Advanced Angioplasty 2008

Hilton London Metropole Hotel

January 25, 2008

Josiah N. Wilcox, Ph.D.

Vice President and Resident Scholar Science & Technology

Medtronic CardioVascular

Overview of the Endeavor Resolute Overview of the Endeavor Resolute Preclinical and Clinical ProgramsPreclinical and Clinical Programs

Unmet Clinical Needsin the DES era

• TLR and MACE rates remain high in patients at the highest clinical risk of TLR

• Diabetics– 11.3% MACE @ 9 mo—DIABETES Trial, Sabate,

TCT 2004– 10.9% TLR @ 12 mo—TAXUS V Trial, Ellis, TCT 2005

• Small Vessels– 9.3% MACE @ 8 mo—SES SMART, Ardissino, JAMA, Dec 8,

2004– 14.2% TLR @ 12 mo—TAXUS V Trial, Ellis, TCT 2005

• Multi-Vessel Disease– 14.3% TLR—The Milan DES Experience, Columbo, ACC 2004

• Improve clinical outcomes in more complex lesions

• Maintain current safety profile seen with Endeavor™ DES

• Extended drug elution to match the potentially delayed healing times of complex lesions

• Combat the sustained stimulus to the proliferative response

Endeavor Resolute™Design Goals

Endeavor Resolute Incorporates the BioLinx™ Polymer System

Retains three components of the Endeavor Sprint™ Coronary Stent System with a new DES polymer

Driver Cobalt Alloy Stent Stent Delivery System Drug: zotarolimus

▫ Medtronic proprietary polymer design

▫ Hydrophobic/Hydrophilic polymer blend

▫ Extended release kinetics

▫ Biocompatibility equivalent to PC

▫ Compatible with multiple drug platforms

Novel Features of BioLinx Polymer System:

A hydrophilic polymer is compatible with water

A hydrophobic polymer is not compatible with waterEvidence that hydrophilic polymers are more biocompatibile

Polymers can either be hydrophilic or hydrophobic

Hydrophilic = water-lovingHydrophilic = water-lovingHydrophobic = water-hatingHydrophobic = water-hating

Body is approximately 70% waterBody is approximately 70% waterBody is approximately 70% waterBody is approximately 70% water

Hydrophilic vs Hydrophobic Polymers

θ1

Hydrophilic

θ2

Hydrophobic

Hydrophobic Polymer

Hydrophilic Polymer

Contact Angle

PC (Endeavor)

BioLinx (Endeavor Resolute)

83º

94o

PBMA 115º

SIBS 118º

Fluoro Polymer 129º

Water-loving Water-hating

• Angle formed when water drop applied to polymer surface

• Smaller angle = more hydrophilic

Hydrophilic vs HydrophobicContact Angles are used to determine if a polymer is hydrophilic or hydrophobic

θ1 < θ2

• C10 Polymer (Hydrophobic)Based primarily on hydrophobic butyl methacrylate to provide adequate hydrophobicity for zotarolimus

• C19 polymer (Hydrophilic) Manufactured from a mixture of hydrophobic hexyl methacrylate and hydrophilic vinyl pyrrolidinone and vinyl acetate monomers to provide enhanced biocompatibility

• Polyvinyl pyrrolidinone (PVP)Hydrophilic polymer increases initial drug burst and enhances biocompatibility

C O

O

C6H13

CH2 C

CH3

CH2 CH

N

O

CH2 CH

O

C O

CH3

x y z

C O

O

C4H9

CH2 C

CH3

CH2 CH

O

C O

CH3

a b

CH2 CH

N

O

a

C19

C10

PVP

Overall the BioLinx polymer blend displays a very hydrophilic surface

to the body for biocompatibility

The BioLinx Polymer SystemComposed of Hydrophilic and Hydrophobic Polymers

Vinyl pyrrolidinone groups

NO

[ ]

BioLinx

Phosphorylcholine(PC) Headgroup

PC Technology

O

P OO

ON

Hydrophilic outer surface

Cell Membrane

Hydrophobic layer

Medtronic Polymer TechnologiesPC and BioLinx Polymers Hydrophilic Surface Chemistry

Greater than 85% of zotarolimus is eluted at 60 daysComplete drug content exhausted by 180 days

100

80

60

40

20

0

% Z

otar

olim

us L

oadi

ng

0 50 100 150 200Days

<2% (LOQ)

