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
% 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
% Cumulative Paclitaxel Release
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
In Collaboration w/Drs. Rogers and Edelman,MITIn Collaboration w/Drs. Rogers and Edelman,MIT
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
Effect of Animal Model and Implant SiteEffect of Animal Model and Implant Site
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
Effect of Animal Model and Implant SiteEffect of Animal Model and Implant Site
Vascular CompatibilityVascular CompatibilityTransluteTransluteTMTM
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
Vascular CompatibilityVascular CompatibilityTransluteTransluteTMTM
In Collaboration w/Drs. Rogers and Edelman,MITIn Collaboration w/Drs. Rogers and Edelman,MIT
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