The Long and Short of DAPT An Industry

The Long and Short of DAPT – An Industry View FDA Town Hall Meeting DAPT for High Bleeding Risk Patients Hans-Peter Stoll. , MD Chief Medical Officer, Biosensors International 6 March 2018

Disclosures Hans-Peter Stoll, M. D. I am a full-time employee of Group Biosensors International

Design Rationale for Short DAPT Bio. Freedom™ Stent* BA-9 highly lipophilic Drug BA 9 TMTMDrug 10 BA 9 10 Times. More 1 1 Lipophilic than Sirolimus Lipophilic Sirolimus 100 % 80 60 40 20 0 Sirolimus Zotarolimus Everolimus +/- 2. 8% (valid for all drugs test) Potential Advantages: ü Avoid any possible polymer-related adverse effects ü Rapid drug transfer to vessel wall (98% within one month) ü Safe to shorten DAPT? Biolimus A 9 TM • Polymer-free Design • BA-9 drug with 10 x increased lipophilicity • Drug transfers to the vessel wall <30 days • Drug warehoused in vessel > 3 months • Implant converted to a BMS <30 days *Bio. Freedom™ stent not approved for sale in the United States.

Trial Design Optimized for Short DAPT Prospective, double-blind 1: 1 randomized trial 2, 466 High Bleeding Risk (HBR) PCI Patients Bio. Freedom™ DCS vs. Gazelle™ BMS DAPT mandated for 1 month only, followed by long-term SAPT • Primary safety endpoint: Composite of cardiac death, MI, definite / probable stent thrombosis at 1 year (non-inferiority then superiority) • Primary efficacy endpoint: Clinically-driven TLR at 1 year (superiority)

Focus Change after LEADERS FREE* 30 months Benefit of the DCS over BMS Benefit of longer DAPT “Event-free” patients at low bleeding risk 1 month BARC 3 -5: 2. 7% “HBR” patients at high bleeding risk *Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug coated coronary stents in patients at high bleeding risk. NEJM. 2015; 373: 2038 -47 BARC 3 -5: 7. 1%

Definition of High Bleeding Risk - 13 patient selection criteria used in LEADERS FREE* - At least one criterion needed - On average 1. 7 / patient - Trial was completely oriented on bleeding risk ~ 1. 7 criteria / patient - No coronary anatomy-specific exclusion criteria - Strict adherence to DAPT regimen - 90. 5% of patients had switched to SAPT after 30 days “Event-free” patients at low bleeding risk BARC 3 -5: 1. 2% - BARC 3 -5 bleeding rate 7. 3% at 390 days *Urban P, Meredith IT, Abizaid A, et al. Polymer-free drug coated coronary stents in patients at high bleeding risk. NEJM. 2015; 373: 2038 -47

Inhomogeneity of Co-Morbidity and Risk BARC 3 -5 Bleeding Rate per Main Inclusion Critiera 0. 00 Not enough data Stroke <1 y 4. 30 4. 3 NSAID >30 days Non compliance to DAPT Overall Bleeding Rate in LEADERS FREE: Series 1 7. 3% 5. 60 5. 6 5. 90 5. 9 Intracerebral bleed (any) 6. 10 6. 1 Cancer <3 y 7. 00 7. 0 Age > 75 8. 60 8. 6 Planned Surgery <12 M 9. 90 9. 9 OAC (Triple Therapy) 10. 00 10. 0 Severe chronic liver disease Hospitalization for bleeding <12 M 11. 00 11. 0 Renal failure (GFR <40 ml/min) 11. 20 11. 2 15. 40 15. 4 Thrombocytopenia <1000, 000/u. L 16. 00 16. 0 Anemia (HGb <11 g/d. L) 2 4 6 8 10 % 12 14 16 18 20 Bleeding Rate in the DAPT Trial (12 -30 M, long DAPT arm): 2. 7%

Need and Future Questions • Better/safer stent designs • Better insight into bleeding/clotting balance for specific HBR patient subsets (e. g. cancer) • Shift from categorized to personalized DAPT prescription • Harmonized HBR definition effort ….

Need for a Harmonized HBR Definition ARC 2007 VARC 2011 BARC 2011 HBR – ARC 2018

Evaluation of DAPT Guidelines