Abbott)(Abbott)

ABTABT 578578 ElutionElution fromfrom Phosphorylcholine:Phosphorylcholine: ZomaxxZomaxx (Abbott)(Abbott)

AlanAlan Yeung,Yeung, MDMD ProfessorProfessor ofof Medicine,Medicine, InterventionalInterventional CardiologyCardiology Chair,Chair, Chief,Chief, DivisionDivision ofof CardiovaCardiovascularscular MedicineMedicine (Clinical)(Clinical) StanfordStanford UniversityUniversity SchoolSchool ofof MedicineMedicine

Stanford ZoMaxx:ZoMaxx: StentStent PlatformPlatform

TriMaxxTriMaxx™™ StentStent PlatformPlatform

ZoMaxxZoMaxx™™ Drug-Drug- ElutingEluting Stent PCPC ABT-578ABT-578 Stent CoatingCoating TriMaxxTriMaxx CoronaryCoronary StentStent TriplexTriplex™™ MaterialMaterial

O.C.C.O.C.C.™™ TechnologyTechnology

StentStent DeliveryDelivery CatheterCatheter

PCPC TechnologyTechnology™™

Triplex is a trademark of Uniform Tubing, Inc; PC Technology is a trademark of Biocompatibles Ltd., Inc. TriMaxxTriMaxx StentStent PatternPattern

88 oror 1010 cellscells aroundaround perimeterperimeter 22 connectorsconnectors betweenbetween ringsrings forfor optimumoptimum scaffoldingscaffolding forfor optimumoptimum flexibilityflexibility

Offset

™™ O.C.C.O.C.C. (Offset(Offset CrownCrown Connector):Connector): proprietaryproprietary DistalDistal connectingconnecting footfoot pullspulls thethe ringsrings closercloser togethertogether andand offsetsoffsets thethe apexesapexes ofof thethe crownscrowns forfor improvedimproved scaffoldingscaffolding StentStent ScaffoldingScaffolding (Mean(Mean interstrutinterstrut diameter) diameter)

1.2

1.0

0.8

0.6

0.4

Scaffolding Diameter (mm) Scaffolding Diameter 0.2

0.0 Driver TriMaxx Express 2 Vision BX Sonic

Stainless Steel/Tantalum/Stainless Steel Composite

• 0.0007” Tantalum layer Stainless Steel

• 0.0029” strut thickness Tantalum

= 0.074mm Stainless Steel

Triplex is a trademark of Uniform Tubing, Inc. StentStent MaterialMaterial andand StrutStrut ThicknessThickness

0.0060

0.0050

0.0040

0.0030 StainlessStainless SteelSteel

Cobalt Chrome 0.0020 Cobalt Chrome TriplexTriplex™™

0.0010 Labeled Thickness (inches) Labeled Thickness

0.0000 TriMaxx Vision Driver Liberte Express 2 BX Sonic

DriverDriver isis aa trademarktrademark ofof Medtronic;Medtronic; ExpressExpress22 && LibertéLiberté are are trademarkstrademarks ofof BostonBoston Scientific;Scientific; VisionVision isis aa trademarktrademark ofof Guidant;Guidant; BxBx Sonic Sonic isis aa trademarktrademark ofof JohnsonJohnson && Johnson;Johnson; TriplexTriplex isis aa trademarktrademark ofof UniformUniform Tubing,Tubing, Inc.Inc. Data on file at Abbott Vascular Devices RadiopacityRadiopacity

TantalumTantalum 300 Wiktor CobaltCobalt ChromeChrome CobaltCobalt AlloyAlloy 250 StainlessStainless SteelSteel Triplex™™ 200 Triplex

150 Bx Sonic TriMaxx Vision

Radiopacity Driver 2 100 Liberté Express Penta Zeta 50 MultiLink

0 0.001” 0.002” 0.003” 0.004” 0.005” Strut Thickness (inches)

