Biosensors Lunch Symposium

Are Current DES the Final Answer? BioFreedom TM : the Polymer-Free Biolimus A9TM Coated Stent Biosensors Lunch Symposium 25 th April 2013 Prof. Stephen WL Lee, JP 李偉聯 MD FRCP(Lon. Edin. Glas.) FHKCP FHKAM FACC FSCAI Chief of Cardiology, Professor & Senior Consultant Department of Medicine, Queen mary Hospital, University of Hong Kong

Potential conflicts of interest Speaker s name: Stephen Wai-luen LEE (Queen Mary Hospital, University of Hong Kong) I have the following potential conflicts of interest to report: x Research contracts Consulting Employment in industry Stockholder of a healthcare company Owner of a healthcare company Other(s) I do not have any potential conflict of interest to declare The stents were provided by Biosensors as investigational devices. The Core Laboratory Charges are supported by Biosensors.

All current DES = can achieved neointimal suppression PCI objective = purely for achieving revascularization = without complicated issues of But many DES still show Poor Stent Healing :- drug cytotoxicity, polymer hypersensitivity, local inflammatory reactions, loss endothelial and vasomotor functions Acute failure Restenosis Stent thrombosis Prolonged DAPT Bleeding Stent thrombosis MACE

Most powerful histological predictor of stent thrombosis = endothelial coverage Most powerful surrogate indicator of endothelialization = neointimal coverage Best morphometric predictor of LST = ratio of uncovered to total stent struts Finn et al. Circulation 2007;115;2435-2441 Is stent thrombosis genuine?

Myocardial Infarction (%) Target-Lesion Revascularization (%) Stent Thrombosis (%) Death (%) Pooled Analysis of Data Comparing SES With BMS Estimated 4-year cumulative incidence of stent thrombosis, death, MI, and TLR 2.0 10 1.5 1.0 0.5 Sirolimus stent (1.2%) P=.20 Bare-metal stent (0.6%) 0.0 0 1 2 3 4 Years Since Procedure 8 6 Sirolimus stent (6.7%) 4 P=.23 2 Bare-metal stent (5.3%) 0 0 1 2 3 4 Years Since Procedure 10 8 6 4 2 0 Bare-metal stent (6.2%) Sirolimus stent (6.4%) P=.86 0 1 2 3 4 Years Since Procedure 30 25 20 15 10 5 0 Bare-metal stent (23.6%) P<.001 Sirolimus stent (7.8%) 0 1 2 3 4 Years Since Procedure Stone et al. N Engl J Med. 2007;356:998-1008

Myocardial Infarction (%) Target-Lesion Revascularization (%) Stent Thrombosis (%) Death (%) Pooled Analysis of Data Comparing PES With BMS Estimated 4-year cumulative incidence of stent thrombosis, death, MI, and target lesion revasc. 2.0 10 1.5 1.0 Paclitaxel stent (1.3%) 0.5 0.0 Bare-metal stent (0.9%) P=.30 0 1 2 3 4 Years Since Procedure 8 6 4 Bare-metal stent (6.6%) 2 0 Paclitaxel stent (6.1%) P=.68 0 1 2 3 4 Years Since Procedure 10 8 6 4 Paclitaxel stent (7.0%) Bare-metal stent (6.3%) 2 P=.66 0 0 1 2 3 4 Years Since Procedure 30 25 20 15 10 5 Bare-metal stent (20.0%) P<.001 Paclitaxel stent (10.1%) 0 0 1 2 3 4 Years Since Procedure Stone et al. N Engl J Med. 2007;356:998-1008

RESOLUTE All Comers Simple Patients Clinical Outcomes to 12 Months R-ZES (n=376) EES (n=396) P=0.79 P=0.50 P=0.70 P=0.48 P=0.12 P=0.49 % Death Cardiac Death TV-MI Cardiac death or TV-MI ARC ST Def/Prob CI-TLR Stefanini et al., JACC 2011

RESOLUTE All Comers Complex Patients Clinical Outcomes to 12 Months R-ZES (n=764) EES (n=756) P=0.02 P=0.24 P=0.90 P=0.58 P=0.26 P=0.80 % Death Cardiac Death TV-MI Cardiac death or TV-MI ARC ST Def/Prob CI-TLR Resolute-US Trial: Stefanini et al., JACC similar 2011 results between the 2 stents

Biolimus-A9 Eluting Stent Biolimus is a semi-synthetic sirolimus analogue with 10x higher lipophilicity and similar potency as sirolimus. Biolimus is immersed at a concentration of 15.6 g/mm into a biodegradable polymer, polylactic acid, and applied solely to the abluminal stent surface by a fully automated process. Biolimus is co-released with polylactic acid and completely desolves into carbon dioxide and water after a 6-9 months period. The stainless steel stent platform has a strut thickness of 120 m with a quadrature link design.

LEADERS All-comers Trial Clinically-Indicated TVR * p-value for superiority Serruys et al., oral abstract presentation, TCT 2012

Patient Oriented Endpoints (Death, MI, TLR, TVR) LEADERS All-comers Trial Biomatrix (n=850) versus Cypher (n=850). DAPT = 12 months. 81% off-label use. 1 o endpoint: MACE: Cardiac death, MI, clinically-indicated TVR (9 months) 5 years data available. Better outcomes than Cypher at 5 years.

