Robert Falotico, Ph.D Distinguished Research Fellow

Johnson & Johnson

XIV Paris Cardiovascular Interventions Course

Paris, France

October 16, 2012

The Story of Drug-Eluting Stents:

Discovery and Development of Cypher®

The Cypher® Legacy

• World’s first drug eluting stent

• Most widely studied medical device in history

- 47 RCTs, >60 registries, >2,000 research papers

• Over 4,000,000 patients treated

• Unsurpassed efficacy and safety out to 10 yrs.

• Rationally designed for the problems of restenosis

• Established the formula for all successful DES.

Wallstent - Boston Scientific

Ginaturco Rubin II - Cook

Strecker – Boston Scientific

Crossflex I - Cordis

Wicktor - Medtronic

• High stent thrombosis rates

• High restenosis rates

• An imperfect technology

Early Stents Were Used for Abrupt Closure Following PTCA

(late 1980’s - early 1990’s)

The First Stent Approved for Restenosis

• 1994 - J&J Interventional Systems (JJIS) launched the

Palmaz-Schatz® stent.

• Approved by FDA for the treatment of restenosis, based on

two landmark clinical trials (STRESS, BENESTENT).

• Wide acceptance and rapid global adoption (“stent-mania”).

• Represented only a partial solution to the problem of

restenosis.

J&J Palmaz-Schatz stent (1994)

With Stents, Restenos is a Proliferative Disorder

Do not Prevent Neointimal Hyperplasia

Prevent Recoil & Remodeling

+

• Stents provide a rigid scaffold to prevent recoil and negative remodeling but do not reduce neointimal hyperplasia.

• In-stent restenosis is a proliferative problem (exuberant wound healing), which requires a biological solution.

Multiple Therapeutic Options for

Reducing Neointimal Hyperplasia

• Gamma

• Beta Catheter Stent • Catheter

• Stent

• Balloon

Energy Delivery Systemic Local

Radiation Pharmaceuticals

Crescendo™ drug

delivery balloon Hepacoat™ stent

ReoPro Checkmate™ 192Ir-brachytherapy

32P-Isostent™

Gamma 1 Trial – 9 Month Endpoints

Ir-192

n=131

Placebo

n=121

p value

Clinical

TLR (%) 24.4 42.1 <0.01

TVR (%) 31.1 46.6 <0.01

Death, MI, TLR* (%) 28.2 43.8 <0.01

Angiographic

In stent LLL (mm) 0.73 1.14 <0.001

Restenosis (%) 21.6 50.5 <0.005

Safety

Late thrombosis (%) 5.3 0.8 <0.07

Late MI (%) 9.9 4.1 <0.09

Storage and Delivery Device

M.Leon, et al NEJM 2001; 344:250-6

Cordis CheckMate™ Ir-192 Intravascular

Brachytherapy System

Profound Edge Restenosis (“Candy Wrapper”)

with a Radioactive 32P Stent (IsoStent™)

stent

balloon

Radiation Concerns

• Narrow therapeutic window – potential for toxicity

• Late thrombosis requiring extended antiplatelet Rx

• Positive remodeling and aneurysms

• Radiation exposure for cath lab personnel

• Logistics of handling radioactive materials

• Not approved for de novo lesions

• Edge restenosis (“candy wrapper”)

Formation of the Stent Therapeutics

Team (1996)

• Small focused research group with strong biological and

polymer expertise

- Developed heparin coated stents (Hepacoat™)

- Studied radioactive stents (Isostent™)

• Established a stent-based drug strategy for restenosis

- Identified key therapeutic agents

- Formed strategic alliances (internal/external)

- Evaluated numerous drugs and stent coatings

• Established proof-of-concept for drug-eluting stents

Key Members of the Stent Therapeutics Team

Gerard Llanos

Robert Falotico (Team

Leader)

John Siekierka

Gregory Kopia

Awarded the Johnson Medal in 2003

“Fortune (luck) favors the prepared mind.”

Lecture, University of Lille December 7, 1854

Louis Pasteur

Cordis Corp

Therapeutics

Stents Polymers

Drug Eluting

Stent

Drug Eluting Stents Involved the

Integration of Existing Technologies

Drug Criteria

Scientific criteria:

• Potent, stable, small molecule

• Inhibits proliferating smooth muscle cells

• Cytostatic mechanism

• Wide margin of safety

• Favorable pharmacokinetics

Business

criteria:

• Late stage development or approved drug

• Exclusive license

• Drug supply and masterfile

• Strong patent position

The key to developing an antirestenotic stent

is to find the right drug!