DriverDriver isis aa trademarktrademark ofof Medtronic;Medtronic; ExpressExpress22 isis aa trademarktrademark ofof BostonBoston Scientific;Scientific; VisionVision isis aa trademarktrademark ofof Guidant;Guidant; BxBx Sonic Sonic isis aa trademarktrademark ofof JohnsonJohnson && Johnson;Johnson; TriplexTriplex isis aa trademarktrademark ofof UniformUniform Tubing,Tubing, Inc.Inc. Data on file at Abbott Vascular Devices CrimpedCrimped StentStent CrossingCrossing ProfileProfile

0.045 0.044 0.043 0.042 0.041 0.040 0.039 0.038

3.0 mm Mean Profile (inches) 3.0 mm Mean Profile 0.037 0.036

r te e xx s 2 a er riv s M Vision b D ri Li re T p BX Sonic Ex

DataData onon filefile atat AbbottAbbott VascularVascular DevicesDevices StentStent FlexibilityFlexibility InIn VitroVitro BenchBench TestingTesting

10g 10g

Bx OC

10g 10g

Express2 Vision

10g 10g

Driver TriMaxx

DriverDriver isis aa trademarktrademark ofof Medtronic;Medtronic; ExpressExpress22 isis aa trademarktrademark ofof BostonBoston Scientific;Scientific; VisionVision isis aa trademarktrademark ofof Guidant;Guidant; BxBx Sonic Sonic isis aa trademarktrademark ofof JohnsonJohnson && JohnsonJohnson Data on file at Abbott Vascular Devices TriMaxxTriMaxx TrialTrial PI:PI: AlexAlex AbizaidAbizaid 100100 SubjectsSubjects Single-vessel, de novo coronary lesions (Type A-B), length > 10 mm and < 15 mm; RVD 3.0-3.75 mm UpUp toto 55 SitesSites ––BrazilBrazil Stent Diameters Stent Lengths ––GermanyGermany 3.0 mm 18 mm 3.5 mm 18 mm

ClinicalClinical followfollow-up-up 30d 6mo

AngioAngio followfollow-up-up

Primary Endpoint: MACE at 30 days Secondary Endpoints: MACE, TLR, TVR, ABR, Late Loss at 6 months Platelet Inhibition: Clopidogrel/Ticlid (30 days), ASA 100 mg cont.

Presented by A. Abizaid, TCT 2004, Washington, DC StentStent

PrePre

CaseCase #1#1

PostPost Presented by A. Abizaid, TCT 2004, Washington, DC ZoMaxx:ZoMaxx: PolymerPolymer

TriMaxxTriMaxx™™ StentStent PlatformPlatform

ZoMaxx™ Drug- Eluting TM Stent PharmaCoatPharmaCoatTM ABT-578ABT-578 PolymerPolymer CoatingCoating Polymer

PCPC TechnologyTechnology™™ –– Thrombo-Resistant Thrombo-Resistant

•• Non-thrombogenic Non-thrombogenic 1.0 (hemocompatible)(hemocompatible) 0.9 Uncoated stent

10 0.8 PC-coated stent –– Non-inflammatory Non-inflammatory × 0.7 –– Hydrophilic: Hydrophilic: 0.6 InhibitsInhibits proteinprotein 0.5 adhesionadhesion 0.4 0.3 •• PC PC coatedcoated stentsstents Platelets Adhered 0.2 showedshowed significantlysignificantly 0.1 lessless plateletplatelet 0 1.0 1.5 adhesionadhesion comparedcompared Time Point (Hours) toto uncoateduncoated stentsstents

Lewis AL, Coll Surf B; Biointerfaces, 2000, 18, 261 (Baboon-Shunt Flow Model) TheThe ZoMaxxZoMaxx StentStent -- PharmaCoat PharmaCoat

Not approved for sale in or outside the United States.

