Magmaris Stent

(Biotronik)

A Pichard,

Ron Waksman.

Medstar Washington Hospital Center

Washington, DC

Conflict of Interest

•None for this presentation

Downside of Metallic Stents

1. Restenosis

• No longer a problem if optimal PCI accomplished.

• More frequent in Diabetes and Diffuse disease

• Still a problem in small vessels

Downside of Metallic Stents

2. Thrombosis

• Often a devastating clinical event

• Mostly prevented by optimal PCI technique and adequate DAPT.

• More prevalent in patients with acute coronary syndrome, complex lesions and long stents

Downside of Metallic Stents

3. Neo Atherosclerosis

• Develops in BMS and DES

• Plaque rupture/thrombosis can lead to STEMI.

• Appears not be related to hyperlipidemia (inflammatory?).

• At this time, an unpredictable event (specially now that routine NI testing is no longer approved).

Downside of Metallic Stents

4. Stent Fracture

• Occurs in up to 17% of patients (CT data)

• Can develop aneurysm, restenosis, acute thrombosis

Downside of Metallic Stents

5. Eliminates physiologic vasomotion of the coronary artery.

• Issue for athletes (hyper thrombogenicity of exercise).

• Associated with neoatherosclerosis

Advantage of Spot Stenting

The less metal in the coronary artery, the less chance of:

• restenosis,

• thrombosis,

• stent fracture,

• neoatherosclerosis,

• inhibition of physiologic vasomotion.

Stent should be used for the short segment of 90% stenosis and leaving the 50% borders unstented. Medical therapy is better for intermediate lesions than stenting them.

The Magmaris backbone is flexible and robust

8

Corrugated rings 2 links, 90° shifted

Uniform flexibility in

all 3D directions

6 crown design.

Radial support

Strut dimension 150x150µm

Radial support

Open cell design for

acute flexibility

Magmaris description

9

Backbone

Double eye radiopaque marker (Tantalum)

resorbable

resorbable

permanent

Backbone

resorbable Coating

Mg

Mg

10

Document identifier

Magnesium alloy scaffold

Mg Alloy Grain size reduction & homogenization

Design

Mixture of ≥2

metals or other elements.

Alloy Structure can modify: Mechanical

properties Resorption

behavior Biocompatibility

Design define the final scaffold performance.

First Step: Magnesium Hydroxide

Magnesium + Water Magnesium hydroxide

0m 12m 1m 3-9m

Magnesium Magnesium hydroxide

Magnesium phosphate

Amorphous Calcium phosphate

Physiological environment with high water content

Mg + 2 H2O Mg(OH)2(s) + H2(g)

11

Second and Third Step: Magnesium Phosphate and Amorphous Calcium Phosphate (ACP)

Magnesium hydroxide Magnesium

0m 12m 1m 3-9m

Magnesium Magnesium hydroxide

Magnesium phosphate

Amorphous Calcium phosphate

Physiological environment with high water content + Calcium ions

Amorphous Calcium Phosphate

Mg(OH)2 (s) + HPO42- (aq) + Ca2+ (aq) + H2O (l) Cax(PO4)y∙n H2O (s) + H3O+ (aq) + Mg2+(aq)

+ Magnesium ions + Phosphate ions phosphate

12

Magnesium inhibits platelets and prevents thrombosis

1Castiglioni et al. (2015). BioNanoMat; 16(1): 23–29; 2Kolte et al. (2014) Cardiology in review;22(4):182-92.

Mg concentration

Platelet activation

Prevention of thrombosis

Magnesium Reduces Vascular Calcification

1Castiglioni et al. (2015). BioNanoMat; 16(1): 23–29; 2Kircelli et al. (2011). Nephrology Dialysis Transplantation; 0: 1–8; 3de Oca et al. (2014). PloS one ;9(2):e89525.; 4Hruby et

al., (2014): JACC Cardiovasc Imaging; 7(1): 59–69. Similar conclusions from another study: Posadas-Sánchez et al. (2016) Nutrition Journal; 15:22

*Increase of Mg levels is associated with reduced calcification in the tunica media

**The systemically available magnesium from Mg intake per day tested in this study was 15 mg, while the magnesium released locally by the BIOTRONIK Mg Scaffold during

one year is around 10 mg.

