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DREAMS and BIOSOLVE Trials Bioabsorbable scaffolds Update Dr. Rumoroso 28 Noviembre 2014 BIOTRONIK // Coronary Intervention Innovation

Dreams & papyrus

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Page 1: Dreams & papyrus

DREAMS and BIOSOLVE Trials Bioabsorbable scaffolds

Update

Dr. Rumoroso

28 Noviembre 2014

BIOTRONIK // Coronary Intervention Innovation

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Key characteristics of absorbable scaffold materials

Material PLLA Iron Magnesium Alloy

Tensile Strength (MPa) ~30-45 300 280

Elongation (%) 2 – 6 25 23

Total Degradation Time 2-3 Years > 4 years 9-12 months

Iron @ 28dMagnesium @ 28d

1 Ratner DB, et al. Biomaterials Science: Introduction to Materials in Medicine, 2nd Edition. Elsevier Academic Press, 2004. 2/3 Hermanwan H, et al. “Developments in metallic biodegradable stents. Acta Biometerialia. 6 (2012):1693-1697. 4 “A Cautionary Tale”, Ormiston, J., Serruys, P., et al., Circ Cardiovasc Interv 2011;4;535-538, Oct. 2011

PLLA @ 1m4

Biocompatibility

! Mechanics

!Absorption

Absorbablescaffolds

For coronary scaffolds, tailor-made Magnesium alloys provide the best balance

Iron @ 28d

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AMS  

165µm80µm

28-­‐day  histology

AMS 1.0: Absorbable Magnesium Scaffold from BIOTRONIK (2004)

No  drug  coating

!▪ Proprietary Mg-alloy

Low crossing profile (1.2 mm) High radial strength (~1 bar) Low bending stiffness Low recoil (<5%) !

▪ Excellent biocompatibility !

▪ 4-crown design !!

Clinical Study: !!

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Clinical studyPROGRESS-AMS

Study design ▪ Prospective, multi-center, consecutive,

non-randomized First In Man (FIM) trial !

Primary endpoint (reached) ▪ MACE *at 4 months <30 % !

Results (at 4 months) ▪ LLL 1.08 mm ▪ TLR 23.8% !

Conclusion ▪ Bare AMS (Absorbable magnesium

Scaffold) concept is safe and feasible ▪ Need for prolonged scaffolding time and

an anti-proliferative drug

Long-term FUP (~7 yrs) Clinical, angiographic, IVUS

4-month FUP Clinical, angiographic, IVUS

63 patients enrolled at 8 international clinical sites

6-month clinical FUP (n=61)

12-month clinical FUP (n=60)

Source: Erbel et al. Lancet 2007; 369: 1869–75. Waksman et.al, JACC Cardiovasc Interv 2009;2:312-320

* Composite of cardiac death, nonfatal MI, ischemia driven TLR

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Lessons learned from the bare AMS

PROGRESS-I showed the bare AMS concept to be safe and feasible

Optimization of device with prolonged scaffolding time and an anti-proliferative drug

Improvements for future AMS

Loss of scaffolding area (55%)

In-stent neointima (45%)

Post implantation 4 month follow-up

Contribution to lumen loss

! Source: Erbel R. et al., Lancet 2007;369:1869-75.

Waksman et.al, JACC Cardiovasc Interv 2009;2:312-320.

Results: ▪ LLL 1.08 mm ▪ TLR 23.8%

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From AMS to DREAMS G1Device evolution

AMS (Absorbable magnesium Scaffold)

165µm80µm

28-­‐day  histology

No  drug/polymer  coating

130µm120µm

DREAMS G1 (Drug Eluting AMS 1st Generation )

28-­‐day  histology

Paclitaxel  +  PLGA

▪ Refined Mg-alloy High radial strength (~1 bar) Normal ‘stent like’ deployment behavior

▪ Excellent biocompatibility ▪ 6-crown, 3-link design !Clinical Study: !!

