The Science Behind Taxus Advanced Angioplasty 2004 Christian Vander Velde, Boston Scientific Europe,...

The Science Behind TaxusThe Science Behind TaxusThe Science Behind TaxusThe Science Behind Taxus

Advanced Angioplasty 2004Advanced Angioplasty 2004

Christian Vander Velde, Boston Scientific Europe, Marketing

TAXUS Technology TAXUS Technology TAXUS Technology TAXUS Technology

• Binds tubulin

• Microtubular dynamics

• Multifunctional

• Binds tubulin

• Microtubular dynamics

• Multifunctional

• Uniformity

• Durability

• Biphasic Controlled Release Kinetics

• Uniformity

• Durability

• Biphasic Controlled Release Kinetics

• Express™ Stent

Tandem Architecture

Flexibility

• Maverick™ BalloonDeliverability

• Express™ Stent

Tandem Architecture

Flexibility

• Maverick™ BalloonDeliverability

PaclitaxelPaclitaxel PolymerPolymer PlatformPlatform

TAXUS Technology - Paclitaxel TAXUS Technology - Paclitaxel

Restenotic Cascade

The IdealPharmaceuticalShould Control

The IdealPharmaceuticalShould Promote

Inflammatory Cells

SMC Proliferation

SMC Migration

ECM

0–2Days

2–4Days

4–10 Days

10–14 Days

2–4 Weeks

Platelet Aggregation

Endothelialization

Table adapted from the experimental models by Ferns et al.

– Paclitaxel is a multi-functional drug which effectively:

• Inhibits proliferation

• Inhibits migration

• Inhibits inflammation

• Inhibits secretion

TAXUS Technology - PaclitaxelTAXUS Technology - PaclitaxelTAXUS Technology - PaclitaxelTAXUS Technology - Paclitaxel

Promotes

Endothelialization

Restenosis

Prevents

Paclitaxel selectively impacts smooth muscle cells, platelets, and white blood cell activity without affecting endothelial cells

– Paclitaxel enables healing by selectively impacting the cells that cause restenosis while allowing healthy healing of endothelial cells

• TAXUS shows similar healing between control bare metal stent and paclitaxel

Endothelialization of a paclitaxel-eluting stent in a porcine coronary artery

Axel et al, AHA 1997, Karsch et al, SIC 1998

Polymer Carrier ConsiderationsPolymer Carrier Considerations Chemical/Physical and BiologicalChemical/Physical and Biological

Formulate/Formulate/processprocess

CoatingCoatingIntegrityIntegrity

SterilizationSterilization

Drug LoadingDrug LoadingDrug releaseDrug release

BiocompatiblBiocompatiblee

VascularVascularcompatiblecompatible

• Smooth, Uniform CoverageSmooth, Uniform Coverage• No Cracking, Flaking or DelaminatingNo Cracking, Flaking or Delaminating

Coating Integrity Coating Integrity BSC Carrier- TransluteBSC Carrier- TransluteTMTM

200x200x40x40x

Coated, Loaded, Sterilized, ExpandedCoated, Loaded, Sterilized, Expanded

Uniform PTx Content Along StentsUniform PTx Content Along Stents of Different Lengths of Different Lengths

Uniform PTx Content Along StentsUniform PTx Content Along Stents of Different Lengths of Different Lengths

(15, 24, 32 mm stents -- 1ug/mm2)(15, 24, 32 mm stents -- 1ug/mm2)

Uniformity of Paclitaxel Distribution Along StentComparison of % Paclitaxel Recovery from Consecutive 4cm Segments Along Stent

0

20

40

60

80

100

120

140

1 2 3 4 5 6 7 8

Stent Segment (Approximately 4cm length per each segment)

Paclita

xel %

Reco

very

( [

HP

LC

/gra

vim

etr

ic]

x 1

00%

)

15mm NIR (85ug) 24 mm Express WH (151ug) 32 mm Express WH (209ug)

% Cumulative Paclitaxel Release

0.0%

1.0%

2.0%

3.0%

4.0%

0 2 4 6 8 10 12

TIME (Days)

% P

aclita

xel R

ele

ased


0.0%

1.0%

2.0%

3.0%

4.0%

0 2 4 6 8 10 12

TIME (Days)

% P

aclita

xel R

ele

ased


0.0%

1.0%

2.0%

3.0%

4.0%

0 2 4 6 8 10 12

TIME (Days)

% P

aclit

axel

Rel

ease

d

Uniform PTx Release From ExpressUniform PTx Release From ExpressTMTM Stents of Different LengthsStents of Different Lengths

1.0 ug/mm2, Slow release16 mm

1.0 ug/mm2, Slow Release24 mm

1.0 ug/mm2, Slow Release32 mm

Polymer-based Clinical DataPolymer-based Clinical DataPolymer-based Clinical DataPolymer-based Clinical Data

TRIAL DOSE OF PTx LATE LOSS mmTRIAL DOSE OF PTx LATE LOSS mm

TAXUS I 1.0ug/mm2 SR 0.36 +/- 0.48TAXUS I 1.0ug/mm2 SR 0.36 +/- 0.48

TAXUS II 1.0ug/mm2 SR 0.31 +/- 0.39 TAXUS II 1.0ug/mm2 SR 0.31 +/- 0.39

TAXUS II 1.0ug/mm2 MR 0.30 +/- 0.39TAXUS II 1.0ug/mm2 MR 0.30 +/- 0.39

TAXUS IVTAXUS IV 1.0ug/mm2 SR 1.0ug/mm2 SR 0.39 +/- 0.50 0.39 +/- 0.50

Confirmed by IVUS analysis (TAXUS II - Circulation Confirmed by IVUS analysis (TAXUS II - Circulation January 20, 2004)January 20, 2004)

