Reservoir Based Drug DeliveryReservoir Based Drug Delivery

The CoStarThe CoStar™ System and Beyond™ System and Beyond

Jeff Shanley

Founder and Chief Technology Officer

ConflictsConflicts

Founder and Chief Technology OfficerFounder and Chief Technology Officer Conor Medsystems, Inc.Conor Medsystems, Inc.

CoStarCoStar™™ Cobalt Chromium Stent Cobalt Chromium Stent

Bridge ElementsBridge Elements Reservoirs withReservoirs with

Bioresorbable PolymersBioresorbable Polymers

Ductile HingesDuctile Hinges

Reservoir Based Drug DeliveryReservoir Based Drug Delivery

Reservoirs are:Reservoirs are: Non DeformingNon Deforming – materials versatility – materials versatility DeepDeep – structure and directionality – structure and directionality ProtectiveProtective – against mechanical and – against mechanical and

biochemical damagebiochemical damage MinimizeMinimize tissue/polymer contact area tissue/polymer contact area

Programmable Loading:Programmable Loading: Multiple Drugs with Multiple Drugs with IndependentIndependent Release Kinetics and Directions Release Kinetics and Directions

Reservoir Mapping and Filling ProcessReservoir Mapping and Filling Process

Pimecrolimus Eluting StentPimecrolimus Eluting Stent

InflammationInflammation is thought to play a is thought to play a central role in restenosiscentral role in restenosis

PimecrolimusPimecrolimus is a potent anti- is a potent anti-inflamatory agent (but inflamatory agent (but notnot an an MTOR inhibitor)MTOR inhibitor)

A A Dual Release-Mode InlayDual Release-Mode Inlay was was developed developed Higher drug release rate in first Higher drug release rate in first

several days (peak inflamatory several days (peak inflamatory response period)response period)

Lower rate, linear release over Lower rate, linear release over extended periodextended period

100% resorption100% resorption of both drug and of both drug and polymerpolymer

320 ug Dose Release in Plasma

0

50

100

150

200

250

0 5 10 15 20 25 30 35

Time (days)

Cumu

lative

P-L

imus

(ug)

Dual Drug Program:Dual Drug Program:

Combine 2 Agents for Restenosis Prevention Combine 2 Agents for Restenosis Prevention

Attack different pathways, e.g.:Attack different pathways, e.g.: Anti-inflammatory (pimecrolimus)Anti-inflammatory (pimecrolimus) Anti-mitotic (paclitaxel)Anti-mitotic (paclitaxel)

Completely independent dose and Completely independent dose and release kineticsrelease kinetics Different polymers and formulationsDifferent polymers and formulations PTX: 11 PTX: 11 μμg, extended releaseg, extended release PLS: 160 PLS: 160 μμg, dual release-modeg, dual release-mode

Complete resorption of all drugs and Complete resorption of all drugs and polymers (late thrombosis)polymers (late thrombosis)

Dual Pimecrolimus / Paclitaxel Eluting StentDual Pimecrolimus / Paclitaxel Eluting Stent

PaclitaxelPaclitaxel

PimecrolimusPimecrolimus

160 160 μμg Pimecrolimus and 11 g Pimecrolimus and 11 μμg Paclitaxelg Paclitaxel

The Genesis TrialThe Genesis Trial

Both the Pimecrolimus Eluting stent and the Dual Both the Pimecrolimus Eluting stent and the Dual paclitaxel / pimecrolimus eluting stent will be paclitaxel / pimecrolimus eluting stent will be evaluated in Conor’s upcoming Genesis clinical trialevaluated in Conor’s upcoming Genesis clinical trial

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

Mural Drug Elution For RestenosisMural Drug Elution For Restenosis

+Luminal Drug+Luminal Drug Elution For MyocardiumElution For Myocardium

Vascular Drug Delivery – Acute MIVascular Drug Delivery – Acute MI

Myocardial PreseMyocardial Preservationrvation

DrugDrugDeliveryDelivery

Target Insulin Release KineticsTarget Insulin Release Kinetics

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

In Vitro Release Rates vs. ECLA Glucose Insulin Potassium (GIK) IV Infusion Rates Normalized by Blood Flow and Heart Weight

0

1

10

100

0 12 24 36 48 60 72Time (hours)

Lo

g In

su

lin R

ele

as

e R

ate

(u

g/h

r)

Porcine Efficacy Study #1

Porcine Efficacy Study #2

Porcine Efficacy Study #2Alternate

High / Low Rates From ECLA Pilot Test Estimate By Heart Wt.: 0.2 - 0.8 ug / hr

Estimate By Blood Flow: 0.5 - 7.6 ug / hr

More complex inlays for combinations of More complex inlays for combinations of water soluble and lipid soluble drugswater soluble and lipid soluble drugs

Hydrophobic outer layers to control Hydrophobic outer layers to control direction and rate of insulin releasedirection and rate of insulin release

Discrete Hydrophilic inner matrix Discrete Hydrophilic inner matrix forms protective microenvironment forms protective microenvironment for insulinfor insulin

Lipophilic Pimecrolimus inlay added Lipophilic Pimecrolimus inlay added to mural side as anti-restenotic to mural side as anti-restenotic agentagent

Pre-clinical research program is Pre-clinical research program is underwayunderway

Insulin

Insulin

Pimecrolimus

Drug Eluting, Absorbable Metal StentDrug 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-1Filled AMS-1

1 day in plasma1 day in plasma

AMS-1 Release Kinetics in PlasmaAMS-1 Release Kinetics in Plasma

Total drug load = 440 µg

ConclusionConclusion

Programmable, Reservoir based DES systems Programmable, Reservoir based DES systems provide potential opportunities to improve efficacy provide potential opportunities to improve efficacy and to expand indications for DESand to expand indications for DES

The combination of fully erodable polymers with new The combination of fully erodable polymers with new classes of drugs and combinations of drugs can classes of drugs and combinations of drugs can now be studied in clinical trialsnow be studied in clinical trials

DES indications ‘beyond restenosis’ are technically DES indications ‘beyond restenosis’ are technically feasible and pre-clinical work is underwayfeasible and pre-clinical work is underway