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Daniel J. Abrams, MD December 2012

CNS Drug Delivery: Beyond the Spinal Cord Mission: I mprove outcomes for e pileptic patients who don’t respond to conventional treatments by administering reformulated, micro-doses of anti-epileptic drugs directly to the brain. Daniel J. Abrams, MD December 2012.

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Daniel J. Abrams, MD December 2012

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  1. CNS Drug Delivery: Beyond the Spinal CordMission: Improve outcomes for epileptic patients who don’t respond to conventional treatments by administering reformulated, micro-doses of anti-epileptic drugs directly to the brain. Daniel J. Abrams, MD December 2012

  2. Disclaimer on Product Use • This presentation includes the description of drugs, devices and their therapeutic uses that are in early stages of development, are not commercially available and have not been approved by regulatory institutions. • Before commercialization is possible the drugs, devices and their therapeutic uses need to undergo additional preclinical and clinical evaluation and obtain regulatory approval.

  3. Significant Unmet Medical Need for Neurological Disorders and Disease Epilepsy ~15M US Patients • Large # of Indications • Growing patient populations • Feweffective therapies • Enormous cost of care

  4. U.S. Epilepsy Market 1http://www.epilepsyfoundation.org/aboutepilepsy/whatisepilepsy/statistics.cfm 2http://www.touchneurology.com/articles/update-and-overview-international-league-against-epilepsy-consensus-definition-drug-resista

  5. Gabapentin, small molecule (0.2kD) Prialt, peptide (3kD) protein – antibody (150kD) Factors Frustrating CNS Drug Therapy . . . despite most dense vascular bed of any organ. The Blood Brain Barrier excludes most drugs from Brain and Spinal Cord . . . * radioactively labeled tracer drug given intravenously Drugs keep getting bigger: siRNA (13kD)

  6. Selectivity of the Blood Brain Barrier Peripheral Capillary Brain Capillary Protein permeability restricted to: • small molecules (<600D) Glucose • lipophilic substances

  7. Anatomy of the Blood Brain Barrier Electron Micrograph of Tight Junctions

  8. Crossing the Blood Brain Barrier 1. between permeabilize tight junctions 2. through enhance transport across the endothelium 3. around direct intracranial drug delivery

  9. IT Therapy Development History(Selected Highlights) First human implant of SynchroMed pump (Medtronic) SynchroMed pump receives FDA approval (Medtronic) Infumorph (IT morphine) approved (Medtronic) • Lioresal (IT baclofen) approved for spasticity (Medtronic) • MedStream (constant flow) pump approved (Codman – JnJ) SynchroMed II pump receives FDA approval (Medtronic) Prialt (IT Ziconitide) approved for chronic pain (Azur) Gablofen (IT baclofen) approved for spasticity (CNS Therapeutics) Prometra Programmable Pump approved for IT pain (Flowonix) • MedStream Programmable Pump System approved for IT spasticity (Codman – JnJ)

  10. Several Infusion Systems Available for Targeted Drug Delivery MEDSTREAM™ Programmable Infusion Pump and Control Unit Prometra Pump and Programmer SynchroMed II Infusion Pump & N’vision Clinical Programmer

  11. Common Features of ImplantableDrug Infusion Systems Catheter Access Port – bypasses drug reservoir, used to check for catheter patency Reservoir Refill Port – septum through which drug enters the pump upon refill Titanium Housing – typically rigid outer housing that protects pump from mechanical damage Programmer – used with ‘smart’ pumps, controls drug infusion rate, records drug history Drug Catheter – flexible tubing that runs from the pump with special tip for drug delivery Medtronic SynchroMed® II pump and N’Vision® Programmer shown above

  12. Interior of a Drug Infusion Pump Electronics Module Refill Port Catheter Access Port Pumphead Drive Gear Rotor Assembly (x-Ray) Pumphead Drive Gear Example of a battery-driven electro-mechanical pump, other pump models use a variety of drive and valve mechanisms to deliver drugs Battery Images taken from a Medtronic SynchroMed®II Pump

  13. FlowonixPrometra - Pain Infusion System Features: • Dose Accuracy • 98% • Longevity • >10 years • Weight • 10% lighter • Easy refill • Designed to deliver any compound • Can deliver micro-doses • Can be programmed off

  14. Codman MedStream™ - Spasticity Drug Infusion Pump Programmer Ceramic Drive Valve Refill Port MEDSTREAM™ Control Unit Fill Sensor  Ceramic actuator (when charged) opens valve and allows fluid flow into catheter.  Valve is closed when actuator is discharged. Fluid Flow Flow Restrictor Filter Propellant Gas

