.Pact DCB: n=5, POBA: n=4

P=0.004 P=0.02

0

1

2

3

4

Lutonix 035 IN.PACT POBA Lutonix 035 IN.PACT POBA

28 days 90 days

P=0.01 P=0.02

0

1

2

3

4

Lutonix 035 IN.PACT POBA Lutonix 035 IN.PACT POBA

28 days 90 days

0

1

2

3

4

Lutonix 035 IN.PACT POBA Lutonix 035 IN.PACT POBA

28 days 90 days

P=0.01 P=0.007 P=0.41 P=1.00

Kolodgie, FD et al. J Vasc Interv Radiol. 2016 Sep 15. pii: S1051-0443(16)30338-4.