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

Conflicts  Founder and Chief Technology Officer  Conor Medsystems, Inc.

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

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

Reservoir Mapping and Filling Process

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

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)

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

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

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

Mural Drug Elution For Restenosis +Luminal Drug Elution For Myocardium Vascular Drug Delivery – Acute MI Myocardial Preservation DrugDelivery

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

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

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

Filled AMS-1

1 day in plasma

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

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