Presented by L. Schwartz, TCT 2004, Washington, DC TheThe EffectEffect ofof AddingAdding aa PolymerPolymer TopcoatTopcoat onon thethe ElutionElution RateRate fromfrom Drug-ElutingDrug-Eluting StentsStents

120 For in vitro testing, stents (n=12 per group) were placed in a 1% 100 solution of solutol in acetate 80 buffer, and aliquots removed at 60 0 ug/mm designated time points and 40 2 ug/mm assayed for ABT-578 via HPLC. 5 ug/mm % Drug Eluted Eluted Drug Drug % % 20 10 ug/mm 0 For in vivo testing, 128 stents (32 per group) were implanted 0 5 10 15 20 25 in the common iliac arteries of Time (hr)) New Zealand White rabbits and 100 expanded to a 1:1.1 balloon-to- 80 artery ratio. At set time (4 0 ug/mm 60 stents per group per time point), 2 ug/mm animals were euthanized, stents 40 5 ug/mm explanted, and the amount of

% Drug Eluted % 20 ABT-578 remaining on the 10 ug/mm explanted stent was measured 0 using HPLC. 0102030 Time (days) Stanford Comparison of in vivo Elution Rates Rabbit iliac models 120120 120120 ZoMaxx™ZoMaxx™ 100100 Cypher™Cypher™ 100100 8080 8080 Endeavor™

6060 6060

40 4040 % Drug eluted % Drug 40 % Drug eluted % Drug

~75% elution in 2 days eluted % Drug ~75% elution in 10 days % Drug eluted % Drug 100% elution in 10 days 100% elution in 30 days 2020 2020

00 00 0102030010203001020300102030 TimeTime (days)(days) TimeTime (days)(days)

ZoMaxx and Cypher data from B. Chevalier, EuroPCR 2004 Endeavor data from G. Laarman, EuroPCR 2004 Stanford ARE ALL DES THE SAME ? PISCES (n=221): QCA at 4 Months 1 0.88 0.8 0.72 0.67 0.70 0.6 0.48 0.4 0.38 0.30

0.2 Late loss (mm) Late loss (mm)

D0 D1 D2 D3 D4 D5 D6 N 43 29 28 28 38 26 29 Dose (ug) - 10 10 10 10 30 30 Release (d) - 5 10 10 30 30 10

StanfordStanford SAT Rates Across Trials Out of Hospital to 30 Days

Cypher Stent Endeavor Stent TAXUS Stent 5.0

4.0

3.0 2.0 1.8 1.6 2.0 1.5 1.2 1.1 1.0 0.8

% Thrombosis 1.0 0.4 0.4 0.5 0.5 0.2 0.3 0.2 0 0.0 I er R VI Y S US US h V U US RI RIUS RI p pher US X I PHE VOR I AX AXUS SI Cy -Cy A T T E-S C-SI -CY TAXUS II TAX AXUS -REALIT X-TA TAXUS IV T A DES AX US ARCH- N ENDE N DES- IRT Cypher-REALITY RT AX A EARCH- S SE ILA SI T S H/T M MIL RC SEA RE RESEARCH/T Data sources available on file. TAXUS Stent = TAXUS® Express2™ Stent; Cypher is a trademark of Cordis Corp. ENDEAVOR is a trademark of Medtronic. ZoMaxx:ZoMaxx: DrugDrug CompoundCompound

TriMaxx™ Stent Platform

ZoMaxx™ Drug- Eluting PharmaCoat™ ABT-578ABT-578 Stent Coating N N Tetrazole Ring N ABT-578ABT-578 N O O O

O OHO

• ABT-578 is Abbott’s proprietary N O compound for use on drug- O O O eluting stents HO O

• ABT-578 is structurally different

from Sirolimus through the cell responds to substitution of a tetrazole ring at growth factor stimulation the 42- position mitosis GG0 • Delivered locally, ABT-578 cytostatic agents MM GG allow cells in inhibits inflammation and the 1 G0 to re-enter proliferation of SMCs the cell cycle Checkpoint ABT-578 is cytostatic: • ABT-578 is cytostatic by halting GG2 SS blocks entry into S phase the cell cycle in the late G1 phase prepares for mitosis DNA synthesis

