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Absorbable Metal Stent, Clinical Update and DREAMS: Concept and preclinical Data

Ron Waksman, MDRon Waksman, MDProfessor of Medicine (Cardiology) Georgetown University,Professor of Medicine (Cardiology) Georgetown University,

Associate Director Division of CardiologyAssociate Director Division of Cardiology

Washington Hospital Center Washington DCWashington Hospital Center Washington DC

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Complete occlusion of the left pulmonary artery after de-banding and closure of the arterial duct with a clip (the device with three markers is for calibration purposes)

Peter Zartner, M. D., Pediatric CardiologyUniversity of Erlangen-Nuremberg, Germany

3Peter Zartner, M. D., Pediatric CardiologyUniversity of Erlangen-Nuremberg, Germany

Crossing the stenosis with a guide wire angiography revealed reperfusion

4Peter Zartner, M. D., Pediatric CardiologyUniversity of Erlangen-Nuremberg, Germany

Implantation procedure of Mg Stent 3.0/10mm with a contrast filled balloon catheter

5Peter Zartner, M. D., Pediatric CardiologyUniversity of Erlangen-Nuremberg, Germany

At one week follow up after Mg Stent the left lung was reperfused

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Different to permanent stents: • Leaves no stent behind long-term (no chronic

inflammation, no long-term impact on local vasomotion)

• No “Full metal jacket” makes later treatments of the same segment easier (e.g., surgical bypass)

• MRI / CT compatibility (allows non-invasive follow-ups)

• Potentially: no late stent thrombosis and no need for prolonged antiplatelet therapy

Why bio-absorbable stents?

Provides stent scaffolding and radial strength properties as long as needed to ensure an open lumen - same as a permanent stent

AND

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Absorbable Metal Stent

Magnesium and the human body

Essential element for human body, involved in the synthesis of more than 300 enzymes

Physiologically occurrence: 4th most common mineral

Quantity in human body: ~ 20 g

Daily need (adult): ~ 350 mg

Quantity in the intracellular space: > 40%

BIOTRONIK AMS features

Weight of a 3.0x10mm stent: ~ 3 mg

Complete absorption: ≈ 12 weeks

Biocompatibility – BIOTRONIK Magnesium Alloy

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First generation AMS device (AMS 1)

Available sizes

• Diameter: 3.0 and 3.5mm

• Length: 10mm and 15 mm

Magnesium alloy device• Weight of a magnesium stent: ~

3 mg• Complete absorption: several

months• High collapse pressures

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Analysis of degradation products by EDX analysis

Mg alloy beforedegradation

Conversion layer:

soft shell of Ca(PO4)2 Mg alloy after 13 days

in porcine blood

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Compatibility of AMS in MRI and multi-slice CT

Magnetom (Sonata, 1.5 T, Siemens)

• No stent artefact• Optimal vessel

lumen imaging

Dr. R. Erbel, ACC06 presentation

16 Multi Slice CT

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CT compatibility of AMS

A B

C D

Bare Metal Stent

AbsorbableMetal Stent

Lind et al, Heart 91:1604, 2005

16-row MSCT

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First in Man Coronary Study

of AMS 1: PROGRESS 1

Clinical Performance and Angiographic Results of the Coronary Stenting with Absorbable Metal Stents

Principal Investigator: Prof. Raimund Erbel

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PROGRESS AMS 1

Purpose To evaluate the clinical feasibility of the Absorbable Metal Stent in the treatment of a single de novo lesion in a native coronary artery

Design Prospective, multi-center, consecutive, non-randomized FIM (First In Man –coronary) study

Patients The study included 63 patients at 8 international clinical sites

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PROGRESS: Clinical Results

MACE MACE 0 00 0 15 23.815 23.8 2 3.32 3.3 17 27.917 27.9

DeathDeath 0 00 0 0 00 0 0 00 0 0 00 0

Myocardial Myocardial InfarctionInfarction

0 00 0 0 00 0 0 00 0 0 00 0

Ischemic Driven Ischemic Driven TLRTLR

0 00 0 15 23.815 23.8 2 3.32 3.3 17 27.917 27.9

In In HospitalHospital

N %N %

4 4 MonthsMonthsN %N %

44--12 12 MonthsMonthsN %N %

12 12 MonthsMonthsN %N %

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0

20

40

60

80

100

0 30 60 90 120 150 180 210 240 270 300 330Days Post Intervention

Isch

em

ic T

LR

Occ

urr

en

ce

4-m

on

th A

NG

IO

TLR occurrence in PROGRESS 1

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NLD 014-002

Post Implantation

4 Months

28 Months

17 17

AUS 004-001

Post Implantation

4 Months

16 Months

18

0

50

100

150

200

250

300

Index 4month FU long term FU

Stent Volume

Lumen Volume

Vessel Volume

Stent CSA

IH Volume

IVUS AnalysisIVUS Analysis

IVUS Stent VolumeIVUS Stent Volume

0

20

40

60

80

100

120

140

160

180

0 10 20 30

FU time(month)

Sten

t Vol

ume

PTID 4 1

PTID 9 2

PTID 12 5

PTID 12 7

PTID 14 2PTID 14 3

PTID 14 7

PTID 14 11

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IVUS CSA

0

1

2

3

4

5

6

7

8

9

0 10 20 30

FU time(month)

Ste

nt C

SA

PTID 4 1PTID 9 2PTID 12 5PTID 12 7PTID 14 2PTID 14 3PTID 14 7PTID 14 11

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IVUS Intimal Hyperplasia Volume

0

5

10

15

20

25

30

35

0 5 10 15 20 25 30

FU time(month)

IH V

olum

ePTID 4 1PTID 9 2PTID 12 5PTID 12 7PTID 14 2PTID 14 3PTID 14 7PTID 14 11

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pre I.S.D.N.

post I.S.D.N.