800 Different Drugs Considered

100 Different Contenders

4 Promising Leads nitric oxide, angiopeptin,

paclitaxel, sirolimus

One Winner!

Systematic Drug Screening Process

O H

O O C H 3

O

O H O O N

O

O C H 3

H 3 C O

O

H O

O

Anticancer

Immunosuppressive

Antifungal

Autoimmune diseases and aging

Restenosis

Sirolimus – Multiple Applications (the “Magic Bullet” for Restenosis)

Wyeth: Discovery and Development of Rapamycin (Sirolimus)

Cordis DES program initiated 1997

1973

1974

1980

1988

1991 Phase I Clinical Trials (Renal Transplantation)

Unique Vascular Pharmacology Demonstrated in Transplantation Models (Morris)

Elucidation of Chemical Structure

Immunosuppressive Activity Found in Animal Models

Isolation from Easter Island Soil Sample and Characterization

of Antimicrobial Activity (Sehgal)

Phase II Clinical Trials 1994

1996 Phase III Pivotal Trials

FDA Approval 1999 Rapa Nui (Easter Island)

Key People in the History of Sirolimus • Suren Sehgal (Wyeth) – biochemist, discoverer of sirolimus

• Randall Morris (Stanford) – immunologist, identified unique pharmacologic

properties of sirolimus

• Andrew Marks (Columbia) – molecular biologist, elucidated role of sirolimus

in smooth muscle proliferation

• Juan Badimon (Mt Sinai) – pharmacologist, antirestenosis studies in animals

Randall E.

Morris Suren Sehgal

” father of

sirolimus”

Juan Badimon Andrew Marks

Gallo, et. al. - Circulation 1999; 99:2164-2170

“Proof of Concept” - Sirolimus Inhibits

Restenosis in a Porcine Angioplasty Model

(Dr Juan Badimon, Mt Sinai-Wyeth Sponsored Study)

Elevated p27 levels in rapamycin-

treated tissues

0 10 20 30 40 50 60

p < 0.0001

Thrombus

Hematoma

Hyperplasia

Control Sirolimus

Sirolimus 0.5 mg/kg, i.m. for 3 days

prior to PTCA; continued for 14 days

% change 70

G0

Arterial Injury

Thrombosis Inflammation

Growth Factors / Cytokines

Receptor activation

Signal

transduction

G1

S

G2

M

Cell cycle

SMC Proliferation

Migration Matrix

Secretion

Mechanism of Action of Sirolimus

mTOR

Sirolimus

FKBP

Sirolimus

FKBP

X

X

X

Van der Giessen et. al.,

Circulation 1996;94,1690-7

Biodegradable polymers Stable polymers

PLGA

PHBV

PEO/PBTP

Silicone

POE PU

PETP

PCL

Conventional Wisdom Held That Polymer-Coated

Stents Were Not Biocompatible

Coating Options

Absorbable

PDLA, PLGA, PLLA

Advantages:

• Used in controlled delivery

• Compatible with siolimus

• Deep knowledge at J&J

Disadvantages:

• Unstable drug platform

(bulk erosion)

• Biocompatibility questions

Non-absorbable

PBMA, PEVA, PVDF

Advantages:

• Stable drug platform

• Nonreactive with drug

Disadvantages:

• Permanent implant

• Log term tissue reactivity

Development of a Controlled-Release Stent Coating

0

20

40

60

80

100

0 5 10 15 20

Time (days)

Perc

ent

Rele

ase

In Vivo Release Kinetics

25 30

SLOW=CYPHER™ FAST

Elution profile:

80% in 30 days

Complete in 90d

Stent

Basecoat (FR)

+ Topcoat (SR)

Control

Sirolimus

0

0.5

1

1.5

2

2.5

3

Control Sirolimus

(mm2)

*

Neointimal Area

50%

140 µg/cm2

Suzuki, et al., Circulation 2001.

Sirolimus-Eluting Stents Reduce Neointimal

Hyperplasia in a 30-Day Porcine Coronary Model

CYPHER® FIM: a Safety Study with Huge Impact

• December 1999: 15 patients receive a Fast Release sirolimus-eluting

stent in Sao Paulo.

