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

DISCLOSURES Robert Falotico I’m an employee of the Cordis Corporation and shareholder in Johnson & Johnson.

Why Would We Want a DES With More Than One Drug? Complex pathological mechanisms underlie vascular disease Current DES are very effective at treating one problem – restenosis. If we want to treat more complex vascular disease - e.g. diabetes, stent thrombosis, vulnerable plaque, etc. - then we need additional therapeutic agents that affect specific pathologic mechanisms. Systemic therapy may have undesirable side effects, lack specificity or be unable to achieve effective local concentrations. Opportunity to solve unmet patient needs, create more value, and develop transformational new products.

Problems in Delivering Multiple Drugs from a Polymer-Coated Stent Limited drug loading capacity Increased coating thickness and higher profile Increased coating fragility and potential for delamination Potential for unwanted drug interaction Inability to control release rate or direction independently for each drug

NEVO™ sirolimus-eluting NEVO™ with Reservoir (RES™)Technology: A Major Advance in Drug-Eluting Stents 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 only 90 days Drug: sirolimus and future drug combinations Process: high speed nanodroplet injection system NEVO™ sirolimus-eluting coronary stent

Key Features of RES™ Technology NEVO™ Reservoir (cross section) Uses bioabsorbable PLGA (75:25); degrades in only 90 days to CO2 and H2O; leaves behind only a bare metal stent Minimizes vessel exposure to polymer; delivers like a bare metal stent Minimizes polymer load to the amount required to control drug release Protects drug-polymer matrix from physical damage during passage to the lesion Variables: drug/polymer ratio, lactide:glycolide ratio, base/cap design Vessel side Luminal side Base 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 of drug release (toward lumen or vessel) Potential to add surface treatments to bare metal

Dual Drug Loading of Reservoirs

Rationale for an Antithrombotic Dual-Drug Stent Reduce potential for stent thrombosis, both subacute and late, while retaining antirestenotic efficacy Reduce long-term dependence on dual antiplatelet therapy Improve outcomes in complex patient groups (acute MI, diabetics, bifurcation, small vessels, LM, etc.) where stent thrombosis rates can be significantly higher)

Antithrombotic Stent Strategies 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 © Cordis Corporation 2009 - Confidential

Sirolimus-Elution from an Alternate Reservoir Formulation is Equivalent to NEVO™ Cumulative Sirolimus Release In Vivo 0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 5.0 10.0 15.0 25.0 30.0 35.0 Time (Days) Sirolimus (ug) Sirolimus-Cilostazol Sirolimus-PLGA NEVO Sirolimus Tissue Concentration 2 4 6 8 10 12 14 16 18 20 30 Sirolimus Tissue Conc. (ug/g) Sirolimus content and release kinetics from alternate reservoir design match NEVO™

Cilostazol-Sirolimus Dual-Drug Stents with Multiple Elution Options 0% 20% 40% 60% 80% 100% 7 14 21 28 35 42 49 56 63 Time (days) Fast-eluting Slow-eluting Cilostazol Release D/P = A D/P = B D/P = C D/P = D Cilostazol (Pletal®) Antiplatelet agent Vasodilator Antirestenotic PDE III Inhibitor

Tirofiban Fast and Slow Eluting Stents Based on RES™ Technology 0% 20% 40% 60% 80% 100% 2 4 6 8 10 12 14 16 Time (days) Cumulative Tirofiban Release FAST FAST SLOW SLOW Tirofiban Tirofiban

Sirolimus-Eluting Stent with Heparin Surface Treatment Key Features : Heparin (high ATIII affinity ) can be covalently bound to bare metal (nonelutable) Provides improved stent thromboresistance Well-characterized mechanism of action 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 Dual Drug Eluting Stent: Efficacy in an In Vitro Blood Flow Loop In111 Platelet Deposition 20 40 60 80 100 120 Group 1 (control) Group 2 (test) Percent of control * * P < 0.0001 vs Control Treated Control

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) Control Dose 1 Dose 2 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

Summary Combination drug therapy offers the potential to treat complex vascular problems beyond restenosis. Reservoir (RES™)Technology is a versatile platform that makes dual drug stent-based therapy possible. Combination stents eluting sirolimus and an antithrombotic agent (cilostazol, tirofiban or thrombin inhibitor) have shown feasibility in preclinical models. Harnessing additional therapeutic agents may solve unmet patient needs and once again transform PCI.

Thank You Achnowledgements: Campbell Rogers Ted Parker Thai Nguyen Vipul Dave Sylvia He Jonathon Zhao Shri Ranade Yan Cheng Cheng Li