Transcript Presentation Title
The Future of Targeted Drug Delivery
Lisa Shafer, PhD Director, CNS Drug Therapy R&D Medtronic Neuromodulation [email protected]
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
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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
SynchroMed II Deep Brain Stimulation
• 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
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 )…
6 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.
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 8 Spinal Catheter
SynchroMed ® II pump
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
Accuracy Reliability Commercial Therapies
Specification: +/-14.5% Actual Clinical Refill Msrmt Error: 3% 97% approved drugs 93% unapproved drugs
Importance for Future TDD
• • • • • 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) • • • 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 9
Medtronic Infusion System Platforms*
SynchroMed® II Infusion System Ventricular Catheter Anchor* Chronic ICV Infusion System* Chronic IPA Infusion System* SynchroMed® II Infusion System Intraparenchymal Catheter Anchor* MANTIS* Paradigm® Veo Acute Infusion Systems* Implantable* Micro-pump* IT and ICV) Access Port* *Products in Development / Investigational Use
Infusion Catheter Tip
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 Drug Concentration
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Factors that may influence drug distribution in the CNS
Medtronic’s CNS Drug-Device Therapy Portfolio
Drug / Biologic Route of admin & Indication
-amyloid antibody ICV – Alzheimer’s BACE inhibitor rGDNF ICV – Alzheimer’s IPA – Parkinson’s Htt siRNA rPDGF rVEGF Clonidine IPA - Huntingtons ICV – Parkinson's ICV - ALS Remodulin IT - Refractory Hypertension IA – Pulmonary Arterial Hypertension
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Unpartnered Undisclosed Eli Lilly Unpartnered NeuroNova NeuroNova Wake Forest Phys Spons United Therapeutics
Pre clin
I/II
Clinical Phase
II b III Launch
Complexity of drug delivery therapies requires extraordinary collaboration
Drug/Biologic Device Conc: 16 mg/ml Flow Rate: 0.5 ul/min Therapy Success V efficacy (total) = 4,611mm3
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Biology & Delivery Principles +