Can Biodeggyradable DES Be Better than 2nd Generation DES?

G. Nakazawa, MD Tokai Univ. Japan CVCV--HILLsHILLs Receiving Research Grant From Abbott Vascul ar Japan Boston Scientific Japan Medtronic Vascular Japan Cordis Johnson & Johnson Terumo Corp. Biosensors Japan

Adv isory Con trac t With Abbott Vascular Japan Terumo Corp. Components of DES

Metal/Design Thick struts ~ 81-140 microns

Polymer Drugs Non-erodable Sirolimus-135µg Erodable Drug and Release kinetics Everolimus – 100 µg Determine Paclitaxel- 80 µg Antiproliferative effects Biolimus A9 – 225 µg Localized Hypersensitivity Reaction in Cyp her LAD: Cypher (17months) RCA: Cypher (17months) A B E

F C D

Nakazawa, G et al. J Am Coll Cardiol 2011: 57(4).390-8 Long Term Safety : Future Directions

LLonongg--TSftfDESFtDitiTTSftfDESFtDitiTermerm SSaaffeettyy ooff DESDES:: FFuuttureure DiDirecrectitionsons

Asymmetric Biodegradable No Polymer Polymer NoDrugDrug General criteria for selecting a pollymer for use as bioma ter ia l • Does not evoke an inflammatory/toxic response, disproportionate to its beneficial effect • Is metabolized in the body after fulfilling its purpose, leave no trace • Is easily processed into the final product form • Has acceptable shelf life • Is easily sterilized

Middleton JC and Tipton AJ. Biomaterials 2000;21:2335 Syygynthetic Biodegradable

• Poly(lactide) (PLA) • Poly(glycolide) (PGA) • Poly(glycolic-co-) (PLGA) • Pl(Poly(e-caprolactone)(PCL)) (PCL) • Poly(dioxanone) (PDS) • Poly(glycolide-co-trimethylene carbonate) (PGA-TMC) Degradation Speed in Various Biod egred abl e PlPolymers Material Degradation Period Polylactic acid (PLA) 9 months Polyglycolic acid (PGA) 2-3 months Poly-L-lactic acid (PLLA) 12-18 months Poly(d, l-lactide/glycolide) copolymer (PGLA) 2-3 months Polyorthoester (POE) 10 months (60%) Pl(hdPoly(hydroxy btbutyra t/hdte/hydroxyva lera t)te)copo lymer 6th6 months (PHBV) Polycaprolactone (PCL) 36 months Degradation

9 The degradation- 9 Factors which accelerate absorption mechanism is are the result of many the following: interrelated factors, — More hy drop hilic monomers including: — More hydrophilic, acidic — The ch emi cal st abilit y o f the endgroups polymer backbone — More reactive hydrolytic — The presence of catalysts group in the backbone — Additives — Less crystallinity — Impurities or plasticizers — Small device size — Geometry of the device — LtifthdiLocation of the device

Middleton JC and Tipton AJ. Biomaterials 2000;21:2335 PLA Metabolic Pathway

H2O PLA Hydrolysis

Molecular weight

Mass loss

Lactic acid

Mass transport of lactic acid

Krebs cycle CO2+H2O Bioerodable polymer breaks down into Polymer degradation products ands side products. The side products, mostly responsible for titoxic eff fftects

Commandeur S, J Interven Cardiol 2006 NOBORI Stent Platform

Biodegradable Drug/Carrier: - Biolimus A9® / Poly (Lactic Acid) 50:50 mix - abluminal surface only (contacts vessel wall) - 11 µmeter coating thickness

- degrades in 9 months releasing CO2+ water S-Stent™ Platform: - Stainless steel ((129129µm) - Open cell design - Quadrature-link™ connectors BioM atri x S tent strut PlParylene C - Different models for small and large vessels

Drug: Biolimus A9 15.6 µg/mm-stent length

2.5-3.0mm (6 crown 2 link) 3.5mm (10 crown 2 link) NOBORI– Strut and polymer thickness

