BP-DES Update:Bioresorbable Polymer SYNERGY and Beyond

Dean J. Kereiakes, MD FACC FSCAIDean J. Kereiakes, MD FACC FSCAIMedical Director, The Christ Hospital Heart &Medical Director, The Christ Hospital Heart &Vascular Center and the Lindner Research Center atVascular Center and the Lindner Research Center atThe Christ Hospital, Cincinnati, OhioThe Christ Hospital, Cincinnati, OhioProfessor of Clinical Medicine, Ohio State UniversityProfessor of Clinical Medicine, Ohio State University

Disclosure Statement of FinancialInterest

• Modest Consulting Fees• Modest Consulting Fees

• HCRI• SINO Medical Sciences Technologies, Inc.

W ithin the pas t12 months , Iormy s pou s e/partnerhave had afinanc ialinteres t/arrangementoraffiliation with the organization(s )lis ted below.

A ffiliation/Financ ialRelations hip C ompany

• Modest Consulting Fees• Significant Consulting Fees• Significant Consulting Fees• Significant Consulting Fees• Significant Consulting Fees• Significant Consulting Fees• Major Stock Shareholder/Equity

• SINO Medical Sciences Technologies, Inc.• Boston Scientific Corporation• Abbott Vascular• Svelte Medical Systems, Inc.• Micell Technologies, Inc.• Caliber Therapeutics• Ablative Solutions, Inc.

MACE After Metallic StentsA Patient-Level Pooled Analysis of 17 RCTs (N=18,250)

BMS

Bare Metal StentFirst Generation DESSecond Generation DES

18.3%20

30

2G-DES

Number at Risk

BMS 2,850 2,538 2,277 2,168 2,127 2,061 1,837 1,438 1,385 1,321 463

1st DES Gen. 6,916 6,447 6,203 5,982 5,842 5,684 4,780 3,238 2,921 2,525 1,455

2nd DES Gen. 8,484 8,196 8,007 7,841 7,668 7,524 6,895 3,912 3,375 2,702 1,912

8.4%

4.3%

11.4%10.6%8.5%

Time in M onths0 6 12 18 24 30 36 42 48 54 60

10

0

M a dha ve n,Stone ,e ta l.J A m C oll C a rdiol.2 0 16; 68 (1 8 _S ): B 1 29-B 130 . d oi: 1 0 . 1 0 16/j. jac c . 2 0 16. 0 9. 444

Meta Analysis of 13 RCCT Involving 17,097 PatientsEES vs non-EES DES

Stent Thrombosis TVR MI

Statistical Model

Random (13)

Fixed (13)

ClopidogrelDurationDuration

6 months (5)

12 months (7)

Follow-up

≤ 1 year (12)

> 1 year (7)

0 . 1 1 1 0EES Non-EES

Favors

Baberetal.JA CC 2011;58:1569-77

0 . 4 4EES Non-EES

0 . 4 4EES Non-EES

Thromboresistance of PVDF Polymer Coating

0.8

1.0

1.2 P=0.002

for

Ste

nt

Form

uation]/

VIS

ION

(81μm

)]

Relative Platelet Adhesion in Ex-vivo flow loop model

Kolandaivelu,K.etak.,Circulation2011

1.00

0.76

0.0

0.2

0.4

0.6

CoCr VISION PVDF[LD

HAdsorb

ance

for

Ste

nt

[LD

HA

dsor

banc

efo

rCoCr

VIS

ION

(81

XIEN CE

Stent Design Iterations that Impact Thrombosis/MACE

I. Strut Thickness (thinner)• Rapid /c omplete s tentcove ra ge /he a ling• Infla m m a tion• Throm boge nicity (zones oflow s hears tres s )

II. Polymer• Composition (thrombores is tant–P VD F)• Composition (thrombores is tant–P VD F)• BP vs . D P• Distribution (Abluminal only vs . C onformal)• Time Course for B P Resorption (< 3-4 vs . 9 -1 8 months

vs permanent)

III. Platform Flexibility/Conformability• Geometric D is tortion• Frac tu re Res is tanc e (thrombos is /res tenos is )

“Best in Class” Permanent polymers

HypersensitivityMalappositionLate catch-upLate thrombosisNeoatherosclerosisS trut

T hickness140 µm 89 µm 91 µm

Cypher

X ience/P rom us

P VDFR esoluteIntegrity

BioL inx

Neoatherosclerosis

T h T h

N eoatherosclerosisL atecatch-up(S ES ) Hypersensitivity reactionM alappositionfrom

excessivefibrindeposition

T h

T hickness140 µm 89 µm 91 µm

CoatT hickness

7µm 8µm 6µm

0

0.1

0.2

0.3

≥1 to <9 ≥9 to <18 ≥18

N eointim althickness

O tsukaFetal.EurHeartJ.2015;36(32):2147-59.O tsukaFetal.Circulation.2014;129(2):211-23.

