Non-Polymeric and Bioabsorbable Polymers Will Reign Supreme in Near Future Instituto Dante Pazzanese de Cardiologia Sao Paulo - Brazil Sao Paulo - Brazil Alexandre Abizaid, MD, PhD, FACC Columbia University New York - USA New York - USA

First Generation DES - Drug-Eluting Stents (DES) dramatically reduced restenosis as compared to bare-metal stents (BMS) But the problem is… - Late stent thrombosis (LST) has emerged as a major safety concern Daemen J et al. Lancet 2007; 369: % per year

DES – Late incomplete apposition and Cypher ® stent thrombosis 6 m 18 m PostPre

DES – Late incomplete apposition and Cypher ® stent thrombosis 40 m Post PCI

DES – Late incomplete apposition and Taxus® stent thrombosis Pre Post 8 m Post

DES – Late incomplete apposition and Taxus® stent thrombosis 12 m Post PCI PCI

Shortcomings often associated with polymers during stent delivery Non uniform polymer coating “Webbed” polymer surface leading to stent expansion issues” Polymer delamination Current Problems with Polymers ● Durable Coatings-Potential for: - Continuing source of inflammation - Continuing source of inflammation - Poor healing/thrombosis risk - Poor healing/thrombosis risk

Delayed Healing - DES Rabbit 28 days Lack of neointimal growth (uncovered Struts) * * *Inflammation Persistent fibrin deposition Incomplete endothelialization Porcine 28 days Severe inflammation Fibrin deposition with malapposition CYPHERTAXUS Vermani et al.

Polymer Evolution  Durable Polymers  Non-Polymeric  Bioabsorbable Polymers

Polymer Evolution  Durable Polymers  Non-Polymeric  Bioabsorbable Polymers

(mm 2 ) Bioabsorbable Polymer with Sirolimus in the porcine model (SurModics Inc.) Neoinimal Area 3090(day) Sustained efficacy DES (bioabsorbable polymer) BMS Bioabsorbable polymer (SynBiosys) + sirolimus BMS Vermani et al.

(Day) Grade of inflammation Bioabsorbable polymer (SynBiosys) + sirolimus BMS Cypher (historical) Taxus (historical) Bioabsorbable Polymer (SynBiosys GACL-LA) with Sirolimus in the porcine model (SurModics Inc.) Bioabsorbable Polymer (SynBiosys GACL-LA) with Sirolimus

Bioabsorbable Polymer DES Systems  BioMatrix (Biosensors)  JACTAX (Boston Scientific)  Nevo (Cordis)  Supralimus (Sahajanand)  Sirolimus + EPC capture (Orbus)

Bioabsorbable Polymer DES Systems  BioMatrix (Biosensors)  JACTAX (Boston Scientific)  Nevo (Cordis)  Supralimus (Sahajanand)  Sirolimus + EPC capture (Orbus)

Biodegradable Drug/Carrier: - Biolimus A9 ® / Poly (Lactic Acid) 50:50 mix - abluminal surface only (contacts vessel wall) - 10 microns coating thickness - degrades in 9 months releasing CO 2 + water BioFlex I BioFlex™ II BioMatrix ® III Stent Platform

LEADERS: Primary Endpoint Cardiac Death, MI, or 9 months

Definite Stent Thrombosis Sirolimus Stent 2.0% Biolimus Stent 1.9% Rate Ratio = 0.93, 95% CI Cumulative Incidence (%) Months of Follow-up Definite stent thrombosis Number at risk BES SES

LEADERS Bifurcation Subanalysis MACE* Bifurcation Group BES vs. SES HR 0-2 days : 1.62 [ ] p= days : 0.46 [ ] p=0.02 Sirolimus Bifurcation group Biolimus Bifurcation group Sirolimus Non-bifurcation group Biolimus Non-bifurcation group *MI, cardiac death and clinically driven TVR

Uncovered struts Hyperplasia of neointima LA 2.36 mm², SA 3.39 mm ² Covered malapposed strut Well covered struts

