1. The Future of Targeted Drug Delivery
Lisa Shafer, PhD
Director, CNS Drug Therapy R&D
Medtronic Neuromodulation

2. 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
As the title of my talk suggests, I will be discussing future therapies enabled by Medtronic’s technology. None of which have regulatory approval or are commercially available.

3. 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
Let me start with the Summary knowing its been a long day…
Medtronic is dedicated …
Our mission compels us to expand beyond treating symptoms of diseases and towards DMT.
Our experience and technology enable us. But that’s only part of what is required for success-success in this field requires extraordinary partnership..

4. 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
With over 7 million people suffering from a neurodegenerative disease, it is clear that neurodegenerative diseases constitute a massive and growing drain on healthcare costs on the individuals and on the families that care for the patients.

5. Medtronic’s Experience
SynchroMed II
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
Deep Brain
Stimulation
Medtronic’s experience is particularly relevant to solving this massive problem. First, ..Second,

6. 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.
Medtronic’s Investigational Intraparenchymal catheter with SynchroMed II pump

7. Growing need for delivery of drugs into the CNS beyond the intrathecal space
Intracerebroventricular (ICV)
Intraparenchymal (IPa)
Anatomically, we mean delivering drugs beyond the intrathecal space-to the intracerebroventricular space (much like a shunt is placed) and to the intraparenchymal space (much like placing a lead).
Intrathecal (IT)

8. SynchroMed® II Implantable Programmable Pump
N’vision Programmer
Catheter Access Port
Reservoir Refill Port
Titanium Housing
Spinal Catheter
The Key enabling technology of the future for targeted DD is our fully implantable, programmable Synchromed pump.
SynchroMed® II pump
Battery driven, peristaltic drive – up to 7 years implant duration
20 & 40 ml reservoir volumes
Infusion rates from to 20ml/day
Remote programing, capable of multiple dosing paradigms; variable flow rates, intermittent bolus, day/night.

9. Enabling Features for Future TDD
Commercial 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 drugs
93% 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/yr
300,000 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
There are several additional features of the SynchromedII that future TDD.
Accuracy, within 3% when tested clinically, is important for drugs that produce delayed biological/clinical responses ---such as the DMT we are currently developing.
Reliability, confidence of testing new drug vs new drug+ new pump.
For MRI Compatibility:
Imparts flexibility and precision to the design and execution of R&D as expected for next-generation therapies for neurodegenerative disorders.
For Experience:
Leverage decades of preclinical and clinical experience to de-risk the development of future therapies with less time and money
3% variation in engineering specs is typically driven by variability in the components/mfg process/materials/etc. Larger specs are typically required to accommodate variability from lot to lot, even though the variability within a lot or small # of lots (likely represented by a clinical trial) would be much tighter. I think it’s fine to report this number as actual clinical data. However, I would be careful to not represent it as the “actual” specification.
Wesemann K, Ivanhoe CB, Kosek P, et al. Performance and safety: SynchroMed II implanted programmable drug infusion system: a multicenter, prospective open-label post-approval study [AAPM abstract 271]. Pain Med. 2011;12(3):527. “Refill Measurement Error” is defined as the difference between calculated and expected volume at each refill. 3% represents the average error across all refills in study subjects.80 subjects were evaluated in 9 investigational sites. The manuscript is currently under development for publication.

10. Medtronic Infusion System Platforms*
Chronic ICV Infusion System*
SynchroMed® II Infusion System
Ventricular Catheter
Anchor*
Intraparenchymal
Catheter Anchor*
Chronic IPA Infusion System*
SynchroMed® II Infusion System
While Synch II is the work horse, our infusion platform consists of other elements-to make a portfolio of delivery solutions to fit pharma/biotech’s delivery needs, fully integrated with our navigation technology.
MANTIS*
Acute Infusion Systems*
Paradigm® Veo
Implantable*
Micro-pump*
IT and ICV)
Access Port*
*Products in Development / Investigational Use

11. Factors that may influence drug distribution in the CSF
Dosing Regimen
e.g. Continuous vs Bolus
Target Location
e.g. Cervical vs Lumbar
Infusion Rate
e.g. Slow vs Fast
Drug Properties
e.g. Small vs Large Molecule
Infusion
Catheter
Tip
In addition to the engineering rigor that goes toward building the device, the other critically important facet for future of TDD is the robust research that goes toward understanding the factors that influence drug distribution. _
Drug Concentration

12. Factors that may influence drug distribution in the CNS
And these factors get more complex going from intrathecal to intraparenchymal brain infusion. The complexity is why we have a dedicate group consisting of neuroscientists, chemists and engineers, working together to do the careful translational research required for success. We’ve developed the tools to study these important parameters.

13. Medtronic’s CNS Drug-Device Therapy Portfolio
Drug / Biologic
Route of admin
& Indication
Partner
Pre-clin
Clinical Phase
I/II
II b
III
Launch
-amyloid antibody
ICV – Alzheimer’s
Unpartnered
BACE inhibitor
Undisclosed
rGDNF
IPA – Parkinson’s
Eli Lilly
Htt siRNA
IPA - Huntingtons
rPDGF
ICV – Parkinson's
NeuroNova
rVEGF
ICV - ALS
Clonidine
IT - Refractory Hypertension
Wake Forest
Phys Spons
Remodulin
IA – Pulmonary Arterial Hypertension
United
Therapeutics
All of this has brought us to an expanded portfolio of CNS targeted Drug Therapy programs in development, some of them listed here. We are gaining experience with a broad range of molecules (…), routes of administration, indications and various partnerships and business models.
And all of which I and my colleagues would love to have the opportunity to show you supporting data on in future meetings-one such meeting being the Targeted Drug Delivery Meeting in San Fran, first week of May.

14. Complexity of drug delivery therapies requires extraordinary collaboration+
Therapy
Success
Drug/Biologic
Biology & Delivery
Principles
Device
Our long history of targeted drug delivery, combining an understanding of the drugs/biologics, with the device and the delivery principals can get us quite far. But success in treating the over 7 million people who collectively suffer from these diseases will only come from continued collaboration with our physician and surgeon partners as well as pharma/biotech partners.
Our long history of targeted drug delivery, combined with targeting discrete regions of the brain in our DBS therapies,

15. Thank You, Medtronic Neuromodulation’s CNS Drug Therapy R&D Team lisa
Thank You, Medtronic Neuromodulation’s CNS Drug Therapy R&D Team