% Eluted

% Remaining

Endeavor ResoluteBioLinx Polymer In Vivo Drug Elution

A Robust Durable Coating

• BioLinx is the first polymer system designed specifically for DES applications

• The BioLinx Polymer System provides a durable and robust coating

• The stent surface is primed to improve adhesion of the BioLinx Polymer System

Primer

BioLinx PolymerSystem

A deployed stent after tracking 3 times in a 5 Fr guide catheter

Atomic Force Microscopy (AFM) studies indicate that the interface between the BioLinx Polymer System and the primer is very strong

Endeavor ResoluteInhibition of Neointimal Development at 28 Days

Driver Control Endeavor Resolute Endeavor Resolute

Significant inhibition of neointimal development compared to Driver controls

28 day porcine study results

Endeavor Resolute Extended Efficacy out to 90 days

Significant inhibition of neointimal development at both 28 and 90 days in porcine coronary arteries

Ste

no

sis 40

50

30

10

20

60

0Day 28 Day 90

Endeavor Resolute

Driver (bare)

Developing a New Understanding of the Science of DES Polymer

Biocompatibility

ContactAngle: 83°

Negative Control PC

118° 115° 129°Hydrophobic

PBMASIBSFluoro Polymer

Positive Control

Hydrophilic

BioLinx

94°

Correlates With Polymer HydrophobicityMonocytic Adhesion

Low inflammatory scores seen with Endeavor and Endeavor RESOLUTE stents compared to DES containing hydrophobic polymers platforms in porcine coronary arteries

Endeavor Resolute with BioLinxBest in Class biocompatibility equivalent to Endeavor with PC

Comparison of Inflammation Scores

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

28 days 90 days 180 days 365 days

Time after stenting

Infl

am

ma

tio

n S

co

re

Endeavor*

Endeavor Resolute*

Fluro Polymer DES

PBMA DES

*Data on File Medtronic CardioVascularEndeavor not tested at 365 days **Data from Abbott US Physician presentation SE2924433D

The Design of DES Polymers Hydrophobic vs. Hydrophilic• First generation drug eluting stent (DES) coatings have been based on hydrophobic

polymers to hold and elute hydrophobic drugs

– SIBS– PBMA– Fluoro Polymer

• Hydrophobic polymers may stimulate inflammatory reactions

• Hydrophilic polymers may be more biocompatible in the aqueous body environment

• The phosphorylcholine (PC) based polymer used in the second generation Endeavor DES, is a hydrophilic polymer that shows good biocompatibility

• The next generation Endeavor Resolute DES coating based on the BioLinx Polymer System, is a unique blend of hydrophilic and hydrophobic polymers, that offers both biocompatibility and extended drug elution

• Hydrophobic polymers may contribute to the problem of Late Stent Thrombosis by increasing inflammation, endothelial dysfunction and/or expression of procoagulant proteins in the vessel wall

Endeavor RESOLUTE Clinical Update

Caution: Endeavor and Endeavor Resolute are investigational devices with an investigational drug, not approved for sale or commercial use.

RESOLUTEClinical Trial Design

Single De Novo Native Coronary Artery LesionsLesion Length: 14-27mm

Stent Diameters: 2.5, 3.0, 3.5mmStent Lengths: 18, 24, 30mm (8/9mm bailout)

Drug Dose: 1.6 g/mm2 stent surface areaAntiplatelet therapy for 6 months

Pre-dilatation required

130 Patients (9 additional PK Sub-Study Patients enrolled after original 130 patients)12 Sites (New Zealand and Australia)

Endeavor Resolute Stent

Clinical/MACE

Angio/IVUS30d 6mo 4 yr3yr2yr9mo 12mo 5 yr

Primary Endpoint: Late lumen loss (in-stent) at 9 mths by QCA

Secondary Endpoints: MACE at 30 days, 6, 9 and 12mths and IVUS and

angiographic parameters at 9mths

30 pt Subset: 4mth MACE and angiographic, IVUS parameters*

4mo

N=30 N=100

*Meredith et al: EuroInterv 2007; 3:50-53

130 Patients Enrolled130 Patients Enrolled

4 Month4 MonthFollow-UpFollow-Up

Angiographic F/UAngiographic F/U30/3030/30

Clinical F/UClinical F/U30/3030/30

9Month9MonthFollow-UpFollow-Up

Angiographic F/UAngiographic F/U95/10095/100

Clinical F/UClinical F/U130/130130/130

12 Month12 MonthFollow-UpFollow-Up

Clinical F/UClinical F/U129/130129/130

99.2%99.2%100%100% 100%100%

95%95%100%100%

RESOLUTE Patient Flowchart

Male 75.4% (98/130)Age 61 +10yrs (130)Prior MI 45.7% (59/129)Prior PCI 18.5% (24/130)Diabetes Mellitus 17.7% (23/130) Insulin Dependent 2.3% (3/130)Unstable Angina 29.7% (38/128)Hyperlipidemia 94.6% (123/130)Current Smoker – within last 30 days