BP-DES Platforms in Perspective

Biomatrix Nobori SYNERGY MiStent Orsiro Slender BuMA

316L-BES 316L-BES PtCr-EES CoCr-SES CoCr-SES CoCr-SES CoCr-SES

Strutthickness

120µm0.0046”

125µm0.0047”

74µm0.0029”

64µm0.0025”

61µm0.0024”

81µm0.0032”

80µm0.0031’’

Polymer PLA PLA PLGAConformal

PLGA

ConformalPLLA/

Probio*

Conform PEA(Poly(ester)a

mide)

ConformalPBMA/PLGA

Distribution /thickness

Abluminal10µm

Abluminal20µm

Abluminal 4µmConformal

5µm / 15µmConformal

3.5µm / 7.5µmConformal 6-7

microns

Conformal3-10µm

*silicon carbide

9

9

9

6-9

6-8

3

≤4

≤2

6

6

1

3

6-8

9

3

≤2

NOBORI (PLA)

BIOMATRIX (PLA)

FIREHAWK (PLA)

ELIXIR DESyne BD (PLA)

ABLUMINUS (PLA)

MiStent (PLGA)

SYNERGY (PLGA)

BuMA (PLGA)

Time Course For Polymer Bioabsorption

Drug ReleaseBioabsorbable PolymerBioResorbable Scaffold (BRS)

42

36

24

12-18

12

15

12

9

3

3

3

3

3

2

6

0 5 10 15 20 25 30 35 40 45

REVA ReZolve (Polycarb)

BVS (PLLA)

ELIXIR DESolve (PLLA)

ART (PDLLA)

DREAMS 2 (Mg w/ PLLA* Coat)

ORSIRO (PLLA)

SVELTE (Amino Acid)

NOBORI (PLA)

Time (Months)

(no drug)

*P L L A ~24 m onths

SYNERGY Stent design elements : enhanced healing

Drug& P olym erCoatingDrug& P olym erCoating Ablum inal(4Ablum inal (4μμm )m )

S EM ofcoating(x5000)S EM ofcoating(x5000) L um inalL um inalEverolim usDrugEverolim usDrugP L GA P olym erP L GA P olym er

P latformP latinum chrom ium

• 74 μ m (0.0029in)

• R adialS trength,>visibility

• R ecoil

• Flexibility,conform ability

P olym erCoatingP L GA

• A blum inal

• 4 µm thick

• 85:15ratio

DrugEverolim us

•100 μg/cm 2

Stent Thrombosis at 2 years:EVOLVE II Pivotal Trial for FDA Approval

Definite/Probable : ITT Population

P R O M U SElem entP lus

S ubacute(2-30 d) L ate(30 d– 1 y)

0.8%

(N=6)

Acute (≤1 d)

N=5(2 Definite/3 Probable)

Very L ate(1 – 2 y)

N=1(Def)

S YN ER GY

Elem entP lus

0.4%

(N=3)

P=0.31

N=1(Prob)

N=2(Definite)

N o definiteS T in theS YN ER GY arm after24 hours

Kereiakes etalACC 2016

(PtCr-PVDF-EES)

(n=838

(PLGA-EES)n=846

ST Landmark Analysis: EVOLVE IIDefinite/Probable ST after 24 hours

PROMUS Element Plus vs SYNERGY>24 h Landmark HR 0.16 [0.02, 1.37]

P=0.056

Definite/P

robable

ST

(%) 4

2

3

1d 6 mo 12 mo 24 mo

0.8%

0.1%Definite/P

robable

ST

(%)

