One DES Eluting Two Drugs: Is it Feasible? Robert Falotico, PhD Distinguished Research Fellow Cordis Corporation

Disclosures I am an employee of the Cordis Corporation and a Johnson & Johnson shareholder.

Rationale for a Dual-Drug Stent To treat complex vascular problems more effectively (diabetes, stent thrombosis, vulnerable plaque), we need therapeutic agents that target additional pathways. Systemic therapy may produce unwanted side effects, lack specificity or produce sub- therapeutic local concentrations. Combination therapy provides an opportunity to develop new products with improved safety and efficacy to solve unmet needs in PCI. Complex pathological mechanisms underlie vascular disease

Problem of Delivering Multiple Drugs from a Conventional Polymer-Coated Stent Limited drug loading capacity Increased coating thickness; higher crossing profile Loss of coating integrity (flaking, delamination) Potential for chemical interactions Inability to independently control drug release (rate & direction)

RES Technology™: A Novel Platform for Stent-Based Drug Delivery Stent: thin strut, cobalt chromium alloy, open-cell with a uniform array of reservoirs designed for drug delivery Polymer: bioabsorbable PLGA, reduced polymer mass, fully absorbed in about 90 days Drug: sirolimus (NEVO™) and drug combinations Process: high precision droplet injection

Key Features of RES™ Technology NEVO™ Reservoir (cross section) Drug-polymer matrix is recessed into reservoirs - Protected on passage to the lesion - Minimizes polymer contact with the artery - Delivers like a bare metal stent Polymer resorbs in ~ 90 days and is metabolized to CO2 and H2O - Leaves behind a bare metal stent Base layer Poly-DL-lactide-co-glycolide (PLGA)

Advantages of RES Technology™ for Therapeutic Applications base Expanded drug loading capacity Delivery of multiple drugs Independent control of release kinetics Directional control (toward lumen or vessel wall) Potential to add surface treatments to bare metal

Dual Drug Loading of Reservoirs

Antithrombotic Stent Strategy Using RES Technology™ Sirolimus (abluminal) Elutable Antithrombotic (luminal) Vessel Lumen Surface-modification Heparin Nitric oxide Endothelial cell promoter Thrombin inhibitor GP2b/3a inhibitor Direct platelet inhibitors

Drugs Are Loaded Independently in Alternating Reservoirs Dual Drug-Eluting Reservoir Stent Sirolimus Antithrombotic Drugs Are Loaded Independently in Alternating Reservoirs

Sirolimus Delivery from Alternate Reservoirs: Equivalence to NEVO™ Sirolimus content Release kinetics Tissue levels Equivalent to NEVO™

Sirolimus/Cilostazol Dual-Drug Stent Using RES Technology™ 0% 20% 40% 60% 80% 100% 7 14 21 28 35 42 49 56 63 Time (days) Fast-eluting Slow-eluting Cumulative Cilostazol Release (%) D/P = 65/35 D/P = 45/55 D/P = 35/65 D/P = 25/75 Cilostazol (Pletal®) Antiplatelet agent Vasodilator PDE III inhibitor

Sirolimus/GP2b/3a Inhibitor Eluting Stent Using RES Technology™ Cumulative Release (%) Tirofiban (Aggrastat®) Small molecule GPIIb/IIIa inhibitor Potent antiplatelet agent

Sirolimus-Eluting Stent with Heparin Surface Treatment Key Features: Heparin is covalently bound to bare metal surface (nonelutable); active surface inhibits local thrombin activity Provides improved stent thromboresistance Potential to inhibit early and late stent thrombosis Reservoirs are loaded with sirolimus in the same dose and formulation as NEVO™ Heparin covalently bound to metal surface Sirolimus loaded reservoirs

Antithrombotic Activity of RES Technology™ Stents in a Baboon AV Shunt Model Control Antithrombotic P<0.004 P<0.001

Thrombus Area (image analysis) Antithrombotic Dual Drug Stents: Reduction in Thrombosis in a Porcine Model 50% stent overlap No post-procedural aspirin/plavix Necropsy: Day 7 Thrombus Area (image analysis) Polymer Control PGLA 75/25 Riva - Slow PLGA 75/25 + RVX (85 µg) Riva - Fast PLGA 75/25 + RVX (100 µg) Control Dose 1 Dose 2 P<0.05 Control Dose 1 Dose 2

Summary Combination drug therapy offers the potential to treat complex vascular problems beyond restenosis. RES Technology™ is a versatile platform that makes dual drug stent therapy possible. Combination stents eluting sirolimus and an antithrombotic agent (cilostazol, GPIIb/IIIa inhibitor, thrombin inhibitor) have shown feasibility in preclinical models. Harnessing additional therapeutic agents will provide safer and more efficacious DES and solve unmet patient needs.

Thank You