Novel, microcrystaline paclitxel coated

balloon - preclinical evaluation and

insights into First in Man application

Piotr P. Buszman M.D., PhD

Center for Cardiovascular Research and Development

American Heart of Poland, Katowice, Poland

Silesian Center for Heart Diseases, Zabrze, Poland

Peripheral Atherosclerosis: A Different Pathological State

Iliacs (in-flow) 10-20%

SFA/ Popliteal

Artery 20-60%

Tibio-peroneal 50-75%

PTA Restenosis Rates Complex Biomechanical Behavior

Different biological

architecture

consistent of

significant amount of

medial calcification

compared to other

vascular territories

Two ideas of leaving nothing behind

Bioresorbable scaffolds Paclitaxel Coated Balloons

BVS PCB

Vessel scaffolding ++ - / BMS bail out 20-30%

Implant free - (pending 2-3 years) +++

Tissue drug retention ++ +

Anti restenotic efficacy +++ ++

Positive vessel remodeling ++ ++

Restoration of vasomotive function ++ ++

Healing / DAPT requirement 1 year 1 month

Trial Design TerritoryPCB

ControlPt.#

Bail out

stenting

Patency at

6 m – 1y

Restenosis

6m-1y

TLR/

Amputation/

Death

6m-1y

TLR

6m-1yLL

1. Micari et al RegistryFemoro-

poplitealIn Pact 105 12.3% 83.7% 7.6%

2.DEBATE

BTK

Registry-

CLI

Infra-

poplitealIn Pact 104 4.8% 72.6% (3m) 27.4% (3m) 38.3 17.3%

3. DEBATE-

BTK

CRT –

CLI + DM

Infra-

poplitealIn Pact 57 27%

POBA 61 65%

4. PACIFIER CRTFemoro-

Popliteal

In Pact 44 20.5% 90% 8.6% 7.3% 7.1% -0.01

POBA 47 30.4% 69% 32.4% 26.8% 21.4% 0.65

5. LEVANT 1 CRTFemoro-

Popliteal

Moxy 49 24.5% 72% 13.4% 13% 0.46

POBA 52 27% 49% 42.8% 22% 1.09

6. FEMPac CRTFemoro-

Popliteal

Paccocath 45 9% 94% 19% 8.9% 7% 0.3

POBA 42 14% 94% 47% 42.8% 33% 0.8

7. THUNDER CRTFemoro-

Popliteal

Paccocath 48 12% 98% 17% 8.3% 4% 0.4

POBA 54 22.0% 92% 44% 42.6% 37% 1.7

1. Micari A. et al. J Am Coll Cardiol Intv. 2012;5:331-338.

2. Schmidt et al. J. Am. Coll. Cardiol. 2011;58;1105-1109

3. Lisstro et al. TCT 2011 LBCT

4. Werk et al. LINC 2012

5. Scheinert et al. TCT 2010 LBCT

6. Circulation. 2008; 118: 1358-1365

7. Tepe et al. N Engl J Med 2008;358:689-99

PCB clinical prospective registries and randomized trials

0.001 0.01 0.1 1 10

Thunder

FEMPac

LEVANT 1

PACIFIER

Pooled estimate

Odds 95% CI p

0.0348 0.00943 to 0.128 <0.05

0.108 0.0304 to 0.385 <0.05

0.0614 0.019 to 0.199 <0.05

0.128 0.0326 to 0.499 <0.05

0.0737 0.0391 to 0.139 <0.05

Composite of Death/Amputation/TLR:

Meetanalysis Of 4 CRT’s

Favors PCB Favors POBA

Piotr Buszman et al. Drug Coated Balloon Technologies 2012

Paclitaxel-Coated vs. Uncoated Balloon Angioplasty

Reduces TLR in Femoropopliteal Disease

Conclusion: In femoropopliteal lesions, a paclitaxel-coated balloon reduces the need for reintervention vs. conventional angioplasty with no safety signal.

Meta-analysis of 4 randomized trials involving 381 pts.

Cassese S, et al. Circ Cardiovasc Interv.

2012;Epub ahead of print.

Angiographic, Clinical

Outcomes

Paclitaxel

Balloon(n = 186)

Uncoated

Balloon(n = 195)

P Value

Restenosis 18.7% 45.5% 0.001

Late Lumen Loss (Range), mm -0.05 to 0.50 0.61 to 1.7 0.0001

TLR 12.2% 27.7% < 0.00001

There was no mortality difference between groups.