15

CONFIDENTIAL – Internal Use Only

• Mg suppresses the transformation of

vascular smooth muscle cells into

calcifying (osteogenic) cells1-3

• Mg intake correlate with reduced

calcification of the coronary arteries4*

- with Magmaris

17

Limus drug - antiproliferative drug The Limus drug is a natural antibiotic and potent immunosuppressive agent.

PLLA - resorbable polymer Providing a controlled drug release up to 90 days and is metabolized by the body into carbon dioxide (CO2) and water (H2O)

18

Document identifier

Mg vs polymeric backbone

Polymeric Scaffold Mg Scaffold Polymeric Scaffold

Mg Scaffold

3.0/ 18 3.0/ 15

Strut thickness

150 µm 150 µm

Strut width 180 µm 150 µm

Cross section

Rectangular Square

Sharp edges Rounded

edges

µCT comparison

sharp round

Polymeric scaffold Mg Scaffold

Magmaris allows single step inflation

19

“Inflate the dilatation balloon slowly to expand the scaffold to the diameter in accordance with the compliance chart on the label. Maintain inflation pressure for at least 15-30 seconds for full expansion of the scaffold.”2

Single step inflation of the balloon Stepwise inflation of the balloon

Magmaris Absorb

“Deploy the scaffold slowly, by pressu-rizing delivery system in 2atm increase-ments, every 5 seconds, until scaffold is completely expanded. Maintain pressure for 30 seconds.”1

1 ABSORB IFU 2013 2 Magmaris IFU 2016

Magmaris: deliverability

* vs leading polymeric scaffold 20

Lesion crossing Trackability Pushability

Source: IIB, BIOTRONIK data on file

Magmaris: mechanical acute robustness

21

* vs the leading polymeric scaffold

Radial resistance no significant diameter change under increasing physiological

load

Less recoil conventional polymeric

scaffold diameter decrease >20% within 1st hour*

Source: IIB, BIOTRONIK data on file

23

Document identifier

Magmaris resorption on OCT

Immediately after implantation,

struts are well apposed to the

vessel wall.

While the Magnesium resorption

process continues, endothelialization

progresses.

At 12 months after implantation,

the Magnesium resorption is

almost completed.

Post-Implantation 6 month 12 month

24

Document identifier

MLD Proximal (mm ± SD)

2.61 ± 0.51

2.45 ± 0.63

2.68 ± 0.54

MLD Scaffold (mm ± SD)

MLD Distal (mm ± SD)

2.54 ± 0.34

2.42 ± 0.40

2.62 ± 0.31

2.27 ± 0.36

2.00 ± 0.41

2.36 ± 0.42

Ach = Acetylcholine Nitro = Nitroglycerine

Vasomotion at 12-month follow-up (n=16)

81% (13/16) demonstrate ≥ 3% vasomotion after

Ach or Nitro

Magmaris clinical program – from FIM to RCT

25

BIOSOLVE–I 46 EU

+ Switzerland FIM

TLF at 6 and 12 months Completed

BIOSOLVE–IV

1065 Worldwide PMS Registry

TLF at 12 months

To start Dec 2016

BIOSOLVE–V TBD Worldwide RCT TBD To start

BIOSOLVE–II 123 Worldwide In-segment LLL

at 6 months 12 months FU

available FIM

BIOSOLVE–III 61 EU

+ Switzerland

In hospital Procedural success Enrolling

Pivotal trial

26

Document identifier

Device generation

AMS 4-month

DREAMS 1G 6-month

DREAMS 2G 6-month

Desig

n Strut thickness/width 165/80 μm 120/130 μm

120/120 μm (Ø 2.5)

150/150 μm (Ø 3.0 & 3.5 )

Markers none none Ta-composite

Coating - drug none PLGA/PTX PLLA/SIR

Kin

etics

Drug elution kinetics n.a. like Taxus like Orsiro

Absorption (mos.) 1-2 3-4 (Mg) ≈12 (Mg)

Results

In-segment LLL (mm) 0.83±0.51 0.52±0.48 0.27±0.37

In-scaffold LLL (mm) 1.08±0.49 0.65±0.50 0.44±0.36

TLF* (%) 23.8 4.3 3.3%

Def/Prob Thrombosis 0.0 0.0 0.0

Evolution of the Biotronik Magnesium Scaffold

*Composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization and CABG

27

Document identifier

6-month 12-month

N=120 % N=118 %

TLF1 4 3.3 4 3.4

Cardiac Death 12 0.8 12 0.8

Target Vessel MI 1 0.8 1 0.8

TLR 2 1.7 2 1.7

CABG 0 0.0 0 0

Scaffold def/Prob Thrombosis

0 0.0 0 0.0

FIM

1. Composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization and CABG

2. 58 old smoker, CV RF: hypertension and hyperlipidemia, stable angina CCS Class II, treated with a DREAMS 2G 3.0x20mm in the distal RCA. Patient experienced an unwitnessed death 134 days post procedure. Since a cardiac cause could not be ruled out, patient was adjudicated as cardiac death by the Clinical Event Committee