22.3% (29/130)

N=130

Meredith et al: EuroInterv 2007; 3:50-53

RESOLUTE Patient Demographics

LAD (%) 34.4% (45/131)

B2/C Lesions (%) 81.7% (107/131)

Pre-procedure RVD (mm) 2.81 ± 0.41

Lesion Length (mm) 15.49 ± 6.23

Pre-procedure MLD (mm) 0.82 ± 0.34

Pre-procedure DS (%) 70.50 ± 11.42

Device success 99.2% (130/131)

Procedure success 96.2% (125/130)

N=130 patients, 131 lesions

Meredith et al: EuroInterv 2007; 3:50-53

Device success <50% residual in-stent % ds with assigned stentProcedure success <50% residual in-stent % ds & without in-hospital MACE

RESOLUTE Procedural Characteristics

In-stent In-segment

Pre-procedure RVD (mm) 2.79 ± 0.40

Lesion Length (mm) 15.87 ± 6.51 MLD (mm) pre 0.82 ± 0.35

post 2.74 ± 0.41 2.33 ± 0.44

Acute Gain 1.91 ± 0.47 1.51± 0.50 9 mo f/u MLD (mm) 2.51 ± 0.48 2.21 ± 0.45

Late Loss (mm) 0.22 ± 0.27 0.12 ± 0.27

Late Loss Index 0.12 ± 0.16 0.08 ± 0.21

9 mo f/u % DS 10.13 ± 12.63 21.08 ± 10.62

ABR n (%) 1 (1%) 2 (2.1%)

n=96

RESOLUTE: 9 Month Follow Up Angiographic Results

9 months

n=130 patients

Death (all) - % (#) 1.5 (2)

Cardiac 0.8 (1)

MI (all) - % (#) 5.4 (7)

Q Wave 0

Non Q wave 5.4 (7)

Death (cardiac) + MI (all) - % (#) 6.2 (8)

Stent Thrombosis (all) - % () 0

0-30 days 0

31-360 days 0

TLR - % (#) 0

TVR (non-TL) - % (#) 0

TVR - % (#) 0

MACE - % (#/) 6.9 (9)

TVF - % (#/) 6.2 (8)

9-12 months

n=129

12 months

n=129

0.8 (1) 2.3 (3)

0 0.8 (1)

0 5.4 (7)

0 0

0 5.4 (7)

0 6.2 (8)

0 0 (0)

0 0 (0)

0 0 (0)

0.8 (1) 0.8 (1)

0 0.0

0.8 (1) 0.8 (1)

1.6 (2) 8.5 (11)

0.8 (1) 7.0 (9)

RESOLUTEClinical Events to 12 months

Comments

57 year old Prox RCA

Type C Lesion

Acute Marginal side branch of obstructed by lesion during post dilatation

67 year old Mid RCA

Type B2 Lesion

No reflow of PDA, prior to stenting

65 year old Mid RCA

Type C Lesion

RV Marginal branch has decreased flow after balloon dilatation prior to stenting

52 year old Mid LAD

Type C Lesion

Decreased flow in 1st diagonal side after post balloon dilatation

51 year old 1st OMA

Type C Lesion

Prior MI with MB still 2x baseline at time of intervention

50 year old Mid LAD Wire trauma leading to plaque rupture during follow- up angiography

75 year old Mid LAD Fully patent stent at follow-up. Non Q-wave MI due to lack of anti-coagulation during IVUS

RESOLUTENQMI to 12 months

History Index Procedural Info Time DAPT Event Description Outcome up to 12M FU

69 yo male Diabetic Mid RCA 3.5x30mm stent 1.3 months Laparoscopy; small bowel resection No MACE

38 yo female Non-diabetic Mid RCA 3.5x18 mm stent 3.0 months Pericardial window for pericarditis No MACE

66 yo male Non-diabetic 1st Obtuse Marginal 2.5x18 mm stent 3.0 months Anterior bowel resection for cancer No MACE

77 yo female Non-diabetic Mid RCA 3.0x24 mm stent 3.2 months Total hip replacementLaminectomy