LEADERS all-comers Trial Definite ST (ARC) Landmark Analysis @ 1 Year P for interaction=0.022 * p-value for superiority Serruys et al., oral abstract presentation, TCT 2012

ESC guidelines 2010 But these are guidelines based on clinical outcomes. Is there any more scientific approach:- (In-vivo assessment of stent healing guiding of DAPT duration) Wijns et al., Eur Heart J. 2010; 31(20): 2501-55.

Highest lipophilicity of the common limus drugs 1 1 Biomatrix (Biolimus-A9 PLA) DES Biofreedom (Biolimus-A9 ) DCS Polymer-free drug elution via porous surface Potential Advantages Reduced late adverse effects due to polymer hypersensitivity Improved surface integrity with no polymer to be sheared or peeled away from the stent struts Possible shorter DAPT with better healing without polymer and inner BMS surface

Components of BioFreedom DCS Metal / Design Strut Thickness ~ 81-140 microns Polymer Durable Biodegradable Drug and Release kinetics determine Anti-proliferative effects Drugs Sirolimus-135 g Everolimus 100 g Paclitaxel- 80 g Biolimus A9 225 g

Pre-clinical efficacy evaluation BFD SD BFD LD Standard Dose BioFreedom Low Dose BioFreedom Sirolimus-eluting stents Bare metal stents Tada et al., Circ Cardiovasc Interv 2010;3;174-183

BioFreedom FIM design First Cohort 4 Month Angio FU 75 patients BioFreedom FIM 182 patients 12 Month Clinical FU 99% Second Cohort 12 Month Angio FU 107 patients Angio FU 92% Angio FU 92% BioFreedom standard dose (BFD SD) N=25 BioFreedom low dose (BFD LD) N=26 TAXUS Liberté N=24 BioFreedom standard dose (BFD SD) N=35 BioFreedom low dose (BFD LD) N=36 TAXUS Liberté N=36 Enrollment Period Sept 2008 Jan 2009 Enrollment Period Jan 2009 Jun 2009 1 o End-point: In-stent Late Lumen Loss at 4 months (LD) and 12 months (Standard Dose)

Antiplatelet Agent Utilization All patients- 1 st and 2 nd Cohorts BFD SD BFD LD Taxus P value* Aspirin At 30 days 56/58 (97%) 61/62 (98%) 58/59 (98%) 0.55 At 4 months 56/58 (97%) 61/62 (98%) 56/57 (98%) 0.57 At 1 year 56/58 (97%) 60/61 (98%) 58/60 (97%) 0.97 At 2 years 52/58 (90%) 57/59 (97%) 53/59 (90%) 0.98 At 3 years 52/56 (93%) 54/57 (95%) 53/57 (93%) 0.98 Clopidrogel or ticlopidine At 30 days 57/58 (98%) 61/62 (98%) 59/59 (100%) 0.31 At 4 months 57/58 (98%) 61/62 (98%) 57/57 (100%) 0.32 At 1 year 48/58 (83%) 41/61 (67%) 47/60 (78%) 0.54 At 2 years 4/58 (6.9%) 7/59 (12%) 13/59 (22%) 0.020 At 3 years 7/56 (13%) 7/57 (12%) 7/57 (12%) 0.97 Dual antiplatelet therapy At 30 days 56/58 (97%) 61/62 (98%) 58/59 (98%) 0.55 At 4 months 56/58 (97%) 61/62 (98%) 56/57 (98%) 0.57 At 1 year 47/58 (81%) 40/61 (66%) 45/60 (75%) 0.43 At 2 years 3/58 (5.2%) 7/59 (12%) 11/59 (19%) 0.025 At 3 years 7/56 (13%) 6/57 (11%) 5/57 (8.8%) 0.52 * P-values compare BFSD vs TAXUS Grube E., oral presentation, TCT 2012

(mm) In-stent Late Lumen Loss (12 months) 2 nd Cohort PRIMARY ENDPOINT 0.5 P = 0.001* (p=0.11**) 0.4 P = 0.21* (p=0.55**) 0.35 [0.22, 0.57] 0.3 0.2 0.17 [0.09, 0.39] 0.22 [0.17, 0.66] 0.1 0.0 BFD SD BFD LD TAXUS N = 31 N = 35 N = 31 *Non-inferiority tests based on the mean. **Superiority tests. All values are presented as median [IQR]. Grube E., oral presentation, TCT 2010

