The Latest Experimental Results of Endothelialization with BuMA stent. Renu Virmani, MD CVPath Institute, Inc. Gaithersburg, Maryland, USA

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1 The Latest Experimental Results of Endothelialization with BuMA stent Renu Virmani, MD CVPath Institute, Inc. Gaithersburg, Maryland, USA

2 In Stent Re -stenosis [%] Neointimal Thickness [mm] A Great Success in Drug-Eluting Stents BMS 23 months SES 13 months RAVEL trial (N Engl J Med 22;346:1773-8) Restenosis % in SES (vs. 26.6% in BMS) SIRIUS trial (N Engl J Med 23;349: ) TLR 4.1% in SES (vs. 16.6% in BMS) BMS DES BMS DES

3 Late and Very Late Stent Thrombosis (LST/VLST) Following 1 st -generation DES Cumulative probability of acute occlusion (%) Mean % Endothelialization BMS DES Steady Increase in Cumulative Probability of LST/VLST Months Joner M & Finn AV. J Am Coll Cardiol. 26;48: Thr The SCAAR Registry (n=73,798 stents) Years after PCI DES BMS Lagerqvist, et al. Circ Cardiovasc Intervent 29 Annual Rate of LST/VLST.4-.6%/year up to 4 years (Bern/Rotterdam registries: SES and PES).26%/year up to 5 years (j-cypher: SES) Wenaweser P, et al. J Am Coll Cardiol 28;52: Kimura T, et al. Circulation 212;125:

4 % Struts % Uncovered struts Pathological Correlates of Late DES Thrombosis: Strut Coverage as a Marker of Endothelialization > 3 days implants > 3 days implants uncovered covered uncovered covered P<.1 The odds ratio for thrombus in a stent with a 3 ratio of uncovered to total stent struts per 15 section >3% is 9. (95% CI, 3.5 to 22). The most powerful histological predictor of stent % Struts with endothelium thrombosis was endothelial coverage. 8 n=28 p<.1 7 Thrombus 6 No Thrombus n= % Uncovered Struts/section Finn AV, et al., Circulation 27;115:

5 4F with 2 SES in LAD and RCA, died suddenly 4 days after surgical removal of melanoma. DAPT was discontinued 5 days before surgery. (a)-(d) LAD: SES 17months a c Hypersensitivity Reaction to SES b d 39F SES in LMCA for 5 yrs. The patient recently stopped taking medication due to lack of insurance. OCT (e), (f) RCA: SES 17months e f a to f: Nakazawa G, et al. JACC 211;57: MIH = Multiple interstrut hollow OCT: Tada T. AHA211

6 PES (3 months) Fibrin accumulation & Malapposition (Positive remodeling) in PES A B C Thr Thr * PES (4 months) D E F Thr * * Thr * * Nakazawa G, et al. JACC 211

7 Endothelial cell Endothelial cell β-cat The Structure and Function of Healthy Endothelium Claudin JAMs (Junctional adhesion molecules) VE-cadherin Weibel Palade body PECAM-1 Connexins Monocyte Transcellular pathway Molecules >3nm M r caveolae Paracellular pathway Molecules <3nm M r Integrin Tight junction Claudin occludin JAMs Ang-1 Ang-2 VEGF TIE2 β-cat β-cat Gap junctions Adherens junction TIE2 Ang-1 PI3K Acetylcholine, Serotonin Calmodulin NADPH BH 4 L-arginine Ang-2 Ca ++ enos NO Akt Survivin Extracellular matrix SMCs VN MMP s FN VN Antithrombotic and Prothrombotic Factors in Endothelial cells Antithrombotic Prostacyclin (PGI 2 ) Nitric oxide (NO) Thrombin/thrombomodulin Antithrombin Heparin sulphate proteoglycan Tissue Factor Pathway Inhibitor Tissue Plasminogen activator PC apc Protein S VIIIa Va IIa, Xa, XIa IXa VIIa/TF/Xa Platelets Coagulation Fibrinolysis Thrombin IXa IX Prothrombin Prothrombotic Von Willebrand factor Xa X VIIa TF PAI-1 Otsuka F et al. Nat Rev Cardiol; 212:

8 alchimer The eg base-layer technology: polymer chains precursor molecules ultra-thin (nanometric) organic (polymeric) layers; grafting = covalent bonding to the surface = strong adhesion; hyper conformal and uniform on complex shapes. SE eg electric current (eg )

9 Alchimer The eg + Biodeg technology: biodeg + drug(s) imaging polymer resin eg BuMA metal eg polymer (ca. 2 nm) stent strut release biodeg polymer matrix (3-7 µm) eg BuMA base layer secures adhesion of the biodegradable polymer matrix hosting the drug, and prevents cracking and delamination upon expansion and over time.