No MACE

71 yo male Non-diabetic Prox Circumflex 2.5x18 mm stent 4.9 months Thoracentesis for right pleural effusion Yes : Death, non-cardiac, mesothelioma

75 yo male Non-diabetic Prox LAD 3.5x18 mm stent 4.9 months Elective resection of the prostate No MACE

76 yo male Non-diabetic Mid RCA 3.5x18 mm stent 5.6 months Catarct surgery No MACE

61 yo female Non-diabetic Dist Circumflex 2.5x18 mm stent 5.7 months Eye surgery to remove malignant nerve sheath tumor

No MACE

54 yo male Non-diabetic Prox Circumflex 2.5x24 mm stent 5.8 months Right knee medial menisectomy No MACE

59 yo male Non-diabetic 1st Obtuse Marginal 3.0x30 mm stent 5.8 months Total laryngectomy and neck dissection No MACE

58 yo, male Non-diabetic PDA 3.0x18mm stent 6.0 months Surgical repair of retinal detachment No MACE

68 yo female Non-diabetic Mid LAD 2.5x18 mm stent 6.0 months Arthroscopic surgery of shoulder No MACE

65 yo male Non-diabetic Mid RCA 3.5x30 mm stent 6.1 months Elective cholecystectomy No MACE

64 yo male Non-diabetic 1st Obtuse Marginal 3.0x18 mm stent 6.3 months Elective Cardioversion for atrial flutter No MACE

75 yo male Non-diabetic Mid LAD 2.5x18 mm stent 6.5 months Patient died Yes: Death, non-cardiac, melanoma with metastisis

RESOLUTE: DAPTPatients with a Surgical Procedure

15 Patients discontinued AP Therapy and had surgical procedures 5 females10 males1 diabetic

2 MACE Events by 12 months Both deaths due to Cancer

MelanomaMesothelioma

US Studies OUS Study

Angiographic/IVUS Studies

Randomized to Taxus n = ~430

RESOLUTE II

38 mm n=~100RESOLUTE Long

2.25 mm n=~150RESOLUTE Small

4.0 mm n=~100RESOLUTE Large

Pivotal Study

Randomized to Taxusn = ~1500

RESOLUTE IV

All Comers(CE Mark)

Randomized to Xience n = 2300

RESOLUTE III

Randomized to Xience n = 2300

RESOLUTE III

RESOLUTE Clinical ProgramCurrent Outline

All ComerDual APT ≥ 6 months

N = 230015-20 International Sites

Randomization 1:1

Endeavor ResoluteN=1150

Clinical Follow-up30d 6mo 4 yr3yr2yr 5 yr

Primary Endpoint: Non-inferiority TLF (Cardiac Death, TLR, MI) at 12 months

Secondary Clinical Endpoints: Cardiac death/MI or TLR

Secondary Angiographic Endpoints: (n=460)In-stent and In-segment DS%, In-stent and In-segment LL at 13 months

Secondary OCT Endpoints: (n=~50)Stent Strut Tissue Coverage, Stent Apposition at 13 months

XienceN=1150

1yr

RESOLUTE IIIInternational RCT vs Xience: PI: Patrick Serruys

Angiographic Follow-up 13 mo

Thank You

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

0 360 720 1080 1440

Endeavor 1301 1287 675

No. at Risk

Cypher 863 848 823

Taxus 1351 1300 1117

1 Year 2 Years 3 YearsPooled Data

*Xience 397 377 n/a

DES In Perspective DES In Perspective ARC Definite and Probable to 3 yearsARC Definite and Probable to 3 years

AR

C S

T %

Days

Mauri et al. N Engl J Med 2007;356:1020-9.Endeavor: Mauri et al. TCT. 2007Xience: FDA Panel Meeting Nov. 29, 2007

*Represents “SPIRIT II and III 2-year Complete Analysis” from Panel

0%

3%

6%

9%

0 360 720 1080 1440

Car

dia

c D

eath

an

d M

I %

Days

DES In Perspective DES In Perspective Cardiac Death and MI to 3 yearsCardiac Death and MI to 3 years

Mauri et al. N Engl J Med 2007;356:1020-9.Endeavor: Mauri et al. TCT. 2007Xience: FDA Panel Meeting Nov. 29, 2007

*Represents “SPIRIT II and III 2-year Complete Analysis” from Panel

Endeavor 1301 1287 675

Cypher 863 848 823

Taxus 1351 1300 1117

1 Year 2 Years 3 YearsPooled Data

*Xience 397 377 n/a