Safety Concerns

Emboli with Crystalline material

Surface Thrombus/FibrinImpaired healing

SCCR 2012

Late coronary aneurysm with

severe stent malapposition

within the segment treated

with a PCB2

Aneurysm formation

after PCB treatment of

DES-ISR: first case

report3

Occurrence of

aneurysm

formation at

preclinical studies1

1Skirball Research Center2Eur Heart J. 2011 June; 32(11): 1432

3Vassilev D. Catheter Cardiovasc Interv. 2012 Mar 14

Potential for Toxic Vascular Effects

Defining the PAST: Technical Characteristics of the Original PACOCCATH Technology

Exp. Radiologie, Charité Mitte (Berlin, Germany)

Ulrich Speck

First Generation Coating:

• Clinically effective formulation

• Manual “dip coating” technique

• Inconsistent drug coating concentration

• Significant drug loss at insertion

• High balloon-artery transfer rates

• High particulate formation

Slide courtesy Juan F. Granada

Similar concept but the difference is clear…

DES / BVS vs. DCB

Second Generations CoatingsPaclitaxel Coated Balloon Technologies

• Manual dipping process

• Inconsistent D:E mixture

•Limited scale production

•Automated and controlled

drug coating

• Improved and controlled

coating mixture and

uniformity

•Low particle size

•Large scale reproducibility

1st Gen PCB 2nd Gen PCB

Technology Evolution versus PerformanceCotavance® PCB: Technical Improvements

Figure courtesy of MEDRAD, INC.

Particle Diameter (mm)

Nu

mb

er

of

part

icle

s, %

54.7650.50

78.22

0

10

20

30

40

50

60

70

80

90

100

1st Gen PCB 2nd Gen PCB POBA

%

20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 950

1

2

3

4

5

25 30 35 40 45 50 55 60 65 70 75 800

1

2

3

4

5

%AS %AS

1st Gen PCB 2nd Gen PCB

Optimizing Coating Homogenity Improves

Drug - Neointimal Distribution and Healing

0

10

20

30

40

50

60

70

80

Proximal ReferenceProximal Medial Distal Distal Reference

ng

/mg

1st gen PCB 2nd gen PCB

p=0.07

p=0.54 p=0.01

Treatment segment

Piotr P. Buszman et al., JACC Cardiovascular Interventions 2013

p=ns

p<0.05 p<0.05p=ns

p<0.05 p<0.05

p=ns

p<0.05 p<0.05p=ns

p<0.05 p<0.05

p=ns

p<0.05 p<0.05

2nd Gen PCBPOBA1st Gen PCB

Piotr Buszman et al., JACC Cardiovascular Interventions 2013

Optimizing Coating Homogenity Improves

Drug - Neointimal Distribution and Healing

AS 50.5%* AS 54.8%*# 78.2%

Taxus Stent 2nd Gen PCB + BMS BMS

AS 21.5%* AS 29.6%*# AS 55.1%#

Vascular Healing of Coronary BMS Following

Post-Dilatation with a 2nd Gen PCB

p=nsp=0.01

p=0.01

p=0.01p=0.01

p=0.02

p=0.01

p=0.01

p=0.01

p=ns

p=ns

p=ns

Piotr P. Buszman et al., Eurointervention 2013

p=0.02

p=0.11

p=ns

*p=ns

#p<0.05

Microcrystalline Paclitaxel Balloon

Coating Technology

The first, novel polish DCB

mcPCB, PAX®, Balton, Warsaw, Poland:

• Over-the-wire balloon catheter coated with a microcrystalline form of

paclitaxel at a dose of 3 μg/mm2 and a proprietary excipient.

• The coating of this device is achieved by semi-automatic

microsyringe surface drug deposition and a proprietary drying

process which allow to achieve more consistent, uniform and micro-

particle paclitaxel coverage

Data on file at Balton

Tissue Transfer Study

3 DS

12 Iliofermoral segments

Vascular Response Study

8 DS

16 Iliofemoral segments

mcPCB

n=9

Injury:

Balloon overstretch

SE BMS implantation

mcPCB

N=10POBA

N=5

Terminal imaging and

histology

Paclitaxel uptake at 1 hour, 3

and 7 days

Baseline

procedur

e

(Day 0)

Follow up:

28 days

Study design Time point (day)

Angiography

Study flowchart

Piotr P. Buszman et al., Catheterization and Cardiovascular Interventions 2013

mc PCB Paclitaxel Vessel Baseline

Uptake And Temporal Retention

152.9

36.5

0.9

0.1

1.0

10.0

100.0

1000.0

1 hour 3 days 7 days

[ng/m

g]