Xience ENDEAVOR® DES NOBORI Stent Stent

Stent Cobalt Cobalt Stainless Material Chromium Chromium Steel

BMS Strut Thickness (in.) 0.0032” 0.0036” 0.0053”

BMS Strut Thickness (µm) 81µm 91µm 130µm

Polymer Thickness (µm) 7µm 6µm 18µm Drug Dose in various DES

280

240 µg)

d (µg 200

160 g Loa uu 120 Dr

80

40 88 µg 150 µg 180 µg 280 µg

0 XIENCE VTM Cypher Endeavor NOBORI 3.0x 18 mm 3.0x 18 mm 3.0x 18 mm 3.0x 18 mm Comparative Elution Profiles

100 ENDEAVORENDEAVOR™™ CYPHER® sedsed 80 XIENCE™ Relea Relea

%%%% 60 NOBORI

lative lative 40 u uuu

CumCum 20 TAXUS®

0 5 10 15 20 25 30 Days Percent Stenosis in Single DES in Rabbit Iliac Arteries following Deployment of Cypher, Taxus and Nobori stents at 28-days

Proximal Middle Distal

25

20 P = .0229 Cypher

enosis 15 tt

10 ercent S

PP 5

0 Taxus Cypher Taxus Nobori

Nobori Data from CVPath Institute, Inc. Fibrin Deposition in Single DES in R abbit Ili ac A rt eri es at 28 -days

Cypher 12.5 in 10.0

7.5 ith Fibr ww Taxus 5.0 truts SS 2.5 No.

0.0 Cypher Taxus Nobori

Nobori

Data from CVPath Institute, Inc. Inflammation in Single DES l

150 eterophi

Cypher HH

100 Eosinophil/ 50

0 No. Lumen Cypher Taxus Nobori Taxus

15.0 P = <.0001

12.5

10.0

ant Cells 7.5

5.0 No. Gi Nobori 2.5

0.0 Cypher Taxus Nobori Data from CVPath Institute, Inc. Overlapping Drug-Eluting Stents (Cypher, Taxus and Nobori) at 28-day

Proximal Middle Distal

Cypher )) 0.25

0.20 ness (mm

kk 0.15 Taxus 0.10 mal Thic ii 0.05

Neoint 0.00 Cypher Taxus Nobori Nobori

Data from CVPath Institute, Inc. Fibrin D epositio n in Ove rla pped DES at 28 d ays

Cypher™

20 P=0.01

15 Fibrin hh

Taxus™ 10 truts wit

SS 5 No.

0 Cypher Taxus Nobori

Nobori™

Data from CVPath Institute, Inc. Giant cells in Overlapped DES at 28-Days

Cypher™ 30

25

20

15 iant Cells GG 10 P=0.0007 Taxus™ No. 5

0 Cypher Taxus Nobori

Nobori™

Data from CVPath Institute, Inc. Single Nobori™ Biolimus A9-Eluting Coronary Stents 14 Dayyg Single 28 Dayyg Single Comparison of Various BMS and DES In Rabbit Iliac Arteries at 28-days Bx Velocity Cypher Express Taxus Tsunami Nobori apped ll over 28 Day Endothelialization

이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손 상되었습니다 컴퓨터를 다시 시작한전히 빨간색 후x가 파일을 나타나면 다시 이미지를 여십시오 삭제한 여 다음 다시 삽입해야 합니다 P0002P=0.002

P=0.02

이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손 상되었습니다 컴퓨터를 다시 시작한전히 빨간색 후x가 파일을 나타나면 다시 이미지를 여십시오 삭제한 여 다음 다시 삽입해야 합니다

) 100 %% 80 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손 상되었습니다 컴퓨터를 다시 시작한전히 빨간색 후x가 파일을 나타나면 다시 이미지를 여십시오 삭제한 여 다음 다시 삽입해야 합니다 Cypher tion ( aa 60 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손 상되었습니다 컴퓨터를 다시 시작한전히 빨간색 후x가 파일을 나타나면 다시 이미지를 여십시오 삭제한 여 다음 다시 삽입해야 합니다 Taxus