10 Study design for Atherosclerotic Rabbit Model Blood Collection for Cholesterol measurements wks. Balloon injury after 1 week 4 wks. 4 wks. New Zealand White Rabbits, n=45 Study duration Diver Endeavor Xience Cypher 5 w 9 w 13w 1% Atherogenic Diet.25% Atherogenic diet Euthanasia Stent Implantation

11 Light Microscopic Analysis (mm 2 ) Neointimal Area * * * 35 %Stenosis.3 Neointimal Thickness (%) (mm) (%) * *.2 * 2 *.15 * * * Uncovered Struts * * Cypher Xience Endeavor Driver *significant

12 Macrophage %Area Score BMS ZES EES SES Cholesterol clefts (underlying plaque) Incidence 1 3 P=.6 Calcification (underlying plaque) * * 2 1 P= (neointima) (underlying plaque) 3 * * * P<.1 Macrophage 2 1 P=.9

13 SEM Analysis BMS EES ZES SES P value Treatment n=18 n=8 n=8 n=6 (ANOVA) Scanning Electron Microscopy Endothelialization, % * *.1 (Above) Endothelialization, % (Between) * Significantly different from BMS by Dunnett s post hoc test

14 enos expression by Confocal Microscopic Analysis Treatment BMS n=18 EES n=8 ZES n=8 SES n=6 P value (ANOVA) Confocal Microscopy enos expression, % *.3 * Significantly different from BMS by Dunnett s post hoc test

15 BMS ZES EES SES enos expression, % Endothelial enos Expression in DES vs. BMS (Driver) at 28-days in a Rabbit Atherosclerosis Model 6 p< * *

16 Near-to-complete short term re-endothelialization of a sirolimus-eluting stent using electro-grafting (eg ) coating technology

17 Xience SEM 14 days rabbit iliac BuMA

18 Xience SEM 28 days rabbit iliac BuMA

19 Swine Coronary Comparator Study: BUMA DES vs. Xience V (OCT analysis of strut coverage and overlapping) Duration : 14 days and 45 days Overlap (LAD and LCX) and Single (RCA) Stent area, lumen area, and neointimal thickness were measured by OCT at 14 days and 45 days Histopathological analysis were performed between BuMA DES and Xience V.

20 14 days Histology results (mm 2 ) (mm) (%) EEL area IEL area Lumen Neointima Area Neointima Thickness % Stenosis (%) (%) Fibrin Score Endothelialization Granuloma Giant cell Inflammation Adventitial Inflammation Xience V N=5 BuMA N=5

21 45 days Histology results (mm 2 ) (mm) (%) EEL area IEL area Lumen Neointima Area Neointima Thickness % Stenosis (%) (%) Fibrin Score Endothelialization Granuloma Giant cell Inflammation Adventitial Inflammation Xience V N=6 BuMA N=6

22 OCT Analysis: Xience V vs. BuMA in Porcine Coronary Arteries at 14 Days (mm 2 ) (mm 2 ) (%) p=.78 p=.93 p=.9 p=.81 p=.8 p=.9 p=.87 p=.9 p= (mm) Xience V Stent area Mean neointimal thickness (mm) Lumen area Maximum neointimal thickness No significant differences were observed between Xience V and BuMA. Non-Overlapped (14 days) BuMA n=18 (all), 18 (non-ol), 7 (OL with underlying BuMA) n=15 (all), 15 (non-ol), 7 (OL with underlying XIENCE V) All Non-overlap Overlap (%) Area stenosis All Non-overlap Overlap All Non-overlap Overlap Uncovered struts p=.91 p=.82 p=.96 p=.73 p=.89 p=.91 p=.2 p=.15 p=.15 All Non-overlap Overlap All Non-overlap Overlap All Non-overlap Overlap No stent malapposition was identified. Overlapped (14 days) Xience V BuMA Xience V with underlying BuMA BuMA with underlying Xience V