• February 2000: 15 patients in Sao Paulo and 15 patients in

Rotterdam receive Slow Release sirolimus-eluting stent.

• April - June 2000: angiographic follow-up (4-6 month)

• Findings:

- Minimal late lumen loss

- Angiographic images (pre/post) almost identical

- No restenosis or thrombosis

The FIM Team in Sao Paulo

FIM - Analysis and Discussion

PRE

POST

4-MONTH FU

Angiographic Images from FIM- Sao Paulo

4-Month Angiographic Results from

First In Man: “Proof of Concept”

Feres et al, ACC 2001

0

0.2

0.4

0.6

0.8

1

0.11

0.84

Lumen Loss (mm)

0.05

LL LL LL

p = NS

p < 0.0001

p < 0.0001

0

10

20

30

4039.01

(mm3)

p = NS

2.04 0.23

p < 0.0001

p < 0.0001

Sirolimus SR Bx Velocity Control Sirolimus FR

QCA IVUS

"I can tell you I have never seen

this in interventional cardiology.

There is a phenomenon there.

Please don't pinch me, don't wake

me up, I want to keep dreaming.”

Patrick Serruys, M.D.

European Society of Cardiology

August 21, 2000

RAVEL: First Randomized, Double-Blind Trial of a Drug Eluting Stent

De Novo Native

Coronary Lesions

Diameter: 2.5-3.5 mm

Length: <18 mm

Sirolimus-eluting

Bx VELOCITY®

n=120

• Primary Endpoint: Angiographic late loss at 6 months

• Secondary Endpoints: IVUS at 6 mo. and clinical at 6 and

12 months and annually for 5 years

• Antiplatelet therapy for 2 months (clopidogrel/ticlopidine)

Angio F/U at 6 Months = 92.4%

Clinical F/U at 12 Months = 92.0%

Control

Bx VELOCITY®

n=118

RAVEL: 6-Month QCA

p<0.001 p<0.001

(mm)

p<0.001 p<0.001

1/109 0/109

(%)

n=109

n=109 Sirolimus

Bx Velocity

Late Lumen Loss Restenosis Rate

SIRIUS – Pivotal US Trial

All Randomized Patients n = 1101

Sirolimus-eluting Bx VELOCITYTM

n = 533

Control Bx VELOCITYTM

n = 525

Angio FU at 8 Months = 85.4% Clinical FU at 9 Months = 95.7%

Angio FU at 8 Months = 84.7% Clinical FU at 9 Months = 95.8%

SIRIUS QCA Analysis @ 8 Months

P<0.001

83%

P<0.001

91%

Late Loss (mm) Restenosis (%)

SIRIUS - Clinical Events

Sirolimus (n=533)

Control (n=525)

P-value

Death 0.9% (5) 0.6% (3) 0.726

MI (all) 2.8% (15) 3.2% (17) 0.723

Q-wave 0.8% (4) 0.4% (2) 0.687

Non Q-wave 2.1% (11) 2.9% (15) 0.433

TLR (all) 4.1% (22) 16.6% (87) <0.001

TVR (non-TL) 3.2% (17) 4.8% (25) 0.210

MACE 7.1% (38) 18.9% (99) <0.001

TVF (1ry endpoint) 8.6% (46) 21.0% (110) <0.001

All Events (to 9 months)

(-75%)

(-62%)

) (-59%)

SIRIUS Trial: Freedom From TLR

After 7 Years

100

95

90

85

80

75

70

65

60

55

50 Time After Initial Procedure (days)

Fre

ed

om

Fro

m T

LR

(%

)

0 270 360 720 1080 1440 1800 2160 2520

CYPHER® Stent

BMS

SES 533 492 482 467 450 433 391 244

BMS 531 418 392 372 361 343 308 192

LR P<.0001

7-Year Freedom From TLR

Internal data, Cordis Corporation.