30

Document identifier

Advances in Scaffold Design

0.83±0.51

0.52±0.48

0.27±0.37

0,00

0,25

0,50

0,75

1,00

PROGRESS BIOSOLVE-I BIOSOLVE-II

In-Segment Late Lumen Loss [mm]

- 48%

4-month 6-month 6-month

- 37%

32

Document identifier

6-month 12-month

N=120 % N=118 %

TLF1 4 3.3 4 3.4

Cardiac Death 12 0.8 12 0.8

Target Vessel MI 1 0.8 1 0.8

Clinically driven TLR 2 1.7 2 1.7

CABG 0 0.0 0 0

Scaffold Thrombosis definite or probable

0 0.0 0 0.0

Clinical Results until 12-month follow-up

1. Composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization and CABG

2. 58 old smoker, CV RF: hypertension and hyperlipidemia, stable angina CCS Class II, treated with a DREAMS 2G 3.0x20mm in the distal RCA. Patient experienced an unwitnessed death 134 days post procedure. Since a cardiac cause could not be ruled out, patient was adjudicated as cardiac death by the Clinical Event Committee

34

Document identifier

In Vivo Serial Assessment of Vessel Geometry Restoration

34 degrees 14 degrees 25 degrees

31 degrees

Pre-procedure Post-procedure 6-month 12-month

Angulation was defined as the angle in degrees that the tip of an intracoronary guideline would need to reach the distal part of a coronary bend1

Curvature was defined as the infinitesimal rate of change in the tangent vector at each point of the lumen centerline1

1Stone P.H. and Feldman C.L., JACC 2010; 3(11): 1199-1201

31,29

46,52 43,68

4,57

10,27 6,77

29,27 25,96

28,64

34,88

17,25

20,91

0

5

10

15

20

25

30

35

40

45

50

Post-procedure 6 months 12 months

Perc

en

tage

(%

)

Fibrous

Dense Calcium

Necrotic Core

Fibrous Fatty

Serial IVUS Virtual Histology. (11 patients)

37

Document identifier

OCT Light Intensity analysis

41

Document identifier

1° endpoint Study completed Publication submitted1° subject in last subject in

Enrolment period

Design # subjects Status / Comment

Study Name PI Country

FUP=Follow-up LLL=Late lumen loss

2016 2017 2018 2019 2020 2021

MAGMARIS Study Portfolio

150915 clinical study roadmap 2015-2020, SPM Q3 2015, ege1

FIM Registry 46/50 subjects

Completed – 1° LLL 6m

Published in Lancet, 2013 3 year FUP publ. in June issue of EuroIntv: 10.4244/EIJY16M06_01

Koolen NL 3y FUP

FIM Registry 123/121 subjects

Lancet publication 2015 TCT 2015, EuroPCR 2016 European Heart: doi:10.1093/eurheartj/ehw196

3y FUP Haude DE 1y FUP

Postmarket Registry 1065 subjects

Verheye BE (EU) Lee HG (APAC)

1° EP

TLF 12m

1° EP

TLF 12m

Endpoint analysis every 200 subjects possible

TBD

RCT TBD subjects

1° EP

TBD12m

Planning phase V

Haude DE 3y FUP

FIM Registry 54/61 subjects

1° EP

Proc. Success

Enrollment 2° EP

1y LLL

TBD

India Registry TBD 100 subjects 1° EP

TLF 1m

Regulatory trial for Indian market access

VI 6m FUP

42

Document identifier

Conclusions

• Clinical outcome showed low TLF (3.4%) and TLR (1.7%), comparable to other absorbable scaffolds and permanent drug-eluting stents.

• There was no definite-or-probable scaffold thrombosis until 12-month FUP.

• Vasomotion is preserved

• Virtual Histology IVUS showed a decrease in dense calcium content over time, a surrogate endpoint for scaffold degradation.