BioFreedom 12-Month Outcomes All patients 1 st and 2 nd Cohorts (98.9%) EVENT BFD SD N = 60 BFD LD N = 62 TAXUS N = 60 MACE (All Death, MI, Emergent Bypass or TLR) 3 (5.1%) 7 (11.5%) 3 (5.0%) All Death 1 (1.7%) 0 (0.0%) 0 (0.0%) MI 1 (1.7%) 1 (1.6%) 0 (0.0%) Q Wave MI 0 (0.0%) 0 (0.0%) 0 (0.0%) Non-Q Wave MI 1 (1.7%) 1 (1.6%) 0 (0.0%) Emergent Bypass 0 (0.0%) 0 (0.0%) 0 (0.0%) TLR 1 (1.7%) 6 (9.8%) 3 (5.0%) Definite/probable stent thrombosis (ARC) 0 (0.0%) 0 (0.0%) 0 (0.0%) All P values are non-significant. Tests were performed for BFD SD vs. TAXUS and BFD LD vs. TAXUS. Grube E., oral presentation, TCT 2010

BioFreedom 36-Month Outcomes All patients 1 st and 2 nd Cohorts (96.1%) EVENT MACE (All Death, MI, Emergent Bypass or TLR) BFD SD N = 60 BFD LD N = 62 TAXUS N = 60 7(11.9%) 11(18.1%) 6(10.0%) All Death 3(5.1%) 2(3.3%) 1(1.7%) MI 1(1.7%) 2(3.4%) 1(1.7%) Q Wave MI 0(0.0%) 0(0.0%) 0(0.0%) Non-Q Wave MI 1(1.7%) 2(3.4%) 1(1.7%) Emergent Bypass 0(0.0%) 0(0.0%) 0(0.0%) TLR 3(5.2%) 8(13.2%) 4(6.7%) Definite/probable stent thrombosis (ARC) 0(0.0%) 0(0.0%) 0(0.0%) All P values are non-significant. Tests were performed for BFD SD vs. TAXUS and BFD LD vs. TAXUS Grube E, TCT 2012

BioFreedom FIM Conclusions A polymer free BA9 stent. Non-inferiority (with trend towards superiority) in the primary endpoint (in-stent LLL 12M) vs. Taxus (P=0.001 for non-inferiority; P=0.11 for superiority) Similar rates of MACE and TLR up to 3 years vs. Taxus Liberté. Sustained safety up to 3 years, including absence of definite/probable stent thrombosis. Could be promising better healing (no polymer hypersensitivity). May reduce DAPT duration. Less late stent thrombosis.

Leaders Free Trial Randomise, double-blind, 1:1 control study. 60+ centres world-wide 2400+ patients with high risk of bleeding. FU for 2 years. Two stents Biosensors BioFreedom BA9 Drug-Coated Coronary Stent (DCS) Biosensors Gazelle Bare Metal Coronary Stent (BMS) One DAPT regimen ASA 100-160 mg OD, indefinitely 1 month DAPT (Clopidogrel 75 mg OD or another P2Y12 inhibitor) Co-Primary Endpoints (1) Safety (non-inferiority) MACE (Death, MI, Stent Thrombosis) (2) Efficacy (superiority) - clinically-driven TLR

Participating Centers Canada Brazil Austria Belgium Denmark France Germany Israel Italy Latvia Netherlands Norway Spain Switzerland Poland UK Hong Kong Malaysia Singapore Thailand Australia Argentina Principal Investigators: P. Urban (Switzerland) A. Abizaid (Brazil) I. Meredith (Australia)

EGO-BioFreedom Study Real World, All Comers With symptomatic coronary artery disease N = 100 patients Single Center BioFreedom DCS Stent Initial PCI procedure angiogram (baseline OCT) Randomly assigned to 6 FU groups at 1,2,3,4,5 & 6 months (OCT) Final restudy angiogram & OCT at 9 months OCT Clinical Endpoint Baseline 1mo 2mo 3mo 4mo 5mo 6mo 9 mo 12mo 24mo 1 st Angiographic & OCT FU 2 nd OCT FU Primary Endpoint: OCT % strut coverage from 1 to 6 months. Secondary Endpoints: Clinical Endpoints (MACE) QCA & OCT Findings at 9 months Drug therapy: ASA and clopidogrel (per guidelines for 9 months) Clinical Follow up: 30d, 6mo, 9mo, 12mo, 1yr, 2yr.

The EGO-BioFreedom Study EGO-BioFreedom Study Stringent Classification of Early Strut Coverage

1 Month FU 2 Month FU

Sequential longitudinal OCT FU with a very stringent strut coverage classification OCT should be adopted as a vigorous & novel step for guiding any new stent platform. Baseline OCT 5 groups (1 to 5 months) OCT strut coverage 9 months OCT (late loss NIH) Proper stent apposition Degree of early coverage (healing profile) Guiding appropriate DAPT duration Little late loss as a DES Reduced stent thrombosis A B C No Stent Thrombosis D E F Minimal late catch-up Very stringent strut coverage classification May predict / prevent late stent thrombosis, rather than waiting for years to observe for adverse effects. BioFreedom Stent : could be a Novel Device?!!

The Leaders-Free & EGO-Biofreedom Study Thank you

BMS vs. DES All current DES = can achieved neointimal suppression PCI objective = purely for achieving revascularization = without complicated issues of But many DES still show poor Stent Healing = drug cytotoxicity, polymer hypersensitivity, local inflammatory reactions, loss endothelial and vasomotor functions Acute failure Restenosis Stent thrombosis Prolonged DAPT Stent thrombosis MACE