  15. Concentrations & Doses of Intrathecal AgentsPolyanalgesic Consensus Panel, 2007 Deer, Krames et al, Neuromodulation: Technology at the Interface 11: 300-328, 2007

  16. Non-Opioid Drugs used for Treatment of Chronic Pain by the Spinal Route • Local Anesthetics • Bupivicaine • Ropivicaine • Tetracaine • Adrenergic Agonists • Clonidine • Tizanidine • NMDA Antagonists • Ketamine • Other • Adenosine • Aspirin • Baclofen • Droperidol • Gabapentin • Ketorolac • Midazolam • Octreotide • Neostigmine • Ziconitide (Prialt)* *FDA approved for IT therapy for chronic pain

  17. IT Baclofen for Spasticity Motor Cortex • Large % of refractory spasticity patients • Intrathecal baclofen (ITB) has been used to treat spasticity since 1988, particularly dystonia secondary to cerebral palsy or traumatic brain injury • ITB is an approved use of the Medtronic Infusion System • The site of action is thoughtto be at the anterior horn cell • It would be expected that intrathecal infusion would havegood access to this site Medulla Anterior Horn Spinal Cord

  18. Compartments of the Brain • The brain can be modeled as having three compartments Blood ↔ CSF ↔ Brain • CSF is held within a defined set of compartments > yellow – ventricles > light blue – subarachnoid & intrathecal • Volume of CSF: 140ml • Rate of CSF production: 35ml/hr • CSF turnover: 4-6x/day • Blood flows through the brain at a rate of 60 l/hr

  19. Schematic Equilibrium of Brain Compartments Blood Arachnoid Villi Blood Brain Barrier Choroid Plexus Diffusion Brain CSF Ependyma Bulk Flow

  20. Advantages of Continuous Infusion over BolusDrug Delivery Wasted Drug Overdose Toxicity 6 Adverse effects 5 4 Drug Concentration Efficacy 3 2 No effect Bolus Administration 1 Underdose Loss of Effect Continuous Pump Infusion 0 0 4 8 12 16 20 24 Time (hours-days)

  21. Analgesic Outcome: Efficacy of Opioids in Cancer Pain – by Route of Administration adapted from Ballantyne, Carwood 2009

  22. ICV Baclofen for Dystonia (Albright) • Results: • 8 of 10 patients responded to the treatment • 2 non-responding patients also did not respond to previous IT treatment • 3 pump-related adverse effects Motor Cortex Primary Motor Area Medulla Spinal Cord Albright et al, Neurosurg Pediatrics 3:000–000, 2009

  23. Comparison IT and ICV Chemotherapy • CSF Chemotherapy used for 30 years by IT and ICV routes • Useful for overcoming the BBB limitation on distribution of drugs and metabolites • PK studies demonstrate high CSF drug concentrations can be achieved • Effective for treatment of meningeal leukemia in humans • Not as effective treatment for deep parenchymal distribution into the brain Blasberg et al, Cancer Treat Rep 61:1977

  24. Topotecan ICV Advantage

  25. Key Elements for Drug : Device Therapy Development Device Drug/Biologic Therapy Success Delivery Principles

  26. Around the BBB: Intracerebroventricular (ICV) Drug Delivery Lateral view of brain with the cerebral ventricles shown in blue Cross section of the brain shown with a catheter placed in the lateral ventricle (blue)

  27. Technology: CombiningDrugs & Pumps for Brain Delivery • Several benefits of delivering drugs directly to the brain fluid: • Significantly Lower dose • Less risk of side effects andorgan toxicity • Improved Tolerability • Target effectiveness • Consistent drug levels lessens difficulty finding therapeutic ratio for an each patient • “Last pass metabolism”: Drugs do not go first through GI tract, then liver, etc… • Adherence- Overcome patients inability to take medication • Additional drug options for refractory disease- targeted nature of the delivery platform allows additional drug candidates

  28. Intracerebroventricular Drug Therapy Product Concept: ICV Drug Therapy for Epilepsy

  29. Factors Driving Site-DirectedDrug Delivery for Treating CNS Disease • Significant unmet medical need • Large, and growing, patient • populations • Substantial revenue potential • Blood Brain Barrier (BBB) stops • most drugs from entering CNS • Combined with other therapeutic advantages, BBB creates need for targeted drug delivery 36.6M Patients/20 disorder $95.5B Market across 7MM >21% share of Pharma

  30. The Future of Medicine: Drug-Device Therapies • Drugs-Biologics • small molecule • peptide - protein • oligonucleotides • plasmids • Implantable Pumps • targeted delivery • controlled delivery

  31. Thank You …..

  32. Clinical Trials of Intracerebroventricular Morphine Therapy

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