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

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

3. 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.

4. 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

5. 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

6. 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)

7. 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

8. Dual Drug Loading of Reservoirs

9. 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)

10. 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

11. Drugs Are Loaded Independently in Alternating Reservoirs
Dual Drug-Eluting Reservoir Stent
Sirolimus
Antithrombotic
Drugs Are Loaded Independently in Alternating Reservoirs
© Cordis Corporation Confidential

12. 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™

13. Cilostazol-Sirolimus Dual-Drug Stents with Multiple Elution Options0%
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

14. Tirofiban Fast and Slow Eluting Stents Based on RES™ Technology0%
20%
40%
60%
80%
100% 2 4 6 8 10 12 14 16
Time (days)
Cumulative Tirofiban Release
FAST
FAST
SLOW
SLOW
Tirofiban
Tirofiban

15. 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

16. 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 < vs Control
Treated
Control

17. 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

18. 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.

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