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1  6  pts  withdrew  consent  for  imaging  FUP  (2  at  6-­‐month  and  4  at  12-­‐month  FUP)  2  1  pt    died  a  non-­‐cardiac  death  (Cohort  1).  2  pts  withdrew  consent  (1  Cohort  1  and  1  Cohort  2)  3  1  pt    died  of  a  non-­‐cardiac  death  1  pt  withdrew  consent

46  patients  with  de  novo  coronary  artery  stenosis

Mandatory  6mo:Clinical  FUP  (n  =  22)Imaging  FUP  (n  =  201)

Cohort  1  (n  =  22) Cohort  2  (n  =  24)Optional  6mo:

Clinical  FUP  (n  =  24)Imaging  FUP  (n  =  16)

Mandatory  12mo:Clinical  FUP  (n  =  232)Imaging  FUP  (n  =  201)

Optional  12mo: Clinical  FUP  (n  =  202)Imaging  FUP  (n  =  13)

Mandatory  24mo:Clinical  FUP  (n  =  202)

Mandatory  24mo:Clinical  FUP  (n=24)

Clinical studyBIOSOLVE-I

Study design ▪ Prospective, multi-center First In Man

(FIM) trial. Single, de novo lesions 3.0-3.5mm and ≤ 12mm long !

Primary endpoints

Cohort 1: TLF at 6 months Cohort 2: TLF at 12 months

!

Source:  M  Haude.  et  al.  Lancet  2013;  381:836-­‐44.    

Mandatory  36mo:Clinical  FUP  (n  =  203)

Mandatory  36mo:Clinical  FUP  (n=24)  

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BIOSOLVE-I study results 6-and 12-month late lumen loss (LLL)

6-­‐month  LLL  0.64  ±  0.50  mm

12-­‐month  LLL  0.52  ±  0.39  mm

LLL  of  the  bare  AMS  in  the  PROGRESS  study      at  4-­‐month:  1.08  ±  0.49  mm

Cumulative  Freq

uency  (%

)

In-­‐scaffold  LLL  (mm)

M Haude. et al. Lancet 2013; 381:836-44.

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BIOSOLVE-I study results Six to 36-month clinical & angiographic follow-up

Device Success 100% (47/47)

Procedure Success 100% (46/46)

Clinical Results 6-Month 12-Month 24-Month 36-Month

TLF 4.3% (2/46) 6.8% (3/44) 6.8% (3/44) 6.8% (3/44)

Cardiac death 0.0% 0.0% 0.0% 0.0%

MI2 0.0% 2.3% (1/44) 2.3% (1/44) 2.3% (1/44)

Scaffold Thrombosis 0.0% 0.0% 0.0% 0.0%

TLR (clinically driven) 4.3% (2/46) 4.5% (2/44) 4.5% (2/44) 4.5% (2/44)

In-scaffold LLL 0.64 ± 0.50 mm 0.52 ± 0.39 mm NA NA

1 M Haude. et al. Lancet 2013; 381:836-44. 2 Target vessel peri-procedural MI. 3 TLR occurred during 6M FUP, both pts had angina. 1 pt received an additional DREAMS during the initial procedure due to a flow-limiting bailout. 4 LLL not available at 24-month as no imaging FUP was performed 5 M Haude, oral presentation EuroPCR 2013. 6 R Waksman, oral presentation EuroPCR 2014.

