Device and Clinical Program Highlights: SINOMED BuMA Stent

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1 Device and Clinical Program Highlights: SINOMED BuMA Stent Runlin Gao, MD, FACC, FESC, FSCAI Fuwai Hospital, National Center for Cardiovascular Diseases, China CAMS, PUMC BuMA Supreme Platform and Pre-Clinical Results Alexandra Lansky, MD Professor of Medicine Yale University School of Medicine March 18, 2016

2 BuMA Supreme DES Components Bare metal stent A thin (80 µm) CoCr stent designed for deliverability and durability Base layer A thin ( nm) permanent poly n-butyl methacrylate (PBMA) coating electro-grafted (eg) onto CoCr stent to improve adhesion of the top coat Top coating A poly lactic -co-glycolic acid (PLGA) biodegradable coating containing sirolimus (~1.2 µg/mm 2 ). The PLGA is absorbed in ~8 weeks with drug measurable in the artery for 45 days.

3 BuMA Components A Novel Sirolimus Eluting Stent utilizing electro-grafting technology Electro-grafting base layer, covalently bonded to stent Biodegradable PLGA drug carrier, fully degraded after 2-3 mo Sirolimus Co-Cr open cell stent platform

4 Electro-Grafting (eg TM ) Technology ultra-thin (nanometric) organic (polymeric) layers; grafting = covalent bonding to the stent surface = strong adhesion hyper conformal and uniform on complex shapes. SE From precursor molecules to polymer chains via electro-chemical reactions eg

5 eg TM coating is a barrier to metal ion release ng/cm 150 days in 37 Saline (ICPMS) Molybden um eg base layer suppresses corrosion and ion release from metals (due to covalent bonding onto the metal surface) Shifts corrosion potential to passivation Contributes to lower local inflammation L BMS eg Coating on 316L BMS Nickel Chromium Nickel Chromium Molybdenum

6 eg TM + Biodegradable Drug Carrier biodegradable coating µm eg base layer 200nm metal 0.1mm Interdigitation Mechanical integrity of coating (expanded in air) BuMA another DES in the market 1 eg base layer secures adhesion of the biodegradable polymer matrix hosting the drug, prevents cracking and delamination upon expansion and over time. 1 John Ormiston et al. Prensentation at TCT 2004

7 Percentage of Drug Released BuMA Stent Drug Release Profile 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Drug Release Profile Comparison Endeavro BuMA Supreme Cypher Xience Resolute Time (Day) 100% drug release from the stent surface within 30 days after implantation, no sirolimus residues on the stent due to the biodegradable PLGA carrier.

8 BuMA Stent Arterial Drug Concentration Drug concentration peaks in the artery within 30 days and is below the therapeutic threshold by 60 days after implantation. Arterial Sirolimus Concentration Sirolimus Concentration (µg/g) Daays after Implantation

9 BuMA Stent PLGA Degradation Profile Polymer completely degraded by 6 weeks after stent implantation In Vivo PLGA Degradation Results 100% 700 Percent Molecular Weight Loss 90% 80% 70% 60% 50% 40% 30% 20% 10% % Mw Loss mass of PLGA (ug) Mass of PLGA (μg) 0% Time Point (Weeks) 0

10 Functional Restoration of Endothelium within 3 Months Time Course for Drug Delivery & Polymer Dissolution ABSORB (PLA) ORSIRO (PLA) BIOMATRIX (PLA) FIREHAWK (PLA) ELIXIR DESYNE (PLA) ABLUMINUS (PLA) SYNERGY (PLGA) BuMA SUPREME (PLGA) Polymer Drug months Timed drug release to prevent SMC but maintains healing with endothelium cell recovery Polymer designed to degrade simultaneously with the drug to minimize inflammatory response

11 Functional Restoration of Endothelium within 3 Months Strut Thickness in Perspectives ABSORB BioMatrix Flex Resolute Integrity Promus Element Xience V BuMA Synergy Supreme Osiro Thin strut thickness Excellent Radial Strength High polymer integrity Low thrombogenicity Faster healing (low surface area requiring endothelial coverage)

12 BuMA Stent 28 Day Implantation Biocompatible tissue response seen 28 days after implantation in porcine coronary arteries

13 eg TM Coating Promotes Endothelial Healing The present study examines the feasibility of local drug release with a biodegradable polymer matrix hosting Sirolimus, coated onto a BMS using proprietary electro-grafting technology (eg ), with a specific focus onto the propensity of eg films to promote recolonization by active EC s. Dr. Renu Virmani eg BuMA eg SES Cypher eg BuMA eg SES Cypher eg BuMA eg SES Cypher 14 days 28 days 90 days

14 Clinical Programs of 1 st Gen BuMA stent PANDA I vs. Endeavor 224 Pts Late 9M PANDA II Registry Single-arm 2600 Pts 1 yr BUMA OCT vs. EXCEL 1: 1 RCT 80 Pts Struts 3M BUMA vs. Xience OCT vs. Xience V 1: 1 RCT 20 Pts Struts 3M PANDA III RCT vs. EXCEL All comers 1: 1 RCT 2350 Pts 1 yr Over 200,000 BuMA stents implanted world wide!

15 2 nd Gen: BuMA Supreme PIONEER Global Clinical Program PIONEER FIM EU Trial 168 Pts, vs. Resolute Enrollment Complete Chairman: Prof. Patrick Serruys 1 st Gen (StSl) 2 nd Gen (CoCr) Co-Cr stent platform Improved delivery system Reduced crossing profile Enhanced x-ray visibility Diameter 2.25 to 5.0 mm 3 rd Gen (Mg BVS) PIONEER II China Trial 1319 Pts, vs. BuMA Enrollment Ongoing PI: Dr. Junbo Ge PIONEER III US-JAPAN 1500~ 2000 Pts, vs. Xience US, JAPAN

16 Global Clinical Strategy FIM PIONEER Trial in Europe Chair: Patrick Serruys PI: Clemens von Birgelen Co-PI: Manel Sabate CRO: Cardialysis NB: DAKRA PIONEER III IDE Pivotal Trial in US, Europe and Japan Chair: TBD US PI: Martin Leon Japan PI: Dr. Shigeru Saito Europe PI: TBD CRO: TBD ARO: Yale University Regulatory: Cardiomed PIONEER Post Market Study (One-month DAPT) in Europe and China Chair: TBD PI: TBD PI: TBD CRO: TBD ARO: TBD NB: DAKRA PIONEER II RCT Trial in China PI: Ge Junbo (Zhongshan) Co-PI: Shubin Qiao (Fu Wai) Co-PI: Shaoping Nie (An Zhen) Co-PI: Yundai Chen (Beijing) Co-PI: Yawei Xu (Shanghai) Co-PI: Bo Xu (Haerbin) PIONEER STEMI Registry Trial in US PI: TBD Co-PI: TBD CRO: TBD ARO: Yale University Regulatory: Cardiomed PIONEER IV Post Market Study in US, Japan, Europe and China Chair: TBD PI: TBD PI: TBD CRO: TBD ARO: TBD Regulatory: Cardiomed

17 Thank You!