LEADERS FREE II – Lessons Learned

Hans-Peter Stoll, MD Chief Medical Officer Biosensors International Hans-Peter Stoll, MD Disclosure: I am a full-time employee of Biosensors International Group LEADERS FREE 2,466 HBR Patients 30 day DAPT

Primary Endpoints and Major Bleeding at 1 Year

DCS BMS

Efficacy (TLR) Safety (cardiac death, MI, ST) Bleeding (BARC 3-5) % 12 % HR 0.50, (95% CI = 0.37‒0.69) % HR 0.71, (95% CI = 0.56‒0.91) p < 0.001 for superiority 9.8% 15 p < 0.0001 for non-inferiority 12.9% p = 0.005 for superiority 9 12 7.3%

9 6 9.4% 7.2% 5.1% 6 3

3 Cumulative Cumulative Percentage with Event 0 0

0 90 180 270 390 Days 0 90 180 270 390 Days

*Urban P et al, NEJM 2015, N Engl J Med 2015;373:2038-47 BioFreedom™: Polymer-free Biolimus A9™ Drug-Coated Stent (DCS)

1. Tada et al., Circ Cardiovasc Interv 2010;3; 174-183 LEADERS FREE II: Inclusion Criteria Identical to LEADERS FREE

Age (≥ 75 yrs)

Courtesy of Davide Capodanno and the High Bleeding Risk Academic Research Consortium Initiative. LEADERS FREE II Statistical Analysis Plan

➢ Controls: Leaders Free BMS patients (n=1,189) ➢ Primary Safety Endpoint: Composite of cardiac death and MI at 1 year (non-inferiority then superiority) ➢ Primary Efficacy Endpoint: Clinically-driven TLR at 1 year (superiority)

DC BMS Propensity Analysis: S • 40 baseline variable propensity profile • 5 strata (quintiles)

– Compute Primary Endpoint per treatment within quintile 1 2 3 4 5 – Average treatment effect over quintiles Overall Outcome per Treatment Group Clinical Trial Operations Supporting SAP

Optimizing single arm design in the absence of equipoise for randomization

• Identical inclusion / exclusion criteria • Identical case report forms • Identical angiographic core laboratory • Identical CEC adjudication processes and committee • Identical outcome endpoints • Overlap of European sites Enrollment: LFII and LF Controls DCS BMS N=1,203 N=1,211

12 (1.0%) patients withdrew before 12 month visit or were lost to FU 22 (1.8%) patients withdrew before 12 month visit or were lost to FU 43 (3.6%) 12 month visit pending

1,148 (95.4%) 1,189 (98.2%) completed completed 12 month visit 12 month visit or died or died Inclusion Criteria Applied (1.74 criteria / patient) Baseline Characteristics LEADERS FREE II: Primary Endpoints

33% Relative Risk Reduction for Death and MI at 1M DAPT 47% Relative Risk Reduction for Repeat Revascularization Benefit reproducible and generalizable to clinical practice and patients in the USA Selected Secondary Safety Endpoints % 10 p = 0.21 DCS BMS 9 8.7 8 7.3 7 6 5 4 p = 0.63 3 1.9 2.2 p = 0.87 2 p = 0.75 1.2 1.2 0.9 0.9 1 0 All Death ST* ST* Acute / ST* Late Subacute

*ARC definite / probable. Time to Bleeding BARC 3-5 Conclusions ✓ Designed to support pivotal registration decision for polymer-free, Biolimus A9™ coated stent used with 30 day DAPT in HBR

✓ Demonstrates reproducibility of Leaders Free findings of superior safety (1 year death, MI) and efficacy (1 year TLR) vs. BMS

✓ Suggests generalizability to patients and practice in North America Thank You ! Components of Safety Endpoint

% 10 DCS BMS p = 0.0097 9 8.8 8

7 p = 0.0329 5.9 6 5.1 5 4 3.4 3 2 1 0 Cardiac Death MI Pivotal Study of the Biolimus A9™ Drug-Coated Stent in High Bleeding Risk Patients: Primary Report

Mitchell W. Krucoff on behalf of Philip Urban (EU-PI), Study Leadership and the LEADERS FREE II Investigators LFII: Trial Leadership and Logistics

PIs M. Krucoff, P. Urban

Executive M. Leon (Chair), J-F. Tanguay, S. Rao, M-C. Morice, M. Price, D. Cohen, Committee S. Pocock, H-P. Stoll

Statistics CRF, LSHTM (T. McAndrew, J. Gregson, S. Copt)

