The Future of Targeted Drug Delivery

Lisa Shafer, PhDDirector, CNS Drug Therapy R&DMedtronic Neuromodulation

lisa.l.shafer@medtronic.com

DISCLAIMERS

This presentation includes the description of devices and therapeutic uses that are in early stages of development.

The devices and therapeutic uses are not commercially available and have not been approved by regulatory institutions

Medtronic does not market its products for unapproved indications and can make no representation regarding the safety and/or efficacy of the devices when used for unapproved claims

Before commercialization is possible the devices and therapeutic uses need to obtain regulatory approval

Summary

• Dedicated to achieving greater depth in our current therapies

• Compelled by the opportunity to expand to disease modifying therapies

• Medtronic’s infusion technology, scientific foundation and combination device experience enables success

• The complexity of targeted drug delivery requires extraordinary collaboration

The Problem

• The incidence of neurodegenerative disease is rapidly increasing as the population ages as previous causes of mortality decline

• Unfortunately, neurodegenerative diseases are extremely difficult to address because the blood brain barrier excludes most drugs (and all biologics) from entering brain

• Despite a significant number of drug targets and funding, most drugs aimed at neurodegenerative disease have failed due to the inability to deliver enough drug locally or systemic side effects associated with current peripheral delivery methods

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Medtronic’s Experience

• Medtronic is the worldwide leader in drug delivery directly to the central nervous system (CNS), bypassing the blood brain barrier for local, continuous delivery

– SynchroMed® II is a fully implantable, programmable pump that has been used for over 20 years and 300,000+ patients to treat chronic pain and severe spasticity through direct delivery to the intrathecal space

• Medtronic is also the worldwide leader in electrical stimulation directly to the brain for chronic diseases

– Deep Brain Stimulation utilizes an implantable pulse generator connected to leads in the brain that has been used for over 10 years and 68,000+ patients to treat Parkinson’s disease, Essential Tremor, and Dystonia

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SynchroMed II

Deep BrainStimulation

The Solution• By combining Medtronic’s significant experience in the local

delivery of drugs (SynchroMed® II) with our expertise in targeting discrete structures in the brain (Deep Brain Stimulation)…

…Medtronic has created a system that can solve the problem of delivering drugs directly to the brain, bypassing the blood brain barrier, to effectively address neurodegenerative disease.

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Medtronic’s Investigational Intraparenchymal catheter with SynchroMed II pump

Growing need for delivery of drugs into the CNS beyond the intrathecal space

Intraparenchymal (IPa)

Intracerebroventricular (ICV)

Intrathecal (IT)

SynchroMed® II Implantable Programmable Pump

• Battery driven, peristaltic drive – up to 7 years implant duration• 20 & 40 ml reservoir volumes• Infusion rates from 0.048 to 20ml/day• Remote programing, capable of multiple dosing paradigms; variable flow rates,

intermittent bolus, day/night.8

N’vision Programmer

Catheter Access Port

Reservoir Refill Port

Titanium Housing

Spinal Catheter

SynchroMed® II pump

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Enabling Features for Future TDDCommercial Therapies Importance for Future TDD

Accuracy Specification: +/-14.5%Actual Clinical Refill Msrmt Error: 3%

• Informs dosing regimen & labeling• Important for dose escalation trials• Critical for drugs that have narrow therapeutic windows, potent drugs

and highly concentrated drugs• Important for drugs that produce delayed biological/clinical responses

(growth factor vs. baclofen)• When delivery target is small and specific (IT vs. IPA)

Reliability 97% approved drugs93% unapproved drugs

• Dependable for achieving longer term, disease modifying outcomes• Confidence of testing new drug, vs new drug + new pump.• Important for drugs for which therapy interruption may produce clinical

sequelae, e.g., rebound hypertension

MRI Compatibility

1.5T and 3.0T Conditional. Designed to restart after MRI

• Confirm IPA and ICV targeting • Enables Imaging related diagnostics /theranostics/prognostics• Permits therapies in complex patients with comorbid disease conditions

Experience 1 Billion patient hrs/yr300,000 pumps Drug : Device compatibility

• Registry • Lessons learned & applied (ie. computational modeling / scaling)• Translational research & drug:device interface , E/L expertise• Integrated surgical solutions • Experience with a variety of biologic agents: proteins, peptides, nucleic

acids, viral vectors

Chronic ICV Infusion System*

SynchroMed® II Infusion System

Chronic IPA Infusion System*

Paradigm® Veo

Acute Infusion

Systems*

Implantable*Micro-pump*

MANTIS*IT and ICV) Access Port*

SynchroMed® II Infusion System

Ventricular Catheter Anchor*

Intraparenchymal Catheter Anchor*

*Products in Development / Investigational Use

Medtronic Infusion System Platforms*

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Factors that may influence drug distribution in the CSF

Drug Concentration

InfusionCatheterTip

Dosing Regimene.g. Continuous vs Bolus

Target Locatione.g. Cervical vs Lumbar

Infusion Ratee.g. Slow vs Fast

Drug Propertiese.g. Small vs Large Molecule

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Factors that may influence drug distribution in the CNS

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Medtronic’s CNS Drug-Device Therapy Portfolio

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Drug / Biologic Route of admin & Indication

Partner Pre-clin

Clinical PhaseI/II II b III Launch

-amyloid antibody ICV – Alzheimer’s Unpartnered

BACE inhibitor ICV – Alzheimer’s Undisclosed

rGDNF IPA – Parkinson’s Eli Lilly

Htt siRNA IPA - Huntingtons Unpartnered

rPDGF ICV – Parkinson's NeuroNova

rVEGF ICV - ALS NeuroNova

Clonidine IT - Refractory Hypertension

Wake ForestPhys Spons

Remodulin IA – Pulmonary Arterial Hypertension

UnitedTherapeutics

Complexity of drug delivery therapies requires extraordinary collaboration

+TherapySuccess

Drug/Biologic

Biology & DeliveryPrinciples

cRcDctc

v

Vefficacy (total) = 4,611mm3

Conc: 16 mg/mlFlow Rate: 0.5 ul/min

Device

Thank You,

Medtronic Neuromodulation’s CNS Drug Therapy R&D Team

lisa.l.shafer@medtronic.com