First evidence of vessel flexibility in AMS stented area by angio pre/post nitroglycerin

GRB009-007RCA, Ø3.0

asyptomatic TLR at 4 months FU

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-10

0

10

20

30

40

PMS AMS PMS AMS

Stented segment

Reference segment

p = 0.0017

p = 0.3806

% c

hang

e in

cro

ss s

ectio

nal a

rea

post

ic IS

DN

Courtesy of Dr Miles DalbyRoyal Brompton & Harefield

Intracoronary ISDN induced vasodilatation in Permanent Metal Stent (PMS) control patients and Absorbable Metal Stent (AMS) patients within stent and in proximal reference segments at 4 months post implant.

Vessel Reactivity

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15 months after AMS implantation in human

Dr. Carlo di Mario, London

• Very thin neointima

• Perfect ingrowth of AMS

• Completed healing of the stented vessel

OCTIVUS

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Conclusions - PROGRESS 1

• The AMS technology is feasible (high technical and procedural success), absorption of the device as intended

• The AMS provided safety (no death, no MI, no stent thrombosis)

• The study met the primary endpoint (MACE <30%)

• Further improvement of the AMS 1 technology are needed to improve efficacy for coronary use

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Results PROGRESS 1 - IVUS

Negativeremodeling/recoil

Thickeningof extra-stenttissue

In-stentneointima

42% 13.5% 41%

Contribution to lumen loss

Post implantation4 months follow-up

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Improvement of AMS 1

AMS 1 is currently improved by ...

... prolonged mechanicalstability

Surface passivation

Modified Alloy

Improved stent design

... reduction ofneointima hyperplasia

“DREAMS” = Drug elution

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Selection trial - Stent structure after 4 weeks

AMS 1

AMS 1 alloy &New design

AMS 1 design &

New alloy

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Description of new AMS 2 device

Bare stent (no coating)

Special Magnesium alloy

Refined stent design

Stent range

Diameters: 3.0 and 3.5mm

Lengths: 10 and 15 mm

6F compatible system, RX catheter

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Combination trial - Angiography

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

2 weeks 4 weeks

Late

Lum

en L

oss

(mm

), m

edia

nAMS 1AMS 2

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Combination trial-Representative histology 4 weeks

AMS 1 AMS 2

Source: R. Virmani, CVPath

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Combination trial -Representative stent structure at 2 weeks

AMS 1 AMS 2

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Combination trial -Representative stent structure at 4 weeks

AMS 1 AMS 2

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Histology 4 weeks

Source: R. Virmani, CVPath

AMS 1 AMS 2

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Stent structure at 3 month

AMS 1 AMS 2

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0

1

2

3

4

5

6

7

8

9

EEL IEL Stent Lumen Neointima

Are

a (m

m2)

AMS 1 (n=6)AMS 2 (n=7)

0

1

2

3

4

5

6

7

EEL IEL Stent Lumen Neointima

Are

a (m

m2)

AMS 1 (n=7)AMS 2 (n=7)

Combination trial - Histomorphometry

Source: R. Virmani, CVPath

p<0.01

p<0.01 p<0.01

p=0.20

p=0.77

p=0.027

p=0.034 p=0.034

p<0.01

p=0.75

2 weeks 4 weeks

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Status AMS 2 - Summary

• The optimization of both the Magnesium alloy and the stent design contribute to a longer stent integrity in animal

• The new AMS generation with increased integrity shows significantly improved efficacy in animal

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DREAMS concept

• Degradable carrier from Magnesium alloy

• Effective anti-proliferativ drug • Specialized proprietary matrix to

cope with degradation of Magnesium alloy- Non-permanent polymer - Optimized rate of drug elution

DREAMS=

DRug Eluting AMS

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Stent: Stent: Bioabsorbable

Magnesium AlloyDiscrete Drug

Delivery Reservoirs

Drug:Drug:

Carrier:Carrier:Bioresorbable Matrix

DREAMS DRUG-Eluting Stent System

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Brachytherapy and AMS - Study design

Domestic Pigs Domestic Pigs

24 Gy beta radiation 24 Gy beta radiation

AMS 1 stent implantation AMS 1 stent implantation

AMS 1 stent implantationAMS 1 stent implantation

Vision stent implantationVision stent implantation

SacrificeSacrifice

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Brachytherapy and AMS - Histopathology

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Brachytherapy and AMS - representative images

Vision AMS 1 AMS 1 + VBT

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AMS program

AMS 1

AMS 3Drug-eluting AMS (DREAMS) incl. surface passivation and X-ray markers

AMS 2Improved mechanical integrity by modified alloy and improved stent design

First clinical experience:AMS is “safe”

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• Safe in human coronaries

• Safe in peripheral arteries (tibial)

• Absorbed as intended < 90 days

• Fully compatible with CT or MRI angiography

• Restenosis mainly due to early recoil and neointima formation

• New Generations AMS under preclinical testing

• Resume Clinical testing to be announces

Status of AMS 2007

Thank You Thank You Thank You