Distribution of Uncovered Struts within Lesions Cypher Biomatrix

Bioabsorbable Polymer DES Systems  BioMatrix (Biosensors)  JACTAX (Boston Scientific)  Nevo (Cordis)  Supralimus (Sahajanand)  Sirolimus + EPC capture (Orbus)

Fully bioresorbable PLGA polymer (exclusively housed in reservoirs): Benefits Complete resorption in 3-4 months Fully metabolized Highly biocompatible and hemocompatible Future applications could use different co- monomer ratios to permit variable resorption times (few weeks-many months) The NEVO™ Polymer 8 DAY 30 DAY 60 DAY 90 DAY

NEVO’s™ sirolimus release kinetics approximate CYPHER ® stent’s NEVO™ achieves similar sirolimus arterial tissue levels to CYPHER ®. Sirolimus Release from NEVO™ StentSirolimus Content in Tissue NEVO™: Sirolimus Release & Tissue Content Normal porcine coronary arteries, 10-15% implant overstretch; NEVO Data from: AP-061 Implant Duration (Days) Arterial Sirolimus Content (µg/mg artery) NEVO™ Prototype Stents CYPHER ® Stents

NEVO RES-I Study Overview 40 sites worldwide Europe, South America, Australia and New Zealand 394 subjects, stratified by diabetic status, and randomized 1:1 Single De Novo Native Coronary Artery Lesions Reference Vessel Diameter: mm Lesion Length: ≤28 mm Primary Endpoint: 6-month in-stent late loss Sub-Study: IVUS subset (50 patients per arm) Dual antiplatelet therapy for ≥6 months NEVO™ Sirolimus-eluting Stent (n=202) TAXUS ® Liberté™ Paclitaxel-eluting Stent (n=192) 30 Day 6Mo1Yr2Yr3Yr4Yr Angiographic/ IVUS 5Yr Clinical/ MACE 87% Angiographic follow up* 95% 180 day clinical follow up* * Follow-up as of April 16, 2009

DRAFT Slides: Awaiting final quality control review: CONFIDENTIAL Late Lumen Loss at 6-Months P<0.001 Primary Endpoint Late Loss (mm) ±0.31 ±0.46 ±0.32 ±0.39 n=180n=162 n=180n=162

DRAFT Slides: Awaiting final quality control review: CONFIDENTIAL 6-Month MACE and Components P=0.19 P=0.37 P=0.75 No reports of Emergent CABG % of Patients 8/19313/1871/1933/187 4/1935/187 5/1938/187 3/1936/187 P=0.37 P=0.33 Taxus LiberteNEVO

Bioabsorbable Polymer DES Systems  BioMatrix (Biosensors)  JACTAX (Boston Scientific)  Nevo (Cordis)  Supralimus (Sahajanand)  Sirolimus + EPC capture (Orbus)

JACTAX Trial PI: Eberhard Grube Stent Platform Liberté ® Pre-mounted stent (BSC) JA  Coating 9.2 μg. of Paclitaxel and 9.2 μg. DLPLA (16 mm) 2700 microdots (16 mm) Mass of polymer approx 3.4 ng. per microdot < 1 micron thick, abluminal and low molecular weight biodegradable polymer decreases persistence time

JACTAX HD Results vs. ATLAS Matched (9 months) TaxusLiberté(n=223) TaxusLiberté(n=223) LabcoatLiberté(n=96) LabcoatLiberté(n=96) Binary Restenosis (%) In-StentIn-Segment p=0.14 p=0.12

Bioabsorbable Polymer DES Systems  BioMatrix (Biosensors)  JACTAX (Boston Scientific)  Nevo (Cordis)  Supralimus (Sahajanand)  Sirolimus + EPC capture (Orbus)

Supralimus™ Biodegradable Polymer Based Sirolimus Eluting Stent Supralimus-Eluting Stents Platform  Millennium Matrix  ‘Intermediate Cell Geometry’, Slotted Tube Design  ” strut thickness  Drug: Sirolimus  Drug Dosage: 102  g-16mm  Unique Biodegradable Polymeric Blend  Single layer of coating with drug free top coat  4-5  m coating thickness