이미지를 표시할 수 없습니다. 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가. 컴퓨터를 손 상되었습니다 다시 시작한 후 파일을 다시. 여전히 여십시오 빨간색x가 나타나면 이미지를 삭제한 다음 다시 삽입해야. 합니다 elializ 40 Nobori hh

20 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손 상되었습니다 컴퓨터를 다시 시작한전히 빨간색 후x가 파일을 나타나면 다시 이미지를 여십시오 삭제한 여 다음 다시 삽입해야 합니다 Endot 0 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손 상되었습니다 컴퓨터를 다시 시작한전히 빨간색 후x가 파일을 나타나면 다시 이미지를 여십시오 삭제한 여 다음 다시 삽입해야 합니다 Non-overlapNon-Overlap Overlap Overlap

Data from CVPath Institute, Inc. Endothelial Function in NOBORI

Hamilos, MI et al. J Am Coll Cardiol 2008;51:2123–9 Is the really better than durable ones? Ongoing Pre-clinical Study

Study Title : Comparison of long -term safety following new generation drug eluting stents implantation in porcine coronary artery Purpose: Hypersensitivity reaction due to lack of biocompatibility has emerged as one of the major concerns in 1st generation drugrug--eeltiluting st ent s (DES) (DES)N. Newer generati on DES DESh has applied better polymer but the longlong--termterm safety is still unclear. The aim of this study is to evaluate the long -term safety following Xience V, Cypher, and Nobori DES in porcine coronary artery model. Test Articles:1. Xience V everolimus eluting stent 2. Cypher Select sirolimus eluting stent 3. NbNobor iBio limus el uti ng st ent Collaborators Kobe University Graduate School of Medicine Toshiro Shinke, MD (Study Co-Director) Daisuke Matsumoto, MD Hiromasa Otake, MD Junya Shite, MD

Tokai University School of Medicine Takeshi Ijichi, MD

Abbott Vascular Japan Masaharu Osa GOODMAN CO., LTD. Masaru Uchiyama Uchiyama Kentaro Asada Akiji Kato Toshio Kimura Yoshihiro Odagawa Study Design

Implantation of DES Sacrifice 6 animals for Histo Animal N=12 • Ach challenge test Each animal receives 3 DESs • OCT observation (XV, CS , an d NB) BfBefore sacr ifice

N=6 03M NN6=6 0 1M 6M

Sacrifice 6 animals for Histo • Acetylcholine challenge test • Ach challenge test • OCT observation • OCT observation 6 animals for 6M Before sacrifice Protocol ffyor Acetylcholine challeng e test

Baseline Angiography

10--66mol/l of acetylcholine (1ml/min) 2.5 mins 10--55mol/l of acetylcholine 2.5 mins (1ml/ mi n)

ISDN (200 -400ug)

Final Angiograph y

OCT Imaging Distal Proximal 100 100 75 75 MLD following Ach Challenge@1M

Baseline Baseline Xience Ach 10-6 Ach 10-6 Ach 10-5 Ach 10-5 ISDN ISDN

Baseline

Baseline Cypher Ach 10-6 Ach 10-6 Ach 10-5 Ach 10-5 ISDN ISDN

Baseline Baseline NOBORI -6 Ach 10-6 Ach 10 -5 Ach 10-5 Ach 10 ISDN ISDN Maximum Change in MLD following Ach Challenge@1M Proximal Distal

Xience ChCypher NbNobor i Xience ChCypher NbNobor i 0

-10

-20

-30 (%) - Preliminary OCT results -

1 and 3 months 1-month group OCT Analysis Status

6 pigs 18 lesions enrolled

XienceTM NoboriTM CypherTM

6 cases received 6 cases received 6 cases r eceiv ed Void: 1 case (poor image quality) 6 cases analyzed 5 cases analyzed 6 cases analyzed

17 lesions available Kobe Univ. Follow-up OCT Results ~ Neointima proliferation ~