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Post-implantation 12M FUP

Side Branch

Side Branch

Guide wire

shadow

Guide wire

shadowCalcium

Calcium

**

*

*

Source: Garcia-Garcia HM et al. Work in progress. Data presented at the EuroPCR 2014

Serial OCT analysis in DREAMS

* Strut Remnants

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Conclusions

▪ DREAMS demonstrates an excellent safety profile up to 12 months

▪ A TLF rate of 7.0% at 12 months after DREAMS implantation is similar to the results of ABSORB (7.1%; Cohort B)

▪ DREAMS demonstrated significantly improved efficacy at 12 months compared to the bare AMS:

▪ Reduction in LLL of 61% compared to the 4-month data of the bare AMS (1.08 vs. 0.52 mm)

▪ Reduction of TLR rate by 82% (26.7 vs. 4.7%)

▪ The late lumen loss remained stable between 6-and 12-month follow-up

▪ Vasomotion and natural vessel angulation were completely restored at 6-month follow-up

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study&name BIOFLOW1I BIOFLOW1IIIidentifier NCT01214148 NCT01553526

date4(main4end4point) 2010 2013study4type FIM,4single4arm all4comers4registry

PI Dr4Hamon Prof.4Waltenberger

number4of4centers 2 42geography Romania international

primary4end4point inLstent4LLL TLFsecondary4end4point TLR,4ST,4MACE... TVR,4ST,4sucess,4MACE...

41st4FUP 30d 6m2nd4FUP 4m 12m3rd4FUP 9m 36m

Other4FUP 12,4244&436m 60m

product&name Orsiro Orsiro Xience&Prime Orsiro Orsiro Xience

N 30 298 154 1356 1063 1056

InLstent4LLL4(mm) 0.054±40.224(9m)0.104±40.324

(9m)0.141±40.294(9m)

ST4(%)4(cumulative,4probable4&4definitive)

04(9m) 0.04(12m) 0.04(12m) 0.44(12m) 2.84(12m) 3.44(12m)

TLF4(%) 6.54(12m) 8.04(12m) 5.14(12m) 6.74(12m) 6.74(12m)CILTLR4(%) 6.74(9m) 3.54(12m) 4.74(12m) 3.04(12m) 3.44(12m) 2.44(12m)TVR4(%) 4.54(12m) 4.64(12m) 3.04(12m)TVF4(%) 8.14(12m) 7.84(12m)

cardiac4death4(%) 0.74(12m) 0.74(12m) 1.34(12m) 1.94(12m) 2.14(12m)TVMI4(%) 2.74(12m) 2.64(12m) 2.34(12m) 2.94(12m) 3.04(12m)

Binary4Restenosis4(%)4(inLstent)

04(9m) 2.164(9m) 1.344(9m)

All4MI4(%) 04(9m) 3.94(12m) 4.44(12m)

publicationHamon4et4al,4

EuroIntervention42013;8:1006L1011

other internal internal

primary4end4point

24m36,460m

results

source

Pilgrim4et.4al,4The4Lancet,4doi:10.1016/S0140L6736(14)61038L2

internal

TVR,4TLR,4ST,44MACE...9m 30d12m 12m

Prof.4Windecker

24 9international Switzerland

LLL TLF

BIOFLOW1II BIOSCIENCE

design

NCT01356888 NCT014431042013 2014RCT RCT4all4comers

Prof4WindeckerDr4Lefevre

Programa clínico DES Orsiro

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The  Lancet,  published  online  September  1,  2014

BIOSCIENCE  publicado  en  the  Lancet,  incluye  un  metaanálisis  con  BIOFLOW-­‐II

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META-­‐ANALYSIS  OF  BIOSCIENCE  AND  BIOFLOW  II

Risk  ratio  (95%  CI)Favours  BP  SES   Favours  DP  EES  

Target  lesion  failure            Bioflow-­‐II              Bioscience              Overall

Cardiac  death            Bioflow-­‐II              Bioscience              Overall

Target  vessel  myocardial  infarction            Bioflow-­‐II              Bioscience              Overall

Target  lesion  revascularisation            Bioflow-­‐II              Bioscience              Overall

BP  SES DP  EES

0.82  (0.41-­‐1.64)  0.98  (0.71-1.35)  0.95  (0.71-1.27)

19/298  69/1,063

12/154  70/1,056

1.03  (0.09-11.31)  0.90  (0.50-1.64)  0.91  (0.51-1.63)

