MiStent SES® Program Technology and Clinical Data Update David Kandzari, MD Monday, February 22 11:41-11:48 pm

Affiliation/Financial Relationship Company Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below Affiliation/Financial Relationship Company Grant/Research Support Abbott Vascular, Boston Scientific, Medtronic CardioVascular, Biotronik, Thoratec Consulting Fees/Honoraria Boston Scientific Corporation, Medtronic CardioVascular, Micell Major Stock Shareholder/Equity None Royalty Income None Ownership/Founder None Intellectual Property Rights None Other Financial Benefit None

REDEFINING DES – CRYSTALLINE SIROLIMUS WITH A RAPIDLY ABSORBED POLYMER COATING MiStent Crystalline Sirolimus Unique to MiStent SES, the sirolimus is maintained in a micro-crystalline morphology for controlled and prolonged elution, as opposed to use of an amorphous, rapid-release form of the drug. MiStent Thin-Strut Stent Cobalt-chromium Highly deliverable (64 microns) Reference: Carlyle et al, JCR 162 (2012) 561–567.

MISTENT SES: COMPARATIVE STRUT THICKNESS Strut Thickness (µm) BVS 150µm BioMatrix Flex 120µm Resolute Integrity 89µm PROMUS Element 81µm XIENCE V 81µm SYNERGY 74µm MiStent 64µm Adapted from K. Dawkins, CRT 2013. Thinner struts are associated with more rapid healing and lower risk of acute thrombogenicity Kolandaivelu, K., et al. Circulation 2011, 123(13), 1400-1409.

DRUG DELIVERY VS POLYMER DISSOLUTION MiStent SES – Crystalline drug presence in the tissue after elimination of polymer Minimizes duration of inflammatory effect of polymer Retains anti-restenotic drug for 3X longer than polymer is present References: Carlyle et al, JCR 162 (2012) 561–567. Adapted from Dawkins TCT2014 & product websites

UNIQUE MECHANISM OF DRUG DELIVERY Crystalline sirolimus provides sustained elution to limit disease progression Controlled drug release from moment of deployment MiStent SES An initial uncontrolled burst of drug may delay re-endothelialisation and coverage of the stent struts1 1 Deconinck E, et al. Pharmaceutical Aspects of Drug Eluting Stents. Journal of Pharmaceutical Sciences, 97(12), 5047-5060 (2008).

DESSOLVE I: STUDY DESIGN First-in-Human, 30 patients, 5 sites PROCEDURE 30D 4M 6M 8M 12M 18M 2Y 3Y 4Y 5Y 4M (n=10) Angio, IVUS, OCT 6M (n=10) 8M (n=10) 8M (n=30) Clinical 12M (n=30) Clinical Follow-Up (n=27) Angio, IVUS, OCT 18M 2, 3, 4, 5Y Long-term Clinical Follow-up Enrolled (n=30) 5 sites Mechanistic design to investigate quality of vessel healing 4, 6, 8-month data - angiography, IVUS, OCT 18-month data - angiography, IVUS, OCT 4-Year Completed Ormiston, J., et al. (2013). JACC Cl 6 (10), 1026-1033.

DESSOLVE I: SAFETY AT 4 YEARS No Target Lesion Failure No Target Lesion Related MACE 1 MI – Non-Target Vessel NQW-MI at 44 days 1 MI – Non-Target Vessel NQW-MI at 732 days 1 TVR at 1280 days No Stent Thrombosis MACE TLF 1 year 3.3% (1/30) 0% (0/30) 2 years 3.4% (1/29) 0% (0/29) 3 years 6.9% (2/29) 4 years 10.3% (3/29)

DESSOLVE I: IMAGING RESULTS Healing demonstrated by OCT through 18 months OCT Results Imaging with OCT demonstrated thin, homogeneous coverage with high rates of stent strut coverage at 6 - 8 months No evidence of definite neoatherosclerosis at 18 months Thin homogeneous tissue coverage Median 4-Month Group 6-Month Group 8-Month Group 18-Month Group % Strut Coverage 93% 97% 96% 100% References: Ormiston J, et al. JACC CI 2013 Attizzani G, et al. Am J Card 2013

DESSOLVE II: STUDY DESIGN 2:1 RCT design for superiority of in-stent LLL at 9 months with Endeavor 184 patients at 26 sites PROCEDURE 30D 6M 9M 12M 2Y 3Y 4Y 5Y 2:1 RCT 26 sites MiStent SES n=123 Endeavor n=61 9M - MiStent SES Angio, OCT, EFT, Clinical 12M n=175 Clinical Follow-Up 2, 3, 4, 5Y Long-term Clinical Follow-up 9M - Endeavor Angio, OCT, EFT, Clinical MiStent SES LLL was significantly lower than Endeavor at 9 months 4-Year Completed 0.27 ± 0.46 vs 0.58 ± 0.41 P<0.001 Wijns W et al. EuroInterv 2015;10:1383-1390

DESSOLVE II: 4-Year Clinical Outcomes P=0.27 P=1.00 P=0.72 P=0.18 P=1.00 P=0.31 P=0.33

ABSENCE OF LLL CATCH-UP TRANSLATES TO LOW TLR PROGRESSION No Progression of In-stent Late Lumen Loss From 6/8 to 18 Months Follow Up Results in low progression of target lesion revascularization (TLR) at 4 Years CD-TLR Over Time Angiography In-Stent Late Lumen Loss N=152 Ormiston, J., et al. (2013). JACC Cl 6 (10), 1026-1033 Data on file - Micell

Comparison of Late-Term TLR with EES Lansky, Byrne, et al. EuroPCR 2015

ONGOING CLINICAL STUDIES Building on the success of the DESSOLVE I and II studies, three additional studies initiated in 2015 China Approval Study RCT vs Tivoli DES N = 400 pts 9-Month LLL, 12-Month TLF Initiated Q2 2015 DESSOLVE III Study Post-Marketing RCT vs Xience N = 1400 pts 12-Month TLF Enrollment completed 12/2015 DESSOLVE III Sub-Study OCT RCT Sub-Study N = 60 pts Superiority for progression of NIH over time Initiation Q4 2015

SUMMARY OF MISTENT PERFORMANCE MiStent converts to a BMS in 45 - 60 days and all polymer is absorbed in 90 days Therapeutic levels of sirolimus in tissue is maintained beyond the polymer absorption due to use of crystalline drug 4-year pooled DESSOLVE I and II CD-TLR rate is 2.7% No probable or definite ST through 4 years MiStent has no late catch-up resulting in a low progression of TLR over long-term follow-up potential for significant health economic benefits based on fewer f/u TLRs

MiStent Design Capitalizing on Lessons Learned and Novel Discovery 1. There is an undesirable consequence of both extremes, when the scaffolding is removed or inordinately thick— we have experienced this with both thick struts stents but also bioresorbable scaffolding 2. Elution of drug from the polymer is only a limited component of controlled drug delivery—formulation of drug, dispersion throughout tissue, duration of effect and dwell time are all essential and yet underappreciated components 3. MiStent incorporates advantages of stent-based and balloon-based systems, representing delivery of stent coating and drug yet independent of stent scaffolding 4. Crystalline formulation of sirolimus permits more uniform dosing, without focal excess or minimal concentrations, and without initial burst of drug release 5. Both by flow of coating and delivery of crystalline drug, there is a distinct advantage of drug persistence after polymer dissolution