DSMB J. Ambrose (Chair), H. Dauerman, M. Hong, B. Meier, S. Waxman

S. Cook (Co-Chair), G. Dangas (Co-Chair), A. Baumbach, P. Kala, CEC J. Machecourt, F. Mauri, G. Olivecrona, S. Petronio, F. Ribichini, L. Thuesen CRO Syntactx, NYC (Corie Diaz Project Manager) North America CRO CERC, Massy, France (M. Carvalho Project Leader) Europe Data DCRI, Durham Management

Sponsor Biosensors Research, USA LEADERS FREE II Study Pivotal Trial Supporting U.S. Device Registration Decision

Reproducibility of LEADERS FREE findings • Safety of DCS with 30 day DAPT in HBR patients • Effectiveness of DCS with 30 day DAPT in HBR patients

Generalizability of LEADERS FREE findings • North American patients and clinical practice

Single arm design: • No equipoise for BMS randomization LFII: Top Enrollers

Principal Investigator State / Province Country Number of Subjects Jeffrey Tauth Arkansas U.S. 120 Mohamed Abdel-Wahab / Ralph Toelg Bad Segeberg Germany 63 Benjamin Faurie Grenoble France 58 Brent McLaurin South Carolina U.S. 52 Janusz Lipiecki Clermont-Ferrand France 47 Luc Maillard Aix-en-Provence France 44 Shamir Mehta Ontario Canada 41 Jacques Berland Rouen France 41 Marco Stefano Nazzaro Rome Italy 32 Keith G. Oldroyd Scotland U.K. 31 Matthew Price California U.S. 31 Ian Menown Ireland U.K. 29 Derek So Ontario Canada 28 Josep Rodés-Cabau Quebec City Canada 27 Michael Butler Alabama U.S. 27 Robert S. Iwaoka North Carolina U.S. 26 Didier Carrié Toulouse France 25 Peter O'Kane England U.K. 25 Guy Piegari Pennsylvania U.S. 25 Amr Abbas Michigan U.S. 21 Determination of Trial Size

Known Event Rates in BMS Control Arm: Primary Safety Endpoint: 12.3% (Cardiac death and MI) Primary Efficacy Endpoint: 9.3% (Clinically-driven TLR)

LFII DCS Group: 1,200 Endpoints: Safety > 80% power to demonstrate non-inferiority with margin 3.92% Efficacy > 80% power to evaluate superiority in Clinically-driven TLR

Both With One-sided Alpha 0.025 Secondary Efficacy Endpoints

% 14 DCS BMS p = 0.014 11.6 12 p =0.006 10.0 10 8.7 8 p = 0.022 6.8 6 5.6

4 3.7

2

0 Urgent TLR TVR Any Revasc Subgroups: Composite Safety Endpoint (Cardiac Death, MI) LF2 DCS: LF1 BMS: Hazard Ratio P-value for Category N Events (%) Events (%) (95% Cl) Interaction No 1658 69 (8) 87 (11) Age >80 0.40 Yes 756 31 (10) 61 (15) No 1663 72 (9) 98 (12) Female 0.25 Yes 751 28 (8) 50 (14) No 1348 47 (7) 68 (10) ACS at admission 0.59 Yes 1066 53 (10) 80 (16) No 1609 48 (6) 88 (11) Diabetes 0.15 Yes 805 52 (13) 60 (16) No 1992 78 (8) 97 (10) Renal failure at admission 0.35 Yes 422 22 (14) 51 (21) No 1573 70 (9) 98 (13) Planed OAC at randomization 0.66 Yes 841 30 (7) 50 (12) No 1396 46 (7) 63 (9) Crusade score > median (35) 0.20 Yes 1018 54 (11) 85 (18) Anemia, transfusion / bleeding No 1977 74 (8) 108 (11) 0.50 leading to hospitalization Yes 437 26 (12) 40 (20) Planned major surgery No 2005 87 (9) 124 (13) 0.70 in following year Yes 387 12 (7) 24 (11) No 2181 90 (9) 133 (12) Cancer in last 3 years 0.86 Yes 231 10 (9) 15 (13) Multi-vessel disease No 770 10 (3) 40 (9) 0.17 at admission Yes 1644 90 (10) 108 (15) No 1384 42 (7) 66 (9) Total stent length > 30 mm 0.72 Yes 1030 58 (11) 82 (17) No 1183 47 (9) 58 (10) Minimal stent diameter < 3 mm 0.14 Yes 1226 53 (9) 90 (15) The p-value is calculated from a Cox proportional hazards model 0.0 0.5 1.0 1.5 2.0 2.5 LF2 Better BMS Better Subgroups Continued Efficacy Endpoint (Clinically-driven TLR)

