The Future of Targeted Drug Delivery
Lisa Shafer, PhD
Director, CNS Drug Therapy R&D
Medtronic 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
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
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Deep Brain
Stimulation
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’s Investigational Intraparenchymal
catheter with SynchroMed II pump
…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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Growing need for delivery of drugs into the
CNS beyond the intrathecal space
Intracerebroventricular (ICV)
Intraparenchymal (IPa)
Intrathecal
(IT)
SynchroMed® II Implantable
Programmable Pump
Catheter Access Port
Reservoir Refill Port
Titanium Housing
Spinal Catheter
SynchroMed® II pump
•
•
•
•
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N’vision Programmer
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.
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
1.5T and 3.0T
MRI
Compatibility Conditional. Designed
to restart after MRI
Experience
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1 Billion patient hrs/yr
300,000 pumps
Drug : Device
compatibility
• Confirm IPA and ICV targeting
• Enables Imaging related diagnostics /theranostics/prognostics
• Permits therapies in complex patients with comorbid disease conditions
•
•
•
•
•
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
Medtronic Infusion System Platforms*
SynchroMed® II Infusion System Ventricular Catheter
Anchor*
Chronic ICV
Infusion
System*
SynchroMed® II Infusion System
Intraparenchymal
Catheter Anchor*
Chronic IPA
Infusion
System*
Paradigm® Veo
MANTIS*
Acute
Infusion
Systems*
*Products in Development / Investigational Use
Implantable*
Micro-pump*
IT and ICV)
Access Port*
Factors that may influence drug
distribution in the CSF
Dosing Regimen
e.g. Continuous vs Bolus
Target Location
e.g. Cervical vs Lumbar
Infusion
Catheter
Tip
Infusion Rate
e.g. Slow vs Fast
Drug Properties
_
_
_
_
_
Drug
Concentration
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e.g. Small vs Large Molecule
Factors that may influence drug
distribution in the CNS
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Medtronic’s CNS Drug-Device Therapy
Portfolio
Drug / Biologic
Route of admin
& Indication
Partner
-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 Forest
Phys Spons
Remodulin
IA – Pulmonary
Arterial
Hypertension
United
Therapeutics
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Preclin
Clinical Phase
I/II
II b
III
Launch
Complexity of drug delivery therapies
requires extraordinary collaboration
Drug/Biologic
Conc: 16 mg/ml
Flow Rate: 0.5 ul/min
Therapy
Success
Vefficacy (total) = 4,611mm3
c
t
Device
   c v  D  c   R c
Biology & Delivery
Principles
+
Thank You,
Medtronic Neuromodulation’s
CNS Drug Therapy R&D Team
lisa.l.shafer@medtronic.com