The OrbusNeich EPC Capture Biodegradable Polymer Sirolimus-eluting Stent Program Michael JB Kutryk, MD, PhD St Michael’s Hospital, Toronto

Michael JB Kutryk, MD, PhD Consultant ORBUS- NEICH.

Combo Bio-engineered Sirolimus Eluting Stent Designed to combine the pro-healing EPC capture technology found in the Genous™ Bio-engineered R stent™ for rapidly achieving endothelial coverage abluminal sirolimus sustained drug elution for the control of neointimal proliferation. 4 4

Applying EPC Capture Technology to DES Genous 3 Days 14 Days CD34/Cypher Cypher Nakazawa G et al., JACC Cardiovasc Interv. 2010 Jan;3(1):68-75.

% of Endothelial Cells Expressing PECAM Control Control AbC 25 50 75 (70.5) (27.7) 3 Days 14 Days % PECAM P= 0.07 Antibody coated P=0.07 Courtesy of Renu Virmani, MD 6

Can the compatibility be improved by abluminal coating? Control Abluminal Coating

Porcine Coronary Model at 14 and 28 Days Objective: To demonstrate the effect of sirolimus dose on healing (anti-CD34 effect) and reduction of neointimal proliferation (sirolimus effect) Test Devices: Combo ¼ Dose/Low Dose (LD) = 2.5 µg sirolimus/mm, n= 5 Combo ½ Dose/Half Dose (HD) = 5 µg sirolimus/mm, n= 5 Cypher, Xience V, Genous Endpoints: 14 days: SEM & IMH (4 stents in each HD and LD) In vivo OCT evaluation: (4 in each group) 28 days: OCT & LM (6 stents in Genous, HD and LD, 4 stents in DES controls) IMH=immunohistochemistry with PECAM (anti-CD31) staining and confocal microscopy; LM=light microscopy Courtesy of Juan Granada, MD, Skirball Center for Cardiovascular Research/CRF

Endothelial Expression of PECAM at 28 d Mean % Endothelial Coverage was calculated by determining the percent coverage (by SEM) that was also positive for PECAM expression Courtesy of Juan Granada, MD, Skirball Center for Cardiovascular Research/CRF

28 Days OCT Images (Porcine Study) Combo Stent: Accelerated Healing with Control of Neointima 28 Days OCT Images (Porcine Study) Combo Genous Cypher Xience V Courtesy of Juan Granada, MD, Skirball Center for Cardiovascular Research/CRF

Neointimal Formation Evaluation HD had the lowest degree of neointimal thickness, (0.173±0.088mm) compared to Cypher (0.358± 0.225mm) LD (0.316±0.228mm), Genous (0.300±0.156mm) and Xience (0.305±0.252mm); p<0.00001 for all pairwise comparisons to HD Courtesy of Juan Granada, MD, Skirball Center for Cardiovascular Research/CRF

*Cypher>Xience and HD; **Xience>Genous, HD and LD (p<0.0001) 28 Day Histology Results Genous n=6 Cypher n=3 Half Dose n=5 Low Dose Xience Stenosis (%) 36.55±10.88 33.48±5.41* 19.92±5.60 26.04±8.74 22.22±6.27 NI Thickness (mm) 0.29±0.12 0.21±0.019 0.12±0.050 0.18±0.073 0.15±0.049 Fibrin Score 0.067±0.16 2.00±0.72 0.60±0.75 1.32±0.50 0.53±0.42 Int. Inflam. Score 0.27±0.16 1.20±0.20 0.28±0.23 0.24±0.33 0.67±0.83 Giant Cells (%) 13.82±9.51 44.94±8.32 10.06±7.13 6.04±7.55 33.24±14.14** *Cypher>Xience and HD; **Xience>Genous, HD and LD (p<0.0001) Courtesy of Juan Granda, MD and Renu Virmani, MD

Summary In pre-clinical studies, the OrbusNeich Bio-engineered Sirolimus Eluting Stent (Combo Stent) demonstrated significantly lower neointimal hyperplasia improved endothelial coverage relative to other commercially available DES lower presence of inflammation and foreign body reaction appeared effective at inhibition of neointimal growth while enhancing endothelial coverage potentially resulting in low rates of in-stent restenosis comparable to commercially available DES and in reduced rates of late stent thrombosis Favorable preclinical data prompted initiation of the REMEDEE clinical trial 14 14

Randomized Evaluation of an abluMinal sirolimus coatED bio-Engineered stEnt

Combo Bio-engineered Sirolimus Eluting Stent Granada J et al., CIRC Cardiovasc Interv, June 2010; 3

Drug Elution Drug – Sirolimus Polymer - biodegradable Surmodics SynBiosys™ Drug content is 5 µg/mm stent length, approximately half the dose of CYPHER™ but with a similar release profile 20 40 60 80 100 0.25 1 3 7 14 28 35 Time (days) % Elution over time Combo Cypher In vitro elution of Combo and CYPHER® (% of total drug eluted over time) 17 17

REMEDEE Study Design Prospective, multicenter, randomized study (n=180) 16 investigational sites in Europe, Australia, Asia, and South America Randomized 2:1 to the Combo Stent vs. TAXUS® Liberté® ≥ 2.5 mm and ≤ 3.5 mm (lesion length ≤ 20 mm) Dual anti-platelet therapy for 6 months Primary end-point: In-stent late lumen loss of the Combo Stent compared to the TAXUS Liberté DES at 9 months post procedure Principal Investigators: A. Abizaid, M. Haude, I. Meredith, S. Windecker 18 18

REMEDEE Enrollment (n=183)

REMEDEE Timeline Last Patient Enrolled August 2010 Complete 9m Follow Up Q2 2011 Final Report Q3 2011 Data for Presentation Q4 2011 20

THANK YOU 21 21