Reservoir Based Drug Delivery The CoStar ™ System and Beyond

1. Reservoir Based Drug Delivery The CoStar™ System and Beyond Jeff Shanley Founder and Chief Technology Officer

2. Conflicts • Founder and Chief Technology Officer • Conor Medsystems, Inc.

3. CoStar™ Cobalt Chromium Stent Bridge Elements Reservoirs with Bioresorbable Polymers Ductile Hinges

4. Reservoir Based Drug Delivery Reservoirs are: • Non Deforming – materials versatility • Deep – structure and directionality • Protective – against mechanical and biochemical damage • Minimize tissue/polymer contact area Programmable Loading: Multiple Drugs with Independent Release Kinetics and Directions

5. Reservoir Mapping and Filling Process

6. Pimecrolimus Eluting Stent • Inflammation is thought to play a central role in restenosis • Pimecrolimus is a potent anti-inflamatory agent (but not an MTOR inhibitor) • A Dual Release-Mode Inlay was developed • Higher drug release rate in first several days (peak inflamatory response period) • Lower rate, linear release over extended period • 100% resorption of both drug and polymer

7. Dual Drug Program: Combine 2 Agents for Restenosis Prevention • Attack different pathways, e.g.: • Anti-inflammatory (pimecrolimus) • Anti-mitotic (paclitaxel) • Completely independent dose and release kinetics • Different polymers and formulations • PTX: 11 μg, extended release • PLS: 160 μg, dual release-mode • Complete resorption of all drugs and polymers (late thrombosis)

8. Dual Pimecrolimus / Paclitaxel Eluting Stent Paclitaxel Pimecrolimus 160 μg Pimecrolimus and 11 μg Paclitaxel

9. The Genesis Trial • Both the Pimecrolimus Eluting stent and the Dual paclitaxel / pimecrolimus eluting stent will be evaluated in Conor’s upcoming Genesis clinical trial

10. Insulin Eluting Acute MI Stent (AMI)Controlled luminal release of a water-soluble drug

11. Myocardial Preservation Vascular Drug Delivery – Acute MI Mural Drug Elution For Restenosis +Luminal DrugElution For Myocardium Drug Delivery

12. Target Insulin Release Kinetics • Target Insulin doses and release rates were estimated from infusion rates reported in the ECLA GIK pilot studies.

13. More complex inlays for combinations of water soluble and lipid soluble drugs • Hydrophobic outer layers to control direction and rate of insulin release • Discrete Hydrophilic inner matrix forms protective microenvironment for insulin • Lipophilic Pimecrolimus inlay added to mural side as anti-restenotic agent • Pre-clinical research program is underway Insulin Pimecrolimus Insulin

14. Drug Eluting, Absorbable Metal Stent • An effective, bio-absorbable stent that “disappears,” leaving a healthy artery is a sought after device. • Biotronik has developed a bio-absorbable magnesium alloy for use in stenting • Surface Coatings may interfere with the metal resorption process • Migration of stent degradation biproducts through a coating may harm drug • A “Conorized” Reservoir based AMS is under development for drug delivery

15. Filled AMS-1

16. 1 day in plasma

17. AMS-1 Release Kinetics in Plasma Total drug load = 440 µg

18. Conclusion • Programmable, Reservoir based DES systems provide potential opportunities to improve efficacy and to expand indications for DES • The combination of fully erodable polymers with new classes of drugs and combinations of drugs can now be studied in clinical trials • DES indications ‘beyond restenosis’ are technically feasible and pre-clinical work is underway