Presented by L. Schwartz, TCT 2004, Washington, DC LipophilicitiesLipophilicities of of SomeSome ClinicalClinical DESDES AgentsAgents

45000 P<0.0001 40000 ABT-578 is 2.2 times more 35000 lipophilic than rapamycin

Lipophilicity improves drug ) 30000 transport into the tissue cells Water 25000 of the arterial wall and /C /C improves tissue retention of the drug octanol 20000

P (C P (C 15000

10000

5000 n=16 n=16 n=9 n=10 n=10

0 1 ABT-578 Rapamycin EstadiolPaclitaxel Dexamethasone

Determination of Partition Coefficients for ABT-578, Rapamycin, Paclitaxel, Dexamethasone, and Estradiol at 22 deg C, Abbott Laboratories Report on File, 2004

Presented by L. Schwartz, TCT 2004, Washington, DC ZoMaxx™ Stent vs. Cypher™ Stent Drug Elution

120

100

60 ZoMaxx™

% Drug eluted 40 Cypher™

0 0 5 10 15 20 25 30 Time (days)

A 28-day elution study to assess the tissue distribution of ABT-578 from polymer coated stents in rabbit iliac arteries; Study TE03-058; R&D/04/672; Data on file at Abbott Laboratories; n= 4 stents/timepoint; mean ± SEM; Cypher is a trademark of Johnson & Johnson; Results not indicative of clinical effectiveness. ZoMaxx™ Stent vs. Cypher™ Stent Drug Penetration

160

140 ZoMaxx™ 120 Cypher™

100

40 Drug in Tissue (ug/g)

0 0 5 10 15 20 25 30 Time (days)

8 ZoMaxx™ 7 Cypher™

Drug in Whole Blood (ng/mL) 2

0 0 5 10 15 20 25 30 Time (days)

A 28-day elution study to assess the tissue distribution of ABT-578 from polymer coated stents in rabbit iliac arteries; Study TE03-058; R&D/04/672; Data on file at Abbott Laboratories; n= 4 stents/timepoint; mean ± SEM; Cypher is a trademark of Johnson & Johnson; Results not indicative of clinical effectiveness. ABT-578ABT-578 inin vivovivo PorcinePorcine EvaluationEvaluation –– MayoMayo ClinicClinic

• ABT-578 delivered from BiodivYsio® PC-coated stent in porcine coronary arteries

ABT-578 stent Control Stent: PC Coating only

CourtesyCourtesy ofof RobertRobert S.S. Schwartz,Schwartz, MDMD MinneapolisMinneapolis HeartHeart InstituteInstitute FoundationFoundation

Presented by L. Schwartz, TCT 2004, Washington, DC Effect of TriMaxx, ZoMaxx, Cypher, and Taxus Stents on Swine Coronary Morphometry at 28 days (mean + SEM)

• 18 animals received a single ZoMaxx, Cypher, and Taxus stent implanted in one of three Neointimal Area (mm2) randomized coronary arteries 3 • An additional 3 animals received 3 * ** TriMaxx stents each 2 ** • Balloons were expanded to achieve

a 1.3:1 stent:artery ratio mm2 1 • After 28 days, the hearts were excised, the arteries perfusion- fixed at 100 mmHg, sectioned, and 0 TriMaxx Taxus Cypher ZoMaxx stained with hematoxylin and eosin for morphometric evaluation *p<0.05 vs. TriMaxx ABT-578, paclitaxel, and rapamycin-eluting stents show similar efficacy in a **p<0.01 vs. TriMaxx porcine model of coronary restenosis (abstract). Cardiovascular Revascularization Therapeutics 2005 (accepted). Data on file at Abbott Laboratories; n= 4 stents/timepoint; mean ± SEM; Cypher is a trademark of Johnson & Johnson; Taxus is a trademark of Boston Scientific.