23 OCT Analysis: Xience V vs. BuMA in Porcine Coronary Arteries at 45 Days (mm 2 ) (mm 2 ) (%) p=.82 p=.75 p=.39 p=.34 p=.41 p=.18 p=.27 p=.36 p= (mm) Xience V Stent area Mean neointimal thickness Lumen area BuMA n=8 (all), 7 (non-ol), 3 (OL with underlying BuMA) n=8 (all), 7 (non-ol), 3 (OL with underlying XIENCE V) All Non-overlap Overlap Maximum neointimal thickness p=.24 p=.35 p=.16 (mm) 1. p=.28 p=.53 p= All Non-overlap Overlap All Non-overlap Overlap Area stenosis All Non-overlap Overlap All Non-overlap Overlap No uncovered struts at 45 days for both XIENCE V and BuMA No significant differences were observed between Xience V and BuMA. Non-Overlapped (45 days) Sections with granulomas were excluded. No stent malapposition was identified. Overlapped (45 days) Xience V BuMA Xience V with underlying BuMA BuMA with underlying Xience V

24 Stent (IEL) area (histology) Area stenosis (histology) Neointimal THK (histology) Correlation Between OCT and Histology (14 Days) Xience V BuMA n=5 (non-ol) n=4 (non-ol) (mm 2 ) Stent (IEL) area (%) Area stenosis (mm) Mean neointimal thickness OCT Histology OCT Histology OCT Histology r 2 =.48 p=.3 r 2 =.68 p<.1 r 2 =.61 p=.2 Stent (IEL) area (OCT) Area stenosis (OCT) Neointimal thickness (OCT) Xience V (14 days) BuMA (14 days)

25 Stent (IEL) area (histology) Area stenosis (histology) Neointimal THK (histology) Correlation Between OCT and Histology (45 Days) Xience V n=6 (non-ol) BuMA n=6 (non-ol) (mm 2 ) Stent (IEL) area (%) Area stenosis (mm) Mean neointimal thickness OCT Histology OCT Histology OCT Histology.8 r 2 =.63 p<.1 r 2 =.95 p<.1 r 2 =.91 p<.1 Stent (IEL) area (OCT) Area stenosis (OCT) Neointimal thickness (OCT) Xience V (14 days) BuMA (14 days)

26 Xience V BuMA Xience V BuMA OCT Analysis Summary: Xience V vs. BuMA Stent area Lumen area (mm 2 ) (mm 2 ) (%) (mm) Xience V 14d: n=18 (all), 18 (non-ol), 7 (OL with underlying BuMA) 45d: n=8 (all), 7 (non-ol), 3 (OL with underlying BuMA) 14d 45d 14d 45d 14d 45d All Non-overlap Overlap Mean neointimal thickness 14d 45d 14d 45d 14d 45d All Non-overlap Overlap (mm) BuMA 14d 45d 14d 45d 14d 45d All Non-overlap Overlap Maximum neointimal thickness 14d 45d 14d 45d 14d 45d All Non-overlap Overlap 14d: n=15 (all), 15 (non-ol), 7 (OL with underlying XIENCE V) 45d: n=8 (all), 7 (non-ol), 3 (OL OL with underlying XIENCE V) No significant differences were observed between Xience V and BuMA. 14 Days 45 Days (%) Area stenosis 14d 45d 14d 45d 14d 45d All Non-overlap Overlap Uncovered struts 14d 45d 14d 45d 14d 45d All Non-overlap Overlap Sections with granulomas were excluded. No stent malapposition was identified.

27 Summary Both BuMA and XIENCE V showed complete endothelialization in 45 days, and also excellent neotintimal coverage even in 14 days. All histologic parameters were comparable between BuMA and XIENCE V. Neotintimal thickness was accurately measured by OCT, with excellent correlation with histology.

28 Acknowledgments CVPath Institute Masataka Nakano, MD Fumiyuki Otsuka, MD Kenichi Sakakura, MD Frank D Kolodgie, PhD Elena Ladich, MD Russ Jones Robert Kutz, MS Ed Acampado, DVM Youhui Liang, MD Abebe Atiso, HT Michael Cooper Jinky Beyer Giselle Magsalin Hedwig Avallone, HT Lila Adams, HT Hengying Ouyang, MD CVPath Institute CVPath Institute, Inc. Washington, DC