0

2

1

‡Day 715 – DefiniteS T w hileon AS A,no P 2Y12 inhibitor

*

IT T ;P atientsw ho didnotreceiveastudy stentw erecensoredat1 year;KM EventR ate;log-rankP values

KereiakesetalACC 2016

1d 6 mo 12 mo 24 mo

Definite or Probable Stent Thrombosis: NetworkMeta-Analysis of 147 Trials / 126,526 Patients

Kang S, et al. JACC CI 2016; doi:10.1016/j.jcin.2016.03.038

(SYNERGY)

SCAAR Registry Definite ST RatesSYNERGY vs Other Current Generation DES

0.6

0.5

0.4

0.3

Cum

ula

tive

rate

of

def

ST

(%)

Cum

ula

tive

rate

of

def

ST

(%)

0.6

0.5

0.4

0.3

All Patients ACS Subset

n-DES*, N=64,429SYNERGY, =7,886

0.2%

0.4%

0.3%

0.5%n-DES*, N=44,845SYNERGY, N=5,294

0.2

0.1

0

0 2 4 6 8 10 12

Cum

ula

tive

rate

of

Time after PCI (months)

adjusted HR: 0.69;95% CI: 0.37-1.37; p=0.29

*n-DES includes:BioM atrix,O rsiro,P rom us Elem entP lus,P rom us P R EM IER ,XienceXpedition,R esolute/R esoluteIntegrity,U ltim aster,&R esoluteO nyx.S arno CR T 2016

Cum

ula

tive

rate

of

adjusted HR: 0.68;95% CI: 0.38-1.19; p=0.17

0 2 4 6 8 10 12

Time after PCI (months)

0.2

0.1

0

No def ST past 6 months for SYNERGY in both groups

0.2%

• P ros pec tive, two-c enters tu d y evalu ating42 patients rec eivingS YN ERGY P tC r-EES

• O C T as s es s mentof22 patients (30 s tents )in the 3 monthgrou pand20 patients (30 s tents )in the 6 monthgrou p

Early healing assessment with OCT of SYNERGY at 3 and 6months after implant

O CT findingsatstrutlevelanalysis

S YN ER GY3-m onth

S YN ER GY6-m onth

P-valuelevelanalysis 3-m onth

N =30 stents6-m onth

N =30 stents

Covered(% ) 94.5± 4.4 96.6± 2.7 <0.001

A pposed(% ) 93.8± 5.7 96.2 ± 4.4 <0.001

U ncoveredM alapposed(% ) 3 ± 3.6 1.8± 2 <0.001

U ncoveredA pposed(% ) 2.5± 3.7 1.9 ± 2.2 0.03

DelaT orreHernandez,etal.Catheterization andCardiovascularInterventionsDO I10.1002/ccd.

T R AN S FO R M O CT *

R andom ized1:1

S YN ER GYBiodegradableA blum inalP L GA

P olym er(4 m os)-EES

Index:

R ES O L U T EIN T EGR IT YP erm anentConform al(BioL inx)

P olym er-ZES

P re+ P ostS tentO CT / Q CA

*Giulio Guaglium i.T CT 2016 L BCT

Index: P re+ P ostS tent

3 m os:

18m os:

S trutCoverage

N eoatherosclerosis

O CT / Q CA

O CT

O CT / Q CA

T R AN S FO R M O CT :S erialO CT S trutCoverage

BP-EES SYNERGYDP-ZES RESOLUTE

3 m onthsm edianpercentageofcoveredstruts

79.1 (IQ R 60.4,89.8)

78.4 (IQ R 62.1,87.8)p = 0.93

* % ofcom pletely em beddedstruts

18m onthsm edianpercentageofcoveredstruts

99.4 (IQ R 96.6-100)

98.0 (IQ R 94.4-99.8)p = 0.14

Gu agliu mietal, TC T 20 16

*

P rim ary Endpoint: % P atients w ithfram es show ingN eoatherosclerosis

BP -EES S YN ER GY DP -ZES R ES O L U T E

20

25

30

P =0.25

%

30

40

50

P =0.59

%

Gu agliu mietal, TC T 20 16

(546± 52 days)L ipidladenneointim a

2.4%

0

5

10

15

0.8% 2.4%

EES ZES

P =0.25

% P atientsw ithN eoatherosclerosis

0

10

20

30

11.6%15.9%

EES ZES

BIO-RESORT Trial Design

R andom ized,prospective,m ulticenter,single-blind,all-com ertrialN =3540

R andom ized1:1:1Stratified for Diabetes Mellitus

S YN ER GYBiodegradableA blum inalP L GA

O R S IR OBiodegradableConform alP L L A

R ES O L U T EIN T EGR IT YP erm anentConform al(BioL inx)