Drug-Eluting Stents that Have Failed

• Actinomycin D (Guidant)

• Batimistat (Abbott)

• Dexamethasone (Biodyvisio)

• Angiopeptin (Biodyvisio)

• Estradiol (Biodyvisio)

• Tacrolimus (Jomed, Sorin)

• Pimecrolimus (Biotronik, Avantec, Conor)

• C-myc antisense (Medtronic AVE)

• Mycophenolic acid (Avantec)

• Paclitaxel stent sleeve (Quanam)

• Paclitaxel nonpolymeric (Cook/Guidant)

• Paclitaxel bioabsorbable (Conor)

Wrong

drug

Wrong

formulation

PROMUS

SIBS

BioLinx

PEVA/PBMA

PVDF/HFP Everolimus

Sirolimus

Zotarolimus

Paclitaxel

Stent Drug Polymer

Major Drug Eluting Stent Competitors Follow the Same Design Concepts

Resolute

BSC

BSC

ABT

MDT

Cordis

Meta-Analysis of 38 RCTs (~18,000pts):

TLR for Cypher, Taxus or BMS

Stettler C., et al., Lancet 2007;370:937-48.

BMS

PES

SES

Cu

mu

lati

ve I

ncid

en

ce o

f T

LR

(%

)

24

22

20

18

16

14

12

10

8

6

4

2

0

0 1 2 3 4

SES vs. BMS: HR 0.30 (95%-CI 0.24-0.37, p<0.0001)

PES vs. BMS: HR 0.42 (95%-CI 0.33-0.53, p<0.0001)

SES vs. PES: HR 0.70 (95%-CI 0.56-0.84, p<0.0021)

Years After Initial Procedure

Events/patients

(n)

BMS 4763 820/4746 53/2795 22/1871 10/1543 PES 6328 448/6280 98/3950 15/1999 6/832 SES 6621 356/6580 68/3801 16/2153 14/999

Late Stent Thrombosis with DES: the Bern/Rotterdam Experience

Ste

nt T

hro

mb

osis

(%

)

P. Wenaweser and P.W. Serruys, ESC 2006

0

1

2

3

4

0 365 730 1095

Days after stenting

Days after PCI 9 30 365 730 1095

Incidence SES (%) 1.0 1.1 1.3 1.9 2.5

Incidence PES (%) 1.2 1.3 2.0 2.7 3.2

Pts at risk 8146 7162 7002 2841 971

P=0.06 PES

SES 3.2%

2.5%

Strategies for Improving DES

Stent Drug Coating

• Reduced dose

• Optimized PK

• Combination therapy

• Thinner struts; new alloys

• Improved delivery systems

• Bioabsorbable scaffolds

• Bioabsorbable polymers

• Abluminal drug delivery

• Reduced polymer mass

• Nonpolymeric coatings

NEVO™ with Reservoir Technology

• Thin strut CoCr platform

• PLGA polymre absorbs in ~90 days

• Elutes sirolimus abluminally

• Capable of delivering multiple drugs

independently Base layer

Cross section of NEVO reservoir

Day 8 Day 30 Day 60 Day 90

Explosive Growth of Limus-Based DES Company -Limus Drug Stent

Cordis Sirolimus Cypher

Abbott Everolimus Xience

Boston Scientific Everolimus Promus

Medtronic Zotarolimus Endeavor

Biosensors Biolimus A9 Biomatrix Flex

Terumo Biolimus A9 Nobori

Biotronik Sirolimus Orsiro

Microport Sirolimus Firehawk

CID Sirolimus Cre8

Biosensors/JW Medical Sirolimus Excel

Sahajanand Sirolimus Supralimus

Cardionovum Sirolimus Prolimus

Micell Sirolimus MiStent

Meril Merilimus Mitsu

Elixir Novolimus DESyne

Atrium Corolimus Cinatra

ICON Rofirolimus Nuloy

Current State of DES Technology

• Coronary DES are a mature technology

• Similar platform architecture:

- Metallic stent, polymer coating, antiproliferative agent

- Generic adoption of –limus or paclitaxel (no new drugs)

• Increasing competition, falling prices

• Reached the endgame in restenosis – can’t improve upon

efficacy of current limus products

• Making incremental improvement to technology with

emphasis on safety and deliverability

Cordis Announcement: June 15th, 2011

• Discontinue NEVO™ stent development

• End manufacturing of Cypher and Cypher Select+

• Close DES manufacturing facilities and an R&D center

Rationale: Changing market dynamics

• Declining procedure numbers

• Price erosion

• Increased competition and shrinking market for Cypher

• More stringent regulatory requirements for new DES

• Sharply rising cost of bringing a new product to market

Over 4,000,000 patients treated!

10-Year Follow-up from First-in-Man

Sousa J., et al., JACC : Cardiovascular Interventions 2010; 3: 556 – 58.

IVUS / OCT confirmation Angiographic results

Thank You!