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

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

3. 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

4. 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)

5. 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

6. 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)

7. 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

8. Dual Drug Loading of Reservoirs

9. 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

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

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

12. 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

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

14. 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

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

16. 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

17. 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.

18. Thank You