Piotr P. Buszman et al., Catheterization and Cardiovascular Interventions 2013

mcPCB

n=10

POBA

n=5p

EEL area [mm2] 27.60±6.5 22.55±2.6 0.13

IEL area (stent area) [mm2] 24.58±6.8 19.37±2.1 0.13

Medial area [mm2] 3.03±0.4 3.19±0.8 0.6

Lumen area [mm2] 19.32±4.6* 12.65±2.8 0.01

Area of stenosis [%] 19.8±8.7* 34.2±15.7 0.03

Neointimal thickness [mm] 0.29±0.15 0.47±0.26 0.1

Vascular response study:Histomorphometric analysis

19.78

34.16

0

10

20

30

40

50

60

[%]

Percent area stenosis

0.29

0.47

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

[mm

]

Neointimal thickness

Pax

POBAP=0.03 P=0.1

Vascular response study:Healing and Biocompatibility

0.16

0.92

1.77

1.97

0.67

0.19

1

1.73

1.93

0.65

0

0.5

1

1.5

2

2.5

3

Injury Inflammation Endothelialization Neointimalimmaturity

Fibrin deposition

Score

0.61

0.40

0.871.00

0.470.00 0.07

1.40 1.40

0.73

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Medial mineralization Media hypocellularity Medial Inflammation Adventitialinflammation

Adventitial fibrosis

Pax

POBA

p=ns

p=ns

p=ns p=ns

p=ns

p<0.05 p=0.14

p=0.09 p=ns

p=ns

Piotr P. Buszman et al., Catheterization and Cardiovascular Interventions 2013

*p<0.05 vs. uncoated

Vascular response study:Sustained efficacy, despite low paclitaxel tissue retention

Piotr P. Buszman et al., Catheterization and Cardiovascular Interventions 2013

First in Man, CE approval Trial

Prospective, Pivotal, First - in Man Clinical Trial of the Safety and Efficacy of a Novel

Microcrystalline Paclitaxel Coated Balloon for Treatment of Femoropopliteal Restenotic

Disease.

PAX-r

Aim: The purpose of this pivotal, first in man study will be to evaluate safety and

efficacy of the novel, microcrystalline paclitaxel coated balloon (mcPCB, PAX, Balton)

in the treatment of femoro-popliteal restenotic disease.

Design: multicenter, pivotal, prospective, controlled, randomized

Study sites: 3 Cardiovascular Centers of American Heart of Poland

Collaborator: Silesian Center for Heart Diseases

Principal Investigators: Piotr P. Buszman M.D. PhD, Przemysław Nowakowski M.D. PhD

Bioethical committee approval: April 2014, obtained

Clinical Trials: pending

Enrollment start: June 2014,

Estimated completion: June 2015

PAX-r, First in Man Trial

Patient eligibility

Inclusion Criteria:

•Age > 18 y.o.

•Claudication in Rutherford Class 1-5

•Prior femoro-popliteal revascularization procedure utilizing plain balloon

angioplasty or atherectomy

•Prior femoro-popliteal revascularization procedure with stent

implantation

•Restenosis within previously revascularized segment defined as >50%

and < 99% diameter stenosis with length of up to 10 cm in vessel

diameter of 3-7 mm

•Chronic total restenotic occlusions of lenght less than 60 mm

•Ability to cross the lesions with a guidewire.

PAX-r, First in Man Trial

Patient eligibility

Exclusion Criteria:

• Critical limb ischemia

• Acute coronary syndrome

• Chronic kidney disease stage III-V

• De novo femoro-popliteal lesion

• Femoro-popliteal graft

• Known allergy to clopidogrel or aspirin

• History of stroke within past 6 months

• age > 80 y.o.

• Life expectancy < 2 years

PAX First in Man, CE Approval Study

40 patients

Femoro-popliteal

restenosis

mcPCB

(Balton, PAX)POBA

Primary efficacy outcome measure: Late Loss at 6 months – hypothesis

generating

Secondary endpoints: Primary patency, TLR, TVR,ABI, flow velocity of

treated limb, Walking Impairment Questionarre

Safety outcome measures: Device related adverse events, CLI, amputation

Summary

• As the 2nd generation PCB technologies evolve and the tissue

delivery and distribution of paclitaxel becomes more consistent,

the introduction of this technology into the clinical practice

becomes more appealing.

• These new generation coatings appear to induce lower degrees of

delayed healing, there is a potential to expand the use of this

technology to a broader range of applications – i.e. de novo

coronary lesions, adjunctive use of BMS

• New PCB’s trials and policies are required to increase the

availability of this technology in Poland