2/298  20/1,063

1/154  22/1,056

1.03  (0.32-3.38)  0.96  (0.59-1.58)  0.97  (0.62-1.53)

8/298  30/1,063

4/154  31/1,056

0.74  (0.29-1.90)  1.51  (0.90-2.54)  1.18  (0.61-2.30)

10/298  35/1,063

7/154  23/1,056

0.25      0.5            1                2                4          

Risk  ratio  (95%  CI)

BIOSCIENCE  confirma  los  resultados  de  BIOFLOW-­‐II  en  una  gran  población  de  pacientes  más  compleja.  Especialmente  para  los  criterios  de  valoración  más  dificiles:  IM  y  muerte  .

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DREAMS G1 (Drug Eluting AMS 1st Generation )

120µm

90-Day Faxitron, porcine explant

Paclitaxel + PLGA

DREAMS G2 (Drug Eluting AMS 2nd Generation )

150µm

Sirolimus + PLLA (BIOlute)

90-Day Faxitron, porcine explant

DREAMS evolution from 1st to 2nd generation

▪ Optimized design: 6-crown 2-link ▪ 120-150µm strut thickness* ▪ Addition of 2x markers at each end ▪ Improved delivery system !!!!! Clinical Study:

*3.0 and 3.5 scaffolds :150µm strut thickness 2.5 scaffold: 120µm strut thickness

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At the beginning T  =  0:  Immediately  following  scaffold  deployment  ▪ Drug  starts  to  elute  ▪ No  signs  of  degradation  in  coating  or  metalT = 0

Vascular restoration therapy: Bioabsorption in single steps

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Vascular restoration therapy: Bioabsorption in single steps

Second phaseT  =  1  month    ▪ Drug  elutes  from  the  polymer  ▪ Healing  begins  with  minimal  tissue  growth    ▪ The  magnesium  core  starts  to  corrode  and  converts  

gradually  to  Mg-­‐oxide

T = 1 month

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Vascular restoration therapy: Bioabsorption in single steps

T = 3 months

Third phaseT  =  3  months    ▪ Drug  elution  is  completed  ▪ Magnesium  is  further  corroded  and  converted  to  Mg-­‐

oxide.  Bioabsorption  of  Mg  has  not  yet  started  ▪ Struts  are  mostly  covered  with  tissue

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Vascular restoration therapy: Bioabsorption in single steps

T  =  9  months    ▪ Magnesium  core  is  fully  converted  into  Mg  oxide.  

Mg  oxide  converts  to  hydroxyapatite  ▪ Cracks  appear  and  are  infiltrated  by  SMCs;  material  is  

getting  bioabsorbed

T = 9 months

Fourth phase

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Vascular restoration therapy: Bioabsorption in single steps

T  =  1  year    ▪ Most  of  the  scaffold  material  has  been  bioabsorbed

T = 1 year

Fifth phase

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Vascular restoration therapy: Bioabsorption in single steps

T  =  1.5+  years    

▪ All  foreign  material  is  gone,  only  cells  are  left  

▪ Vessel  has  returned  to  its  natural,  healed  state

T = 1.5 years

Completed

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121 patients with de novo coronary artery stenosis

1 month Clinical FUP

6 month Clinical FUP Angiographic FUP (mandatory) IVUS / OCT (Subgroup only)

Vasomotion (if patient consents)

12 month Clinical FUP Angiographic FUP (voluntary) IVUS / OCT (Subgroup only)

Vasomotion (if patient consents)

3 year, Clinical FUP

2 year, Clinical FUP

DESIGN

▪ Prospective, multi-center, FIM. Single de novo coronary artery lesions in up to two coronary arteries, RVD between 2.2-3.8 mm and ≤ 21 mm long

!PRIMARY ENDPOINT

▪ In-scaffold late lumen loss @ 6-month !

COORDINATING CLINICAL INVESTIGATOR

▪ Prof. M.Haude, Lukaskrankenhaus GmbH, Neuss, Germany !