P olym er(4 m os)-EES

*Com positeofall-causedeath,any M I,any revascularization; L am ,O .,etal.A m HeartJ2014;vonBirgelenetal.T CT 2016

• P rim ary Endpoint:IncidenceofT VFat1 year(com positeofcardiacdeath,T V-M I,orclinically-driven T VR )

• S econdary Endpoints:Death,M I,revascularization,AR C S T ,T L F,M ACE,P O CE*,increm entalcost

• Follow -up: 30 days,1 and2 years (follow -up beyond2 years is intended)

1 N on-inferiorityEndpoint:1-yearT VF

1 N on-inferiorityEndpoint:1-yearT VF

P olym er(15-18 m os)-S ES P olym er-ZES

BIO-RESORT: Clinical Events During 1-Year Follow-up

4.7

5.4

4.7

4

5

6S YN ER GY (m =1172)

R ES O L U T E(m =1173)

O R S IR O (m =1169)

%

** **

0.4

1.5

0.5

1.5

0.4

1.6

0

1

2

3

T argetVesselFailure A R C Def/P robS T * T argetL esionR evasc

*~86% DA P T adherenceat1-year/ longer-term f/u Von Birgelen T CT 2016 L BCT /L ancet(eP ub)

%

** P noninferiority < 0.0001

Orsiro Hybrid Drug Eluting Stent

Stent platform: PRO-Kinetic Energy• Cobalt Chromium, L-605• 60µm struts, double helix design

Active coating: BIOlute (Conformal)• PLLA* bioabsorbable polymer matrix

Windecker et al. TCT 2013

• PLLA* bioabsorbable polymer matrix• Sirolimus (Drug load is 1.4µg/mm2

Passive coating: PROBIO• Silicon carbide** layer that encapsulates the

stent surface, reducing ion release andprevent corrosive process

* Poly-L-lactide** aSiC:H amorphous silicon carbide

668 Orsiro pts from two historical studies339 Xience Prime pts from two historical studies

BIOFLOW-II(2:1 RCT)

298 Orsiro, 154 XiencePrime

BIOFLOW-IV(2:1 RCT)

370 Orsiro, 185 XiencePrime/Xpedition

BIOFLOW-V(2:1 RCT)

889 Orsiro, 445 XienceInternational, Multi-center

PRINCIPAL INVESTIGATOR

David Kandzari, MD, Atlanta, GA (USA)Jacques Koolen, MD, Netherlands (OUS)

BIOFLOW-V Study Design

22

BIOFLOW-V

1 & 6 month follow-up

12 month follow-up, TLF Secondary Endpoint

2, 3, 4, 5 yr. follow-up

1 & 6 month follow-up

12 month follow-up,TLF Primary Endpoint

2, 3, 4, 5 yr. follow-up

Non-inferiority analysis of 12 mo. TLFBayesian Study Design

Clinical Sites:US: ≤ 100OUS: ≤ 50

CAUTION- Investigational Device. Limited by United States Law to Investigational Use.

SLENDER Integrated Delivery System (IDS)Designed to Facilitate TRI, Direct Stenting

Drug-Eluting Coronary Stent-on-a-Wire Integrated DeliverySystem (IDS)

• Lowest profile DES system available, downsizes sheaths and catheters (0.047” ID* compatible)• Reduces the procedural steps, time and cost of PCI

*5F diagnostic catheter

Technology Designed for Direct Stenting

~ ½ the crimped cross-sectional profileof current DES*

A sahiACT O N E™ w iretip technologyW orld’sleadingguidew irebrand(with co-branding relationship)

Asahi Wire Tip Technology

Incorporates Asahi Wire Tip Technology

Low-compliant balloon material allows high-

pressure inflation; PEA bioresorbableamino acid drug coating (DIS CR EET )

Ultra-low Profile, Conformable Stent

Co-PRINCIPAL INVESTIGATORSDean Kereiakes, MD, Cincinnati, OH (USA)

Laura Mauri, MD, Boston, MA (USA)

Clinical Sites:

1630 Patients (815 Slender IDS / DIRECT Rx / 815 Xience or Promus)

1 & 6 month follow-up

150 patient angiographic, 60 patient IVUS sub-studies

OPTIMIZE International IDE

CAUTION- Investigational Device. Not available for sale in the USA. SLENDER IDS is CE approved. Indications, contraindications,warnings and instructions for use can be found in the product labeling supplied with each device.