In VivoIn Vivo Considerations for Considerations for Polymers and DrugsPolymers and Drugs

• Animal ModelAnimal Model– RatRat– RabbitRabbit– SwineSwine– CanineCanine

• Implant TimeImplant Time

• ImplantImplant LocationLocation– Sub QSub Q– IMIM– IliacIliac– CoronaryCoronary

• OtherOther

In Vivo Studies,

#&@% !!!!

Polymer CarriersPolymer CarriersVascular CompatibilityVascular Compatibility

Bare StentBare Stent Polyurethane-coated Stent Polyurethane-coated Stent (2 months)(2 months)

In Collaboration w/Drs. Rogers and Edelman,MITIn Collaboration w/Drs. Rogers and Edelman,MIT

Sub-optimal drug carriers can cause severe inflammatory Sub-optimal drug carriers can cause severe inflammatory responseresponse

Failed candidatesFailed candidates(normal porcine coronary model)(normal porcine coronary model)

Effect of Animal Model and Implant SiteEffect of Animal Model and Implant SiteRat Subcutaneous Implant ModelRat Subcutaneous Implant Model

Bare Stent Bare Stent Polyurethane-coated StentPolyurethane-coated Stent

28 day Implant - H&E Staining28 day Implant - H&E Staining

Effect of Animal Model and Implant SiteEffect of Animal Model and Implant Site

Bare Stent Bare Stent Polyurethane-coated StentPolyurethane-coated Stent


Porcine Coronary 28 dayPorcine Coronary 28 day

28 day PLA/PCL28 day PLA/PCLcoated stent coated stent 56 day PLA/PCL coated stent 56 day PLA/PCL coated stent

In Collaboration w/Drs. Rogers and Edelman, MITIn Collaboration w/Drs. Rogers and Edelman, MIT

Rabbit Iliac ArteryRabbit Iliac Artery


35 day PLA/PCL 35 day PLA/PCL

In Collaboration w/Drs. Rogers and Edelman, MITIn Collaboration w/Drs. Rogers and Edelman, MIT

Porcine Coronary ArteryPorcine Coronary Artery


Vascular CompatibilityVascular CompatibilityTransluteTransluteTMTM


180D Bare 180D Bare controlcontrol

180D polymer180D polymercoatedcoated

90D polymer 90D polymer coatedcoated

90D Bare 90D Bare controlcontrol

In collaboration with Dr. Rob Schwartz Mayo Clinic In collaboration with Dr. Rob Schwartz Mayo Clinic and Dr. Greg Wilson Sick Children’s-Torontoand Dr. Greg Wilson Sick Children’s-Toronto

180 180 dayday

Translute onlyTranslute onlyExpress stentExpress stent

• Good safety profileGood safety profile• Polymer similar to controlPolymer similar to control• Reproduced from lot to lotReproduced from lot to lot

0

2

4

6

8

10

12

mm2

Bare Control Translute Coated 28Days

90Days

Lumen Area

Translute Polymer Translute Polymer Long term (180 days) vascular compatibilityLong term (180 days) vascular compatibility

In collaboration with Dr. Rob Schwartz Mayo Clinic In collaboration with Dr. Rob Schwartz Mayo Clinic and Dr. Greg Wilson Sick Children’s-Torontoand Dr. Greg Wilson Sick Children’s-Toronto

0

1

2

3

4

0 60 120 180

0

1

2

3

4

5

0 60 120 180

InflammationInflammation(CD45, 0-4)(CD45, 0-4)

Endothelial coverageEndothelial coverage(PECAM 1, 0-5)(PECAM 1, 0-5)

BarePolymer-coated

020406080

100

0 60 120 180

% Luminal Stenosis% Luminal Stenosis

No significant differencesNo significant differences



TAXUS Technology - Translute™ PolymerTAXUS Technology - Translute™ Polymer TAXUS Technology - Translute™ PolymerTAXUS Technology - Translute™ Polymer

Polymer-based matrices provide:Polymer-based matrices provide:

• ease of handlingease of handling

• uniform dose along stent and dosing in a controlled manner = uniform dose along stent and dosing in a controlled manner = consistencyconsistency

• a matrix by which drug release can be manipulated to achieve a a matrix by which drug release can be manipulated to achieve a desired biological responsedesired biological response

With greater opportunities come greater challengesWith greater opportunities come greater challenges

TransluteTransluteTMTM Polymer stability Polymer stability

TransluteTM coating integrity was maintained in 10-year equivalency tests*

The TransluteTM polymer has shown remarkable stability out to two years in an animal model*

Harsh conditions (alcohol storage, mild heat, agitation) fail to degrade the polymer*

Tests have shown that following physical abrasion of the polymer, the release is not markedly increased*

* data on file

Thank You !Thank You !Thank You !Thank You !

The Science Behind Taxus Advanced Angioplasty 2004 Christian Vander Velde, Boston Scientific Europe,...

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