Average Neointimal Area Average %Neointimal Area (NIA /Stent area) 2 (mm )(%)p=0.005* p=0.01* 2.4 35 2 30 222.2±060.6 31. 5±11. 5 25 1.6 20 24.0±12.2 1.2 171.7±090.9 15 0.8 10 14.1 7.0 0.9±0.5 ± 040.4 5 0 0

* Bonferoni/Dunn test Kobe Univ. Follow-up OCT Results ~ Neointima proliferation ~ Average neointima Neointimal thickness Uneveness Score (µm) P=0.006* (%) 300 4 P=0.01*

269±98 3 3.2±1.5 200

198±103 2 252.5±131.3 100 102±63 1 1.4±0.1

0 0

* Bonferoni/Dunn test Kobe Univ. Follow-up OCT Results ~ Neointimal coverage ~

NbNumber o f %Uncovered Struts (/ stent) Uncovered struts (%) P=0.004* 100 50 P=0.01* 80 40 41. 7±27. 0 60 64.7±53.3 30

40 20 24.5±23.8 36.4±41.3 20 10 0.5±0.8 040.4±080.8 0 0

* Bonferoni/Dunn test Kobe Univ. Histogram of %Uncovered struts (No of Uncovered struts/ total no of struts) XienceTM NoboriTM Cypher(TM) (% of lesions) N=6 N= 5 N= 6

100 Average % 0.4±0.8 24.5±23.8 41.7±27.0 MdiMedian 0 19. 5 42. 9 25% 80 0 11.6 23.7 Quartile 75% 60 0.5 32.0 59.9 Quartile

TM 40 Xience NoboriTM Cypher(TM) 20

0 0 10 20 30 40 50 6070 80 90 100 (%Uncovered struts) Kobe Univ. Follow-up OCT Results ~ Neointimal coverage ~ % of stents with at least 1 Average %CS with CS with RUST>30% RUST>30% (%) (%) P=0.02* 50 100 P=0.01 P=0.01* 100% 80 40 83.3% 38.6±28.5 60 30 34.7±28.0 40 20

20 10 0% 000.0±000.0 0 0

CS: Cross-section, RUST: a ratio of uncovered struts to total struts per cross section * Bonferoni/Dunn test Kobe Univ. 3-month group: OCT Analysis Status

6 pigs 18 lesions enrolled

XienceTM NoboriTM CypherTM Void: 1 case (Occluded at FUP) 6 lesions 5 lesions 6 lesions received received received

6 lesions 5 lesions 6 lesions analyzed analyzed analyzed 17 lesi ons avail abl e

Kobe Univ. Follow-up OCT Results @ 3 months ~ Neointima proliferation ~

Average Neointimal Area Average %Neointimal Area (NIA /Stent area) (mm2)p=0.002* (%) p=0.002* 8 100 p=0.004* p=0.01* 80 6 5.7±1.0 60 78.4±8.3 4 4.1±1.0 40 52.3±15.7 3.7±0.6 50.2±12.9 2 20

0 0

* Bonferoni/Dunn test Kobe Univ. Follow-up OCT Results @ 3months ~ Neointima proliferation ~ Average Neointima Thickness Neointimal Uneveness Score (µm) p=0.0005 (%) 1200 2 * p=0.003* N.S 1000 836±125 800 527±171 600 474±123 1 1.3±0.1 1.3±0.0 131.3±010.1 400 200

0 0

* Bonferoni/Dunn test Kobe Univ. 1- and 3-month OCT Results ~ Neointima proliferation ~

Average neoi nti ma thi ck ness NitilUNeointimal Uneveness S core (µm) 1000 4 836 3.2 800 3 2.5 600 527 474 2 400 269 1.4 131.3 131.3 131.3 198 1 200 102 0 0

Kobe Univ. Results from Histologic Analysis will be coming soon… Summary

• Improvements of DES technology allow us to treat more complilex patients • Althouggyh we intuitively feel that DES with biodegradable polymer would be favorable, it is still not clear that those are clinically better than DESs with good durable pollymers