LF2 DCS: LF1 BMS: Hazard Ratio P-value for Category N Events (%) Events (%) (95% Cl) Interaction No 1658 51 (6) 67 (9) Age >80 0.22 Yes 756 16 (5) 40 (10) No 1163 46 (6) 75 (9) Female 0.94 Yes 751 21 (7) 32 (9) No 1348 33 (5) 66 (10) ACS at admission 0.18 Yes 1066 34 (7) 41 (8) No 1609 33 (5) 70 (9) Diabetes 0.07 Yes 805 34 (9) 37 (10) No 1992 54 (6) 93 (10) Renal failure at admission 0.05 Yes 422 13 (9) 14 (6) No 1573 49 (7) 75 (10) Planed OAC at randomization 0.77 Yes 841 18 (5) 32 (8) No 1396 35 (5) 69 (10) Crusade score > median (35) 0.32 Yes 1018 32 (7) 38 (8) Anemia, transfusion / bleeding No 1977 55 (6) 91 (9) 0.86 leading to hospitalization Yes 437 12 (6) 16 (8) Planned major surgery No 2005 59 (6) 86 (9) 0.26 in following year Yes 387 7 (4) 21 (10) No 2181 63 (6) 96 (9) Cancer in last 3 years 0.42 Yes 231 4 (4) 11 (10) Multi-vessel disease No 770 7 (2) 28 (6) 0.36 at admission Yes 1644 60 (7) 79 (11) No 1384 23 (4) 48 (7) Total stent length > 30 mm 0.49 Yes 1030 44 (9) 59 (13) No 1183 23 (4) 41 (7) Minimal stent diameter < 3 mm 0.82 Yes 1226 44 (8) 66 (11) 0.0 0.5 1.0 1.5 2.0 2.5 LF2 Better BMS Better DAPT During Follow-Up

100.0 92.095.1 92.194.1

80.0 DAPT (Dual Antiplatelet Therapy) 60.0 DAPT or Clopidogrel alone + Vitamin K Antagonist 40.0

20.0 14.0 14.2 16.4 8.7 8.5 11.3

0.0 Discharge 1 Month 2 Months 6 Months 12 Months LFII: Site Locations

Derek So Shamir Ralph Tölg M. Abdel-Wahab Mehta 63 28 41

120 52 47 58 Total 1,203 Enrollment United States 594 Canada 167

Jeffrey Tauth Brent Janusz Benjamin McLaurin Lipiecki Faurie Europe 442

Canada Italy Denmark United Kingdom France United States Germany Number Enrolled Unadjusted Primary Safety Endpoint (Cardiac Death / MI) % 20

15 12.4%

9.0% 10 8.6% 5

0

Cumulative Percentage with Event with Percentage Cumulative 0 90 180 270 365 Days

Number at Risk BMS 1,211 1,118 1,067 1,041 1,013 DCS (LFII) 1,203 1,124 1,086 1,039 469 DCS (LF) 1,221 1,146 1,106 1,082 1,054 Index Procedure DCS BMS p-value Radial access (%) 63.8 58.7 0.0089 Staged procedure (%) 6.5 5.9 0.5631 Multi-lesion procedure (%) 36.0 35.3 0.6847 Multi-vessel procedure (%) 22.2 21.4 0.6414 Number of treated lesions / patient 1.6 ± 0.9 1.6 ± 0.9 0.6092 LMS (%) 5.0 3.9 0.1730 SVG (%) 3.8 1.8 0.0025 Bifurcation (%) 16.0 16.0 0.9931 ISR (%) 11.9 2.6 <0.0001 CTO (%) 6.5 4.4 0.0235 Triple therapy at discharge (%) 28.4 32.0 0.0517 Mean stent diameter (mm) 3.0 ± 0.5 3.0 ± 0.5 0.5558

Mean total implanted stent length (mm) / patient 34.5 ± 23.3 31.6 ± 21.0 0.0009

Mean number of stents implanted / patient 1.9 ± 1.2 1.8 ± 1.2 0.1037

Lesion success (%) 96.8 98.0 0.0150 Device success (%) 98.7 97.7 0.0120 Procedure success (%) 96.7 96.3 0.5870 Bleeding During 12 Month Follow-Up

% 25 DCS BMS

p = 0.56 19.7 20 19.0 p = 0.89 14.5 15 14.3

10 p = 0.88 7.0 7.3

5

0 BARC 1-5 BARC 2-5 BARC 3-5