Data on file at Abbott Vascular Devices ZoMaxxZoMaxx ClinicalClinical ProgramsPrograms

• ZOMAXX I – PI: Bernard Chevalier, MD – First patient enrolled 14 Sept 04 at St. Vincent's Hospital in Melbourne, Australia (Robert Whitbourn, M.D.) bc8

• ZOMAXX II – PI: Alan Yeung, MD

Presented by A. Yeung, TCT 2004, Washington, DC 슬라이드 29 bc8 That seems very short about ZOMAXX II Does Martin present somethingelse? Bernard, 2004-05-12 ZOMAXXZOMAXX II TrialTrial Randomized,Randomized, Non-inferiorityNon-inferiority TrialTrial N=400 Single, de novo coronary lesions (Type A-B) 34 sites with length > 10 mm and < 30 mm, Europe and RVD 2.5-3.5 mm. Australia Pre-dilatation required New Zealand

Stent Diameters Stent Lengths 2.5 mm 8, 18, 23, 28 mm 3.0 mm 8, 18, 23, 33 mm ZoMaxx™ Stent 3.5 mm 8, 18, 23, 33 mm TAXUS™ Stent N=200 N=200 Clinical follow-up

30d 6mo 9mo 12mo 2yr 3yr 4yr 5yr

Radiographic follow-up QCA/IVUS

Primary endpoint: 9-mos. in-segment late loss with equivalency limit of 0.25 mm, σ=0.4 mm; > 99% power; 1-sided α=0.05 Secondary endpoints: MACE, TVF, TLR, TVR, binary restenosis, in-stent late loss, neointimal volume, neointimal volume obstruction Medications: Clopidogrel 75 mg QD for at least 6 months, ASA 100 mg QD ≥ 12 months Stratification: Site

Presented by A. Yeung, TCT 2004, Washington, DC ZOMAXXZOMAXX II TrialTrial Randomized,Randomized, Non-inferiorityNon-inferiority TrialTrial ZOMAXXZOMAXX IIII TrialTrial Randomized,Randomized, Non-inferiorityNon-inferiority Trial,Trial, ClinicalClinical EndpointEndpoint

1670 subjects Single, de novo coronary lesions (Type A-B) ~ 75 sites with length > 10mm and < 28mm USA and and RVD 2.5-3.75mm Canada Pre-dilatation required

Stent Diameters Stent Lengths 2.5 mm 8, 13, 18, 23, 28 mm 3.0 mm 8, 13, 18, 23, 33 mm ZoMaxx™ Stent 3.5 mm 8, 13, 18, 23, 33 mm TAXUS™ Stent N=835 N=835 Clinical follow-up

30d 6mo 9mo 12mo 2yr 3yr 4yr 5yr

Radiographic follow-up QCA/IVUS

Primary endpoint: Non-inferiority to TAXUS using 9-mo ischemia driven target vessel revascularization (TVR) Secondary endpoint: In-segment late loss at 9 mo. (QCA) Additional Analyses: Binary restenosis, MACE, TLR, TVR, in-stent late loss, neointimal volume, clinical outcomes by vessel diameter and lesion lengths Medications: Clopidogrel 75 mg QD for 6 months, ASA 325 mg QD for at least 12 months

Presented by A. Yeung, TCT 2004, Washington, DC ZOMAXXZOMAXX II andand IIII CoreCore labslabs

Data Center – Harvard Clinical Research Institute, Boston QCA – Brigham and Women’s, Boston IVUS – Stanford Interventional Cardiology, Palo Alto ECG – Harvard Clinical Research Institute, Boston

Presented by A. Yeung, TCT 2004, Washington, DC TriMaxxTriMaxx andand ZoMaxxZoMaxx RegulatoryRegulatory StatusStatus

• The TriMaxx™ Coronary Stent is currently CE Mark approved

•The ZoMaxx™ Drug-Eluting Coronary Stent is not approved for sale – The ZOMAXX I & II clinical trial is currently enrolling patients