Clinical Sites:

USA andCanada ≤ 90Japan ≤ 10EU ≤ 20

12 month follow-upTLF Primary Endpoint, NI margin 3.58%, α 0.025 (ITT)

in-stent LLL sub-study endpoint, NI margin 0.15mm, SD +/-0.32, α 0.05

2, 3, 4, 5 yr. follow-up

Study will include collection of data on direct stenting, radial accessand procedural efficiencies (independent economic analysis)

1 & 6 month follow-up

MiStent® Sirolimus Eluting Stent

S tentandDelivery S ystemS tent– GEN IU S ® M agicS tentandR x Catheter• CEM arkthin strut(64µm )cobaltchrom ium coronary stent• Flexibleandtrackablew ithvisibility andaccuracy

P olym er– Conform alP L GA (50:50 L :G ratio)

• Clearedfrom stentin 45-60 days leavingaBM S

Drug– S IR O L IM U S• Crystalline form (form odifiedrelease)• Extensively testedandproven drug• Highly effectiveforsuppression ofN IH

• Clearedfrom stentin 45-60 days leavingaBM S• P olym erelim inatedfrom tissuein 90 days• 96-98% strutcoverageat8-9 m onths1

IllustrativeS EM ofM iS tentDES

S tentP latform

1DES S O L VEIT rial;Dataon file,M icellT echnologies

S tep2 : Fu s ion ofpolymerpartic les into ac onformal, s mooth, well-ad hered film

S tep1 : D ry, prec is e powd erc oatingu s ings u perc ritic alflu id s

Electrostatic coating Particle fusion

CreatingaN ovelDrug-ElutingS tent

P roprietary S upercriticalFluidT echnology

P roprietary coatingprocess enables crystallinedrugw ithin rapidly absorbablecoatingw hichprovides for“dialingin” optim alelution profileandpharm acokinetics

S ubstrateorlow erlayerS ubstrateorlow erlayer

26T heM iS tent® S irolim us ElutingAbsorbableP olym erCoronary S tentS ystem (M iS tentS ES )has receivedtheCEM arkbutis notapproved forsaleorusein theU nitedS tates by theFDA.

MiStent Sirolimus Release Post-DeploymentIn Porcine Coronaries

Fractio

nalR

esidu

alDru

g

1.2

1.0

0.8

0.6

Carlyle,Edelman et al. Journal of Controlled Release 2012;162:561-7

* ”Drug release complete by 45-60 days”**Arterial concentration -endoluminal mural depot of microcrystals 6-9 mos

Fractio

nalR

esidu

alDru

g

0.4

0.2

0

**

*

Therapeutic Tissue Levels Through 9 Months

300

400

500

600

700

Art

eria

lSir

olim

us

(ng

/mg

)

Art

eria

lSir

olim

us(n

g/m

g)

0 . 0 0

0 . 50

1 . 0 0

1 . 50

2 . 0 0

2 . 50

3. 0 0

3. 50

Lansky A. CRT 2014

0

100

200

300

0 50 100 150 200 250 300 350 400

Art

eria

lSir

olim

us

(ng

/mg

)

Days after Implantation

0 . 0 01 8 0 230 2 8 0 330 38 0

GLP Studies in Porcine Coronary Model: Pharmacokinetic Study N=8, averaged results

180-365 day levels

Days after Implantation

DifferentialDrugDistributionU niqueM echanism ofA ctionDistributesDrugBroadly inT issue

•Strut-adherent coatings resultin largepool of drug around area of injury

•Dissociating delivery from the stent strut

‒ An absorbable polym er with crystalline drug thatflows away from the struts

• Highandlow gradients of polymer and drug are eliminated

S

29T heM iS tent® S irolim us ElutingAbsorbableP olym erCoronary S tentS ystem (M iS tentS ES )has receivedtheCEM arkbutis notapproved forsaleorusein theU nitedS tates by theFDA.