SERIES I: Study Design Real world coronary artery lesions Diameter: 2.5 to 4.0mm Length: 11 to 33mm Real world coronary artery lesions Diameter: 2.5 to 4.0mm Length: 11 to 33mm Supralimus™ Sirolimus Eluting Stent N = 100 Primary endpoint: MACE at 30 days & in-stent binary restenosis at 6 months Secondary endpoint: Stent thrombosis and MACE at 9 months Primary endpoint: MACE at 30 days & in-stent binary restenosis at 6 months Secondary endpoint: Stent thrombosis and MACE at 9 months Supralimus-Eluting Stents

TRIALS SERIES I TAXUS IV SIRIUSESIRIUSENDEAVORIIBRANDSSUPRALIMUSTAXUSCYPHERCYPHERENDEAVOR DRUGSirolimusPaclitaxelSirolimusSirolimusZatrolimus Patients MACE (%) TLR AT,SAT,LT LL (IL-mm) LL (IS-mm) RR(%) Supralimus vs. Others

e-series Registry: Baseline Demographics VARIABLEN = 1,223 Age, years63.3 ± 11.0 Female gender30.6 % Hypertension78.6 % Diabetes mellitus38.1 % Insulin dependent8.3 % Dyslipidemia64.2 % Current smoking31 % Family history of CAD46 % History of CHF3.9 % Previous MI (>30 days)22.7 % Previous CABG14.6 % Previous PCI33.5 % Previous CVA2.3 % Renal insufficiency (baseline serum creatinine ≥2.0 mg/dL) 4.7 % CRC

e-SERIES: Adverse Events at 6 Months FU * CRC % of patients N = 718 * Out-of-hospital events

e-SERIES: Kaplan-Meier Survival from MACE CRC

Bioabsorbable Polymer DES Systems  BioMatrix (Biosensors)  JACTAX (Boston Scientific)  Nevo (Cordis)  Supralimus (Sahajanand)  Sirolimus + EPC capture (Orbus)

Early Endothelialization Scanning EM of a Genous stent at 48 hours following stenting shows complete coverage of the stents by endothelium (left). The detail (right) shows leucocyte adherence and incomplete cell-cell contact.

Better than any polymer is no polymer…

Selectively micro-structured surface holds drug in abluminal surface structuresSelectively micro-structured surface holds drug in abluminal surface structures BioMatrix Freedom Stent Micro-structured Surface

BioFreedom Biosensors Polymer-Free FIM Study (PI: E. Grube) Symptomatic, Ischemic heart disease Native Coronary artery ≥ 2.25 mm and ≤ 3.0 mm Lesion length ≤ 14 mm Lesion amenable to percutaneous treatment with DES 30 d 4 mo 12 mo 2yr 3yr 4yr 5yr 30 d 4 mo 12 mo 2yr 3yr 4yr 5yr Primary Endpoint:In stent Late Lumen Loss (LL) at 12 months (25 patients from each cohort will receive angio/IVUS at 4 months, balance 12 months) Secondary Endpoints: MACE and stent thrombosis rate at 30 days, 6 and 12 months In-stent/In-segment binary restenosis at 6 months In-stent, prox and dist, LL at 6 months Neointimal hyperplastic volume at 6 months measured by IVUS BioFreedom DES Standard Dose 15.6µg/mm n=100 7 Sites in Germany Randomized Trial, 3 Arms, Angiographic and IVUS Follow-up BioFreedom DES Low Dose 7.8u µg/mm n=100 Taxus Liberte DES Standard Dose n=100

Translumina Porous Surface Stent PureSirolimus

Bioabsorbable, Silica Sol-Gel Matrix (Cobra system) Polymer-free, biocompatible coating: – Non-thrombogenic – Non-inflammatory Fully bioabsorbable – Hydrates & erodes through dissolution in body fluids – DES becomes BMS within 6 months Controlled release of drug Silica Sol-gel Process: 1.Simple molecular precursors are converted into nanometer-sized particles to form a colloidal suspension, or sol. 2.The colloidal nanoparticles are then linked with one another to form a 3D Network