CORELAB

▪ Cardialysis, Rotterdam, The Netherlands

BIOSOLVE-II Study Design

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Post-dilatation capability of DREAMS scaffold

DREAMS crimped (3.0mm nominal) Expansion to 3.0mm

Over expansion to 5.0mm

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Potential for side branch access

Kissing balloon inflation: MB 3.0 mm / SB 2.5 mm

D = 1.3mm

5.5mm

*Experimental, N=1

Experimental* post-dilatation of DREAMS shows potential side-branch access

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Coating integrity of DREAMS

SEM images of expanded 3.0 mm DREAMS (expansion diameter 3.5 mm)

SEM images of expanded 3.0 mm DREAMS (expansion diameter 4.25 mm)

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Summary

▪ Magnesium offers an ideal balance between biocompatibility, mechanical performances and absorption

▪ The Biotronik absorbable Mg program is most advanced: - BIOSOLVE-I has proven safety of DREAMS 1. generation with

Paclitaxel elution and improved efficacy compared to the bare AMS version

- BIOSOLVE-II is currently testing safety and efficacy of DREAMS 2. generation with Sirolimus elution

!▪ In about a year we will have the DREAMS-2 available in our shelfs

if the BISOLVE II trial gets the primary endpoint in terms of efficacy and safety

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PK Papyrus Covered coronary stent systemIndicated for acute coronary artery perforations

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Crossing profile [mm diameter]

Data on file at BIOTRONIK; * Ø 2.5-4.0 mm

6F 5F

24% reduction

Guide catheter compatibility*

Jostent Graftmaster 3.0/16 Sandwich design

PK Papyrus 3.0/15Covered single stent design

Covered single stent design allows for low crossing profile and 5F guide catheter compatibility*

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High flexibility and low crossing profile for exceptional deliverability – allowing you to seal perforation with confidence

Nmm²

0 27,5 55 82,5 110

Bending stiffness of crimped stent

58% reduction

Jostent Graftmaster 3.0/16

PK Papyrus 3.0/15

Data on file at BIOTRONIK

Expect PK Papyrus to deliver like a conventional stent

Track Force in coronary artery model [N]

0,0

0,6

1,3

1,9

2,5

Distance [mm]

0 50 100 150 200

53% reduction in maximum track force

PK Papyrus 3.0/20Jostent Graftmaster 3.0/19PRO-Kinetic Energy 3.0/20

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PK Papyrus Compliance Chart

Pressure (ATM) Ø (mm)

2.5 3.0 3.5 4.0 4.5 5.05 2.38 2.85 3.33 3.86 4.33 4.826 2.42 2.90 3.39 3.93 4.41 4.91

NP 7 2.46 2.95 3.44 4.00 4.50 5.00NP 8 2.50 3.00 3.50 4.07 4.59 5.09

9 2.54 3.05 3.56 4.14 4.67 5.1810 2.58 3.10 3.61 4.21 4.76 5.2711 2.62 3.15 3.67 4.28 4.84 5.3612 2.67 3.20 3.72 4.36 4.93 5.4513 2.71 3.25 3.78 4.43 5.02 5.54

RBP 14 2.75 3.29 3.83 4.50 5.10 5.6315 2.79 3.34 3.89 4.57

RBP 16 2.83 3.39 3.94 4.64

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Control 11 meses

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Conclusión

▪ Papyrus es un dispositivo que se convierte en un MUST en las estanterías de las salas de hemodinamica para evitar complicaciones graves, ya que tiene una alta capacidad de sellado coronario

▪ Es un dispositivo cuyo performance es equivalente al BEST IN CLASS de los DES de última generación

▪ No hay que utilizar catéteres guía de mayor perfil

▪ Pasa perfectamente por un GuideLiner de 6F

▪ El performance del stent queda patente en los casos testados

▪ La comprobación al año da idea de la eficacia y seguridad del dispositivo

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