Adaptedfrom “T heL inkBetw een P reclinicalT estingandClinicalP erform anceandO utcom es,”presentedatEuroP CR 2015 by Dr.ElazerEdelm an

Carlyle,… T zafririandEdelm an JCR 2012Balakrishnan,T zafriri… andEdelm an Circ2005

BuMA Supreme DES Components

• B are metals tent– A thin (80 µm)CoCr stent d es igned

ford eliverability and d u rability

• B as e layer– A thin (10 0 -20 0 nm)permanentpoly n-

bu tylmethac rylate (PBMA)c oatingbu tylmethac rylate (PBMA)c oatingelectro-grafted (eG) onto CoCr stentto improve ad hes ion ofthe topc oat

• Topc oating– A poly lac tic -c o-glyc olic ac id (PLGA)

biod egrad able c oatingc ontainings irolimu s (~1 . 2 µg/mm 2 ). The P L GA isabsorbed in ~6 weeks withd ru gmeas u rable in the artery for150 d ays .

eGTM + Biodegradable Drug Carrier

bio

degra

dable

coatin

g3.8

-10µ

me

Inte

rdig

itati

BuMA

Mechanical integrity of coating(expand ed in air)

eG

base

laye

r200nm

meta

l0.1

mm

tion

anotherD ES

inmarket1

e G™ bas e layers ec u res ad hes ion ofthe biod egrad able polymermatrix hos tingthed ru g, prevents c rac kingand d elamination u pon expans ion and overtime.

1 JohnO rm istone ta l.Pre nse nta tiona tTC T 2004

PIONEER III TRIAL DESIGN (IDE)Patients with ≤ 3 native coronary artery lesions ≤ 2 m ajor coronary

arteries in RVD of ≥2.25m m to ≤4.00m m , lesion length ≤33m m , %DS

≥50<100.(Chronicstable/unstableanginaor

N S T EM I)

R andom izedcohort(R CT )

1632 patients

U pto110 globalsites(N orthA m erica,EU ,Japan)

BuM A S uprem eN = 1088

A m erica,EU ,Japan)

Everolim uselutingstents(durablepolym er)

X IEN CEfam ily / P rom usElem entfam ily

N = 544

N on-inferioritytrial,globalm ulti-centerP ivotal,singleblind,2:1 random ization

P rim ary endpoint:1 yearT L F(CD,T V-M I,orT L R )at12 m onthFollow -upthrough5yearsDA P T (ASA + clopidogrel, ticlopidine, prasugrel, ticagrelor) ≥ 6 m onths or longer as tolerated

P R IS O N IV: O rsirovs.X ienceforCT O *Clinical(1 Year)andA ngiographic(9 M onths)Endpoints

8.08.0

9.29.2

6.06.0

7.07.0

8.08.0

9.09.0

10.010.0

O rsiroO rsiro XienceXience

P =0.28 P =0.08

n=165 n=165

0.70.70.130.13 0.120.12

2.12.1

4.04.0

0.70.7

0.020.02 0.070.070.00.0

1.01.0

2.02.0

3.03.0

4.04.0

5.05.0

Binary (>50%)Restenosis

CI-TLR In-Segment In-Stent

* > Plaque Burden/Fibro-Calcific Content

StentThrombosis

Teeuwen et. al. TCT 2016 LBCTJACC CI (in press)

P =0.11(N I)

P =0.52(N I)

(MM)

Efficacy and Safety of BP-DES:Conclusions

• Iterationsinm etallicstentplatform com ponents(strutthickness,polym er,drug)canfacilitate/ expeditestentcoverage/ healingandmay reducelateadverseclinicalevents;? shorterDA P T

• BP -DES aredifferentiatedby strutthickness,polym er• BP -DES aredifferentiatedby strutthickness,polym ercom position,distributionandloadasw ellasthetim ecourseforpolym erresorbtion.? U ltra-thinstrutsm ay havelim itations.

• BP -DES w illdem onstrate> rapidandcom pletestentcoverage/healing,low ratesofS T and> easeofdeliverability.T heseplatform sw illbethew orkhorsedevicesofthevery nearfuture.