PLUS-One Study Design Clinical Follow-up 1 m4 m1 y2 y3 y4 y5 y de novo lesions in native coronary arteries RVD: 3.0 mm mm Lesion length: ≤20 mm Stent diameters: mm Stent length: 12, 18, 24 mm Dose A: 4 mcg/ 18mm stent (0.03 mcg per mm 2 ); n = 30 Dose B: 8 mcg/ 18mm stent (0.06 mcg per mm 2 ); n = 30 Primary Endpoint 4-month MACE event rate, defined as cardiac death, MI (Q wave & non-Q wave), and ischemia-driven TLR Secondary Endpoints Lesion, Device & Procedure Success with <30% residual stenosis MACE at Hospital Discharge & 30 days, 1, 2, 3, 4 & 5 years 4-Month Diameter Stenosis (%), in-stent and in-segment angiographic late loss (mm) and binary restenosis rate (%) by QCA and 4-month NIH volume by IVUS (mm 3 ) QCA/ IVUS Follow-up Clinical Follow-up

 Abluminal coating – 5µ thickness applied on crimped stent.  Consistent coating ensuring 98% of the drug delivered to the site.  Polymer free Paclitaxel.  2.5µg/mm² dose.  Boost-release (60% in 2 days)  Profile release established in 30 days (98% of the drug)  Back to regular Chromium Cobalt after 45 days.  Abluminal coating – 5µ thickness applied on crimped stent.  Consistent coating ensuring 98% of the drug delivered to the site.  Polymer free Paclitaxel.  2.5µg/mm² dose.  Boost-release (60% in 2 days)  Profile release established in 30 days (98% of the drug)  Back to regular Chromium Cobalt after 45 days. Polymer Free Paclitaxel

PAX A (PI: A Abizaid) First In-Man randomized randomized n = 30 Taxus Liberte n = 15 AMAZONIA Pax n = 15 Primary Endpoint: Late Loss % obstruction OCT tissue coverage at 4 Months Sub-analysis: Endothelial function in 30 ptsEndothelial function in 30 pts

PAX B (PI: A Abizaid) MulticenterRegistry n = 100 AMAZONIA Pax n = 100 Primary Endpoint: Late Loss And MACE at 9 Months

Bi PAX (Bifurcation) (PI: J Fajadet) MulticenterRegistry n = 100 Nile Croco n = 100 Primary Endpoint: Late Loss And MACE at 9 Months

3D MicroPorous Nanofilm HAp

4 months (n=15) 9 months (n=12)VariableIn-StentIn-LesionIn-StentIn-Lesion MLD, mm 2.34 ± ± ± ± 0.29 % Diameter stenosis 13.8 ± ± ± ±9.50 Late lumen loss, mm 0.29 ± ± ± ± 0.31 Restenosis *, % (n) 0000 Abizaid et al. ACC QCA Results Follow-up

IVUS Volumetric Analysis Baseline / 4 month / 9 month follow-up IVUS variables Baseline N= 14 P* 4-month follow-up N= 14 P* 9-month follow-up N= 14 P* Vessel Volume (mm 3 ) ± ± ± 85.6 Stent Volume (mm 3 ) ± ± ± 41.4 Lumen Volume (mm 3 ) ± ± ± 38.2 NIH Volume (mm 3 ) N/A 4.3 ± ± 4.9 Mallapposition Volume (mm 3 ) 0.34 ± ± ± 0.36 % Stent Obstruction N/A 2.8 ± ± 2.3 * 1 pt refused to undergo invasive FU at 9 months and therefore were excluded from this sub analysis.

PRE POST 4 MONTH- FU 9 MONTH- FU Lower LLL (-0.1 mm)

PRE POST FOLLOW-UP 4 MONTHS

VESTASYNC II Polymer-Free Sirolimus-Eluting Stent First In-Man 3:1 randomized n = 90 Bare Metal Stent n = 30 Vestasync Eluting Stent n = 60 Primary Endpoint: Late Loss at 6 Months IVUS subanalysis: 30 pts OCT sub-analysis : 30 pts Endothelial function: 20 pts

Conclusions  First Genaration Durable Polymers with thick polymer loading are being gradually replaced to more advanced technology.  Non-Polymeric DES with surface modification will dominate the market.  Bioabsorbable Polymers with abluminal release and reservoir technology are slowing replacing the first gen DES.